Gene Therapies for Rare Diseases: Changing Landscape and Pipeline
HER2+ Metastatic Breast Cancer: CNS Metastases and Proper Management
HIV Update: Treatment and Efective Management CAR-T Update: Expanding Landscape and Payer Implications
Summer 2021
ALS: Robust Pipeline and Payer Impact
Published By Magellan Rx Management 15950 N. 76th St. Scottsdale, AZ 85260
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Editor Lindsay Speicher, J.D. Project Manager, Magellan Method lspeicher@magellanhealth.com 401-344-1105
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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.
Contributors
Caroline Carney, M.D., M.Sc., FAPM, CPHQ CMO, Magellan Health, Magellan Rx Management
Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty
Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty
Misty Grefcz Director, Marketing
Joe Tavares SVP, Sales and Business Development, Specialty
Corrado Panno VP, Business Development, Magellan Method
Stacy Inman, Pharm.D.
Senior Clinical Project Manager, Magellan Method
Carole Kallas
Project Manager
Brian Kinsella, Esq.
Senior Legal Counsel
Alina Young
Associate Legal Counsel
Lilly Ackley VP, Corporate Communications
Maria James Director, External Communications
Editorial Advisory Board
Mona M. Chitre, Pharm.D., CGP
Chief Pharmacy Ofcer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield
Dennis Bourdette M.D., FAAN, FANA
Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University
Yousaf Ali M.D., FACR
Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai
Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists
Joseph Mikhael M.D., M.Ed., FRCPC, FACP
Chief Medical Ofcer, International Myeloma Foundation
Natalie Tate, Pharm.D., MBA, BCPS Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee
Steve Marciniak, R.Ph.
Director II, 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
Welcome to our summer 2021 issue of the Magellan Rx Report In the frst half of 2021, widespread vaccine administration and reopening as COVID-19 infections slowed have been front of mind. Despite COVID-related health concerns, there have been many exciting advancements — including 30 new drug approvals. In this issue, Magellan Rx Management continues to provide our readers with the most up-to-date information across health trends, changing treatment landscapes, and clinical advances.
Our cover story (page 6) focuses on amyotrophic lateral sclerosis (ALS), the current treatment landscape, and a robust pipeline. As treatment options have been limited for this condition, which has 5,000 new cases diagnosed annually, new therapies will increase payer awareness in this area.
In another article, we highlight the area of gene therapies, specifcally in the treatment of rare diseases page 1 . The growing availability of these innovative, potentially curative treatments will change many aspects of healthcare and managed care moving forward, including disease management opportunities and economic impact.
We also discuss the complexities of HER2+ metastatic breast cancer, specifcally focusing on central nervous system metastases page 1 . The story addresses the challenges and outcomes of treatment, as well as the resulting impact on payers.
Other timely topics in this issue include developments in human immunodefciency virus HIV treatment page and CAR T (page 35) and the impact of COVID-19 on oncology care (page 40). As always, the issue is rounded out with our pipeline update (page 45) 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!
Sincerely,
Caroline
Carney, M.D., M.Sc., FAPM, CPHQ ie edica cer Magellan Health & Magellan Rx Management
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. SUBSCRIBE TODAY!
U.S. Sens. Jeanne Shaheen, D-N.H., Rob Portman, R-Ohio, and Sheldon Whitehouse, R-R.I., introduced the bipartisan Comprehensive Addiction and Recovery Act (CARA) 3.0 to help combat the opioid epidemic, which has been exacerbated by the COVID-19 pandemic. The bill increases the funding authorization levels for the CARA programs enacted in 2016. The bipartisan national efort was designed to ensure that federal resources were devoted to evidence-based education, treatment, and recovery programs that work. CARA programs were funded at $782 million in 2021. Several key provisions of CARA 2.0 were enacted as part of the SUPPORT Act on Oct. 24, 2018. CARA 3.0 builds on these eforts by increasing the funding authorization levels and laying out new policy reforms to strengthen the federal government’s response to this crisis (e.g., it permanently allows providers to prescribe medication-assisted treatment via audio-only telehealth).
The Department of Health and Human Services (HHS) issued new practice guidelines as it looks for ways to address the opioid epidemic. The new guidelines are slightly different from those issued under the Trump administration, which were rescinded in January. Physicians, nurse practitioners, physician assistants, clinical nurse
specialists, certified nurse anesthetists, and certified nurse midwives may now treat up to 30 patients with buprenorphine under a waiver established under the new guidance. Providers will still need to submit notice of their intention to prescribe buprenorphine to the Substance Abuse and Mental Health Services Administration, but they will now be exempted from training requirements.
The U.S. Government Accountability Ofce GAO recently released a report on issues related to the demand for behavioral health, coverage and payment for these services, and how they have changed during the COVID-19 pandemic. The report, the result of a request made by Sen. Ron Wyden, D-Ore., last year, describes: (1) what is known about the need for and availability of behavioral health services and how these have changed during the COVID-19 pandemic; and (2) what issues selected stakeholders identifed regarding the payment of claims for behavioral health services. Key fndings focus on workforce shortage, denials and delay of payment, and parity issues.
On May 3, the Health Resources and Services Administration (HRSA) announced a new program covering the cost of administering COVID-19 vaccines to patients enrolled in health plans that either do not cover vaccination fees or cover them with patient cost-sharing. This new program is called the HRSA COVID-19 Coverage Assistance Fund (CAF). Providers
must enroll in the CAF program and submit uncovered claims for vaccines administered on or after Dec. 14, 2020. Prior to submitting claims for reimbursement under the program, providers are required to bill the patient’s health plan and receive confrmation that vaccine administration is not covered or includes patient cost-sharing.
The House Committee on Energy and Commerce and the House Committee on Education and Labor held hearings on major drug pricing legislation on May 4 and 5 with the hopes of bringing the bill to the oor in the coming weeks. House Democratic and Republican leaders fled separate bills that were similar in scope to the bills introduced in the last Congress. The Democratic bill, HR3, passed the House in late 2019 nearly along party lines. The Republican bill, HR19, the counter to the Democratic bill, did not receive a vote in the last Congress. The Senate Committee on Finance passed its own drug-pricing bill in 2019, but that bill never made it to the oor. The Democratic bill calls for government negotiation of high-cost drugs that have little or no competition. The bill also proposes a Medicare in ation rebate among the many other provisions. Both bills call for capping out-of-pocket costs for Part D benefciaries and eliminating the coverage gap in the Part D beneft, but they difer on payment responsibilities in the catastrophic phase; the Democratic bill calls for drug manufacturers to bear a greater share of the cost burden in this phase. Witnesses at the hearing said these Part D redesign proposals would do little to control costs but would likely increase premiums and overall program costs. The Congressional Budget Ofce (CBO) estimates that HR3 would save
$450 billion over a 10-year period. The Democratic proposal would use most of those savings to provide dental, hearing, and vision benefts under Medicare.
Following the hearing, a number of Democratic House members have expressed concern over the bill. Recent media reports suggest that as many as eight to 10 Democrats may not support the bill. Democrats hold a six-seat majority and can lose few Democratic members if most — if not all — Republicans oppose the bill. Negotiations are likely to continue in the coming weeks to try and shore up Democratic support for the bill. If it passes, it faces an unlikely future in the Senate. The Senate failed to take up HR3 in 2020 when the Republicans controlled the chamber. Democrats now hold the majority, but the Senate is evenly divided at 50-50, so the bill will likely require all Democratic senators to support it. At this point, passage of a major drug-pricing bill appears unlikely, but the recent hearings and legislative action suggest that drug-pricing will remain a signifcant issue within Congress over the coming years.
The U.S. House voted on a package of 14 mental health bills on May 12. The bills included increased authorization of funding for the National Suicide Prevention Lifeline and funding to conduct a suicide prevention media campaign. Other bills included funding directed to improving suicide awareness in emergency medical facilities and funding to support school-based awareness campaigns. The 988 Suicide Prevention Lifeline is expected to be in place by July 2022. Additional bills included block grants to support individual wellness programs for those involved in communitybased organizations and frst responders
who deal with addiction and mental health issues, as well as funding for school-based mental health services. The package of bills has broad support. It is not clear when the Senate may take up the legislation, but it is expected that the package of bills will pass Congress at some point this year.
On May 28, President Joe Biden released a trillion proposed budget for fscal year 2022. The proposal, which is expected to undergo many changes before being signed into law, presents a significant increase in federal spending and includes signifcant investments in President Biden’s top priorities, including infrastructure, education, research, public health, paid family leave, and child care.
The budget also calls on Congress to act “to further strengthen healthcare by lowering prescription drug costs and expanding and improving health coverage.” The president’s healthcare agenda includes cutting prescription drug costs by letting Medicare negotiate prices, reducing deductibles for Afordable Care Act ACA marketplace plans, improving Medicare benefts, creating a public option and giving people age 60 and older the option to enroll in Medicare, and closing the Medicaid coverage gap to help millions of uninsured Americans gain health insurance.
On June 3, the U.S. Food and Drug Administration (FDA) announced two new fnalized and two draft guidance documents to further enhance the security of prescription drugs in the U.S. supply chain via proper identifcation and tracking. The guidance documents lay out the
FDA’s recommendations for compliance with applicable Drug Supply Chain Security Act (DSCSA) requirements, including those for enhanced drug distribution security at the package level that go into efect in November 0 .
On June 8, the Biden-Harris administration announced its key fndings from the reviews directed under a February Executive Order on America’s Supply Chains, as well as immediate actions the administration will take to strengthen American supply chains to promote economic security, national security, and good-paying union jobs. The administration has called on HHS and other agencies to:
• Establish a public-private consortium — leveraging the Defense Production Act (DPA) and existing partnerships — to bolster the production of critical drugs on U.S. soil.
• Invest around $60 million from the DPA appropriation in the American Rescue Plan to create “novel platform technologies” for domestic active pharmaceutical ingredient (API) production.
