Sleep Disorders: Narcolepsy and Idiopathic Hypersomnia Multiple Sclerosis: New Approvals and Payer Impact
Parkinson’s Disease: Treatment and Management Update
Published By
Magellan Rx Management
4801 E. Washington St., Ste. 100 Phoenix, AZ 85034
Tel: 401-344-1000
Fax: 401-619-5215 magellanrx.com
Editor Lindsay Speicher, J.D.
Project Manager
lspeicher@magellanhealth.com 401-344-1105
Advertising, Sales and Distribution
Carole Kallas ckallas@magellanhealth.com 401-344-1132
The content of Magellan RxTM Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.
Steve Marciniak, R.Ph. Director , Medical Beneft Drug Management, BlueCross BlueShield of Michigan
Saira A. Jan, M.S., Pharm.D. Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey
A NOTE FROM OUR CMO
Dear Managed Care Colleagues,
Welcome to our spring 2022 issue of the Magellan Rx Report! 2022 is o to an e citing start with 7 novel drug approvals so far and many more expected as the year progresses. Millions of Americans are vaccinated against COVID-19 and have received booster doses of the vaccine, while others have benefted from the newly approved CO D-19 treatments. The energy put toward quelling the pandemic through public health e orts and development of preventive and therapeutic drugs is unprecedented. With the pandemic as a backdrop, we must not lose sight of preventing and treating chronic and terminal conditions. Magellan Rx Management is committed to keeping our readers informed and updated across the spectrum of diseases. Our spring issue is full of content focused on trending clinical advances and approvals.
Approximately 14,000 women will develop invasive cervical cancer in the year ahead. Our cover story (page 41) outlines new treatment options for cervical cancer, which is particularly exciting after a long period without much new development in this category.
In another article, we highlight the management of Parkinson’s disease and Parkinson’s disease psychosis. New treatment options and a promising pipeline will create opportunity for better management and outcomes for patients and payers.
Our article on sleep disorders (page ) focuses specifcally on updates in the narcolepsy and idiopathic hypersomnia categories. We touch on new approvals in this space, along with management strategies for payers.
Other timely topics in this issue include updates on multiple sclerosis (page 12) and gout management (page 32), a biosimilar update (page 22), and an outline of new treatments and a pipeline for COVID-19 (page 36). As always, the issue is rounded out with our pipeline update (page 46) and managed care newsstand (page 4).
To learn more about Magellan Rx Management and our support for payer initiatives of the future, please feel free to contact us at MagellanRxReport@magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the report!
Stay on top of managed care trends and become a Magellan Rx Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading.
MANAGED CARE
NEWSSTAND
CMS Wants Rx Discounts
Included at the POS
On Jan. 12, the Centers for Medicare & Medicaid Services (CMS) proposed to modify the defnition of negotiated price to require all pharmacy price concessions in the prescription drug beneft to be included at the point of sale (POS) and remove exceptions for contingency discounts. Successive administrations have considered but repeatedly rejected similar proposals in the past, given the negative impacts on Medicare benefciaries and the broader Part D program. The proposal would remove the current regulatory provision that excludes contingent discounts from pharmacies that cannot reasonably be determined at the POS from the defnition of Part D s negotiated price nder the proposal, the negotiated price would have to refect the lowest possible reimbursement a network pharmacy or other network dispensing entity will receive for a drug, taking into account price concessions and including all contingent discounts. CMS says additional payments that could be made to a pharmacy as an incentive to encourage e cient drug choices, such as higher generic dispensing, would still be permitted. Those contingent amounts would be excluded from the negotiated price and instead would be reported as negative direct or indirect remuneration (D ) during the Part D reconciliation period CMS further proposes a defnition of price concession to mean any form of discount, whether a direct indirect subsidy or rebate received by a Part D sponsor or its intermediary that serves to decrease the costs incurred under the plan by the Part D sponsor
Medicare Prescription Drug Program (Part D) Status Report
The Medicare Payment Advisory Commission (MedPAC) met Jan. 13-14 to discuss Medicare payment policies and provide status updates on the program. This session provided an update on the Medicare Part D program and will be included as a chapter in the March 2022 commission s report otable trends in the Part D program included enrollment being split evenly between standalone prescription drug plans and Medicare Advantage prescription drug plans (MA-PDs), as well as Medicare s expected average payment to plan sponsors in 2022 at $5 per member per month. When published, the March 2022 chapter will also include information regarding PDP market segmentation and results from Part D s D analysis
CMS Issues Final Rule Rescinding Most Favored Nation Model
CMS issued a fnal rule in late December rescinding the Most Favored Nation (MFN) Model nterim inal ule with Comment CMS states that it proposed to rescind the model given that the nationwide preliminary injunction precluded implementation of the MFN Model on January 1, 2021, as contemplated, that multiple courts found procedural issues with the November 2020 interim fnal rule, and that sta eholders expressed concern about the model start date The model would have established a seven-year nationwide, mandatory MFN Model to test an alternative way for Medicare to pay for certain Medicare Part B single source drugs and biologicals (including biosimilar biologicals), under section 1115A of the Social Security Act (the Act)
Rebate Rule Postponed to 2023
The rebate rule was proposed and fnali ed during the Trump administration and would
Notable trends in the Part D program included enrollment being spit evenly between standalone prescription drug plans and Medicare Advantage prescription drug plans (MA-PDs), as well as Medicare’s expected average payment to plan sponsors in 2022 at $5 per member per month.
remove drug manufacturer rebates paid to Medicare Part D plans, or PBMs under contract with them, from the regulatory discount safe harbor s protections and add a safe harbor for certain POS discounts. n response to litigation brought by the Pharmaceutical Care Management Association challenging the rule, the Biden administration agreed to postpone the e ective date of the provisions of the rule relating to the elimination of the regulatory discount safe harbor for retrospective rebates, from Jan. 1, 2022, to Jan. 1, 2023. The bipartisan infrastructure bill was signed into law Nov. 15, 2021, and delays the rule by three years to 2026.
FTC Announces RFI on PBMs
n ebruary, the ederal Trade Commission (FTC) failed to advance a study on how pharmacy beneft managers a ect drug prices and the businesses of pharmacies. Shortly thereafter, the FTC announced it is soliciting public input on the ways that practices by large, vertically integrated pharmacy beneft managers (PBMs) are a ecting drug a ordability and access The request for information covers a wide range of issues in the PBM mar et, including contract terms, rebates, fees, pricing policies, steering methods, conficts of interest, and consolidation. The agency seeks information on these practices and their impact on patients, physicians, employers, independent and chain pharmacies, and other businesses across the distribution system.
PBMs are companies that manage prescription drug benefts on behalf of private health insurers, Medicare Part D drug plans, large employers, and other payers. The largest PBMs are vertically integrated with health insurance companies and specialty pharmacies, giving them fnancial incentives to steer patients to use their a liated services Moreover, in response to the commission s request for public input on contracts terms that may harm fair competition, many independent pharmacies commented that PBM contractual terms are confusing, unfair, opaque, and arbitrary.
The request for information will enable agency sta to study a wide array of PBM business practices and issues and will help inform the agency s policy and enforcement work. Members of the public can comment on any issues or concerns they believe are relevant or appropriate for the agency s consideration by submitting written data, views, facts, and opinions addressing this subject. The comment period will be open for 60 days, extending through April 25.
CMS Releases Bulletin on Third Party Liability in Medicaid
The S Centers for Medicare & Medicaid Services (CMS) released an informational bulletin Aug. 27 to assist states in ensuring that their Medicaid state plans comply with third party liability (TPL) requirements refected in current laws CMS notes that states should update their Medicaid TPL state plan pages and submit amendments to CMS to refect the recent changes in law. As states make changes in their TPL programs, they will likely lead to implications for Medicaid-managed care plan contracts.
Proposed National Coverage Determination (NCD) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (AD)
After reviewing more than 250 peerreviewed documents relevant to the CD analysis, as well as reports from other agencies and the nstitute for Clinical and Economic Review, public comments, feedback from two stakeholder meetings, and numerous meetings with stakeholders, CMS has decided that there is insu cient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Al heimer s disease As CMS indicates in its discussion of evidence in the proposed decision memo, the assessment focused on the key evidence question of whether the use of monoclonal antibodies directed against amyloid for the treatment of AD improves health outcomes for Medicare benefciaries Moreover, the standard is not simply, Could this class of drugs be
helpful to patients with AD , but rather an additional determination to be made that it is necessary for them to access these treatments. As a result, CMS proposes to cover DA-approved monoclonal antibodies directed against amyloid for the treatment of AD under Coverage with vidence Development in CMS-approved randomi ed controlled trials that satisfy certain coverage criteria, and in trials supported by the ational nstitutes of ealth All trials must be conducted in a hospital-based outpatient setting.
CMS has decided that there is insufcient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease.’
Sleep Disorders
pdate on arcolepsy and diopathic ypersomnia
Because individuals with sleep disorders account for high overall healthcare costs, management should aim to improve patient outcomes while containing associated medical utili ation and costs
arcolepsy, which a ects up to 200,000 people in the S , is a chronic neurological disorder that impacts the brain s ability to control sleep-wa e cycles 1 Those with narcolepsy typically frst e perience symptoms during childhood or young adulthood; however, it often goes undiagnosed or misdiagnosed as other conditions There is no nown cause of narcolepsy, but research suggests the condition may be a result of low levels of hypocretin ypocretin is a brain hormone that promotes wa efulness and regulates rapid eye movement ( M) sleep and is believed to be decreased by a number of factors, including autoimmune disorders, family history, and or brain in uries 1
arcolepsy is characteri ed by symptoms including e cessive daytime sleepiness ( DS), often assessed using the pworth Sleepiness Scale ( SS); cataple y, the sudden loss of muscle tone while awa e, leading to wea ness and loss of voluntary muscle control; sleep paralysis, the temporary inability to move or spea while falling asleep or wa ing up; and hallucinations 1 ndividuals with narcolepsy may also e perience fragmented sleep and insomnia or other behaviors such as temporary sleep episodes, during
which they fall asleep for seconds at a time during an activity.1 arcolepsy is often classifed into two types type 1, previously nown as narcolepsy with cataple y, and type 2, previously nown as narcolepsy without cataplexy.1 Those with type 1 typically either have low levels of hypocretin or report cataple y and have DS, while those with type 2 e perience DS but do not e perience cataplexy and often have less severe symptoms overall with normal levels of hypocretin.1
Proper diagnosis requires a clinical examination and detailed medical history, along with two speciali ed tests that are performed at sleep disorder clinics polysomnogram (PS ) and multiple sleep latency test (MSLT) 1 Diagnostic criteria for narcolepsy requires DS in association with any one of the following cataple y; CS hypocretin defciency; M sleep latency 15 minutes on nocturnal PS ; or mean sleep latency 8 minutes on MSLT with at least two sleep-onset M-sleep periods 2
Idiopathic Hypersomnia
diopathic hypersomnia ( ) is a rare, chronic neurological sleep disorder that can cause individuals to have di culty staying awa e and alert during the day.3 a ects about 0 3 of the population in the S , and symptoms often begin during childhood or young adulthood.4 hile the cause is un nown, in some cases individuals with have family members with or other sleep disorders 3
Idiopathic hypersomnia (IH) is a rare, chronic neurological sleep disorder that can cause individuals to ave difcult staying awake and alert during the day.
often presents with symptoms including chronic DS; prolonged periods of sleep without feeling refreshed upon wa ing; nonrefreshing daytime napping; sleep drun enness, or di culty wa ing up and feeling an uncontrollable desire to go bac to sleep after nighttime sleep or naps; brain fog while awa e; and headaches 3 Other less common symptoms associated with include short sleep latency, or ta ing a shorter than normal time to fall asleep; harder time regulating body temperature; aynaud s disease; e cessive sweating; episodes of feeling faint; blood pressure drops upon standing up; sleep paralysis; and sleep-related hallucinations 3
SLEEP DISORDERS |
Recent data suggests at least two-thirds of patients with newly diagnosed IH slept at least 11 hours per night.3
Individuals with IH have increased prevalence of cardiovascular comorbidities, autonomic nervous system dysfunction, sleep apnea, and psychiatric disorders such as anxiety and depression.5, 6 A claims analysis demonstrated that, when compared to patients without IH, more patients with IH had hyperlipidemia, diabetes, anxiety, depressive disorders, headache or migraine, heart failure, stroke, and history of cardiovascular disease.6, 7
Individuals must meet the following criteria to be diagnosed with IH: symptoms of EDS lasting longer than one year and an ESS score of 10 or higher with daytime napping on most days, no improvement after a trial of increased nighttime sleep, more than two sleep-onset REM periods on MSLT when MSLT was performed, no features to suggest cataplexy, and an apnea or hypopnea index of less than 10.8
Current Narcolepsy Management
Symptoms of narcolepsy are often managed with medication and lifestyle changes. According to the American Academy of Sleep Medicine (AASM) clinical practice guidelines, modafnil, pitolisant,
sodium oxybate, and solriamfetol are strongly recommended for the treatment of narcolepsy in adult patients Armodafnil, dextroamphetamine, and methylphenidate are conditionally recommended.9
Recent Approvals
XYWAV ® (calcium, magnesium, potassium, and sodium oxybates)10
The U.S. Food and Drug Administration (FDA) approved Jazz Pharmaceutical’s XYWAV ® (calcium/magnesium/potassium/ sodium oxybates) in July 2020 for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy who are 7 years or older ectiveness was observed in a phase three double-blind, placebo-controlled, randomized-withdrawal, multicenter study of 201 patients. XYWAV® demonstrated statistically signifcant di erences in the wee ly number of cataple y attac s and ESS scores, compared to the placebo. Dosing options are available for adult and pediatric patients, and prescribers can titrate treatment into unequal doses taken throughout the night. Adverse reactions observed most commonly in adults included
headache, nausea, dizziness, anxiety, insomnia, decreased appetite, dry mouth, parasomnia, somnolence, diarrhea, hyperhidrosis, fatigue, tremor, and vomiting. XYWAV® has a boxed warning as a central nervous system depressant — and for its potential for abuse and misuse. Because of the risks of CNS depression and abuse and misuse, XYWAV® is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.
WAKIX® (pitolisant)11, 12
In August 2019, the FDA approved WAKIX® (pitolisant, Harmony Biosciences) for the treatment of EDS in adult patients with narcolepsy. This approval was based on two multicenter, randomized, double-blind, placebo-controlled studies, which included a total of 261 patients randomized to receive pitolisant, placebo, or active control. In both studies, patients treated with pitolisant had statistically signifcant improvement in SS scores Adverse reactions included insomnia, nausea, and anxiety.