• Increase funding of advanced manufacturing technologies for drug and API production.
The U.S. Department of Health and Human Services (HHS) is proposing to rescind the Trump administration drug rule that required community health centers to pass on all their insulin and epinephrine discount savings to patients. The proposal to retract the rule is under review at the White House Ofce of Management and Budget (OMB). Once it clears OMB, HHS can publish it at any time. The rule was previously delayed until July 20, 2021.
The strong ALS pipeline promises innovative treatment possibilities for a debilitating disease that, historically, has had limited options. With several phase-three therapies in the pipeline, this category may become a priority for payers.
Christina Barrington, Pharm.D. Vice President, Pharmacy Programs
Priority Health
Amyotrophic lateral sclerosis ALS is a progressive, disabling, fatal neurodegenerative disorder afecting up to 30,000 adults in the United States, with an estimated 5,000 new cases diagnosed every year.1 The estimated national economic burden of ALS, which includes medical, nonmedical, and indirect costs, ranges from $256 million to $1.023 billion.2 This burden is expected to increase proportionately to the increase in prevalence and may be up 34% by 2040.2 Individually, the total cost of care for an ALS patient can be signifcant around 0,000 annually.2 Contributing factors in total cost of care often include hospitalizations, in-home care, nutrition, physical and occupational therapy, and drug therapy.3 The patient burden extends beyond fnancial cost; patients experience signifcantly decreased quality of life as the disease progresses, with family and caregivers often impacted as well.2
ALS is most common in adults over 60. The cause is unknown, but studies suggest links to both genetics and environmental factors.1, 3 Earlier disease is defned by twitching and cramping of the muscles, loss of muscle control in the hands and arms, impaired use of the arms and legs, weakness and fatigue, tripping and falling, dropping things, slurred or thick speech, and difculty projecting voice. As the disease progresses, symptoms become more severe and include shortness of breath, difculty breathing, difculty swallowing, and paralysis.2 Diagnosis is typically based on a review of symptom history and a physical exam, often accompanied by a series of tests to rule out other diseases that present with similar symptoms.3 The presence of upper and lower motor neuron symptoms strongly suggests ALS. Disease progression is typically measured using the widely accepted ALS Functional Rating Scale ALSFRS R ; point increases in the ALSFRS R can re ect a substantial decline in function.4
Riluzole (Rilutek®)
In 1995, the U.S. Food and Drug Administration (FDA) approved riluzole (Rilutek®) for the treatment of ALS. At the time, it was the only ALS treatment available.5 The frst trial for riluzole showed that time to tracheostomy or death was about 90 days longer for patients treated with riluzole versus placebo. A second trial showed an early increase in survival rates (about 60 days longer) for patients treated with either 100 mg or 200 mg of riluzole per day, compared with placebo.5 Because no diference in survival rates was observed between those treated with 100 mg or 00 mg of riluzole per day and there was an increase in adverse events, such as nausea and asthenia, with the higher dose the recommended dosing of riluzole is 100 mg per day. Adverse events associated with riluzole include asthenia, spasticity, and mild elevations in aminotransferase levels.5
Edaravone (RADICAVA®)
The FDA approved edaravone (RADICAVA®) for the treatment of ALS in 01 .6 Edaravone is an IV infusion treatment administered by a healthcare practitioner with an initial treatment cycle of 14 days of dosing followed by 14 drug free days. Subsequent treatment cycles are dosed on 10 of 14 days followed by 14 drug-free days.6 Edaravone is associated with adverse reactions such as bruising and gait disturbance, as well as more serious risks such as hives, swelling, shortness of breath, and allergic reactions to sodium bisulfte.6
As more treatment options for ALS become available, updated guidelines will be key to provide clear guidance around the appropriate management and place in therapy for these treatments.
The MCI186-19 phase three, double-blind, placebo-controlled clinical trial included patients ages 0 to who met specifc inclusion criteria, including defnite or probable ALS, Japan classifcation grade 1 or 2, a disease duration of less than two years since symptom onset, normal respiratory function defned as forced vital capacity (FVC) >80%), a score of >2 on all items on the ALSFRS-R score, and a deterioration of ALSFRS-R score during the 12-week pre-study observation period of 1 to 4 points. Those treated with edaravone experienced 33% less functional loss during the 24week trial period compared to the placebo group. ,
Challenges around the use of edaravone include strict coverage criteria and the administration burden of infusion treatment for patients. An oral formulation of edaravone is currently undergoing phase three trials, which presents an opportunity for ease of administration and, potentially, access to treatment.
The American Academy of Neurology (AAN) guidelines currently recommend riluzole for the treatment of ALS.9 The AAN guidelines do not mention edaravone in the treatment of ALS, although the guidelines have been reafrmed since the approval of edaravone.9 As more treatment options for ALS become available, updated guidelines will be key to provide clear guidance around the appropriate management and place in therapy for these treatments.
The ALS pipeline is robust, promising innovative treatment possibilities for this debilitating disease. This is an exciting advancement in a space where options have been limited for patients and providers. See Table 1 for a complete ALS pipeline.
ALS management should be multidisciplinary, including a comprehensive team comprised of a combination of the following: physicians; pharmacists; physical, occupational, and speech therapists;
nutritionists; social workers; respiratory therapists; clinical psychologists; and home care and hospice nurses.3 A patient’s treatment team can efectively develop and provide an individualized treatment plan, provide special equipment, and improve quality of life.3 Appropriate management by managed care organizations and the care team can optimize outcomes and potentially delay disease progression.3
Because treatment options for ALS have historically been limited and the patient population is so small, the category has not been a priority for payers. However, with several pipeline therapies in
magellanrx.com/trendreport
phase three, payers may start strategizing how to best manage the space and ensure that patients have access to the most appropriate therapy. Additionally, early research shows the opportunity for potentially curative results with gene therapy in ALS patients. As research and development progresses, this patient
population will become a higher management priority for payers. A robust landscape of treatment options, coupled with high-cost therapies, will create an urgency for payers to address the ALS space, developing creative strategies for cost management and ensuring access to proper treatment for patients.
References
1. ALS Amyotrophic Lateral Sclerosis. Johns Hopkins Medicine, https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_ clinics/als/conditions/als_amyotrophic_lateral_sclerosis.html.
2. Santaniello, Briana. ALS Managed Care Considerations. American Journal of Managed Care, Aug. 01 , https www.ajmc.com view als-managed-care-considerations.
3. Amyotrophic Lateral Sclerosis ALS Fact Sheet. National Institute of Neurological Disorders and Stroke, 1 June 0 1, https www. ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/ Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet.
4. Berry, James, et al. New considerations in the design of clinical trials for amyotrophic lateral sclerosis. Clinical Investigation (London) 011, doi 10.41 cli.11.1 .
5. Miller, R.G., et al. “Clinical trials of riluzole in patients with ALS. ALS/ Riluzole Study Group II. Neurology, Oct. 1996, https://pubmed. ncbi.nlm.nih.gov 0 .
6. FDA approves drug to treat ALS. U.S. Food and Drug Administration, May 01 , https www.fda.gov news events press announcements/fda-approves-drug-treat-als.
. Shefner, J., et al. Long term edaravone efcacy in amyotrophic lateral sclerosis Post hoc analyses of Study 1 MCI1 1 . Muscle & Nerve, 01 , doi 10.100 mus. 40.
8. Palumbo, Joseph, et al. Post hoc analyses of the edaravone clinical trials Study 1 and Study 1 a step toward more efcient clinical trial designs in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 20, no. 5-6, 2019, pp. 4 1 4 1., doi 10.10 0 1 4 1. 01 .1 .
9. “AAN Summary of Evidence-based Guideline for CLINICIANS: The care of the patient with Amyotrophic Lateral Sclerosis: Drug, Nutritional, and Respiratory Therapies. American Academy of Neurology, 11 Jan. 0 0, https www.aan.com Guidelines home GuidelineDetail 0.
10. IPD Analytics.
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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
ENTYVIO (vedolizumab) for injection, for intravenous use
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
ENTYVIO is indicated in adults for the treatment of:
ïmoderately to severely active ulcerative colitis.
ïmoderately to severely active Crohnís disease.
CONTRAINDICATIONS
ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions]
WARNINGS AND PRECAUTIONS
Infusion-Related Reactions and Hypersensitivity Reactions
Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion.
If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.
Infections
Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions
Progressive Multifocal Leukoencephalopathy
PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.
Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.
Liver Injury
There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions]
Live and Oral Vaccines
Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions]
The following topics are also discussed in detail in the Warnings and Precautions section:
ï Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions]
ïInfections [see Warnings and Precautions]
ï Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions]
ïLiver Injury [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.
The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.
In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohnís disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).
Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo).
The most common adverse reactions (reported by 3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and 1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2)
Table 2. Adverse Reactions in 3% of ENTYVIO-Treated Patients and 1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*)
Adverse Reaction
*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.
Ü Patients who received ENTYVIO for up to 52 weeks.
á Patients who received placebo for up to 52 weeks.
Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohnís disease trial, are similar to those listed in Table 2
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions] . In UC Trials I and II and Crohnís Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohnís disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.
In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.
In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.
Infections
In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections.
In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohnís disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohnís disease patients. Over 48 months, there was no increase in the rate of serious infections.
In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohnís disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohnís disease receiving ENTYVIO was two per 1,000 patient-years.
In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.
Liver Injury
There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations 3x ULN was 2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.
Malignancies
In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1),
breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).
Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.
Live and Oral Vaccines
There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO.
In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ENTYVIO. 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 to drug exposure.
Immune system disorders: Anaphylaxis [see Warnings and Precautions]
DRUG INTERACTIONS
Natalizumab
Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab.
TNF Blockers
Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers.
Live Vaccines
Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]
USE
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327).
Risk Summary
Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations) . No fetal harm was observed in
animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data)
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and embryo/fetal risk
Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500g) infants, and small for gestational age at birth.
Fetal/Neonatal adverse reactions
ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.
Data
Animal Data
A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100mg/kg (about 20 times the recommended human dosage).
Lactation
Risk Summary
Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the motherís clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness of ENTYVIO in pediatric patients have not been established.
Geriatric Use
Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohnís and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Manufactured by:
Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015
U.S. License No. 1898
Revised: March 2020
ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc.
All other trademark names are the property of their respective owners.
©2014 ñ 2020 Takeda Pharmaceuticals America, Inc.
For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327).
VMB245 R4_Brf04/20
As the gene therapy market expands, reimbursement and payment models will have to continue to transform.
Kimberly DornbrookLavender, Pharm.D., BCPS Director, Clinical Pharmacy Medica
The expansion of the gene therapy market in the past several years has provided exciting opportunities for treating various rare diseases. The number of these transformative therapies will continue to increase, as the U.S. Food and Drug Administration (FDA) is expected to review 10 to 20 of these drugs every year through 2025.1 The biopharmaceutical industry is increasingly investing in research and development specifcally focused on gene therapy to correct rare disorders, with advances ranging from new gene-insertion methods to innovations allowing therapies to penetrate hard-to-reach tissues.2
Gene therapy works by modifying a patient’s genes to treat or cure a disease via agents that can replace a disease-causing gene with a functioning copy of the gene, deactivate a disease-causing gene that is misfunctioning, or introduce a new or modifed gene to help treat the disease.3 Types of gene therapy products include plasmid DNA, viral vectors, bacterial vectors, human gene-editing technology, and patient-derived cellular gene therapy products.3
Voretigene neparvovec-rzyl (LUXTURNA®)
Voretigene nerparvovec-rzyl (LUXTURNA®, Spark Therapeutics , the frst gene therapy approved in the U.S., is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confrmed biallelic RPE mutation associated retinal dystrophy.4 The FDA approved it in December 2017.4 Real world use of voretigene neparvovec rzyl has shown a signifcant beneft
when treatment is initiated in early childhood. As of 2019, nine treatment centers across the U.S. were designated to administer it, with a few surgeons per site cleared to provide treatment.5 After treating nine children and fve adults, Children’s Hospital Los Angeles reported observing the greatest beneft in young children through enrichment of their social, motor, and cognitive development.5
abeparvovec-xioi
Onasemnogene abeparvovec xioi OLGENSMA®, Novartis) was approved by the FDA in May 2019 for the treatment of pediatric patients under 2 years old who have spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene. As of this March, more than 1,000 children with SMA had been treated with onasemnogene abeparvovec-xioi in clinical trials, managed access programs, or in the commercial setting.7 Real world data suggest that older children, defned as months or older, achieved clinically meaningful beneft with onasemnogene abeparvovec-xioi alone, after, or in combination with another SMA drug.7 Follow-up data from the clinical trials indicate that the children treated experienced a sustained beneft in the years following dosing, with milestones achieved years after treatment and sustained durability in children up to years old and more than fve years post treatment.7
The pipeline for gene therapies is expansive, specifcally around innovative treatments for rare diseases. With dozens of therapies being developed and researched, an in ux of novel gene therapies is on the horizon. See Table 1 for the full pipeline breakdown.
Patient and Provider Awareness
The National Organization for Rare Disorders (NORD) conducted a survey among healthcare professionals to identify knowledge gaps regarding gene therapies.9 The results showed that of respondents were unaware of current FDA-approved gene therapies, and overall, respondents reported low comfort levels in discussing gene therapies with their patients.9 More than half of respondents noted that limited healthcare professional knowledge was a top barrier to gene therapy use, and only 0 discuss gene therapy options with patients.9 These responses indicate a major need for provider and, transitively, patient education around gene
With dozens of therapies being developed and researched, an in u o nove gene t era ies is on the horizon.
therapies, especially as more enter the market. Without robust provider knowledge and comfort around gene therapies, patient access to potentially curative therapies may be limited.
The costs associated with the currently available gene therapies are very high. Voretigene neparvovec-rzyl has a wholesale acquisition cost (WAC) of $850,000, or $425,000 per eye damaged by an RPE gene mutation. The current WAC for onasemnogene abeparvovec-xioi is $2.125 million.10
These high costs are, and will continue to be, a signifcant challenge for payers; moving forward, navigating this space and effciently strategizing will be key to ensuring that patients have access to potentially lifesaving therapy while managing the fnancial burden payers face. The substantial burden of these high-cost therapies has resulted in some exclusionary policies relating to gene therapies.1 Some plans and employer groups have made the decision to cease coverage of any medical or prescription drug charges related to gene therapy, with or without FDA approval.1 Many payers are not currently equipped to efectively manage the cost associated with gene therapies; thus, innovative fnancial solutions will be necessary.1 Payers have expressed concerns around actuarial management, efectiveness and outcomes of the therapies, and payment timing.1
Financial solutions that may be explored to efectively address payer anxiety around some of these concerns include outcomesbased performance contracts, annuities payments, and reinsurance models.1 Manufacturers and payers are often working together to develop innovative models to overcome these barriers. One model is treatment milestone-based, where the payer pays a certain amount upfront and is partially reimbursed if the therapy fails to provide the intended outcomes in a predetermined time frame.11 Another model is subscription based, including a fxed fee for unlimited access to certain therapies.11 Plan members contribute a cer-
Drug Name Manufacturer
Hemophilia
etranacogene dezaparvovec uniQure; CSL Behring IV phase threehemophilia B fdanacogene elaparvovec PF 0 4 Spark Therapeutics; Pfzer IV phase threehemophilia B
giroctocogene ftelparvovec SB , PF 0 0 4 0 Sangamo Therapeutics; Pfzer IV phase threehemophilia A
valoctocogene roxaparvovec (Roctavian) BioMarin Pharmaceutical IV phase threehemophilia A
AskBio009 Baxalta; Takeda Pharmaceutical Company IV phase twohemophilia B
DTX201 Dimension Therapeutics; BayerIV phase twohemophilia A
SB-FIX Sangamo Therapeutics IV phase twohemophilia B
SHP 4
Takeda Pharmaceutical Company IV phase twohemophilia A
SPK 011 Spark Therapeutics; Roche IV phase twohemophilia A
Duchenne muscular dystrophy (DMD) fordadistrogene movaparvovec PF 0 Pfzer IV
phase three (delayed) DMD
delandistrogene moxeparvovec SRP 001 Sarepta Therapeutics IV phase twoDMD
GALGT2
Sarepta Therapeutics injectable phase twoDMD
SGT-001 Solid Biosciences IV phase twoDMD
Epidermolysis bullosa (EB)
beremagene geperpavec B VEC Krystal Biotech topical phase three EB
debcoemagene autofcel D Fi Castle Creek Biosciences; Fibrocell Technologies injectable phase three EB
EB 101 Abeona Therapeutics other phase three EB
Achromatopsia
AAV-CNGA3 MeiraGTx; Janssen Pharmaceuticals other phase twoachromatopsia
AAV-CNGB3 MeiraGTx; Janssen Pharmaceuticals other phase twoachromatopsia
Others
elivaldogene autotemcel (Lenti-D™)bluebird bio IV phase threeadrenoleukodystrophy
lenadogene nolparvovec (GS010) GenSight Biologics ophthalmic phase three Leber’s hereditary optic neuropathy
LYS-SAF302 Lysogene; Sarepta Therapeuticsother phase three mucopolysaccharidosis type IIIA
simoladagene autotemcel (OTL-101)Orchard Therapeutics injectable phase three severe combined immunodefciency SCID
timrepigene emparvovec AAV REP1 Nightstar Therapeutics; Biogenintravitreal phase threechoroideremia
eladocagene exuparvovec PTC AADC PTC Therapeutics injectable phase two aromatic l-amino acid decarboxylase defciency (AADC)
betibeglogene autotemcel YNTEGLO®)bluebird bio IV pendingbeta thalassemia
OTL-200 Orchard Therapeutics; GlaxoSmithKline IV developing metachromatic leukodystrophy
tain monthly amount that is used to pay for these therapies if needed, with the plan taking on the risk as it guarantees to provide as much therapy as required.11 With this model, payers can potentially manage the actuarial uctuation that occurs with the funding of gene therapies.11 Another manufactureradvanced model prices therapies solely on the intrinsic value of the product or how it extends and improves quality of life and returns all cost ofsets to the payers; this approach is vastly diferent from a typical reimbursement model but would undoubtedly ease some of the concerns payers have expressed.1
Value-based contracts currently exist in commercial markets across therapeutic areas, as well as in Medicaid programs under supplemental rebate agreements across fve states.1 Moving forward, these reimbursement agreements based on promised outcomes may be essential in efectively managing this space. The manufacturer behind voretigene neparvovec-rzyl, Spark
Therapeutics, advanced an outcomes-based rebate arrangement that aligned with longer term efcacy of the gene therapy; the manufacturer will share risk with payers by paying rebates if patient outcomes fail to meet a specifed threshold.12
As more gene therapies enter the market, reimbursement and payment models will have to continue to transform; currently, both payers and manufacturers have been open about concerns associated with reimbursement models, citing limitations around program complexity, the burden of information tracking, insurance, regulatory barriers, and government pricing and reporting requirements.1 As additional therapies become available, developing creative payment models through collaboration of all stakeholders will be critical in ensuring the current system works to efectively manage these treatments, the fnancial burdens, and the patient population.
References
1. Neumann, Ulrich. Paying for cell and gene therapy Is the future already here?” Reuters Events, 2 Nov. 2020, https://www. reutersevents.com/pharma/medical/paying-cell-and-gene-therapyfuture-already-here.