The FDA approved pitolisant for an additional indication of cataplexy in adult patients with narcolepsy in October 2020. At the time of these approvals, pitolisant was the frst and only non-scheduled treatment approved by the FDA for people with EDS or cataplexy in adult patients with narcolepsy. Approval for the treatment of cataplexy was based on results from two randomized, controlled trials. After issuing a complete response letter (CRL) in August 2019, the FDA agreed to review a reanalysis of data and ac nowledged the analyses confrmed a statistically signifcant reduction in the rate of cataple y in patients treated with pitolisant, compared to placebo. A resubmission following the CRL resulted in FDA approval.
SUNOSITM (solriamfetol)13
The FDA approved SUNOSI™ (solriamfetol, Jazz Pharmaceuticals) in March 2019 for the treatment of EDS associated with narcolepsy or obstructive sleep apnea. Solriamfetol is a once-daily treatment approved in doses of 75 mg and 150 mg for patients with narcolepsy, and it was the frst dual-acting dopamine and norepinephrine reuptake inhibitor (DNRI) approved to treat EDS in adults with narcolepsy. Results from a phase three clinical program consisting of four randomized placebo-controlled studies demonstrating the superiority of solriamfetol relative to the placebo showed that at week 12, 150 mg of solriamfetol demonstrated improvements in wakefulness, compared to the placebo in patients with narcolepsy. Approximately 6874% of patients treated with 75 mg of solriamfetol and 7890% of patients treated with 150 mg of solriamfetol reported
Insights
magellanrx.com/clinicalinsights
improvement in clinical condition over the 12-week clinical studies. Common adverse reactions associated with treatment with solriamfetol included headache, nausea, decreased appetite, insomnia, and anxiety.
Lifestyle Changes
Because drug therapy does not help all individuals with narcolepsy maintain a typical state of alertness, lifestyle changes are often recommended. Some strategies include taking short naps, maintaining a regular sleep schedule, avoiding ca eine or alcohol before bed, avoiding smoking, exercising daily, avoiding large meals before bedtime, and relaxing before bed.1 It is important for individuals with narcolepsy to take safety precautions with certain activities of daily living, especially driving or wal ing down long fights of stairs 1
Current IH Management
XYWAV™ is the only FDA-approved treatment indicated for IH. Prior to its approval, treatment generally involved o -label use of medications approved for narcolepsy, including wakefulnesspromoting agents such as modafnil and traditional psychostimulants, including amphetamines and methylphenidate.3
SLEEP DISORDERS
nli e in the management of narcolepsy, behavior modifcation is not often e ective in individuals with ; for e ample, daytime naps are typically nonrestorative or disruptive for individuals with Daytime activities that could pose a danger, such as driving or operating machinery, should be avoided if DS is not well-controlled 3
XYWAV ® (calcium, magnesium, potassium, and sodium oxybates)14
n August 2021, the DA approved Y A ® as the frst and only treatment indicated for in adults n a study of 154 adult patients with , patients randomi ed to switch from Y A ® to the placebo e perienced worsening on measures of sleepiness and symptoms of , when compared to patients randomi ed to continue Y A ® treatment Adverse events included nausea, headache, di iness, an iety, and vomiting Treatment with Y A ® is sub ect to strict safety controls under a MS program; it can only be prescribed by a certifed prescriber and dispensed only to an enrolled patient by a certifed pharmacy
Payer Management
An analysis published in 2021 estimated that sleep disorders accounted for 94 9 billion in S healthcare costs each year 15 Adult patients with sleep disorders were found to have increased utili ation of o ce visits, emergency department visits, and prescriptions and had higher healthcare e penses, o ce-based e penditures, prescription e penditures, and self-e penditures for prescriptions 15 Proper diagnosis and management in this category may be critical in o setting the higher utili ation and costs associated with these patients
Because individuals with sleep disorders account for very high overall healthcare costs, management should have the ob ective of improved patient outcomes while containing associated medical utili ation and costs n narcolepsy, pharmacy costs account for ust 28 of the total healthcare costs; thus, while using lower-cost drugs may result in short-term savings in pharmacy spend, this concept may eopardi e patient outcomes and could potentially results in higher medical utili ation and costs 1 ith sleep disorders such as narcolepsy, treatment plans must be tailored to the specifc patient and their symptom
Individualized clinician-patient treatment choices are best practice recommendations, as these will take into consideration clinical manifestations of the disorder in t e s eci c atient in order to identify the optimal treatment regimen.
presentation and burden ndividuali ed clinician-patient treatment choices are best practice recommendations, as these will ta e into consideration clinical manifestations of the disorder in the specifc patient in order to identify the optimal treatment regimen Proper management policies should include regular follow-up assessments upon treatment initiation to ensure e cacy and improve longer-term outcomes
n 2020, the Payer Policy eview Committee of the AASM assessed the alignment between guidelines and private payer policies managing sleep disorders and ultimately developed a scorecard to evaluate how guidelines and payer policies correspond 1 The ob ective of this initiative was to better highlight and communicate discrepancies between medical policies and clinical guidelines to encourage closer alignment and ensure patients with sleep disorders receive high-quality care 17 The publication of the scorecards resulted in ongoing communication between the AASM and payers, which lead to revision of policies to better align with guidelines 17 This ongoing e ort can help achieve consistency in the management of these burdensome disorders
References
1.“Narcolepsy Fact Sheet.” National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/Disorders/Patient-CaregiverEducation/Fact-Sheets/Narcolepsy-Fact-Sheet.
2. uo , Chad, et al The CSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality.” Current Medical Research and Opinion, October 2016, https://pubmed.ncbi.nlm.nih. gov 27359185
3 diopathic hypersomnia Genetic and Rare Diseases Information Center, https rarediseases info nih gov diseases 8737 idiopathichypersomnia.
4. Ohayon, Maurice rom wa efulness to e cessive sleepiness what we now and still need to now Sleep Medicine Reviews, Apr 2008, https www ncbi nlm nih gov pmc articles PMC23 2500
5 Saad, R., et al. “Clinical presentation prior to idiopathic hypersomnia diagnosis among U.S. adults: a retrospective, real-world claims analysis poster 497 Presented at: Annual Meeting of the Associated Professional Sleep Societies, 10-13 une, 2021
6.Vernet, Cyrille, et al. “Subjective symptoms in idiopathic hypersomnia beyond e cessive sleepiness Journal of Sleep Research, Dec 2010, https pubmed ncbi nlm nih gov 20408941
7. Miglis, Mitchell, et al requency and severity of autonomic symptoms in idiopathic hypersomnia.” Journal of Clinical Sleep Medicine, 15 May 2020, https pubmed ncbi nlm nih gov 32039754
8 Anderson, Kirstie, et al dioathic ypersomnia A Study of 77 Cases.” Sleep, 1 Oct. 2007, https://www.ncbi.nlm.nih.gov/pmc/ articles PMC22 27
9 Mas i, Kiran, et al Treatment of central disorders of hypersomnolence an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.” Journal of Clinical Sleep Medicine, 1 Sept. 2021, https://jcsm.aasm.org/ doi 10 5 4 csm 932
10. a Pharmaceuticals Announces S DA Approval of ywav (calcium, magnesium, potassium, and sodium o ybates) Oral Solution for Cataple y or cessive Daytime Sleepiness Associated with Narcolepsy.” Jazz Pharmaceuticals, 22 uly, 2020, https investor a pharma com news-releases news-release-details apharmaceuticals-announces-us-fda-approval- ywavtm-calcium
11. armony Biosciences Announces DA Approval of AK ® (Pitolisant), A irst-in-Class Medication for the Treatment of cessive Daytime Sleepiness in Adult Patients with arcolepsy BioSpace, 15 Aug 2019, https www biospace com article releases harmony-biosciences-announces-fda-approval-ofwa i -pitolisant-a-frst-in-class-medication-for-the-treatment-ofe cessive-daytime-sleepiness-in-adult-patients-with-narcolepsy
12. armony Biosciences eceives DA Approval for panded se of AK ® (pitolisant) for the Treatment of Cataple y in Adult Patients with Narcolepsy.” PRNewswire, 14 Oct. 2020, https://www. prnewswire com news-releases harmony-biosciences-receives-fdaapproval-for-e panded-use-of-wa i -pitolisant-for-the-treatmentof-cataple y-in-adult-patients-with-narcolepsy-301152078 html
13 a Pharmaceuticals Announces S DA Approval of Sunosi (solriamfetol) for cessive Daytime Sleepiness Associated with Narcolepsy and Obstructive Sleep Apnea.” PRNewsWire, 20 Mar 2019, https www prnewswire com news-releases a -pharmaceuticals-announces-us-fda-approval-of-sunosisolriamfetol-for-e cessive-daytime-sleepiness-associated-withnarcolepsy-or-obstructive-sleep-apnea-30081 081 html
14. DA rants irst of its Kind ndication for Chronic Sleep Disorder Treatment U.S. Food & Drug Administration, 12 Aug. 2021, https:// www fda gov news-events press-announcements fda-grants-frstits- ind-indication-chronic-sleep-disorder-treatment
15 avidia, Matthew Sleep Disorders Cost S 94 9 Billion ach Year, Study Finds.” American Journal of Managed Care, 11 May 2021, https www a mc com view sleep-disorders-cost-us-94-9-billioneach-year-study-fnds
16. Thorpy, Michael, et al The Medical and conomic Burden of arcolepsy mplications for Managed Care American Health & Drug Benefts, uly 2017, https www ahdbonline com issues 2017 uly-2017-vol-10-no-5 2421-the-medical-andeconomic-burden-of-narcolepsy-implications-for-managed-care
17.Kaplish, Neeraj, et al. “Addressing gaps between payer policies and AASM clinical practice guidelines using scorecards Journal of Clinical Sleep Medicine, 15 May 2020, https csm aasm org doi 10 5 4 csm 8410
Multiple Sclerosis:
New Approvals and Payer Impact
As the pipeline promises more new therapies in the MS category, clear guidance and consensus will be even more important to achieve e ective management, improve outcomes, and manage costs
Samir Mistry, Pharm.D. Vice President, Pharmacy
Strategy & Services
Capital Blue Cross
Multiple sclerosis (MS) is a central nervous system (C S) disease that a ects nearly 1 million people in the U.S.1 Often considered an autoimmune disease, the condition disrupts the communication between the brain and the rest of the body. Initial onset of MS often occurs between the ages of 20 and 40.2 There are four disease courses in MS: clinically isolated syndrome (CIS), relapsingremitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).2 MS is the most common disease course and is characteri ed by clearly defned attac s of new or increasing neurologic symptoms n MS, attac s or relapses are followed by periods of partial or complete recovery, or remissions.2 An estimated 85% of MS patients are initially diagnosed with RRMS. SPMS is secondary to an initial diagnosis of RRMS; some patients with RRMS eventually transition to SPMS, which occurs with progressive worsening of neurologic function over time.2 A minority of MS patients are diagnosed with PPMS, which is characterized by worsening neurologic function from the onset of symptoms without relapses or remissions.2
The frst symptom of MS is commonly blurred or double vision, red-green color distortion, or even blindness in one eye Muscle wea ness in the e tremities and di culty with coordination and balance are experienced by most MS patients, and these symptoms can be severe enough to impair wal ing or standing 3 Other common symptoms of MS are paresthesias, transitory abnormal sensory feelings such as numbness, pric ling, or pins and needles sensations; pain; speech impediments; tremors; bladder dysfunction; bowel dysfunction; sexual problems; and dizziness. Around 50% of MS patients su er from cognitive impairments such as di culty with concentration, attention, memory, or poor judgment. In severe cases, patients with MS can develop partial or complete paralysis.3
Proper diagnosis of MS often entails a comprehensive process that may include medical history, neurologic e am, and tests such as an M , spinal fuid analysis, and blood tests to rule out conditions
with overlapping symptoms.3 The criteria for an MS diagnosis include: evidence of damage in at least two separate areas of the CNS, including the brain, spinal cord, and optic nerves; evidence that damage occurred at di erent points in time; and no other possible diagnosis.4 The revised McDonald Criteria from the nternational Panel on MS Diagnosis has specifc guidelines for using M and cerebrospinal fuid analysis in the diagnostic process for MRI; according to these guidelines, MRI can be used to look for a second area of damage in a person who has experienced only one attack (or a relapse or exacerbation) of MSli e symptoms and can also be used to confrm that damage has occurred at two di erent points in time 5
Treatment
Treatment courses for MS can be used to modify the disease course, treat relapses, and manage symptoms. The U.S. Food and Drug Administration (FDA) has approved several disease-modifying therapies (DMTs) for MS that may reduce the number of relapses, delay progression, and limit new disease activity. DMTs include injections, such as interferon beta-1a and -1b (AVONEX® and BETASERON®), glatiramer acetate (COPAXONE®), and ofatumumab (KESIMPTA®); oral medications, such as terifunomide (A BA O®), fngolimod ( L YA®), and dimethyl fumarate (Tecfdera®); and infusions, such as alemtu umab (L MT ADA®) and ocrelizumab (OCREVUS®).6 The American Academy of Neurology (AAN) guidelines and other MS guidelines recommend earlier initiation of DMTs, as well as strategies on initiating, switching, and stopping therapy.7
Recent Approvals
PONVORY TM (ponesimod)8, 9
n March 2021, PO O Y (ponesimod, ohnson ohnson) received FDA approval for the treatment of adults with relapsing forms of MS, including CIS, RRMS, and active secondary progressive disease. Ponesimod is a once-daily oral selective sphingosine-1-phosphate receptor 1 (S1P1) modulator. Results from a two-year, head-to-head phase three clinical trial demonstrated ponesimod s superior e cacy in signifcantly reducing annual relapses by 30 5 , compared to terifunomide, in patients with MS n the group treated with ponesimod, 71 had no confrmed relapses, compared to 1 in the terifunomide group esults indicate ponesimod reduced new gadolinium-enhancing T1 lesions and a number of new or enlarging T2 lesions by 59 , compared to 5 in the terifunomide group Common adverse events associated
The FDA has approved several disease-modifying therapies for MS that may reduce the number of relapses, delay progression, and limit new disease activity.
with ponesimod included upper respiratory infection, hepatic transaminase elevation, and hypertension.
KESIMPTA® (ofatumumab)10, 11
The FDA approved KESIMPTA® (ofatumumab, Novartis) in August 2020 as the frst and only self-administered, targeted B-cell therapy for patients with relapsing MS. Ofatumumab is a targeted, precisely dosed B-cell therapy used for the treatment of relapsing MS to include CIS, RRMS, and SPMS. Approval was based on phase three ASCL P OS and studies; results showed that ofatumumab demonstrated superiority when compared to terifunomide in signifcantly reducing the annuali ed relapse rate (0.11 vs. 0.22, respectively, in trial I, and 0.10 vs. 0 25, respectively, in trial ), three-month confrmed disease progression (10 9 vs 15 05 , respectively), and the number of gadolinium-enhancing T1 and new or enlarging T2 lesions. A post-hoc analysis indicated that ofatumumab may delay new disease activity in relapsing MS patients; the odds of achieving no evidence of disease activity with ofatumumab compared with terifunomide were more than three times higher in the frst 12 months and more than eight times higher in the following 12 months. Observed adverse reactions with ofatumumab included upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions.
OCREVUS® (ocrelizumab)
Previously approved for the treatment of RRMS as a twiceyearly infusion, OCREVUS® (ocreli umab, enentech) received FDA approval in December 2020 to shorten the infusion time from 3.5 hours to 2 hours, with doses remaining at twice-yearly intervals.12 enentech released data in October 2021 showing that early and ongoing treatment with ocreli umab signifcantly
MULTIPLE SCLEROSIS
Drug ManufacturerRoute
ublituximab (TG-1101) TG Therapeutics IV
evobrutinib Merck KGaA-EMD Seronooral
fenebrutinib (GDC-0853)Genentech-Roche oral
Status
anti-CD20 antibody relapsing pending (3Q 2022)
Bruton tyrosine kinase inhibitor relapsing; relapsing-remittingphase three
Bruton tyrosine kinase inhibitor relapsing; primary progressivephase three
vidofudimus ( M -838) Immunic Therapeuticsoral pyrimidine synthesis inhibitorrelapsing-remitting phase three
delta-9-tetrahydrocannabinol (Sativex) Pharmaceuticals; a Pharmaceuticals oral cannabinoid spasticity in MS phase three
ocreli umab (OC S®)Roche IV anti-CD20 antibody relapsing; primary progressivephase three
natali umab biosimilar (PB00 ) Polpharma BiologicsSando IV anti-alpha-4-integrin antibody relapsing-remitting phase three hyaluronidase; ocreli umab (OC S SC) oche; alo yme Therapeutics; Genentech SC
anti-CD20 antibody; endoglycosidase MS phase three
glatiramer acetate (GA Depot) Mapi Pharma-Mylan IM immunomodulators relapsing phase three progressive phase two
orelabrutinib nnoCare Pharma-Biogen oral
Bruton tyrosine kinase inhibitor relapsing-remitting phase two
Abbreviations: CAR-T = chimeric antigen receptor therapy; IV = intravenous; SC = subcutaneous; MS = multiple sclerosis
reduced the risk of requiring a walking aid in RRMS (35% reduction after seven-and-a-half years vs. when treatment initiated two years later) and disability progression in PPMS (29 reduction in 48-wee confrmed disability after eight years vs. when treatment initiated after the double-blind period in phase three).13 The study also showed the shorter two-hour infusion of ocreli umab was equally well-tolerated in AfricanAmerican, Hispanic, and Latino populations compared with overall study populations.13
TascensoTM ODT (fngolimod lauryl sulfate)14
In December 2021, the FDA approved TascensoTM ODT (fngolimod lauryl sulfate, anda euroscience) 0 25 mg oral disintegrating tablet (ODT) for the treatment of relapsing forms of MS, including C S, MS, and SPMS, in pediatric patients over the age of 10 years.
Payer Management
Due to the high cost in this category, MS remains a high priority for payers. As the cost of drugs in categories such as MS continue to rise, specialty drug spend is expected to grow more rapidly than the cost of traditional drugs.16 According to the 2020 Magellan Rx Management Medical Pharmacy Trend eportTM, MS was one of the top four
commercial disease states by per-member-per-month spend in the previous year, with a 48% increase in spending from 2018 to 2019.17 To counteract this rise in spend, payers are implementing strategies such as utili ation management on both pharmacy and medical benefts, site of service, and formulary management 17 In fact, a 2020 analysis from IQVIA suggested that 80% of commercially insured patients receiving a new prescription for MS were sub ect to a utili ation management restriction 18
Step therapy is becoming increasingly popular as a means to manage the MS space for payers. According to the American Academy of eurology (AA ), step therapy programs are encouraged when they are driven by evidence-based clinical data, safety data, and cost-e ectiveness data 19 Factors such as relative e cacies of DMT, mechanisms of action, side e ects, treatment schedule, and routes of administration should be considered in treatment decision on an individuali ed level 19 The AA also noted that neurologists must play a role in containing costs, by making well-educated decisions on the appropriate initiation, use, and discontinuation of DMT, when appropriate.19 The MS category is continuously expanding, with currently 19 brand name products from which payers and providers can choose.18 As the pipeline promises more new therapies in the MS category, clear guidance and consensus will be even more important to achieve e ective management, improve outcomes, and manage costs.
COVID-19 FAQs Diagnostic Testing Kits
References
1.“MS Prevalence.” National Multiple Sclerosis Society, https://www. nationalmssociety.org/About-the-Society/MS-Prevalence.
2.“Types of MS.” National Multiple Sclerosis Society, https://www. nationalmssociety.org/What-is-MS/Types-of-MS.
3.“Multiple Sclerosis Information Page.” National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/ Disorders/All-Disorders/Multiple-Sclerosis-Information-Page.
4.“How MS is Diagnosed.” National Multiple Sclerosis Society, https:// www.nationalmssociety.org/Symptoms-Diagnosis/Diagnosing-MS.
5. “Updated McDonald Criteria Expected to Speed the Diagnosis of MS and Reduce Misdiagnosis.” National Multiple Sclerosis Society, 21 Dec. 2017, https://www.nationalmssociety.org/About-the-Society/ News/Updated-McDonald-Criteria-Expected-to-Speed-the-Di.
6.“Medications.” National Multiple Sclerosis Society, https://www. nationalmssociety.org/Treating-MS/Medications.
7. “Practice Guideline Recommendations Summary: Disease-Modifying Therapies for Adults with Multiple Sclerosis.” American Academy of Neurology, April 2018, https://www.aan.com/Guidelines/home/ GuidelineDetail/898.
8.“Janssen Announces U.S. FDA Approval of PONVORY™ (ponesimod), an Oral Treatment for Adults with Relapsing Multiple Sclerosis Proven Superior to Aubagio® (terifunomide) in educing Annual Relapses and Brain Lesions.” Johnson & Johnson, 19 Mar. 2021, https://www.jnj.com/janssen-announces-u-s-fda-approval-ofponvory-ponesimod-an-oral-treatment-for-adults-with-relapsingmultiple-sclerosis-proven-superior-to-aubagio-terifunomide-inreducing-annual-relapses-and-brain-lesions.
9. Kappos, Ludwig, et al Ponesimod Compared with Terifunomide in Patients with Relapsing Multiple Sclerosis in the ActiveComparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.” JAMA Neurology, 1 May 2021, https://pubmed.ncbi.nlm.nih. gov/33779698/.
10.“FDA approves Novartis Kesimpta® (ofatumumab), the frst and only self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis.” Novartis, 20 Aug. 2020, https:// www.novartis.com/news/media-releases/fda-approves-novartisesimpta-ofatumumab-frst-and-only-self-administered-targeted-bcell-therapy-patients-relapsing-multiple-sclerosis.
11. auser, Stephen, et al Ofatumumab versus Terifunomide in Multiple Sclerosis.” New England Journal of Medicine, 6 Aug. 2020, https://pubmed.ncbi.nlm.nih.gov/32757523/.
12.“FDA approves Roche’s OCREVUS® (ocrelizumab) shorter 2-hour infusion for relapsing and primary progressive multiple sclerosis.” Roche, 14 Dec. 2020, https://www.roche.com/media/releases/medcor-2020-12-14.htm.
13.“New Data up to 8-Years for Genentech’s Ocrevus (ocrelizumab) Show arly and Ongoing Treatment Signifcantly educed is of Requiring a Walking Aid in Relapsing Multiple Sclerosis and Disability Progression in Primary Progressive Multiple Sclerosis.” Genentech, 12 Oct. 2021, https://www.gene.com/media/pressreleases/14932/2021-10-12/new-data-up-to-8-years-forgenentechs-oc.
16.“Management of the Multiple Sclerosis Category: An Increasing Focus for Payers.” American Health & Drug Benefts, https://www. ahdbonline.com/web-exclusives/in-the-news/1199-article-1199.
18.Migliara, Gabby. “Payers subject 80% of new RA and MS patients to utilization management restrictions.” PHRMA, 22 July 2020, https:// catalyst.phrma.org/payers-subject-80-of-new-ra-and-ms-patientsto-utilization-management-restrictions.
19.“AAN Position: Availability of Disease Modifying Therapies (DMT) for Treatment of Relapsing Forms of Multiple Sclerosis.” American Academy of Neurology, https://www.aan.com/policy-and-guidelines/ policy/position-statements/availability-of-disease-modifyingtherapies-dmt-for-treatment-of-relapsing-forms-of-multiplesclerosis/.
Parkinson’s Disease: Treatment and Management Update
Properly managing symptoms in this population can decrease emergency department and hospital utilization and can help manage costs.
Andrea Cole Henry, Pharm.D., MBA, BCPS
Specialty, Drug Information Pharmacist
Magellan Rx Management
Parkinson’s disease (PD) is a motor system disorder that causes unintended or uncontrollable movements of the body; it is diagnosed in approximately 60,000 U.S. adults each year.1 In the U.S., around 1 million adults are living with PD — a number that is expected to increase to 1.2 million in the next decade.1 The prevalence of PD is greater than the combined number of U.S. individuals with multiple sclerosis, muscular dystrophy, and amyotrophic lateral sclerosis PD a ects men more commonly than women (1 5 times more), and the incidence of PD increases with age.1
PD has no known cause; however, it may be hereditary in some cases, while a combination of genetics and environmental factors may be the underlying cause in other cases. In individuals with PD, brain cells responsible for producing dopamine are damaged, impacting movement PD is typically defned by four primary symptoms tremor, rigidity or muscle sti ness, dys inesia, and postural instability Additional symptoms associated with PD are di culty swallowing, chewing, or spea ing; emotional changes; urinary problems or constipation; dementia or other cognitive impairments; fatigue; and sleeping problems.2
hile no specifc tests are used to diagnose PD, neurologists will use medical history, a review of symptoms, and neurological and physical exams. Lab tests and imaging tests are often utilized as a means to rule out other conditions.2
The severity of PD manifestations can be assessed using di erent scales; one assessment is the Movement Disorder Society-Sponsored nifed Par inson s Disease ating Scale (MDS- PD S) which is a comprehensive assessment designed to monitor the burden and extent of PD disease across the longitudinal disease course and provide a clinical end point in therapy trials.3 The MDS-UPDRS assesses activities of daily living, balance, behavior, cognition, communication, coordination, depression, dysarthria, eating, functional mobility, gait, life participation, pain, psychosis, quality of life, sleep, swallowing, and upper extremity function.3
More than half of PD patients will develop what is known as PD psychosis (PDP) over the course of the disease.2 PDP mostly presents as visual hallucinations, with delusions occurring less commonly. Evidence suggests that factors both intrinsic to the disease and extrinsic to the disease can contribute to the emergence of PDP. Symptoms of PDP have been associated with sleep disturbances, defcits in visual processing attributable to dopamine defciency, family history of dementia, and the e ects of medications, including those that treat PD.2 While there is a high prevalence of PDP symptoms in patients with PD, this number may be underreported. In a survey of patients with PD, 20% of patients were diagnosed with symptoms of PDP; however, of those undiagnosed, 14 were later identifed as having moderate or severe PDP symptoms through chart review.2
Total U.S. costs associated with PD, both direct and indirect, are estimated to be nearly $52 billion per year.1 With the projected number of PD patients at more than 1.6 million by 2037, the total economic burden is projected to surpass 79 billion by the same year These numbers refect the burden of PD on society, payers, patients, and caregivers.4
Treatment
PD is typically treated with medication to manage symptoms, including tremors and movement di culties The most common therapies used to treat PD are levodopa; dopamine agonists, such as pramipexole, apomorphine, and ropinirole; monoamine oxidase-B (MAO-B) inhibitors; and catechol-O-methyltransferase (COMT) inhibitors.5 Amantadine, an antiviral, has been found to reduce symptoms Safnamide, istradefylline, and opicapone have been found to improve symptoms when used as add-on treatments for patients currently taking levodopa/carbidopa and experiencing OFF episodes.5 An OFF episode is a period when a patient’s symptoms increase due to a medication not working well.6 The medication or combination of medications used to treat a patient with PD will vary by the stage and severity of the disease.
A comprehensive treatment plan for patients with PD often includes supportive care, such as physiotherapy, to relieve muscle sti ness and oint pain; occupational therapy to identify and resolve areas of di culty in daily living activities; and speech and language therapy Lifestyle modifcations, such as diet change, can help improve symptoms.5
In cases where a patient is not responding to treatment, a surgical intervention called deep brain stimulation (DBS) may be appropriate.5 In DBS, electrodes are implanted into the brain and connected to a pulse generator which painlessly stimulates
PD is typically treated with medication to manage symptoms, including tremors and movement difculties.
the brain, blocking signals that cause motor symptoms of PD. DBS does not stop PD from progressing, but it may be valuable for patients with levodopa-responsive PD who are experiencing disabling OFF symptoms despite therapy.5
PDP Treatment
There is currently one drug approved to treat PDP; pimavanserin (NUPLAZID®, Acadia Pharmaceuticals) was approved as the frst and only drug indicated for PDP in 2016.7 A clinical trial showed that pimavanserin was more e ective than placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms.7 Real world case studies have demonstrated that pimavanserin can be added to PD therapy without compromising its e cacy and tolerability; in some cases, after e ectively managing PDP symptoms with pimavanserin, providers could increase the dose of dopaminergic drugs for better motor control.8,9
Results from a 2018 study of PDP patients with or without cognitive impairment and receiving or not receiving cognitive-enhancing medications showed that pimavanserin has a robust antipsychotic e ect in PD patients with cognitive impairment, which may be enhanced by concomitant cognitive-enhancing medication use.10 The mean change in PD-adapted Scale for Assessment of Positive Symptoms was larger for the cognitively impaired (6.62 vs. -0.91; p=0.002) versus the cognitively unimpaired (-5.50 vs. -3.23; p=0.046), and the comparable change was greater in patients treated concomitantly with cognitive-enhancing medications (-6.04 vs. 2.18; p=0.012) versus those who were not (-5.66 vs. -3.15; p=0.041).10 A multi-year, open-label study that assessed the long-term safety and tolerability of pimavanserin showed that long-term treatment demonstrated a favorable beneft ris profle without unexpected safety concerns and no increased mortality risk.11 In more recent studies, pimavanserin has been shown to be associated with lower mortality in PD patients than other atypical antipsychotics.12
Drug Manufacturer Route of AdministrationMechanism of ActionStatus
carbidopa/levodopa (ND0612)NeuroDerm SC aromatic amino acid decarboxylation inhibitor; dopamine receptor agonist phase three e aladcigene resoparvovec (VY-AADC) Voyager Therapeutics other gene therapy phase two
The Movement Disorder Society (MDS) published an update on treatments for non-motor symptoms of PD and concluded that pimavanserin is the only FDA-approved intervention to treat PDP that is e cacious, has acceptable safety ris without speciali ed monitoring, and is clinically useful 13 MDS included the following fndings for the other PDP interventions clo apine is e cacious and clinically useful and has acceptable safety ris with speciali ed monitoring; quetiapine has insu cient e cacy evidence, is possibly clinically useful, and has acceptable safety ris ; and olan apine is not e cacious, has unacceptable safety ris , and is not clinically useful 13 According to the American eriatrics Society Beers Criteria® pdate pert Panel from 2019, all antipsychotics are potentially inappropriate for use in patients with PD, with the e ception of pimavanserin, clo apine, and quetiapine, as dopaminereceptor antagonists have the potential to worsen PD symptoms 14
Pimavanserin is currently being investigated for the treatment of dementia-related psychosis, including that associated with PD A
post-hoc subgroup analysis was conducted from the A MO Y trial, which assessed pimavanserin in the treatment of hallucinations and delusions associated with dementia-related psychosis 15 The post-hoc subgroup analysis studied patients with dementia and psychosis associated with PD in the A MO Y trial, and fndings showed that symptoms of psychosis were reduced during the openlabel treatment and e cacy was maintained 15 owever, A MO Y was not designed to demonstrate the e ects by dementia subgroup and results should be interpreted cautiously 15
Recent Approvals for PD GOCOVRI® (amantadine extended release)16
n ebruary 2021, the DA approved OCO ® (amantadine e tended release ( ), Adamas Pharmaceuticals, nc ) for a second indication as an adjunctive treatment to levodopa/carbidopa in patients with PD e periencing O episodes The drug was
Abbreviations C S central nervous system; intravenous; MAO monoamine o idase inhibitor; MOA-B monoamine o idase B; MDA -methyl-D aspartic acid; SC subcutaneous; S serotonin-norepinephrine reuptake inhibitor
previously approved by the FDA in 2017 for the treatment of dyskinesia in patients with PD receiving levodopa-based therapy, with or without concomitant dopaminergic medications.