2. Weintraub, Arlene. “The next generation of gene therapy for rare diseases forges ahead as developers weather hurdles.” Fierce Biotech, 14 Dec. 0 0, https www.fercebiotech.com biotech next-generation-gene-therapy-for-rare-diseases-forges-ahead-asdevelopers-weather-hurdles.
3. “What is Gene Therapy?” U.S. Food & Drug Administration, 25 July 2018, https://www.fda.gov/vaccines-blood-biologics/cellular-genetherapy-products/what-gene-therapy.
4.“LUXTURNA.” U.S. Food & Drug Administration, July 01 , https www.fda.gov/vaccines-blood-biologics/cellular-gene-therapyproducts/luxturna.
5. Nagiel, Aaron. One Year in Perspectives on Voretigene. Retina Today, July/Aug. 2019, https://retinatoday.com/articles/2019-julyaug/one-year-in-perspectives-on-voretigene.
. OLGENSMA. U.S. Food & Drug Administration, 1 Mar. 0 1, https www.fda.gov/vaccines-blood-biologics/zolgensma.
7. “New Zolgensma data demonstrate age-appropriate development when used early, real world beneft in older children and durability 5+ years post-treatment.” Novartis, 15 Mar. 2021, https://www. novartis.com/news/media-releases/new-zolgensma-datademonstrate-age-appropriate-development-when-used-early-realworld beneft older children and durability years post treatment.
8. IPD Analytics.
9. DonFrancesco, Valaree. “NORD and FMC’s Gene Therapy Survey: A Call to Action for Healthcare Professional Education. NORD, 1 Apr. 2020, https://rarediseases.org/nord-and-fmcs-gene-therapy-surveya-call-to-action-for-healthcare-professional-education/.
10. Melquist, Chanttel. “Gene therapy: A promising future at a high price.” Prime Therapeutics, 10 Apr. 2020, https://www.primetherapeutics. com/en/news/Stories/2020/story-overview-gene-therapy.html.
11. Vaidya, Anuja. “Innovative payment models to support cell and gene therapies on the rise.” MedCity News, 9 Dec. 2020, https:// medcitynews.com/2020/12/innovative-payment-models-to-supportcell-and-gene-therapies-on-the-rise/?rf=1.
12. Spark Therapeutics Announces First of their kind Programs to Improve Patient Access to LU TURNA voretigene neparvovec rzyl), a One-time Gene Therapy Treatment.” Spark Therapeutics, 3 Jan. 2018, https://sparktx.com/press_releases/spark-therapeuticsannounces frst of their kind programs to improve patient access to-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-treatment/.
Stacy Inman, Pharm.D. Senior Clinical Project Manager Magellan Method
An estimated 3.6 million women were living with breast cancer in the U.S. in 2017, with a diagnosis rate of 129.1 cases per 100,000 women per year.1 Around 13% of women will be diagnosed with breast cancer at some point throughout their lifetime; the median age of diagnosis is 62.1 While breast cancer diagnoses are not only found in women, the data around male breast cancer cases are much more limited due to the signifcantly smaller diagnosis rate among men.
Stage IV, or metastatic, breast cancer (MBC) occurs when the breast cancer has spread to another part of the body.2 An estimated 30% of those diagnosed with early-stage breast cancer will develop MBC.2 In breast cancer, metastases in the bones, brain, liver, and lungs are most common.3 In recent years, the rate of central nervous system (CNS) metastasis has more than doubled, from 10% to 22%; liver metastasis has increased by 46%, lung metastasis has remained stable, and bone metastasis has decreased by 32%.4
There are four main female breast cancer subtypes: HR+/HER2- (luminal A), HR-/HER2- (triple negative), HR+/HER2+ (luminal B), and HR-/HER2+ (HER2-enriched).5 Up to 14% of patients diagnosed with early breast cancer have HER2+ breast cancer, which tends to grow and spread faster than other breast cancers and is more likely to recur than HER2- breast cancer.5-8 HER2+ breast cancer is more likely to respond to treatment that targets the HER2 protein.6 In an analysis of more than 7,500 cases of MBC from the SEER database, 26% of those cases were HER2+.9
Up to 50% of patients with HER2+ MBC develop brain metastases, putting this population at a higher risk than patients with breast cancer overall.10-13 Among those with HER2+ MBC who develop brain metastases, more than 50% will be diagnosed by the second line of therapy.14 In a study of patients with
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HER2+ MBC, nearly 40% developed brain metastases, and the median time from initial MBC diagnosis to the frst CNS event was just over 10.8 months.14 HER2+ MBC patients have a 1.5-times-higher three-year cumulative risk for developing brain metastases when compared with HER2- patients.8, 15-17 HER2+ MBC patients with brain metastases have a median survival time of two to three years.
Improvements and advances in breast cancer treatment have extended survival in patients; however, extended survival in turn results in additional time for brain metastases to develop, and there remains poor prognosis for patients with brain metastases.18 Treatment for patients who have HER2+ MBC with brain metastases is more challenging due to their reduced responsiveness to systemic therapies.19, 20
MBC disease progression greatly impacts health-related quality of life, based on patient-reported measures, including physical, functional, and emotional well-being; depression; anxiety; and global quality of life.21 Specifcally, overall breast cancer related quality of life was signifcantly lower among HER MBC patients with brain metastases13; CNS metastasis is often associated with seizures,
altered mental status, headaches, visual impairment, dizziness, ataxia, nausea, and vomiting — substantially impacting physical and emotional functioning.22-24
Among patients with HER2+ MBC, low adherence or nonadherence to treatment is associated with poor quality of life and increased risk of mortality.25 Around one-third of patients with MBC reported difculties with medication and adherence, and in a study of MBC patients, the number of nonadherent behaviors was signifcantly associated with a decrease in functional well-being.25 The most common patient-reported reasons for nonadherence were forgetfulness and intolerance of side efects.25
There are several treatment challenges associated specifcally with HER2+ MBC patients who have developed brain metastases. These patients are typically excluded from clinical trials due to poor functional status and increased risk of toxicity.26 Brain metastases often occur in MBC patients who receive adjuvant chemotherapy, due to the properties of some agents that do not cross the blood-brain barrier.8 Thus, treatment plans may be complex, involving continued systemic therapies for HER2+ MBC in addition to CNS-directed treatments targeting the brain metastases.8 The standard of care for patients with HER2+ MBC with brain metastases includes CNSdirected treatment options such as surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiotherapy (WBRT).27 These locally targeted treatments can be associated with short- and
re uires
ective
anage ent to i rove outcomes; coordinated care is essential to address the poor prognosis resulting from disease progression in this patient population.
long-term toxicities, including cognitive defects.28, 29 A combination of systemic therapies with SRS has been shown to result in high rates of clinically signifcant radionecrosis in HER MBC patients.28
Current guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend screening for brain metastases on the basis of suspicious CNS symptoms, including any neurologic symptoms such as new-onset headaches, unexplained nausea or vomiting, or a change in motorsensory function.27, 30 However, 43% of patients with MBC and brain metastases are asymptomatic, creating a challenge in diagnosing CNS progression.
When compared to early-stage breast cancer, MBC has a substantially higher economic burden, as it is associated with higher shortterm and medium-term direct costs.31 Annual direct healthcare costs for patients with MBC with disease progression are 1.6 times higher than for those whose disease has not progressed; patients with progressive MBC have cost nearly $50,000 more than those without progression in the past year.32 Major cost drivers for HER MBC were outpatient visits and HER2-directed therapy drug costs.31
For MBC patients with brain metastases, healthcare resource use and costs are even higher. The median total cost for MBC patients with CNS metastasis was more than double the cost for those without ($112,402 vs. $50,835, respectively).33 Median outpatient
costs for patients with CNS metastasis were four times higher than for patients without CNS metastases ($41,192 vs. $10,802, respectively).33 Additionally, patients with CNS metastases experienced more outpatient, emergency room, and inpatient visits.
HER MBC requires efective management to improve outcomes; coordinated care is essential to address the poor prognoses resulting from disease progression in this patient population. There is a high unmet need stemming from the unique challenges these patients face, particularly tied to the occurrence of brain metastases and associated treatment obstacles. Due to the higher risk of poor outcomes and mortality among HER2+ MBC patients, proper and close management is key to improving outcomes and quality of life. Proper care coordination, addressing nonadherent behaviors, and appropriate screenings can both ease the cost burden for payers and lead to increased health-related quality of life in MBC patients. Ensuring that HER2+ MBC patients with brain metastases receive the proper treatment targeting CNS metastasis is also critical to improving outcomes, as traditional therapies for breast cancer will not penetrate the blood-brain barrier and will leave the CNS metastasis unaddressed.
References
1. “Cancer Stat Facts: Female Breast Cancer.” National Cancer Institute, 2020, https://seer.cancer.gov/statfacts/html/breast.html.
2. “Metastatic Breast Cancer.” BreastCancer.org, 9 Feb. 2021, https:// www.breastcancer.org/symptoms/types/recur_metast.
3. Berman, Abigail, et al. “Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment.” Clinical Breast Cancer, Apr. 2013, https://pubmed.ncbi. nlm.nih.gov/23218473/.
4. van den Hurk, Corina, et al. “Unfavourable pattern of metastases in M0 breast cancer patients during 1978-2008: a population-based analysis of the Munich Cancer Registry.” Breast Cancer Research and Treatment, Aug. 2011, https://pubmed.ncbi.nlm.nih.gov/21311969/.
5. “Cancer Stat Facts: Female Breast Cancer Subtypes.” National Cancer Institute, 2020, https://seer.cancer.gov/statfacts/html/breastsubtypes.html.
6. “Breast Cancer HER2 Status.” American Cancer Society, 2019, https:// www.cancer.org/cancer/breast-cancer/understanding-a-breastcancer-diagnosis/breast-cancer-her2-status.html.
7. Kennecke, Hagen, et al. “Metastatic behavior of breast cancer subtypes.” Journal of Clinical Oncology, July 2010, https://pubmed. ncbi.nlm.nih.gov/20498394/.
References
8. Musolino, Antonino, et al. “Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study.” Cancer, May 2011, https://pubmed.ncbi.nlm. nih.gov/21509760/.
9. Gong, Yue, et al. “Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study.” Scientifc Reports, Mar. 2017, https://pubmed.ncbi.nlm.nih.gov/28345619/.
10. Pestalozzi, B.C., et al. “Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatments in node positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.” Annals of Oncology, Nov. 2008, https://pubmed.ncbi.nlm. nih.gov/18562328/.
11. Olson, Erin, et al. “Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the posttrastuzumab era.” Breast, Aug. 2013, https://pubmed.ncbi.nlm.nih. gov/23352568/.
12. Bendell, Johanna, et al. “Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma.” Cancer, June 2003, https://pubmed.ncbi.nlm.nih. gov/12784331/.
13. Hurvitz, Sara, et al. “Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.” Clinical Cancer Research, Apr. 2019, https://pubmed.ncbi.nlm.nih.gov/30593513/.
14. Brufsky, Adam, et al. “Central Nervous System Metastases in Patients with HER2-Positive Metastatic Breast Cancer: Incidence, Treatment, and Survival in Patients from registHER.” Clinical Cancer Research, 011, https clincancerres.aacrjournals.org content 1 14 4 4.
15. Azim, Hamdy, et al. “Predicting Brain Metastases in Breast Cancer Patients: Stage Versus Biology.” Clinical Breast Cancer, Apr. 2018, https://pubmed.ncbi.nlm.nih.gov/28888580/.
16. Hung, Man Hsin, et al. Efect of Age and Biological Subtype on the Risk and Timing of Brain Metastasis in Breast Cancer Patients.” PLOS One, 4 Feb. 014, https journals.plos.org plosone article id 10.1 1 journal.pone.00 .
17. Genre, Ludivine, et al. “External validation of a published nomogram for prediction of brain metastasis in patients with extra-cerebral metastatic breast cancer and risk regression analysis.” European Journal of Cancer, Feb. 2017, https://www.sciencedirect.com/science/ article/abs/pii/S0959804916325230.
18. Mounsey, Louisa, et al. “Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies.” Clinical Breast Cancer, Feb. 2018, https://pubmed.ncbi. nlm.nih.gov/28867445/.
19. Frisk, G., et al. “Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden.” British Journal of Cancer, 22 May 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3364124/.
20. Lin, Nancy, et al. “Brain metastases: the HER2 paradigm.” Clinical Cancer Research, Mar. 2007, https://pubmed.ncbi.nlm.nih. gov/17363517/.
21. Marschner, Norbert, et al. “Association of Disease Progression with Health-Related Quality of Life Among Adults with Breast, Lung, Pancreatic and Colorectal Cancer.” JAMA Network Open, Mar. 2020, https://pubmed.ncbi.nlm.nih.gov/32154886/.
22. Cacho-Díaz, Bernardo, et al. “Diagnosis of brain metastases in breast cancer patients resulting from neurological symptoms.” Clinical Neurology and Neurosurgy, Oct. 2018, https://pubmed.ncbi.nlm.nih. gov/30086430/.
23. Oltean, Daniela, et al. “Brain metastases secondary to metastatic breast cancer: symptoms, prognosis and evolution.” Tumori Journal, 2009, https://pubmed.ncbi.nlm.nih.gov/20210232/.
24. Bachelot, Thomas, et al. “Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.” The Lancet Oncology, Jan. 2013, https://pubmed.ncbi.nlm.nih. gov/23122784/.
25. daCosta DiBonaventura, Marco, et al. “Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer.” American Health & Drug Benefts, Oct. 2014, https:// pubmed.ncbi.nlm.nih.gov/25525495/.
26. “Cancer Clinical Trial Eligibility: Brain Metastases.” U.S. Food and Drug Administration, 13 Mar. 2019, https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/cancer-clinical-trialeligibility-criteria-brain-metastases.
27. Ramakrishna, Naren, et al. “Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.” Journal of Clinical Oncology, Sept. 2018, https://pubmed.ncbi.nlm.nih.gov/29939840/.
28. Brown, Paul, et al. Efect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial.” JAMA, July 2016, https://pubmed.ncbi.nlm.nih.gov/27458945/.
29. Brosnan, Evelyn, et al. “Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies.” Annals of Translational Medicine, May 2018, https://pubmed.ncbi.nlm.nih. gov/29911111/.
30. “NCCN Clinical Practice Guidelines in Oncology for Breast Cancer v.6.2020.” National Comprehensive Cancer Network, 2020, https:// pubmed.ncbi.nlm.nih.gov/32259783/.
31. Sussell, Jesse, et al. “HER2-Positive Metastatic Breast Cancer: A Retrospective Cohort Study of Healthcare Costs in the TargetedTherapy Age.” Advances in Therapy, Apr. 2020, https://pubmed.ncbi. nlm.nih.gov/32172510/.
32. Reyes, Carolina, et al. “Cost of Disease Progression in Patients with Metastatic Breast, Lung, and Colorectal Cancer.” Oncologist, Sept. 2019, https://pubmed.ncbi.nlm.nih.gov/30796156/.
33. Pulgar, S., et al. “Economic burden of central nervous system metastases in human epidermal growth factor receptor 2-positive breast cancer.” Abstract for Academy of Managed Care Pharmacy, 0 0, https www.jmcp.org doi pdf
TUKYSA + trastuzumab + capecitabine vs placebo + trastuzumab + capecitabine1
Reduced risk of disease progression or death by 46%
Median PFS: 7.8 months (95% CI: 7.5-9.6) vs 5.6 months (95% CI: 4.2-7.1); HR = 0.54 (95% CI: 0.42-0.71); P <0.00001
Median OS: 21.9 months (95% CI: 18.3-31.0) vs 17.4 months (95% CI: 13.6-19.9); HR = 0.66 (95% CI: 0.50-0.87); P = 0.0048
The trial studied patients who had received prior trastuzumab, pertuzumab, and T-DM1 in the neoadjuvant, adjuvant, or metastatic setting.1
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Warnings and Precautions
• Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 and 0.5% with Grade 4. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. Median time to onset of the frst episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to TUKYSA dose reductions in 6% of patients and TUKYSA discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
CI = confdence interval; HER = human epidermal growth factor receptor; HR = hazard ratio; MBC = metastatic breast cancer; OS = overall survival; PFS = progression-free survival; T-DM1 = ado-trastuzumab emtansine.
Please see full Important Safety Information on the following pages.
In combination with trastuzumab + capecitabine
0.66 (95% CI: 0.50-0.87)
0.0048 NUMBER OF
The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, PPE, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash1
Warnings and Precautions
• Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 and 0.5% with Grade 4. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. Median time to onset of the frst episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to TUKYSA dose reductions in 6% of patients and TUKYSA discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
• Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × and 1. had a iliru in increase rade . Hepatotoxicity led to TUKYSA dose reductions in 8% of patients and TUKYSA discontinuation in 1.5% of patients. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
• Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Serious adverse reactions occurred in 26% of patients who received ; those occurring in 2 of patients were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in 1 of patients were hepatoto icity 1. and diarrhea 1 .
Adverse reactions led to dose reduction in 21% of patients who received ; those occurring in 2 of patients were hepatotoxicity (8%) and diarrhea (6%).
The most common adverse reactions in patients who received 2 were diarrhea palmar plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
PRIMARY ENDPOINT*
reduction in the risk of disease progression or death1
• HR = 0.54 (95% CI: 0.42-0.71); P <0.00001
EXPLORATORY ANALYSIS*†
~3x as many patients were progression-free2 TUKYSA ARM CONTROL ARM VS
• Median PFS: 7.8 months (95% CI: 7.5-9.6) in the TUKYSA arm vs 5.6 months (95% CI: 4.2-7.1) in the control arm (33.1%; 95% CI: 26.6-39.7)(12.3%; 95% CI: 6.0-20.9)
*Study design: HER2CLIMB was a randomized (2:1), double-blind, placebo-controlled trial of 612 patients with HER2+ MBC who received TUKYSA + trastuzumab + capecitabine (TUKYSA arm; n = 410) or placebo + trastuzumab + capecitabine (control arm; n = 202). Primary endpoint was PFS (time from randomization to documented disease progression or death from any cause in the frst 8 randomized patients. econdary endpoints assessed in all randomized patients included OS (time from randomization to death from any cause). PFS was evaluated in accordance with RECIST criteria, version 1.1, by means of BICR.1
†This exploratory analysis is descriptive only. These are estimates and not exact numbers. HER2CLIMB was not powered to assess a statistical difference between treatment groups at this time point.
ICR = lind independent central review; CI = confdence interval; HER = human epidermal growth factor receptor; HR = hazard ratio; MBC = metastatic breast cancer; OS = overall survival; PFS = progression-free survival; PPE = palmar-plantar erythrodysesthesia; RECIST = Response Evaluation Criteria in Solid Tumors.
In HER2C IM rade la oratory a normalities reported in of patients who received TUKYSA were decreased phosphate, increased ALT, decreased potassium, and increased AST. he mean increase in serum creatinine was 2 within the frst 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
Drug Interactions
• Strong CYP3A/Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
• Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
• CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
• P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specifc Populations
• Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
• Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
• Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
Please see Brief Summary of Prescribing Information on adjacent pages.
References: 1. TUKYSA [Prescribing Information]. Bothell, WA: Seagen Inc. April 2020. 2. Murthy RK, Loi S, Okines A, et al. Supplemental appendix for: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.
TUKYSAÆ (tucatinib) tablets, for oral use
Brief summary of Prescribing Information (PI). See full PI. Rx Only
INDICATIONS AND USAGE
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity. Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact. Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal. If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time.