The approval was based on results from two pivotal randomized, double-blind, placebo-controlled phase three studies that showed treatment with amantadine signifcantly reduced both O time and dys inesia A clinically meaningful increase in good O time was observed in patients taking a levodopa-based medication for PD cacy was sustained for at least two years in the phase three, open-label EASE LID-2 study. Adverse reactions observed in patients taking amantadine ER included hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.
KYNMOBI ® (apomorphine hydrochloride sublingual)
The DA approved KY MOB ® (apomorphine hydrochloride sublingual flm, Sunovion Pharmaceuticals) in May 2020 for the acute, intermittent treatment of O episodes in patients with PD 17 The approval was based on a randomized, double-blind, placebocontrolled, parallel-group trial of 109 patients who had at least two hours of total O periods per day, including well-defned morning O episodes, despite being responsive to levodopa treatment 17 Patients were initially given increasing doses of apomorphine hydrochloride until an optimal dose was identifed in an initial open-label phase. Patients were then randomly assigned to either apomorphine hydrochloride or the placebo, and treatment was administered for up to fve O episodes throughout the day for 12 weeks. The primary outcome was the mean change from pre-dose to 30 minutes post-dose in the MDS- PD S Part in the maintenance phase at the 12-week visit. Patients using apomorphine hydrochloride experienced an 11.1-point reduction in their MDS- PD S scores at wee 12, compared to a 3 5-point reduction for the placebo group with a least-squared mean treatment di erence of -7 (95 C , -11 5 to -3 7; p 0 0002) 17, 18 Clinical improvements were observed as early as 15 minutes after dosing and persisted for up to 90 minutes Of the patients treated with apomorphine hydrochloride, 31 achieved full control of their motor symptoms within 30 minutes at wee 12, compared to 14 of the placebo group.17, 18 Treatment-related side e ects included nausea, sleepiness, and dizziness.17, 18
ONGENTYS®
(opicapone)19
n April 2020, the DA approved O TYS® (opicapone, eurocrine Biosciences), a COMT inhibitor, for PD patients e periencing O episodes while on a levodopa carbidopa regimen Opicapone is administered as either 25 mg or 50 mg capsules once a day as ad unctive therapy to levodopa carbidopa t was shown to signifcantly reduce O periods
Properly managing symptoms in this population can lead to a decrease in ED and hospital utilization and can help manage costs.
and e tended the periods of O -time without dys inesia, compared to the placebo in two randomized, double-blind, parallel-group, placebo- and active-controlled or placebocontrolled phase three trials. The approval was based on 38 clinical trials that included more than 1,000 PD patients treated with opicapone. Patients diagnosed at least three years ago, who had been e periencing fuctuations in motor symptoms O time at least 1 5 hours daily while awa e despite being on a stable levodopa carbidopa regimen, were included
The B PA K-1 study included 00 patients who were randomly assigned to receive a 5 mg, 25 mg, or 50 mg opicapone dose; entacapone; or placebo Treatment was administered over 14 to 15 wee s while patients were on a continuous levodopa carbidopa regimen. The primary outcome was the mean change from baseline in absolute o -time documented in patient diaries recorded around the cloc (-1 95 vs -0 93 for opicapone and placebo, respectively); the mean di erence was -1 01 (95 C , -1 2 to -0 407; p 0 002) esults from B PA K-1 showed that both 50 mg opicapone and entacapone signifcantly decreased the duration of daily O periods and increased O time without dys inesia, compared to the placebo Opicapone also led to favorable ratings in both the P -C and C -C scales, unli e entacapone n the B PA K-2 study, 427 patients were randomly assigned either a 25 mg or a 50 mg dose of opicapone or a placebo for 14 to 15 wee s The primary outcome was also mean change from baseline in absolute O -time Patients on opicapone 50 mg dose compared to placebo showed an absolute O -time -1 98 vs -1 07, respectively, with a di erence of -0 9 (C , -1 523 to -0 287; p 0 008) An open-label e tension of both studies showed promising results; the 25 mg dose continued to show reductions in O time and increases in O periods over 12 months of treatment, regardless of whether the patient received opicapone or the placebo in the initial part of the main trials.
Common adverse reactions associated with the opicapone treatment included dyskinesia, constipation, an increase in blood creatine kinase, low blood pressure, and weight loss.
The future of pharmacy is here.
Gene Therapy
According to the American Society of Gene and Cell Therapy, there are 25 ongoing trials for gene therapies treating PD listed in the clinical trials database with the U.S. National Library of Medicine.20 Some phase one clinical trials have shown promising results. In a phase one trial from Genzyme and Voyager Therapeutics, the gene encoding for aromatic amino acid decarboxylase was delivered to the putamen in the brains of patients with PD, and outcomes demonstrated modest improvement in patients who received the therapy.20 While still very much in early development, there is promise on the horizon for innovative treatment approaches for PD in the coming years.21
Managed Care Implications
Payer management in this category is key to improving outcomes. Hospitalizations and emergency department (ED) use are substantial among patients with PD — there were more than 272,000 hospitalizations and 416,000 ED visits in 2014.23 Properly managing symptoms in this population can lead to a decrease in
ED and hospital utilization and can help manage costs. Medicare bears the largest share of cost associated with PD; however, employers are negatively impacted by the loss of productivity and absenteeism from patients with PD as well as those who care for them.23
There is a need in the PD space for integration of the evidencebased management from well-controlled studies and the real-world individual treatment. Currently, the evidence from randomized controlled studies has only informed 11.5% of guideline recommendations for PD management.24 It can be challenging to translate the available evidence from studies into clinical care practice as well as payer management, as patients seen in real-world practice often di er in clinical presentation, comorbidities, and age from the carefully selected trial participants.24 Individualized and custom management for patients with PD is key to improved outcomes. As research in precision medicine expands, the ability to tailor the approach to treatment based on individual patient profles will li ely be enhanced n the meantime, treatment teams are tasked with adjusting evidence-based medicine to determine an e ective treatment plan for each patient
2. Hermanowicz, Neal, et al. “Parkinson’s Disease Psychosis: Symptoms, Management, and Economic Burden.” American Journal of Managed Care, 17 Aug. 2015, https://www.ajmc.com/view/a582_aug15_ parkinsons_s199.
3. Movement Disorder Society-Sponsored nifed Par inson s Disease Rating Scale Revision.” Shirley Ryan Ability Lab, https://www.sralab. org/rehabilitation-measures/movement-disorder-society-sponsoredunifed-par insons-disease-rating-scale
4. Yang, Wenya, et al. “Current and projected future economic burden of Parkinson’s disease in the U.S.” nature, 9 July 2020, https://www. nature.com/articles/s41531-020-0117-1.
5. “Parkinson’s Disease Information Page.” National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/Disorders/AllDisorders/Parkinsons-Disease-Information-Page#disorders-r1.
6. DA approves new add-on drug to treat o episodes in adults with Parkinson’s disease.” U.S. Food & Drug Administration, 27 Aug. 2019, https://www.fda.gov/news-events/press-announcements/fdaapproves-new-add-drug-treat-episodes-adults-parkinsons-disease.
7. “Adamas Announces FDA Approval for Second Indication for GOCOVRI® as an Adjunctive Treatment to levodopa/carbidopa in Parkinson’s Disease Patients Experiencing OFF Episodes.” Business Wire, 1 Feb. 2021, https://www.businesswire.com/news/home/20210201005801/ en/Adamas-Announces-FDA-Approval-for-Second-Indication-forGOCOVRI%C2%AE-as-an-Adjunctive-Treatment-to levodopacarbidopain-Parkinson%E2%80%99s-Disease-Patients-Experiencing-OFF-Episodes.
8. DA approves frst drug to treat hallucinations and delusions associated with Parkinson’s disease.” U.S. Food & Drug Administration, 29 Apr 2016, https://www.fda.gov/news-events/pressannouncements fda-approves-frst-drug-treat-hallucinationsand-delusions-associated-parkinsons-disease#:~:text=The%20 U.S.%20Food%20and%20Drug,some%20people%20with%20 Parkinson’s%20disease.
9. Dashtipour Khashayar, et al. “Pimavanserin Treatment for Parkinson’s Disease Psychosis in Clinical Practice.” Hindawi, 4 Jan 2021, https:// www.hindawi.com/journals/pd/2021/2603641/
10. Espay, Alberto, et al. “Pimavanserin for Parkinson’s Disease Psychosis: ects Stratifed by Baseline Cognition and se of CognitiveEnhancing Medications.” Movement Disorders, 2 Nov. 2018, https:// pubmed.ncbi.nlm.nih.gov/30387904/.
11. Ballard, Clive, et al. “Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson’s disease psychosis.” Parkinsonism and Related Disorders, 28 June 2020, https://pubmed.ncbi.nlm.nih. gov/32712560/.
12. Mosholder, A., et al. “All-cause mortality in pimavanserin and atypical antipsychotic users with Parkinson’s disease in Medicare.” Movement Disorders, 2020, https://www.mdsabstracts. org/abstract/all-causemortality-in-pimavanserin-and-atypical-antipsychotic-users-withparkinsons-disease-in-medicare/#:~:text=Pimavanserin%20use%20 was%20associated%20with,%2D1.01)%20dementia%20were%20 similar.
13. Seppi, Klaus, et al. “Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease — An Evidence-Based Medicine Review.” Movement Disorders, 2019, https://www.movementdisorders.org/MDSFiles1/Resources/PDFs/Seppi_et_al-2019-Movement_Disorders.pdf.
14. “American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.” Journal of the American Geriatrics Society, 29 Jan. 2019, https://pubmed.ncbi.nlm. nih.gov/30693946/.
15. Weintraub, Daniel, et al. “Pimavanserin Treatment of Hallucinations and Delusions in Patients with Parkinson’s Disease Dementia: Post Hoc Analysis of the HARMONY Trial.” Clinical Trials on Alzheimer’s Disease Annual Conference, 12 Nov. 2021.
16. “Adamas Announces FDA Approval for Second Indication for GOCOVRI® as an Adjunctive Treatment to levodopa/carbidopa in Parkinson’s Disease Patients Experiencing OFF Episodes.” Business Wire, 1 Feb. 2021, https://www.businesswire.com/news/home/20210201005801/ en/Adamas-Announces-FDA-Approval-for-Second-Indicationfor-GOCOVRI%C2%AE-as-an-Adjunctive-Treatment-tolevodopacarbidopa-in-Parkinson%E2%80%99s-Disease-PatientsExperiencing-OFF-Episodes.
17. “Sunovion announces U.S. FDA approval of KYNMOBI™ (apomorphine hydrochloride) sublingual flm for the treatment of Par inson s disease o episodes Sunovion, 21 May 2020, https://news.sunovion.com/ press-releases/press-releases-details/2020/Sunovion-Announces-USFDA-Approval-of-KYNMOBI-apomorphine-hydrochloride-SublingualFilm-for-the-Treatment-of-Parkinsons-Disease-OFF-Episodes/default. aspx.
18. Martins, n s DA Approves Kynmobi Sublingual ilm to Treat O Episodes in Parkinson’s.” Parkinson’s News Today, 22 May 2020, https://parkinsonsnewstoday.com/2020/05/22/fda-approvesynmobi-sublingual-flm-treat-o -episodes-par inson
19. Martins, Inês. “FDA Approves Ongentys as Levodopa Add-on for O Periods Parkinson’s News Today, 27 Apr. 2020, https:// parkinsonsnewstoday.com/2020/04/27/fda-approves-ongentys-addon-therapy-par insons-o -periods-with-levodopa
20. Mulholland, Eoghan. “Parkinson’s Disease: Is Gene Therapy the Answer We Have Been Looking For?” American Society of Gene + Cell Therapy, 13 Apr. 2020, https://asgct.org/research/news/april-2020/parkinsonsdisease-awareness-month.
21. Blits, Bas, et al. “Perspective on the Road toward Gene Therapy for Parkinson’s Disease.” frontiers in Neuroanatomy, 9 Jan. 2017, https:// www.frontiersin.org/articles/10.3389/fnana.2016.00128/full#note1.
23. Ostrovsky, Lilly. “Payers’ Perspective: Incorporating Real-World Evidence in Patient Care.” American Health & Drug Benefts, April 2017, https://www.ahdbonline.com/issues/2017/april-2017-vol-10-no2/2351-payers-perspective-incorporating-real-world-evidence-inpatient-care.
24. Klucken, Jochen, et al. “Management of Parkinson’s Disease 20 Years from Now: Towards Digital Health Pathways.” Journal of Parkinson’s Disease, 18 Dec. 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6311358/.