When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m2 orally twice daily taken within 30 minutes after a meal. TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information.
Dosage Modi cations for Adverse Reactions
The recommended TUKYSA dose reductions and dosage modi cations for adverse reactions are provided in Tables 1 and 2. Refer to the Full Prescribing Information for trastuzumab and capecitabine for information about dosage modi cations for these drugs.
Table 1: Recommended TUKYSA Dose Reductions for Adverse Reactions
Dose Reduction
Recommended TUKYSA Dosage
First 250 mg orally twice daily
Second 200 mg orally twice daily
Third 150 mg orally twice daily
Permanently discontinue TUKYSA in patients unable to tolerate 150 mg orally twice daily.
Table 2: Recommended TUKYSA Dosage Modi cations for Adverse Reactions
Severity TUKYSA Dosage Modi cation
Diarrhea1
Grade 3 without anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to Grade 1, then resume TUKYSA at the same dose level.
Grade 3 with anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to Grade 1, then resume TUKYSA at the next lower dose level.
Grade 4 Permanently discontinue TUKYSA.
Hepatotoxicity1,2
Grade 2 bilirubin (>1.5 to 3 ◊ ULN)Hold TUKYSA until recovery to Grade 1, then resume TUKYSA at the same dose level.
Grade 3 ALT or AST (> 5 to 20 ◊ ULN) OR Grade 3 bilirubin (> 3 to 10 ◊ ULN) Hold TUKYSA until recovery to Grade 1, then resume TUKYSA at the next lower dose level.
Grade 4 ALT or AST (> 20 ◊ ULN) OR Grade 4 bilirubin (> 10 ◊ ULN) Permanently discontinue TUKYSA.
ALT or AST > 3 ◊ ULN AND Bilirubin > 2 ◊ ULN Permanently discontinue TUKYSA.
Other adverse reactions1
Grade 3 Hold TUKYSA until recovery to Grade 1, then resume TUKYSA at the next lower dose level.
Grade 4 Permanently discontinue TUKYSA.
1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03
2. Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase
Dosage Modi cations for Severe Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily.
Dosage Modi cations for Concomitant Use with Strong CYP2C8 Inhibitors: Avoid concomitant use of strong CYP2C8 inhibitors with TUKYSA. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the TUKYSA dose that was taken prior to initiating the inhibitor.
CONTRAINDICATIONS
None.
Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the rst episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase > 5 ◊ ULN, 6% had an AST increase > 5 ◊ ULN, and 1.5% had a bilirubin increase > 3 ◊ ULN (Grade 3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity: Based on ndings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not re ect the rates observed in practice.
HER2-Positive Metastatic Breast Cancer (HER2CLIMB)
The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB. Patients received either TUKYSA 300 mg twice daily plus trastuzumab and capecitabine (n=404) or placebo plus trastuzumab and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm. Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in 1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in 2% of patients were hepatotoxicity (8%) and diarrhea (6%).
The most common adverse reactions in patients who received TUKYSA ( 20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
Table 3: Adverse Reactions ( 10%) in Patients Who Received TUKYSA and with a Difference Between Arms of 5% Compared to Placebo in HER2CLIMB (All Grades)
Adverse ReactionTUKYSA + Trastuzumab + Capecitabine (N = 404)
Placebo + Trastuzumab + Capecitabine (N = 197) Grade (%) Grade (%) All 34 All 34
Gastrointestinal disorders
tissue disorders
Adverse ReactionTUKYSA + Trastuzumab + Capecitabine (N = 404) Placebo + Trastuzumab + Capecitabine (N = 197)
Blood and lymphatic system disorders
Investigations
Nervous System Disorders
Peripheral neuropathy 6
Respiratory, thoracic and mediastinal disorders
Epistaxis 12
1. Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and aphthous ulcer
2. Rash includes rash maculo-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rash pruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema, skin toxicity, and dermatitis
3. Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury
4. Anemia includes anemia, hemoglobin decreased, and normocytic anemia
5. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
6. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
Table 4: Laboratory Abnormalities ( 20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of 5% Compared to Placebo in HER2CLIMB
TUKYSA + Trastuzumab + Capecitabine1 Placebo + Trastuzumab + Capecitabine1 All Grades % Grades 3 % All Grades % Grades 3 %
Hematology Decreased hemoglobin
Chemistry
Decreased
Decreased
1. The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal de nition for grade 1 events (NCI CTCAE v5.0).
2. Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2.
3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function.
4. There is no de nition for Grade 2 in CTCAE v.4.03.
Increased Creatinine: The mean increase in serum creatinine was 32% within the rst 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
DRUG INTERACTIONS
Effects of Other Drugs on TUKYSA
Strong CYP3A Inducers or Moderate CYP2C8 Inducers: Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations, which may reduce TUKYSA activity. Avoid concomitant use of TUKYSA with a strong CYP3A inducer or a moderate CYP2C8 inducer. Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations, which may increase the risk of TUKYSA toxicity. Avoid concomitant use of TUKYSA with a strong CYP2C8 inhibitor. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
Effects of TUKYSA on Other Drugs
CYP3A Substrates: Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate, which may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA with CYP3A substrates,
where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.
P-glycoprotein (P-gp) Substrates: Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate, which may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary: TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information. Based on ndings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
Lactation
Risk Summary: TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information. There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for at least 1 week after the last dose.
TUKYSA can cause fetal harm when administered to a pregnant woman. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for contraception and infertility information.
Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA.
Contraception:
Females: Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.
Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.
Infertility: Based on ndings from animal studies, TUKYSA may impair male and female fertility.
Pediatric Use: The safety and effectiveness of TUKYSA in pediatric patients have not been established.
Geriatric Use: In HER2CLIMB, 82 patients who received TUKYSA were 65 years, of whom 8 patients were 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients 65 years compared to 24% in patients < 65 years. The most frequent serious adverse reactions in patients who received TUKYSA and 65 years were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of TUKYSA in patients 65 years compared to younger patients. There were too few patients 75 years to assess differences in effectiveness or safety.
Renal Impairment: The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information in severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min).
Hepatic Impairment: Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (ChildPugh C) hepatic impairment. No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
TUKYSA and its logo, and Seagen and are US registered trademarks of Seagen Inc. © 2021 Seagen Inc., Bothell, WA 98021 All rights reserved Printed in USA REF-5155(1) 4/20
The pipeline for HIV includes methods for prophylaxis, such as potential vaccinations. With these added preventive measures, payers may prioritize strategic management of the overall HIV space.
Pharm.D., MBA Director of Pharmacy Services
In the U.S., an estimated 1. million people are living with human immunodefciency virus HIV , with approximately ,400 new HIV infections occurring annually, per 01 data.1 In 01 , there were 1 , 0 deaths among those diagnosed with HIV in the U.S.1
Per guidelines from the U.S. Department of Health and Human Services HHS , current recommended HIV treatment is antiretroviral therapy ART , which patients should begin as soon after diagnosis as possible to slow progression.2 There are seven classes of ART nucleoside reverse transcriptase inhibitors NRTIs , non nucleoside reverse transcriptase inhibitors NNRTIs , protease inhibitors PIs , fusion inhibitors, CCR antagonists, post attachment inhibitors, and integrase strand transfer inhibitors INSTIs .
Pre exposure prophylaxis PrEP is an HIV prevention strategy recommended by the U.S. Centers for Disease Control and Prevention. There are currently two FDA approved HIV PrEP therapies for daily use emtricitabine and tenofovir disoproxil fumarate TRUVADA for PrEP® and emtricitabine and tenofovir alafenamide DESCOVY for PrEP® . Adherence to PrEP medication as prescribed can reduce the risk of contracting HIV via sexual contact and via drug injection by and 4 , respectively.
There are three phases to appropriate care using PrEP screening, PrEP initiation, and follow up. The initial screening should include an HIV risk assessment, PrEP education, and an initial clinical evaluation that includes assessment of indications for PrEP, a brief medical history, and appropriate lab work. PrEP initiation should occur within seven days of the screening and include a review of PrEP basics and a prescription of PrEP for 0 days or less. Follow up should be consistent and occur every three months, with an HIV blood test; a symptom review; concurrent prescription of PrEP; and assessment and counseling
for HIV risk behavior, adherence, and pregnancy intent. Testing for sexually transmitted infections and kidney function should be done every six months for follow up.
Drug resistance testing helps determine if an HIV patient has a form of the virus that has mutated and does not respond to ART.4 Specifcally, genotypic drug resistance testing examines the genotype of a patient’s HIV to analyze for the presence of specifc genetic mutations that are known to cause resistance to ART.4
In April, HHS updated its guidelines for pediatric HIV treatment. Updates included discussion of and guidance for the use of telehealth and telemedicine in pediatric HIV care; an expansion of preferred regimen designation of dolutegravir TIVICAY plus two NRTIs to be recommended for anyone age 4 weeks or older, provided they weigh at least kg; the addition of bictegravir, as part of bictegravir emtricitabine tenofovir alafenamide BIKTARVY® , in patients at least years old and weighing at least kg; and a distinction that NRTI backbone of abacavir iagen alongside either emtricitabine EMTRIVA or lamivudine Epivir is classifed as
preferred for children at least 1 month old, despite FDA approval for the drugs specifying an age of at least years old.
HHS guidelines for the treatment of HIV in adults and adolescents were most recently updated in 01 and adjusted recommendations for frst line regimens. The update added dolutegravir lamivudine DOVATO to the list of recommended initial regimens alongside bictegravir emtricitabine tenofovir alafenamide BIKTARVY® for a treatment option in acutely or recently infected people for whom genotypic drug resistance testing had not yet been completed.
Adherence and Single-Tablet Regimen vs. MultipleTablet Regimen
Adherence is critical for patients to maintain viral suppression; less efective viral suppression is associated with poor treatment adherence. , The adherence thresholds vary between diferent classes of ART. However, improved outcomes, including viral suppression and, in some cases, reduced risk of resistance mutations, are associated with higher adherence levels.