Biosimilars:
Updates and Pharmacy Management Impact
Biosimilar products covered on the pharmacy beneft will give payers more control as well as the option to drive use of lower-cost options
The biosimilar landscape continues to expand, changing the market across several disease and therapeutic categories There have been 33 biosimilars approved by the S ood and Drug Administration ( DA) and an e pansive pipeline across several indications 1 our new biosimilars were approved in 2021 alone (Table 1) 1 Loo ing forward, 25 biosimilars are e pected to launch in the ne t fve years 2
Biosimilars have changed treatment and management across several disease categories Biosimilar competition has been playing a role in containing drug costs; among biologics, most list prices have not increased since the biosimilar launch, and for many, list prices have declined since 2018 3
ith biosimilars coming to the mar et that will ultimately be covered under the pharmacy beneft, this presents both opportunity and challenges for payers Biosimilar products covered on the pharmacy beneft will give payers more control as well as the option to drive use of lower-cost options 2 Pharmacy beneft managers (PBMs) have strategi ed in innovative ways to manage biosimilars One PBM has used formulary placement preferring biosimilars or reference biologics to drive lowest net costs, while others have implemented drug management strategy programs around the adoption of biosimilars 3 Other PBMs have directly communicated with patients to incentivi e switching to biosimilars when appropriate and coste ective 3 hile biosimilars are not the lowest net cost option in every scenario, interchangeable alternatives and competition create a landscape where costs can be better managed
A recent survey shows a majority of payers agree that biosimilars provide meaningful cost savings (59% completely agree; 35% somewhat agree), with 94% of payers responding that lower price is a primary infuencing factor for designating a preferred product.4 Payers also noted contracting arrangement, therapeutic area, number of indications, physician demand, and length of time on the mar et as secondary infuencing factors 4
As the availability of biosimilars has expanded, providers have become more comfortable using these therapies. However, continued provider education alongside patient education will impact uptake, as patient preference may play a role in adoption of many options in the market.
Recent Activity
The frst M A® biosimilars are expected to launch by 2023, and each has the potential to signifcantly impact pharmacy spend With high list prices on branded adalimumab, interchangeable biosimilars present a unique opportunity to incentivize payers to adopt lower-cost alternatives and e ectively manage spend 5 A potential eight adalimumab biosimilars are slated to launch in 2023, which may lead discounting and pricing competition.5
According to the U.S. Physicians and Payers Forum report, providers are willing to prescribe biosimilar adalimumab as an alternative to branded adalimumab, and depending on payer strategies around the biosimilars, biosimilar adalimumab may be used as an alternative to etanercept (Enbrel®) when appropriate as well.6 The launch of adalimumab biosimilars will change the market, raising questions around how pricing strategies, discounts, and sequence of launches will impact stakeholders.7
The approval of the frst insulin biosimilars in 2021 (S M L ® and Rezvoglar) presents an opportunity for lower-cost treatment options for all stakeholders. Notably, two identical versions of the insulin glargine-yfgn (SEMGLEE®) will launch, including the branded interchangeable product and an authorized interchangeable biosimilar.7 Both of these versions are fully interchangeable with di erent wholesale acquisition cost ( AC) list prices 7 SEMGLEE® was initially launched as a non-interchangeable product, and the WAC was a 65% discount to the reference product, Lantus® 7 Now designated as interchangeable, SEMGLEE® will be relaunched at a WAC amounting to a 5% discount from Lantus®, with the unbranded interchangeable biosimilar at a 65% discount.7 Approximately 8 million Americans use daily insulin injections, and three manufacturers account for more than 95% of the insulin supply.8 These interchangeable biosimilars will impact
market competition, potentially helping to lower costs and improve outcomes.8 There will be added complexity as some insulin manufacturers introduced authorized generics as lowercost alternatives to the branded insulin products.7 The landscape will be challenging for providers to navigate between branded products, generics, and interchangeable biosimilars.
Regulatory Updates
Legislators in the U.S. continually push for lower drug costs, with biosimilars being part of the overall strategy. In 2021, President Biden issued executive orders with the objective of promoting low-cost options such as biosimilars; CMS specifcally was asked to prepare payment models for Medicaid and Medicare coverage of these products to promote utilization.9 The FDA was given instructions to improve the framework for approving biosimilars and develop educational materials for providers and patients to better understand biosimilars.9
Under the Prescription Drug Price Relief Act of 2021, the Department of Health and Human Services (HHS) must annually review all brand name drugs for excessive pricing, and where excessive prices are found, “HHS must (1) void any governmentgranted exclusivity; (2) issue open, nonexclusive licenses for the drugs; and (3) expedite review of corresponding applications for generic drugs and biosimilar products.”4, 10 Other legislation
is currently in development that may address costs as well.4 Some examples include the Increasing Access to Biosimilars Act Demo, which would direct CMS to establish a voluntary, national demonstration project under Medicare Part B to evaluate the beneft of providing a shared savings payment for biosimilars, and the BIOSIM Act, which would increase reimbursement for biosimilars at ASP+6% of the brand name.4
There are varying state-specifc regulations that could impact biosimilar launches, with various factors at play including whether or not interchangeability is certifed, prescriber or payer notifcation requirements, or whether prescriber notations of “brand medically necessary” or “dispense as written” will block substitution.4
Moving Forward
As more biosimilars and interchangeable biosimilars launch across the medical and pharmacy beneft and several disease categories, biosimilar management will continue to be a high priority. The biosimilar pipeline includes products in development across the following classes: targeted immunomodulators, insulins, supportive care, oncology, ophthalmology, immunosuppressants, bone health, growth hormones, and infertility. This market space will continue to expand, creating opportunity and challenges for stakeholders.
References
1.“Biosimilar Product Information.” U.S. Food & Drug Administration, 27 Dec. 2021, https://www.fda.gov/drugs/biosimilars/biosimilarproduct-information.
2. Boutross, Laura, et al Pharmacy beneft is a whole new ball game for biosimilars.” ZS, 12 Jan. 2022, https://www.zs.com/insights/ pharmacy-beneft-is-a-whole-new-ball-game-for-biosimilars
3.“Biosimilars Versus Biologics — How About Both?” PCMA, 20 July 2021, https://www.pcmanet.org/biosimilars-versus-biologics-howabout-both te t Pharmacy 20beneft 20managers 20 (PBMs)%20are,turn%2C%20lowers%20patients’%20costs.
4.Stanley, Edan. “Naviating US Biosimilar Landscape, Insight from a Recent Payer Survey.” First Report Managed Care, 20 Oct. 2021, https://www.hmpgloballearningnetwork.com/site/frmc/conferencecoverage/navigating-us-biosimilar-landscape-insight-recent-payersurvey.
5.Joachim, Rose. “Weighing the Potential of Humira Biosimilars in the U.S. — Competitive Dynamics Analysis.” Biosimilar Development, 29 Sept. 2020, https://www.biosimilardevelopment.com/ doc/weighing-the-potential-of-humira-biosimilars-in-the-u-scompetitive-dynamics-analysis-0001.
6.“Survey of American Dermatologists and Payers Finds AbbVie’s Humira is the Clear Leader in Psoriasis Treatment and that the Availability of Biosimilars and an Increasing Number of IL-17 Inhibitors Will Shape Treatment and Reimbursement Decisions in Coming.” Biosimilar Development, 21 Sept. 2015, https://www.biosimilardevelopment.com/doc/survey-ofamerican-dermatologists-abbvie-humira-psoriasis-treatmentbiosimilars-0001.
7.“Why PBMS and Payers are Embracing Insulin Biosimilars with Higher Prices — and What That Means for Humira.” Drug Channels: Expert Insights on Pharmaceutical Economics and the Drug Distribution, 9 Nov. 2021, https://www.drugchannels.net/2021/11/ why-pbms-and-payers-are-embracing.html.
8.Oskouei, Sonia. “Five Key Things Pharmacists Need to Know as Insulin Biosimilars Come to Market.” Pharmacy Times, 29 July 2021, https www pharmacytimes com view fve- ey-thingspharmacists-need-to-know-as-insulin-biosimilars-come-to-market.
9.“Biden Executive Order Targets Competition in Healthcare, Life Sciences to Spur Economic Activity.” Goodwin Law, 12 July 2021, https://www.goodwinlaw.com/publications/2021/07/07_12-bidenexecutive-order-targets-competition.
10.“S. 909 (IS) - Prescription Drug Price Relief Act of 2021.” GovInfo, https://www.govinfo.gov/app/details/BILLS-117s909is.
USE OF CONCOMITANT IMMUNOMODULATION WITH PEGLOTICASE IN UNCONTROLLED GOUT PATIENTS
COMMON TO BIOLOGIC THERAPIES,
COMMON TO BIOLOGIC
anti-drug antibodies (ADA) can form in response to KRYSTEXXA, which can lead to decreased efficacy and an increased risk of infusion reactions.1
THERAPIES, anti-drug antibodies (ADA) can form in response to KRYSTEXXA, which can lead to decreased efficacy and an increased risk of infusion reactions.1
INDICATIONS AND USAGE
INDICATIONS AND USAGE
IN AN EFFORT TO MITIGATE ADA
IN AN EFFORT TO MITIGATE ADA
FORMATION STUDIES HAVE BEEN PUBLISHED, in which a concomitant immunomodulator has been added to pegloticase therapy.2,3 Data from these studies and other published reports are available for your review.2-12
FORMATION STUDIES HAVE BEEN PUBLISHED, in which a concomitant immunomodulator has been added to pegloticase therapy.2,3 Data from these studies and other published reports are available for your review.2-12
KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.
KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.
Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.
Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.
References: 1. Keenan RT, et al. Rheumatol Ther. 2019;6:299-304. 2. Botson J, et al. J Rheumatol. 2020;47:1-28. 3. Rainey H, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 4. Botson J, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 5. Albert JA, et al. Rheumatol Ther. 2020;7:639-648. 6. Bessen MY, et al. Int J Clin Rheumatol. 2019;14:238245. 7. Berhanu AA, et al. Semin Arthritis Rheum. 2017;46:754-758. 8. Freyne B. Transplant Proc. 2018;50:4099-4101. 9. Masri KR, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 10. Khanna PP, et al. Arthritis Rheumatol. 2021;10.1002/art.41731. 11. Abdellatif A, et al. Poster presented at: 2020 American Society of Nephrology (virtual meeting); October 22-25, 2020. 12. Soloman N, et al. Arthritis Rheumatol. 2020;72(suppl 10):1-5.
References: 1. Keenan RT, et al. Rheumatol Ther. 2019;6:299-304. 2. Botson J, et al. J Rheumatol. 2020;47:1-28. 3. Rainey H, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 4. Botson J, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 5. Albert JA, et al. Rheumatol Ther. 2020;7:639-648. 6. Bessen MY, et al. Int J Clin Rheumatol. 2019;14:238245. 7. Berhanu AA, et al. Semin Arthritis Rheum. 2017;46:754-758. 8. Freyne B. Transplant Proc. 2018;50:4099-4101. 9. Masri KR, et al. Poster presented at: 2020 EULAR European Congress of Rheumatology (virtual meeting); June 3-6, 2020; Frankfurt, Germany. 10. Khanna PP, et al. Arthritis Rheumatol. 2021;10.1002/art.41731. 11. Abdellatif A, et al. Poster presented at: 2020 American Society of Nephrology (virtual meeting); October 22-25, 2020. 12. Soloman N, et al. Arthritis Rheumatol. 2020;72(suppl 10):1-5.
Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.
Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.
The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.
The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.
Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral uratelowering agents while taking KRYSTEXXA.
Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral uratelowering agents while taking KRYSTEXXA.
In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.
In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.
Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.
Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.
CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA
CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED
HEMOLYSIS AND METHEMOGLOBINEMIA
Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.
GOUT FLARES
Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.
GOUT FLARES
An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.
CONGESTIVE HEART FAILURE
An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.
CONGESTIVE HEART FAILURE
KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.
ADVERSE REACTIONS
KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.
The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.
ADVERSE REACTIONS
The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.
Please see Brief Summary of Prescribing Information, including Boxed Warning, for KRYSTEXXA on the following pages.
Please see Brief Summary
including Boxed Warning, for KRYSTEXXA on the
(pegloticase injection), for intravenous infusion
Brief Summary - Please see the KRYSTEXXA package insert for Full Prescribing Information.
WARNING: ANAPHYLAXIS and INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS and METHEMOGLOBINEMIA
• Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA.
• Anaphylaxis may occur with any infusion, including a frst infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported.
• KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions.
• Patients should be pre-medicated with antihistamines and corticosteroids.
• Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA.
• Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.
• Screen patients at risk for G6PD defciency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD defciency. Do not administer KRYSTEXXA to patients with G6PD defciency.
INDICATIONS AND USAGE
KRYSTEXXA® (pegloticase) is a PEGylated uric acid specifc enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy.
Gout refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.
Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.
During pre-marketing clinical trials, anaphylaxis was reported with a frequency of 6.5% (8/123) of patients treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in patients receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/ or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.
KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a frst infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.
The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/ dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.
Infusion Reactions
During pre-marketing controlled clinical trials, infusion reactions were reported in 26% of patients treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of patients treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of patients treated with placebo. These infusion reactions occurred in patients being pre-treated with an oral antihistamine, intravenous corticosteroid and/ or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the frst infusion, and approximately 91% occurred during the time of infusion.
KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.
The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/ dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.
G6PD Defciency Associated Hemolysis and Methemoglobinemia
Life threatening hemolytic reactions and methemoglobinemia have been reported with KRYSTEXXA in patients with glucose-6-phosphate dehydrogenase (G6PD) defciency. Because of the risk of hemolysis and methemoglobinemia, do not administer KRYSTEXXA to patients with G6PD defciency [see Contraindications]. Screen patients at risk for G6PD defciency prior to starting KRYSTEXXA. For example, patients of African, Mediterranean (including Southern European and Middle Eastern), and Southern Asian ancestry are at increased risk for G6PD defciency.
Gout Flares
During the controlled treatment period with KRYSTEXXA or placebo, the frequencies of gout fares were high in all treatment groups, but more so with KRYSTEXXA treatment during the frst 3 months of treatment, and decreased in the subsequent 3 months of treatment. The percentages of patients with any fare for the frst 3 months were 74%, 81%, and 51%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The percentages of patients with any fare for the subsequent 3 months were 41%, 57%, and 67%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. Patients received gout fare prophylaxis with colchicine and/or nonsteroidal anti-infammatory drugs (NSAIDs) starting at least one week before receiving KRYSTEXXA.
Gout fares may occur after initiation of KRYSTEXXA. An increase in gout fares is frequently observed upon initiation of anti-hyperuricemic therapy, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout fare prophylaxis with a non-steroidal antiinfammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated. KRYSTEXXA does not need to be discontinued because of a gout fare. The gout fare should be managed concurrently as appropriate for the individual patient.
Congestive Heart Failure
KRYSTEXXA has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Two cases of congestive heart failure exacerbation occurred during the trials in patients receiving treatment with KRYSTEXXA 8 mg every 2 weeks. No cases were reported in placebo-treated patients. Four subjects had exacerbations of pre-existing congestive heart failure while receiving KRYSTEXXA 8 mg every 2 weeks during the open-label extension study. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.
Re-treatment with KRYSTEXXA
No controlled trial data are available on the safety and effcacy of re-treatment with KRYSTEXXA after stopping treatment for longer than 4 weeks. Due to the immunogenicity of KRYSTEXXA, patients receiving re-treatment may be at increased risk of anaphylaxis and infusion reactions. Therefore, patients receiving re-treatment after a drug-free interval should be monitored carefully.