The introduction of single tablet regimen STR options has increased adherence for HIV patients and resulted in decreased
cenicriviroc
pharmacy costs and hospitalizations when compared to existing multiple tablet regimens MTR . , 10 In an analysis of patients initiating ART, patients on STR were more than twice as likely to be adherent when compared to MTR patients. Persistence was more common among STR patients, as MTR patients were 1 more likely to discontinue treatment.
In a pilot HIV care management program facilitated by Magellan Method, Medicaid patients prescribed at least one HIV medication, with the exception of PrEP, were included in an outreach program aimed to assess the impact of the program on ART adherence and the proportion of patients who are virologically suppressed.11 Prior to the contact period, more than half of the participating patients had a proportion of days covered PDC of less than 0 .11 Overall, patients on STR had higher adherence than patients on MTR; prior to contact, 44 of STR patients had a PDC of less than 0 compared to of MTR patients. Six months after enrollment in the program, there was an increase in PDC to about overall, compared to 0 pre contact period.11 This data shows an opportunity for patient engagement in addressing patient adherence in the HIV patient population. Improved adherence can lead to
sustained viral suppression, better outcomes, and improved cost management.
Cabotegravir and Rilpivirine (CABENUVA) and Cabotegravir (VOCABRIA)12
In January, the FDA approved cabotegravir extended release injectable suspension and rilpivirine extended release injectable suspension CABENUVA, ViiV Healthcare , co packed for intramuscular use, for HIV 1 infected adults. It is the frst FDA approved injectable complete regimen indicated for HIV that is administered once monthly. The two drug co packaged products include cabotegravir, an HIV 1 INSTI, and rilpivirine, an HIV 1 NNRTI. It is indicated as a complete regimen to replace current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no treatment failure and no known or suspected resistance to either drug.
Focused measures to increase treatment adherence in HIV patients can lead to lower costs overall, including pharmacy and hospitalizations.
The FDA also approved cabotegravir 0 mg tablets VOCABRIA indicated to be taken in combination with oral rilpivirine for one month prior to starting treatment with the two-drug extendedrelease injectable to ensure the medications are well tolerated before switching.
Two phase three randomized, multicenter, active controlled, parallel arm, open label, non inferiority trials evaluated the efcacy of CABENUVA. In the FLAIR trial, HIV infected, ART na ve subjects received dolutegravir INSTI containing regimen for 0 weeks, and subjects who were virologically suppressed were randomized to receive either a cabotegravir plus rilpivirine regimen or remain on the current ART regimen.
In February, HHS determined CABENUVA injections can be used to optimize treatment in patients with HIV who are currently on oral ART with documented viral suppression for at least three months and who have no baseline resistance to either medication, prior virologic failures, or active hepatitis B virus; are not pregnant or planning to become pregnant; and are not receiving medications with signifcant interactions.1 In patients who may be drawn to monthly injection over daily pills, CABENUVA may become the preference.
In July 0 0, the FDA approved fostemsavir Rukobia, ViiV Healthcare , indicated for adults living with HIV who have tried multiple HIV medications and whose infection cannot be successfully treated with other therapies due to resistance, intolerance, or safety considerations. A trial of 1 heavily treatment experienced adult participants with high virus levels was conducted with participants in the main trial arm and an additional participants receiving fostemsavir in a diferent arm of the trial. Participants in the main trial arm received either fostemsavir or a placebo twice daily for eight days in addition to the previously failing antiretroviral regimen. On day , participants receiving fostemsavir had a signifcantly greater decrease in virus levels compared to those
receiving the placebo, and after day , all participants received fostemsavir along with other antiretroviral drugs. Fifty three percent of participants achieved viral suppression after 4 weeks of fostemsavir plus other antiretroviral drugs. Finally, after weeks, 0 of participants continued to have viral suppression. The most common side efect was nausea; however, more severe adverse events included elevations in liver enzymes among participants also infected with hepatitis B or C virus and changes in the immune system.
Research shows that with the expansion of Medicaid under the Affordable Care Act ACA came an increase in the identifcation of undiagnosed HIV infections and use of HIV prevention services; an estimated 1 . increase in HIV diagnoses was associated with Medicaid expansion, according to data from the University of Illinois.1 This shift, along with accompanied appropriate treatment and use of preventive services, was linked directly to the improved access to care through Medicaid, as diagnoses were most common in populations likely afected by Medicaid expansion, including low income individuals engaged in injection drug use from rural counties with high uninsured rates prior to the ACA.1
Research shows that with the expansion of Medicaid under ACA came an increase in the identifcation o undiagnosed HIV infections and use of HIV-prevention services; an estimated 13.9% increase in HIV diagnoses was associated with Medicaid expansion.
The data suggests access to health insurance and proper care improved HIV testing rates and use of preventive care, leading to higher rates of individuals living with HIV.1 Access to care and proper management for patients with HIV are critical in improving outcomes.
With several generics entering the market or on the horizon, there is potential for cost management in this category. Combination therapies have created the opportunity for combining several generic therapies where brand only therapies were previously utilized. Strong policy will be key in driving generic utilization in this space. Additionally, by prioritizing the HIV population, payers can better manage this space. Focused measures to increase treatment adherence in HIV patients can lead to lower costs overall, including pharmacy and hospitalizations.11
The pipeline for HIV includes methods for prophylaxis, such as potential vaccinations. With these added preventive measures, payers may prioritize strategic management of the overall HIV space, including identifying appropriate populations and ensuring access to prophylactic therapies. Proper preventive care, coupled with efective management of populations with HIV, could lead to improved long term outcomes and cost management.
With an expanding pipeline, payers may strategize to achieve cost savings by incentivizing and steering patients toward lower cost generic alternatives.
References
1. U.S. Statistics. HIV.gov, 1 Mar. 0 1, https www.hiv.gov hiv basics overview data and trends statistics.
2. HIV Treatment Overview. HIV.gov, Mar. 01 , https www.hiv. gov hiv basics staying in hiv care hiv treatment hiv treatment overview.
. Pre exposure Prophylaxis PrEP Care System. U.S. Centers for Disease Control and Prevention, 10 Sept. 0 0, www.cdc.gov hiv efective interventions prevent prep index.html.
4. HIV Drug Resistance Testing. Stanford Health Care, https stanfordhealthcare.org medical conditions sexual and reproductive health hiv aids treatments hiv drug resistance testing.html.
. Helfand, Myles. What’s New in U.S. HIV Clinical Treatment Guidelines. TheBodyPro, 0 Apr. 0 1, https www.thebodypro. com article whats new in the us hiv clinical guidelines.
. Schaecher, Kenneth. The Importance of Treatment Adherence in HIV. American Journal of Managed Care, Sept. 01 , https www. ajmc.com view a4 sep1 schaecher s 1.
. Hines, Dionne, et al. Treatment Adherence and Persistence Among HIV 1 Patients Newly Starting Treatment. Patient Preference and Adherence, Nov. 01 , https www.ncbi.nlm.nih.gov pmc articles PMC 44 0 .
. Cohen, Calvin, et al. Association between daily antiretroviral pill burden and treatment adherence, hospitalization risk, and other healthcare utilisation and costs in a US Medicaid population with HIV. BMJ Open, 01 , https bmjopen.bmj.com content e00 0 .
. Sax, Paul, et al. Adherence to antiretroviral treatment and correlation with risk of hospitalization among commercially insured HIV patients in the United States. PloS One, 01 , https pubmed.ncbi.nlm.nih. gov 4040 .
10. Langness, Jacob, et al. Comparison of adherence rates for antiretroviral, blood pressure, or mental health medications for HIV positive patients at an academic medical center outpatient pharmacy. Journal of Managed Care and Specialty Pharmacy, 014, https pubmed.ncbi.nlm.nih.gov 0 0 4 .
11. Kangethe, Anne, et al. Analysis of a Pilot HIV Care Management Program. Academy of Managed Care Pharmacy, 0 1, https www1. magellanrx.com documents 0 1 0 analysis of a pilot hiv care management program.pdf .
12. FDA Approves Cabenuva and Vocabria for the Treatment of HIV 1 Infection. U.S. Food and Drug Administration, Jan. 0 1, www. fda.gov drugs human immunodefciency virus hiv fda approves cabenuva and vocabria treatment hiv 1 infection.
1 . HHS Adults and Adolescents Antiretroviral Guidelines Panel Recommendation for the Long Acting Injectable Antiretroviral Regimen of Cabotegravir and Rilpivirine. Clinical Info, 4 Feb. 0 1, https clinicalinfo.hiv.gov en guidelines adult and adolescent arv hhs adults and adolescents antiretroviral guidelines panel.
14. FDA Approves New HIV Treatment for Patients with Limited Treatment Options. U.S. Food and Drug Administration, July 0 0, https www.fda.gov news events press announcements fda approves-new-hiv-treatment-patients-limited-treatment-options.
1 . IPD Analytics.
1 . Nelson, Hannah. Medicaid Expansion Helped Detect Undiagnosed HIV Infections. Health Payer Intelligence, Jan. 0 1, https healthpayerintelligence.com news medicaid expansion helped detect undiagnosed hiv infections.
Kite, a Gilead Company, is dedicated to achieving one of the most ambitious goals of the 21st century: curing cancer. This mission is at the heart of everything we do from early research to product development.
With several CAR T therapies in the pipeline, the oncology space will require strategizing and efective management moving forward.
The oncology management landscape is ever-evolving. The approval and pipeline of innovative new therapies coupled with the way the ongoing COVID-19 pandemic has changed care delivery will create new challenges for payers to navigate in managing members with cancer moving forward.