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
• Anaphylaxis [see Warnings and Precautions]
• Infusion Reactions [see Warnings and Precautions]
• G6PD Defciency Associated Hemolysis and Methemoglobinemia [see Warnings and Precautions]
• Gout Flares [see Warnings and Precautions]
• Congestive Heart Failure [see Warnings and Precautions]
Clinical Trials Experience
The data described below refect exposure to KRYSTEXXA in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, doubleblind 6-month clinical trials: 85 patients were treated with KRYSTEXXA 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA 8 mg every 4 weeks; and 43 patients were treated with placebo.
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.
The most common adverse reactions that occurred in ≥5% of patients treated with KRYSTEXXA 8 mg every 2 weeks are provided in Table 1.
Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with KRYSTEXXA Compared to Placebo
KRYSTEXXA
Adverse Reaction (Preferred Term)
8 mg every 2 weeks (N=85) Na (%)
Placebo (N=43) N (%)
Gout fare 65(77%)35 (81%)
Infusion reaction 22(26%)2(5%)
Nausea10(12%)1 (2%)
Contusionb or Ecchymosisb 9 (11%)2(5%)
Nasopharyngitis6(7%)1 (2%)
Constipation5 (6%)2 (5%)
ChestPain5 (6%)1 (2%)
Anaphylaxis4 (5%)0 (0%)
Vomiting 4 (5%)1 (2%)
aIf the same subject in a given group had more than one occurrence in the same preferred term event category, the subject was counted only once.
bMost did not occur on the day of infusion and could be related to other factors (eg, concomitant medications relevant to contusion or ecchymosis, insulin dependent diabetes mellitus).
Immunogenicity
Anti-pegloticase antibodies developed in 92% of patients treated with KRYSTEXXA every 2 weeks, and 28% for placebo. Anti-PEG antibodies were also detected in 42% of patients treated with KRYSTEXXA. High anti-pegloticase antibody titer was associated with a failure to maintain pegloticase-induced normalization of uric acid. The impact of anti-PEG antibodies on patients’ responses to other PEGcontaining therapeutics is unknown.
There was a higher incidence of infusion reactions in patients with high anti-pegloticase antibody titer: 53% (16 of 30) in the KRYSTEXXA every 2 weeks group compared to 6% in patients who had undetectable or low antibody titers.
As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specifcity and assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the comparison of the incidence of antibodies to pegloticase with the incidence of antibodies to other products may be misleading.
Postmarketing Experience
General disorders and administration site conditions: asthenia, malaise, peripheral swelling have been identifed during postapproval use of KRYSTEXXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
There are no adequate and well-controlled studies of KRYSTEXXA in pregnant women. Based on animal reproduction studies, no structural abnormalities were observed when pegloticase was administered by subcutaneous injection to pregnant rats and rabbits during the period of organogenesis at doses up to 50 and 75 times, respectively, the maximum recommended human dose (MRHD). Decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD, respectively.
All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data
In 2 separate embryo-fetal developmental studies, pregnant rats and rabbits received pegloticase during the period of organogenesis at doses up to approximately 50 and 75 times the maximum recommended human dose (MRHD), respectively (on a mg/m2 basis at maternal doses up to 40 and 30 mg/kg twice weekly, in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD in rats and rabbits, respectively (on a mg/m2 basis at maternal doses up to 40 and 30 mg/kg every other day, in rats and rabbits, respectively). No effects on mean fetal body weights were observed at approximately 10 and 25 times the MRHD in rats and rabbits, respectively (on a mg/m2 basis at maternal doses up to 10 mg/kg twice weekly in both species).
Lactation
Risk Summary
It is not known whether this drug is excreted in human milk. Therefore, KRYSTEXXA should not be used when breastfeeding unless the clear beneft to the mother can overcome the unknown risk to the newborn/infant.
Pediatric Use
The safety and effectiveness of KRYSTEXXA in pediatric patients less than 18 years of age have not been established.
Geriatric Use
Of the total number of patients treated with KRYSTEXXA 8 mg every 2 weeks in the controlled studies, 34% (29 of 85) were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. No overall differences in safety or effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older.
Renal Impairment
No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in effcacy were observed.
OVERDOSAGE
No reports of overdosage with KRYSTEXXA have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein. Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specifc antidote has been identifed.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
General Information
Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment.
Anaphylaxis and Infusion Reactions
• Anaphylaxis and infusion reactions can occur at any infusion while on therapy. Counsel patients on the importance of adhering to any prescribed medications to help prevent or lessen the severity of these reactions.
• Educate patients on the signs and symptoms of anaphylaxis, including wheezing, peri-oral or lingual edema, hemodynamic instability, and rash or urticaria.
• Educate patients on the most common signs and symptoms of an infusion reaction, including urticaria (skin rash), erythema (redness of the skin), dyspnea (diffculty breathing), fushing, chest discomfort, chest pain, and rash.
• Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after the infusion of KRYSTEXXA.
• Advise patients to discontinue any oral urate-lowering agents before starting on KRYSTEXXA and not to take any oral urate-lowering agents while on KRYSTEXXA.
Inform patients not to take KRYSTEXXA if they have a condition known as G6PD defciency. Explain to patients that G6PD defciency is more frequently found in individuals of African, Mediterranean, or Southern Asian ancestry and that they may be tested to determine if they have G6PD defciency, unless already known.
Gout Flares
Explain to patients that gout fares may initially increase when starting treatment with KRYSTEXXA, and that medications to help reduce fares may need to be taken regularly for the frst few months after KRYSTEXXA is started. Advise patients that they should not stop KRYSTEXXA therapy if they have a fare.
Manufactured by:
Horizon Therapeutics Ireland DAC Dublin, Ireland
US License Number 2022
Distributed by:
Horizon Therapeutics
Deerfeld, IL 60015
KRYSTEXXA and the HORIZON logo are trademarks owned by or licensed by Horizon.
out Management Treatment and Management Opportunities
ectively controlling gout and urate levels may have a signifcant impact on this patient population, health outcomes, and payer impact
Brian MacDonald, Pharm.D. Director, Specialty Clinical Strategy Magellan Rx Management
out is a type of infammatory arthritis that a ects around 9 2 million Americans, or roughly 4 of adults in the S 1,2 out is caused by the deposition of monosodium urate crystals in people with hyperuricemia, although hyperuricemia does not always cause gout and alone does not require treatment yperuricemia is typically defned as having a serum urate equal to or higher than 0 42 mmol L (7 mg dL) 1 Most individuals with hyperuricemia are asymptomatic and do not develop gout; less than half of individuals with hyperuricemia will develop gout over a period of 15 years is factors for gout include being male, being obese, ta ing medications such as diuretics, drin ing alcohol, and a having a diet high in fructose or purines ealth conditions that raise the ris of developing gout include congestive heart failure, hypertension, insulin resistance, metabolic syndrome, diabetes, or poor idney function 1
Patients with gout often go through periods of worsening symptoms, or fares, and symptom relief, or remission 1 lares can last days or wee s, and periods of remission can range from wee s to months to years 1 Despite typically presenting as intermittent acute fares, gout is a chronic condition out typically presents with intense pain in a lower limb oint, most commonly the big toe oint, the an le and nees are also often a ected Symptoms include pain that can be intense, swelling, redness, and heat in the a ected oint n tophaceous gout and advanced gout, which is most severe, deposits of uric acid crystals called tophi form under the s in over oints and tissues
out can often be misdiagnosed or mista en for other arthritic conditions because the primary symptoms may also overlap n an acute clinical setting, diagnoses of soft tissue or musculos eletal infections may overlap with gout, but it is important to note that these conditions can occur simultaneously, and the root cause of symptoms should be investigated thoroughly Psoriatic arthritis and gout have similar clinical presentations, specifcally around the involvement of the toe oints, and the two can be di cult to di erentiate These conditions also coe ist frequently Proper diagnosis is ey to initiating e ective therapy and improving symptoms
Recent data suggests that chronic gout may lead to long-term complications. Some studies show that urate crystals can deposit in multiple sites, manifesting as back pain, vascular or cardiac disease, or even ocular symptoms.3 Data from a 2007-2008 National Health and Nutrition Examination Survey determined that 74% of gout patients had hypertension, 71% had chronic kidney disease, 26% had diabetes, 14% had history of myocardial infarction, 11% had heart failure, and 10% had history of stroke; with greater severity of hyperuricemia, the prevalence of these comorbidities increased.4 The strong association of gout with various comorbidities including cardiovascular disease, hypertension, chronic kidney disease, diabetes, and metabolic syndromes could support the hypothesis that gout is systemic, and urate deposition may have a causal role in these comorbidities.3
Treatment
Gout is managed through medical treatment and self-management. out fares are managed through pain control and suppression of oint infammation Pharmacologic treatments can be used to manage pain during a fare; evidence has shown equivalent e cacy between corticosteroids, non-steroidal anti-infammatory drugs ( SA Ds), and colchicine 1,5 The American College of Rheumatology (AC ) strongly recommends colchicine, SA Ds, and glucocorticords as appropriate frst-line therapy for gout fares over L-1 inhibitors or adrenocorticotropic hormone.6 Specifcally, low-dose colchicine is recommended over high-dose colchicine, given similar e cacy and lower ris of adverse e ects 6 To prevent future fares, dietary and lifestyle changes, including limiting alcohol and purine-rich food, and losing weight, may be benefcial 1,5 Preventive therapy, including pegloticase, allopurinol, lesinurad, and febuxostat, is utilized to lower uric acid levels.1, 5 The ACR recommends uratelowering therapy ( LT) for gout patients with any of the following 1 subcutaneous tophi; evidence of radiographic damage any modality) attributable to gout; or frequent ( 2 annually) gout attacks.6 The AC recommends allopurinol as the preferred frstline LT agent 6
KRYSTEXXA® (pegloticase)
KRYSTEXXA® (pegloticase, ori on Therapeutics) was approved by the FDA in 2010 for the treatment of chronic gout in adult patients. Pegloticase, a P ylated uric acid-specifc en yme, was the frst ever treatment approved for chronic gout that is refractory to conventional therapy.7 In clinical trial C0405, the primary end point (plasma uric acid levels of less than 0 mg dL in months three and six) was met in 47% of patients treated biweekly with pegloticase, in 20% of those treated monthly, and in 0% of patients treated with placebo.8 In comparison, in trial C0406, 38% of patients in the
Data suggests that concomitant use of immunomodulators can lengthen the duration of treatment with pegloticase, which could potentially lead to mo e e ectivel cont olled out.
biweekly group and 49% of the monthly group met the primary end point, compared to 0% of the placebo group.7 Combining the trials, 42% of patients treated biweekly with pegloticase and 35% of patients treated monthly reached the primary end point.8
In a 2013 open-label extension study, 45% of patients in the biweekly group experienced tophus complete response compared to 26% of the monthly group and 8% of the placebo group after six months; target tophus complete response was reached in 28%, 19%, and 2% of tophi, respectively.9 Another openlabel study evaluated the e cacy of pegloticase in combination with methotrexate to treat uncontrolled gout; results showed that at six months after initiating pegloticase with methotrexate, 78 of patients met the responder defnition (serum uric acid < 6 mg/dL for >80% of the time), suggesting parallel treatment with methotre ate and pegloticase could be more e ective than treatment with pegloticase alone.10
The use of pegloticase has shown to be limited by immunogenicity, so studies were done to determine whether immunomodulators prolong the e cacy of the drug 11 Pegloticase has a potent immunogenic response, which can lead to clearing antidrug antibodies, limiting clinical response.12, 13 In one study, after 24 weeks, the serum urate level was <6 mg/dl in 68% of patients treated with an immunomodulator (mycophenolate mofetil), compared to 30% in the placebo group.11 In another study, among cases where pegloticase was used alongside immunomodulators, the response rate was 82 9 (87 5 with methotre ate; 8 4 with mycophenolate mofetil; 63.6% with azathioprine; and 7 with lefunomide) 14 Data suggests that concomitant use of immunomodulators can lengthen the duration of treatment with pegloticase, which could potentially lead to more e ectively controlled gout.15
ZURAMPIC® (lesinurad)
In 2015, ZURAMPIC® (lesinurad, AstraZeneca) was approved in combination with a xanthine oxidase inhibitor (XOI) for the treatment of hyperuricemia associated with gout in patients who have no achieved target serum acid levels with an XOI alone.16 In clinical trials, target serum uric acid level was achieved in more patients using lesinurad plus allopurinol (CLEAR 1 and CLEAR 2 phase three trials) or lesinurad plus febuxostat (CRYSTAL phase three trial), when compared to patients receiving an XOI alone.17
DUZALLO® (allopurinol/lesinurad)
DUZALLO® (lesinurad/allopurinol, Ironwood) was approved in 2017 for the treatment of hyperuricemia in patients with uncontrolled gout. The therapy is a combination of standardof-care treatment, allopurinol with lesinurad to treat ine cient e cretion and overproduction of uric acid cacy for lesinurad in combination with allopurinol was shown in previously referenced CLEAR 1 and CLEAR 2 phase three trials.17, 18
Payer Management Strategies
Though not a high priority category for payers, there is opportunity for better management of gout that can drive down spend and improve outcomes for patients. The condition presents a signifcant cost burden as well as reduction in quality of life. A cohort study in the managed care setting showed followup gout-related healthcare costs and inpatient stays, emergency department visits, and ambulatory visits were higher among gout patients with more overall fares (patients with 2 fares versus those with 2 fares) 20 A 2018 review of commercial and Medicare claims showed that patients with uncontrolled gout had higher overall costs, driven largely by increased hospital costs.21 Managing hyperuricemia in gout patients can lead to lower total costs as well as hospital costs, and better long-term outcomes for patients.22 The mean total cost for controlled gout patients was $14,892 annually, compared to $23,339
for uncontrolled gout patients.21 Direct and indirect costs are higher among patients with uncontrolled gout, with higher reported work impairment, activity impairment, and emergency department visits than those with controlled symptoms.22
Given the potential link, as suggested by some more recent studies that gout may be systemic in nature, impacting multiple organ systems, e ectively controlling gout and urate levels may have a signifcant impact on this patient population, health outcomes, and payer impact.3 Proper management of symptoms along with prophylactic treatment where appropriate can lead to more properly controlled gout in this population. With more gout therapies available, there is opportunity to improve symptoms, lower uric acid to prevent fares, and better manage this population leading to cost management and better quality of life
pegadricase (SEL-212)
Selecta Biosciences; Swedish Orphan Biovitrum IV
uricase (recombinant)
phase three
References
1.“Gout.” Centers for Disease Control and Prevention, https://www.cdc. gov/arthritis/basics/gout.html.
2.Dalbeth, Nicola, et al. “Gout.” The Lancet, 30 Mar. 2021, https://www.thelancet.com/journals/lancet/article/PIIS01406736(21)00569-9/fulltext.
3.Khanna, Puja, et al. “Systemic Urate Deposition: An Unrecognized Complication of Gout?” Journal of Clinical Medicine, October 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600842/.
4.Zhu, Yanyan, et al. “Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008.” American Journal of Medicine, July 2012, https://pubmed.ncbi.nlm.nih.gov/22626509/.
5.Tuot, Delphine. “Treatments for gout.” American Kidney Fund, 16 June 2020, https://www.kidneyfund.org/kidney-disease/chronickidney-disease-ckd/complications/gout/treatments-for-gout/.
6.Fitzgerald, John, et al. “2020 American College of Rheumatology Guideline for the Management of Gout.” Arthritis Care & Research, June 2020, https://www.rheumatology.org/Portals/0/Files/GoutGuideline-Early-View-2020.pdf.
7.“FDA Approves KRYSTEXXA™ (pegloticase) for the Treatment of Chronic Gout in Adult Patients Refractory to Conventional Therapy.” Fierce Biotech, 15 Sept 2010, https www fercebiotech com biotech/fda-approves-krystexxa-tm-pegloticase-for-treatment-ofchronic-gout-adult-patients.
8. Sundy, ohn, et al cacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment.” JAMA, 17 Aug. 2011, https://pubmed.ncbi.nlm.nih. gov/21846852/.
9.Baraf, Herbert, et al. “Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy.” Arthritis Research & Therapy, 2013, http://arthritis-research.com/ content/15/5/R137.
10.Botson, John, et al. “Pegloticase in Combination: With Methotrexate in Patients with Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR).” The Journal of Rheumatology, May 2021, https:// pubmed.ncbi.nlm.nih.gov/32934137/.
11.Khanna, Puja, et al. “Reducing Immunogenicity of Pegloticase with Concomitant Use of Mycophenolate Mofetil in Patients with Refractory Gout: A Phase II, Randomized, Double-Blind, PlaceboControlled Trial.” Arthritis & Rheumatology, August 2021, https:// pubmed.ncbi.nlm.nih.gov/33750034/.
12.Khanna, Puja, et al. “A world of hurt: failure to achieve treatment goals in patients with gout requires a paradigm shift.” Postgrad Medicine, January 2016, https://pubmed.ncbi.nlm.nih. gov/26578028/.
13.Cunha, Rita, et al. “Impact of peglicoticase on patient outcomes in refractory gout: current perspective.” Open Access Rheumatology, 18 Oct. 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6201997/.
14. Keenan, obert, et al The e ect of immunomodulators on the e cacy and tolerability of pegloticase a systematic review Seminars in Arthritis and Rheumatism, April 2021, https://pubmed. ncbi.nlm.nih.gov/33601190/.
15.Soloman, Nehad, et al. “Management of Gout with Pegloticase: RealWorld Utilization and Outcomes from Trio Health and the American Rheumatology Network (ARN).” American Rheumatology Network, 2020, https://americanrheum.com/wp-content/uploads/ACR-2020Gout-management-with-pegloticase-Poster-09222020-fc.pdf.
16.“ZURAMPIC® (lesinurad) approved by US FDA for patients with gout.” AstraZeneca, 22 Dec. 2015, https://www.astrazeneca.com/ media-centre/press-releases/2015/ZURAMPIC-lesinurad-approvedby-US-FDA-for-patients-with-gout-22122015.html#.
17. P re - ui , ernando, et al cacy and safety of lesinurad for the treatment of hyperuricemia in gout.” Drugs Context, 29 May 2019, https://pubmed.ncbi.nlm.nih.gov/31191704/.
18.“FDA Approves Duzallo for Hyperuricemia in Patients with Uncontrolled Gout.” The Rheumatologist, 21 Aug. 2017, https:// www.the-rheumatologist.org/article/fda-approves-duzallohyperuricemia-patients-uncontrolled-gout/.
19.“Gout.” IPD Analytics
20.Jackson, Robert, et al. “Flare frequency, healthcare resource utilisation and costs among patients with gout in a managed care setting: a retrospective medical claims-based analysis.” BMJ Open, 24 June 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4480013/.
21.LaMoreaux, Brian, et al. “Increased Cost Burden in an Early Diagnosed Cohort of Uncontrolled Versus Controlled Gout: Analysis of a Large US Payer Database.” American College of Rheumatology, 2018, https://acrabstracts.org/abstract/increased-cost-burden-inan-early-diagnosed-cohort-of-uncontrolled-versus-controlled-goutanalysis-of-a-large-us-payer-database/.
22.Flores, Natalia, et al. “The economic burden of uncontrolled gout: how controlling gout reduces cost.” Rheumatology, 26 June 2018, https://www.tandfonline.com/doi/full/10.1080/13696998.2018.1 532904.
COVID-19:
Treatment and Payer Impact Update
Tracking the available evidence and real-world outcomes of therapies will be key to ensuring that the safest and most e cacious treatments are widely accessible, as CO D outbrea s continue to grow and wane
Project Manager
JD
Magellan Rx Management
The ongoing COVID-19 pandemic has presented challenges for all healthcare stakeholders, including payers. Payers are currently navigating ever-changing regulatory decisions and requirements while managing the available treatments and planning for a future treatment landscape.
Current and Future COVID-19 Treatments
The U.S. Food and Drug Administration (FDA) has approved the intravenous antiviral drug remdesivir (VEKLURY®) for the treatment of COVID-19 in non-hospitalized adults and select pediatric patients. As of December 2021, remdesivir can be administered in an outpatient setting.1 Emergency Use Authorizations (EUAs) have been issued for several monoclonal antibody treatments for the treatment of COVID-19 and, in some cases, prevention.1 In January 2022, the FDA limited the use of certain monoclonal antibodies due to the omicron variant and the lac of e cacy seen in these treatments against the variant 2
The frst oral antiviral drug for CO D-19, nirmatrelvir tablets and ritonavir tablets, copac aged as PAXLOVIDTM, was granted an EUA in December 2021.3 PAXLOVIDTM is indicated for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years and older, weighing at least 88 pounds) with positive results of direct SARS-CoV-2 testing and who are at high risk for progression to severe COVID-19, including hospitalization or death.3 It is not authorized for pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those with severe COVID-19 requiring hospitali ation The treatment should be started within fve days of symptom onset 3 In December 2021, the FDA also issued an EUA for molnupiravir (Merck) for the treatment of mild-tomoderate COVID-19 in adults with positive results of SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19 and for whom alternative FDA-authorized treatment options are not accessible; however, safety and e cacy continue to be evaluated 4
Lindsay Speicher,
Regulatory Impact on Payers
Under the Coronavirus Aid, Relief, and Economic Security (CARES) Act, which passed in March 2020, payers who comply with the A ordable Care Act are required to cover the CO D-19 vaccine Most private payers are covering the vaccine at no cost, with an assurance they will continue coverage for vaccinations as preventive care services after the public health emergency has ended 5 According to S Centers for Medicaid and Medicare Services (CMS) guidance from April 2020, private payers are required to cover diagnostic testing and other CO D-19-associated care, including: urgent care visits, emergency department visits, telehealth visits, in-person visits, DA-authori ed coronavirus tests, CO D-19 tests for which developers have requested emergency authori ation, state-developed and state-authori ed CO D-19 tests, and CO D-19 antibody testing 6 ceptions include shortterm limited duration plans and group health plans that fail to cover at least two not current employees, such as retiree-only plans 6 Additional state-specifc regulations may place di erent, or more burdensome, requirements on private payers
As of an 15, 2022, payers are required to cover the cost of overthe-counter (OTC), at-home CO D-19 tests Private or group health plans are required to cover the costs of these tests up front or to reimburse members when a claim is submitted These OTC tests do not require a prescriber s involvement, and members are not required to obtain an order or prescription from healthcare providers to access these tests or for the tests to be covered 7 The Department of ealth uman Services has made four free athome test its available, which include two tests each, to every residence; these tests can be ordered online 8
hile some states have required or created agreements with payers to waive CO D-19 out-of-poc et treatment costs for
members, there is no federal requirement for payers to waive cost-sharing arlier in the pandemic, around 88 of members covered by private payers would have had out-of-poc et costs waived if they were hospitali ed from CO D-19 More recently, in the second half of 2021, an analysis showed that 72 plans of the two largest payers in each state are no longer waiving costs, with another 10 of plans e pecting to phase out waivers by the end of 2021 9
Looking Ahead
n 2020, the DA launched an accelerated regulatory measure, the Coronavirus Treatment Acceleration Program (CTAP), to e pedite CO D-19-related therapy review 10 Through this program, the DA promises response and review of protocols within one day, ultrarapid, interactive input” on development plans, and completed review of single-patient e panded access requests within three hours 10 As with the traditional accelerated approval process, there are concerns around limited evidence both pre- and postapproval 11 The DA reports that around 50 of products approved through the accelerated approval process completed research to confrm the benefts of therapy 11 n the ever-evolving pandemic landscape, these concerns are heightened as the need for safe and e ective treatments grow with each surge 11 Trac ing the available evidence and real-world outcomes of these therapies will be ey to ensuring that the most safe and e cacious treatments are widely accessible, as CO D outbrea s continue to grow and wane
The e pansive CO D-19 treatment pipeline (Table 1) raises questions about proper management of CO D-19 patients and payer strategy in terms of formulary coverage uidance to determine patient clinical factors, risk, and vaccination status when determining the appropriate treatment will help payers shape policy around treatments as more options become available
isavuconazonium sulfate (CRESEMBA®) Astellas Pharma-Basilea Pharmaceutica IV azole antifungal phase three
AB201 ARCA Biopharma SC TF inhibitor phase three
COVID-19 Treatment Pipeline12
tempol (MBM-02)
Adamis Pharmaceuticals oral anti-infammatory agent phase three
plonmarlimab I-Mab Biopharma IV GM-CSF phase three
Sarconeos Biophytis oral MAS1 receptor agonist phase three
proxalutamide (GT0918) Suzhou Kintor Pharmaceuticalsoral androgen receptor antagonist phase three
L-citrulline
Asklepion Pharmaceuticals IV amino acid supplement phase two
silmitasertib sodium (CX-4945)Senhwa Biosciences oral kinase inhibitor phase two
copper gluconate; disulfram (Dicopp®)
Cantex Pharmaceuticals oral acetaldehyde dehydrogenase inhibitor phase two
Abbreviations B T bromodomain and e tra-terminal motif; C P calcitonin gene-related peptide; M-CS granulocyte-macrophage colony-stimulating factor; g immunoglobulin; L interleu in; M intramuscular; intravenous; AK anus inase inhibitor; MMP matri metalloproteinase; TBD to be determined; T tissue factor
References
1.“Know Your Treatment Options for COVID-19.” U.S. Food & Drug Administration, 27 an 2022, https www fda gov consumers consumer-updates now-your-treatment-optionscovid-19 te t The 20 DA 20has 20approved 20 the, mergency 20 se 20Authori ation 20( A) 20
2. Cava oni, Patri ia Coronavirus (CO D-19) pdate DA Limits se of Certain Monoclonal Antibodies to Treat CO D-19 Due to the Omicron Variant.” U.S. Food & Drug Administration, 24 Jan. 2022, https www fda gov news-events press-announcements coronavirus-covid-19-update-fda-limits-use-certain-monoclonalantibodies-treat-covid-19-due-omicron
3. Coronavirus (CO D-19) pdate DA Authori es irst Oral Antiviral for Treatment of COVID-19.” U.S. Food & Drug Administration, 22 Dec 2021, https www fda gov news-events pressannouncements coronavirus-covid-19-update-fda-authori es-frstoral-antiviral-treatment-covid-19
4. Coronavirus (CO D-19) pdate DA Authori es Additional Oral Antiviral for Treatment of CO D-19 in Certain Adults U.S. Food & Drug Administration, 23 Dec 2021, https www fda gov newsevents press-announcements coronavirus-covid-19-update-fdaauthori es-additional-oral-antiviral-treatment-covid-19-certain
5. addill, Kelsey ow Top Payers are Providing CO D-19 accine Coverage, Support HealthPayer Intelligence, 25 Jan. 2021, https:// healthpayerintelligence com news how-top-payers-are-providingcovid-19-vaccine-coverage-support
6. addill, Kelsey An Overview of the C A, CA S Act Coronavirus Testing ules HealthPayer Intelligence, 13 Apr. 2020, https:// healthpayerintelligence com news an-overview-of-the- cra-caresact-coronavirus-testing-rules
7. Biden- arris Administration equires nsurance Companies and roup ealth Plans to Cover the Cost of At- ome CO D-19 Tests, ncreasing Access to ree Tests U.S. Department of Health & Human Services, 10 an 2022, https www hhs gov about news 2022 01 10 biden-harris-administration-requires-insurancecompanies-group-health-plans-to-cover-cost-at-home-covid-19tests-increasing-access-free-tests html
8. Coronavirus (CO D-19) Testing U.S. Department of Health & Human Services, https www hhs gov coronavirus testing inde html.
9. Ortali a, ared, et al Most private insurers are no longer waiving cost-sharing for CO D-19 treatment Peterson-KFF Health System Tracker, 19 Aug 2021, https www healthsystemtrac er org brief most-private-insurers-are-no-longer-waiving-cost-sharing-forcovid-19-treatment
10. Coronavirus Treatment Acceleration Program (CTAP) U.S. Food & Drug Administration, 14 eb 2022, https www fda gov drugs coronavirus-covid-19-drugs coronavirus-treatment-accelerationprogram-ctap
11. echsler, ill Concerns Mount Over Limited vidence for Accelerated Approvals PharmTech, 26 Jan. 2022, https://www. pharmtech com view concerns-mount-over-limited-evidence-foraccelerated-approvals
12.“COVID-19.” IPD Analytics
In idiopathic hypersomnia (IH)...
GOOD SLEEP MORE SLEEPOUTWEIGHS
People with IH are getting plenty of sleep, but still feel excessively sleepy during the day4,5
IH is different from other sleep disorders like narcolepsy1
IH is a unique condition with specific AASM ICSD-3 criteria4
ICD-10-CM codes: G47.11, G47.124,6
There are currently no FDA-approved treatments indicated for IH7
learn more about IH, contact your Jazz Pharmaceuticals Account
AASM=American Academy of Sleep Medicine; FDA=US Food and Drug Administration; ICD-10-CM=International Classification of Diseases, 10th Revision, Clinical Modification; ICSD-3=International Classification of Sleep Disorders, 3rd ed.
References: 1. Ali M, Auger RR, Slocumb NL, Morgenthaler TI. Idiopathic hypersomnia: clinical features and response to treatment. J Clin Sleep Med. 2009;5(6):562-568. 2. Trotti LM. Idiopathic hypersomnia. Sleep Med Clin. 2017;12(3):331-344. 3. Arnulf I, Leu-Semenescu S, Dodet P. Precision medicine for idiopathic hypersomnia. Sleep Med Clin. 2019;14(3):333-350. 4. American Academy of Sleep Medicine. The International Classification of Sleep Disorders, 3rd ed. 2014. 5. Plante DT. Nocturnal sleep architecture in idiopathic hypersomnia: a systematic review and meta-analysis. Sleep Med. 2018;45:17-24. 6. ICD-10-CM tabular list of diseases and injuries. Centers for Medicare & Medicaid Services website. https://www.cms.gov/Medicare/Coding/ICD10/2020-ICD-10-CM. Accessed May 12, 2021. 7. Trotti LM, Arnulf I. Idiopathic hypersomnia and other hypersomnia syndromes. Neurotherapeutics. 2020. doi:10.1007/s13311-020-00919-1. Epub ahead of print.
Cervical Cancer
With new treatments for metastatic cervical cancer approved and more alternatives in the pipeline, patients and providers now have promising opportunities for e ective treatment
Natalie A. Tate, Pharm.D., MBA, BCPS
Vice President, Pharmacy
BlueCross BlueShield of Tennessee
Cervical cancer is a type of reproductive cancer with approximately 14,000 new cases diagnosed yearly in the U.S. New diagnoses are most frequently found between women ages 35 to 44, with cases rarely found in younger women (under the age of 20). While less common, older women are still at risk of developing cervical cancer, with more than 20% of cases found in women over age 65.1
The most common type of cervical cancer is squamous cell, which accounts for 70% of cervical cancers, followed by adenocarcinoma, accounting for 25%.2, 3 Between 15% and 61% of women with cervical cancer may go on to develop metastatic disease, and metastases will typically develop within the frst two years of completing treatment.3
Cervical cancer is most commonly caused by long-lasting infection with certain types of the human papillomavirus (HPV). HPV is a common virus passed during sexual intercourse; at least half of sexually active people will have HPV at some point in their lives.4
In the past, cervical cancer was a leading cause of cancer deaths in American women; however, the death rate has signifcantly decreased with the increased frequency of preventive measures Regular pap tests can fnd changes in the cervi prior to cancer developing or early stages of cervical cancer, and they have been an e ective tool in preventing cervical cancer or treating cervical cancer early and e ectively The HPV test has been approved more recently as a screening test for cervical cancer; this test looks for infection from high-risk types of HPV more likely to cause cervical cancer. These screening tests can be used alone or together. The American Cancer Society recommends individuals with a cervix initiate screenings at the age of 25 and undergo P testing every fve years until the age of 5; where primary P testing is unavailable, these individuals should be screened with contesting every fve years or cytology alone every three years.
Since its approval, the P vaccine has been shown to signifcantly reduce the number of women who will develop cervical cancer; among women vaccinated before age 17, there was a nearly 90% reduction in incidence of cervical cancer when compared to women who had not been vaccinated. Evidence has shown that receiving the vaccine at a younger age is more e ective, as many women who received the vaccine after age 17 would be more likely to have HPV at the time of vaccination. As of 2018, the overall rate of vaccination with at least one dose of the HPV vaccine in the U.S. was around 68%, with the percentage of adolescents up-to-date with the HPV vaccine series around 51%.
CERVICAL CANCER
Cervical Cancer Treatment
Standard treatments for cervical cancer may include surgery, radiation therapy, chemotherapy, targeted therapy, or immunotherapy — or a combination of these methods. Surgery to remove the cancer could include conization or, in more advanced cases, a hysterectomy. Current drugs used to treat cervical cancer include bevacizumab, bleomycin sulfate, topotecan hydrochloride, pembrolizumab, tisotumab vedotin-tftv, carboplatin-paclitaxel, and gemcitabine-cisplatin.10 Treatment strategies or a combination of treatment will depend on the stage of the disease and histology.
According to the National Comprehensive Cancer Network guidelines for squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma cervical cancers from 2022, cisplatin is the preferred chemoradiation regimen, with carboplatin preferred if cisplatin is not tolerated.11 In recurrent or metastatic cervical cancer, frst-line combination therapies include cisplatin paclita el bevaci umab and carboplatin paclita el bevaci umab, or for PD-L1-positive tumors, pembroli umab cisplatin paclita el bevaci umab or pembroli umab carboplatin paclita el bevacizumab.11 Cisplatin is a preferred frst-line single-agent therapy. The preferred second-line therapy is pembrolizumab for PD-L1-positive or MS - dMM tumors and nivolumab for PD-L1positive tumors.9
Recent Approval
TivdakTM (tisotumab vedotin-tftv)
The FDA approved TivdakTM (tisotumab vedotin-tftv, Seagen) in September 2021 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.12 Tisotumab vedotin-tftv is a tissue factor-directed antibody and microtubule inhibitor conjugate administered by injection.12 Approval was based on results from the innovaT 204 trial evaluating e cacy in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen.12, 13 Notably, 69% of patients in the trial received bevacizumab as part of prior systemic therapy. The confrmed overall response rate was 24 (7 complete responses and 17 partial responses) 12, 13 Median response duration was 8.3 months. Adverse reactions associated with tisotumab vedotin-tftv treatment included alopecia, epistaxis, nausea, conjunctivitis, fatigue, and dry eye.12, 13 More serious adverse events reported in patients included neutropenia, fatigue, ulcerative keratitis, and peripheral neuropathies.12, 13
The FDA approved TivdakTM (tisotumab vedotin-tftv, Seagen) in September 2021 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
KEYTRUDA® (pembrolizumab)
In October 2021, the FDA approved KEYTRUDA® (pembrolizumab, Merck) in combination with chemotherapy, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic PD-L1-positive (CPS 1) cervical cancer determined by an FDA-approved test.14 Pembrolizumab was also approved as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors e press PD-L1 (CPS 1) as determined by an FDA-approved test.14 The companion diagnostic, PD-L1 IHC 22C3 pharmDx was approved in June 2018.14 Approval was determined by results from the KEYNOTE-826 trial, which evaluated e cacy of pembroli umab with paclita el and cisplatin or paclitaxel and carboplatin, with or without bevacizumab. In the trial, 17 patients with persistent, recurrent, or frst-line metastatic cervical cancer who had not been treated with chemotherapy were enrolled, irrespective of PD-L1 expression status.15 Patients were randomized to receive either pembrolizumab 200 mg plus chemotherapy, with or without bevacizumab, or placebo plus chemotherapy, with or without bevacizumab.15 In patients with tumors expressing PD-L1, median overall survival was not reached in the pembrolizumab and was 16.3 months in the placebo arm; median progression-free survival was 10.4 months in the pembrolizumab arm, compared to 8.2 months in the placebo arm; objective response rates were 68% for pembrolizumab and 50% for the placebo, with median duration of response at 18 months and 10.4 months, respectively.15 The most common adverse reactions associated with treatment included peripheral neuropathy, alopecia, anemia, fatigue asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia,
The key to proper management in cervical cancer is prevention and early detection. Coverage for cervical cancer screenings is mandated by the A ordable Care Act, which has increased screening rates by nearly 20% since its passing.17 Increased screening leads to more e ective prevention and earlier diagnosis, improving long-term outcomes. In cases where cervical cancer is detected early, the fve-year survival rate for individuals with invasive cervical cancer is 92%; 44% of individuals with cervical cancer are diagnosed at an early stage.18 This survival rate drops to 58% when cervical cancer metastasizes to surrounding tissues, organs, and/or regional lymph nodes.18 A study of data from the National Breast and Cervical Cancer Early Detection Program, which provides free
cervical cancer screenings to low-income women, demonstrated that if the proportion of women screened by the program increased to 10-25%, it could result in 6,626-34,896 life years saved and 6,153–32,407 quality-adjusted life expectancy gained.19 As rates of screening tests increase, outcomes will improve due to prevention and early detection.
With new treatments for metastatic cervical cancer approved and more alternatives in the pipeline, patients and providers now have promising opportunities for e ective treatment hile incidence for cervical cancer has decreased in recent years, survival has not increased in those diagnosed with metastatic disease, which could be due in part to lack of development in cervical cancertargeted therapies.20 For years, development of new cervical cancer treatment options was not as high a priority as other cancer types, such as lung or breast.20 This category is sure to grow in the future, with more second-line treatments, established immunotherapies, and alternative therapies being researched.
CERVICAL CANCER
References
1.“Key Statistics for Cervical Cancer.” American Cancer Society, 12 Jan. 2022, https://www.cancer.org/cancer/cervical-cancer/about/keystatistics.html.
2.“SEER Cancer Statistics Review, 1957-2003.” National Cancer Institute: Surveillance, Epidemiology, and End Results Program, https://seer.cancer.gov/archive/csr/1975_2003/.
3.“SEER Incidence Data, 1975-2018.” National Cancer Institute: Surveillance, Epidemiology, and End Results Program, https://seer. cancer.gov/data/.
4.“Basic Information About Cervical Cancer.” Centers for Disease Control and Prevention, https://www.cdc.gov/cancer/cervical/ basic_info/index.htm.
5.Fontham, Elizabeth, et al. “Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society.” CA: A Cancer Journal for Clinicians, 30 July 2020, https:// acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21628.
6.Lei, Jiayao, et al. “HPV Vaccination and the Risk of Invasive Cervical Cancer.” The New England Journal of Medicine, 1 Oct. 2020, https:// pubmed.ncbi.nlm.nih.gov/32997908/.
7. Large Study Confrms that P accine Prevents Cervical Cancer National Cancer Institute, 14 Oct. 2020, https://www.cancer.gov/ news-events/cancer-currents-blog/2020/hpv-vaccine-preventscervical-cancer-sweden-study.
8.Walker, Tanja, et al. “National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years — United States, 2018.” Weekly, 23 Aug. 2019, https://www.cdc.gov/ mmwr/volumes/68/wr/mm6833a2.htm.
9.“Cervical Cancer Treatment (PDQ®) — Health Professional Version.” National Cancer Institute, https://www.cancer.gov/types/cervical/ hp/cervical-treatment-pdq.
10.“Drugs Approved for Cervical Cancer.” National Cancer Institute, https://www.cancer.gov/about-cancer/treatment/drugs/cervical.
11.Koh, Wui-Jin, et al. “Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.” Journal of the National Comprehensive Cancer Network, January 2019, https://jnccn.org/ view/journals/jnccn/17/1/article-p64.xml.
12.“FDA D.I.S.C.O Burst Edition: FDA approvals of Tivdak (tisotumab vedotin-tftv) for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, and a af (ru olitinib) for chronic graft-versus-host disease after failure of one or two lines of systemic therapy.” U.S. Food & Drug Administration, 5 Oct. 2021, https://www.fda.gov/drugs/resources-information-approveddrugs/fda-disco-burst-edition-fda-approvals-tivdak-tisotumabvedotin-tftv-recurrent-or-metastatic-cervical#:~:text=On%20 September%2020%2C%202021%2C%20the,progression%20 on%20or%20after%20chemotherapy.
13. Coleman, obert, et al cacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.” The Lancet Oncology, May 2021, https://pubmed. ncbi.nlm.nih.gov/33845034/.
14. DA approves pembroli umab combination for the frst-line treatment of cervical cancer.” U.S. Food & Drug Administration, 13 Oct. 2021, https://www.fda.gov/drugs/resources-informationapproved-drugs fda-approves-pembroli umab-combination-frstline-treatment-cervical-cancer.
15.Colombo, Nicoletta, et al. “Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer.” The New England Journal of Medicine, 11 Nov. 2021, https://www.nejm.org/doi/full/10.1056/ NEJMoa2112435.
16.“Cervical Cancer.” IPD Analytics
17.Huguet, Nathalie, et al. “Cervical and colorectal cancer screening prevalence before and after A ordable Care Act Medicaid expansion.” Preventative Medicine, July 2019, https://pubmed.ncbi. nlm.nih.gov/31077723/.
18.“Cervical Cancer: Statistics.” American Society of Clinical Oncology, January 2021, https://www.cancer.net/cancer-types/cervicalcancer/statistics#:~:text=When%20detected%20at%20an%20 early,year%20survival%20rate%20is%2058%25.
19.Pollack, Lisa, et al. “Estimating the Impact of Increasing Cervical Cancer Screening in the National Breast and Cervical Cancer Early Detection Program among Low-Income Women in the U.S.” Cancer Causes Control, 1 Mar. 2021, https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC7274897/.
20.Kaplan, Debbie. “New Metastatic Cervical Cancer Treatments Give Hope.” Targeted Therapies in Oncology, January 2021, https://www. targetedonc.com/view/new-metastatic-cervical-cancer-treatmentsgive-hope.
Your unrivaled specialty experts
We tend to overshare – but in a good way. Part of making smarter healthcare decisions is having access to all of the information you need to make the best choice, and we don’t keep this information locked up.
Medical Pharmacy Trend Report
Annual source for key trends and statistics on medical injectables
Medicaid Pharmacy Trend Report
Annual insights into key trends and statistics in the Medicaid market
Employer Market Insights Report
Annual pharmacy trends, forecasting and cost management strategies
Magellan Rx Report
Periodic insights into innovative managed care solutions
MRx Pipeline
Quarterly insight into upcoming specialty and traditional drugs
Clinical Alert
Monthly clinical updates on the latest industry news
postsurgical pain (foot and ankle, smallto-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures) instillation sNDA; breakthrough therapy; fast track 08/04/2022
ustekinumab (STELARA®)
betibeglogene autotemcel (Zynteglo) bluebird bio
(transfusion-dependent)
trastuzumab (biosimilar to Herceptin®) Tanvex BioPharma breast cancer; gastric/ gastroesophageal cancer
adalimumab (biosimilar to HUMIRA®) Celltrion Healthcare RA; AS; PSO; PsA; JIA; CD; UC SC BLA August 2022
abacavir/dolutegravir/lamivudine (TRIUMEQ) ViiV Healthcare HIV-1 treatment (pediatrics weighing 14 kg to < 40 kg)
Abbreviations AD D attention-defcit hyperactivity disorder; ALS amyotrophic lateral sclerosis; AMD age-related macular degeneration; AS an ylosing spondylitis; BLA biologics license application; CD Crohn s disease; C C colorectal cancer; 2 human epidermal growth factor receptor 2-positive; -1 human immunodefciency virus-1; M intramuscular; intravenous; JIA = juvenile idiopathic arthritis; NDA = new drug application; NHL = non-Hodgkin lymphoma; NSCLC = non-small cell lung cancer; PsA = psoriatic arthritis; PSO = plaque psoriasis; QIDP qualifed infectious disease product; relapsed refractory; A rheumatoid arthritis; CC renal cell carcinoma; MAT regenerative medicine advanced therapy; TO real-time oncology review; sBLA supplemental biologics license application; SC subcutaneous; SL sublingual; s DA supplemental new drug application; T2DM type 2 diabetes mellitus; C ulcerative colitis; T urinary tract infection
This information is up to date as of March 4, 2022.