Chimeric antigen receptor T-cell (CAR-T) therapy represents an exciting recent advancement in oncology treatment. CAR-T therapy is a type of immunotherapy that works by modifying a patient’s T-cells to attack cancer cells.1 Currently, it is used in the treatment of certain blood cancers; it is also being investigated for efcacy in treating several other types of cancer, with a robust pipeline on the horizon.1, 2
Idecabtagene Vicleucel (ABECMA®)3
In March, the U.S. Food and Drug Administration FDA approved the frst CAR T therapy for the treatment of multiple myeloma in adult patients. Idecabtagene vicleucel (ABECMA®, Celgene is specifcally indicated for adult patients with multiple myeloma who have not responded to, or whose disease has returned after, at least four prior lines of therapy. Idecabtagene vicleucel is a B cell maturation antigen BCMA directed genetically modifed autologous CAR T therapy. In a study of 127 patients with relapsed myeloma and refractory myeloma who had received at
Brexucabtagene autoleucel (TECARTUS®, Kite Pharma) received FDA approval in July 2020 for the treatment of adult patients diagnosed with mantle cell lymphoma (MCL) who have not responded to or who have relapsed following other treatments. This is the frst approved CAR T therapy for the treatment of MCL. A trial of 60 adults with refractory or relapsed MCL showed a complete response rate of 62% after treatment with brexucabtagene autoleucel, with an objective response rate of 87%. The most common associated side efects include serious infections, low blood cell counts, and a weakened immune system; more serious potential side efects include CRS and neurologic toxicities.
least three prior antimyeloma lines of therapy, 72% of patients partially or completely responded to treatment with idecabtagene vicleucel. Overall, 28% showed complete response, and 65% of that group remained in complete response for at least 12 months. Severe associated adverse reactions include cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenias; more common side efects include infections, fatigue, musculoskeletal pain, and a weakened immune system.
The FDA approved lisocabtagene maraleucel (BREYANZI®, Juno Therapeutics) in February for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to or have relapsed after at least two other types of systemic treatment. Lisocabtagene maraleucel is the third CAR-T therapy approved for certain types of non-Hodgkin lymphoma, including difuse large B cell lymphoma DLBCL . In a trial of more than 0 adult patients with refractory or relapsed large B-cell lymphoma, patients treated with lisocabtagene maraleucel showed a complete response rate of 4 . Severe associated side efects include CRS and neurologic toxicities; other side efects include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system.
Currently, CAR-T is used in the treatment of certain blood cancers; it is also being investigated or e cac in treating several other types of cancer, with a robust pipeline on the horizon.
In April, the Institute for Clinical and Economic Review (ICER) released an evidence report that assessed the comparative clinical efectiveness and value of idecabtagene vicleucel and ciltacabtagene autoleucel, which is currently under FDA review. The report noted that both therapies appear to deliver relatively sizeable gains in both progression-free survival and overall survival for triple class refractory multiple myeloma patients exposed to three or more prior lines of treatment, with higher rates of response and longer survival than treatment with current therapies,” concluding there is “high certainty that both therapies provide at least a small net health beneft compared to usual care, with the possibility of substantial beneft. However, ICER noted that idecabtagene vicleucel would require a 4 discount of the currently an-
Drug ManufacturerRoute of AdministrationMechanism of Action
ciltacabtagene autoleucel (JNJ4528)
Janssen Pharmaceuticals; Legend Biotech IV
axicabtagene ciloleucel (YESCARTA) Kite Pharma; Gilead Sciences IV marginal zone lymphoma; difuse large B cell lymphoma pending; phase three
CEA CAR-T Sorrento Therapeuticsinjectable pancreatic cancer phase three
tabelecleucel (ATA129) Atara
Descartes-08Cartesian Therapeuticsinjectable multiple myeloma; myasthenia gravis phase two
Descartes-11Cartesian Therapeuticsinjectable multiple myeloma phase two
With several CAR-T therapies in the pipeline, the oncology space will require strategizing and e ective anage ent moving forward.
nounced wholesale acquisition cost (WAC) of $419,500 in order to fall in the recommended health beneft price benchmark range.
In September 2020, the U.S. Centers for Medicare & Medicaid Services CMS fnalized its proposal to establish a Medicare Severity
Diagnosis Related Group for CAR-T services, with a national, unadjusted payment amount for this new group of $239,929.8 Notably, this amount is less than the recommended amount from the American Society of Clinical Oncology (ASCO) as well as the sales price of CAR-T, which is $373,000.8
With the exciting opportunity and innovation ofered by CAR T therapies come high costs. Determining the appropriate patients for these therapies will be key in properly managing the space.9 While CAR-T is an exciting option, payers need to assess the full treatment landscape and properly identify for which patients CAR-T is appropriate; deference to providers in these instances is important, but proper policy will also be key.9 With currently available CAR T therapies, organizations will typically coordinate payment by using customized agreements on a per patient basis, making the billing and reimbursement for these therapies complicated and burdensome.10 However, as more CAR-T options become available, payers are approving and allowing access to these therapies expeditiously.10 Still, it will take payers time to negotiate and customize these per patient agreements in order to optimize management in the space.10
With several CAR-T therapies in the pipeline, the oncology space will require strategizing and efective management moving forward. Crafting policy that appropriately identifes populations and ensures access to new innovative therapies, whether on a patient-by-patient basis or through broader management, will be critical to payers’ ability to efectively manage the cost burden of CAR-T therapies as these options become increasingly available.
References
1. “CAR-T cell therapy.” National Cancer Institute, https://www.cancer. gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.
2. Huang, Ruihao, et al. “Recent advances in CAR-T cell engineering.” Journal of Hematology & Oncology, 2 July 2020, https://jhoonline. biomedcentral.com/articles/10.1186/s13045-020-00910-5.
3. “FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma.” U.S. Food and Drug Administration, 27 Mar. 2021, https://www.fda.gov/news-events/press-announcements/ fda approves frst cell based gene therapy adult patients multiple myeloma.
4. “FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma.” U.S. Food and Drug Administration, 5 Feb. 2021, https://www.fda.gov/news-events/pressannouncements/fda-approves-new-treatment-adults-relapsed-orrefractory-large-b-cell-lymphoma.
5. “FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL.” U.S. Food and Drug Administration, 24 July 2020, www.fda.gov/news-events/press-announcements/fdaapproves frst cell based gene therapy adult patients relapsed or refractory-mcl.
6. IPD Analytics. “CAR-T Therapy Pipeline.”
7. “ICER Publishes Evidence Report on Therapies for Multiple Myeloma.” Institute for Clinical and Economic Review, 5 Apr. 2021, https://icer. org/news-insights/press-releases/icer-publishes-evidence-report-ontherapies-for-multiple-myeloma/.
8. Medicare Reimbursement Update for CAR T Finalized. American Society of Clinical Oncology, 4 Sept. 2020, https://www.asco.org/ practice-policy/policy-issues-statements/asco-in-action/medicarereimbursement-update-car-t.
9. Minemyer, Paige. “Optum: How payers can prepare now for wave of CAR-T therapies.” Fierce Healthcare, 22 Sept. 2020, https://www. fercehealthcare.com payer optum how payers can prepare now for-wave-car-t-therapies.
10. Cryts, Aine. “CAR T-cell Therapy: How Payers are Responding to Huge Price Tags.” Managed Healthcare Executive, 5 Nov. 2018, https://www. managedhealthcareexecutive.com/view/car-t-cell-therapy-howpayers-are-responding-huge-price-tags.
AT MAGELLAN METHOD, we are uniquely qualified to solve complex healthcare challenges. As a subsidiary of Magellan Health, a Fortune 500 company, we have access to a wide range of resources and expertise from across our PBM, Medicare, and behavioral health divisions.
We leverage up-to-date healthcare data to implement solutions that transform how care is delivered. Our team of analytic experts partners with you to develop a customized solution that delivers results.
How can we put our Method to work for you? Contact us at MagellanMethod@magellanhealth.com to
at magellanrx.com/read to see our insights in action!
Lindsay C. Speicher, J.D. Project Manager Magellan Method
Since the beginning of the COVID 1 pandemic, oncology diagnosis and care have been signifcantly impacted.1, 2 Hospital outpatient evaluation and management visits, new patient visits, established patient visits, and billing for physician-administered oncology products have been similarly lower.1, 2 The current global health crisis has undoubtedly delayed diagnosis and treatment, which can lead to major challenges downstream, potentially increasing cancer morbidity and mortality rates. A physician survey showed a shift away from prescribing immune checkpoint inhibitors, monoclonal antibodies, and corticosteroids during the COVID-19 pandemic.3
In April 2020, when COVID-19 cases were surging in the U.S., breast, colon, prostate, and lung cancer screenings were massively reduced by 85%, 75%, 74%, and 56%, respectively.1, 2 Data indicates a signifcant decline in newly identifed patients with common types of cancer; this could lead to a potential increase in cancer deaths of nearly 34,000.4 Delays in cancer diagnoses, surgery, radiation, and chemotherapy as well as a trend in treatment strategies toward less-intensive approaches could increase cancer mortality by 10,000 deaths from breast and colorectal cancers in the next decade.1-2, 4
Overall, the healthcare system has relied on alternate delivery models to mitigate the impact of reduced in-person care. There has been an emphasis on using telehealth and home care to continue providing care efectively and safely during the pandemic.
Oncology care has been increasingly delivered in the home setting as a response to the ongoing pandemic.
Telehealth visits increased 135% from March to April 2020 and have been a preferred method of care delivery for many during the pandemic.5 The types of in-person visits that can be appropriately delivered via telehealth must be identifed for this modality to be successful. The American Society of Clinical Oncology (ASCO) published a report on care during the pandemic, identifying visits for positive COVID-19 infections, nonurgent highrisk patient populations, and symptom management as eligible for telehealth visits.5 ASCO recommended optimizing the use of telehealth during the COVID-19 pandemic, noting that providers should receive additional training and education specifcally regarding telehealth and its appropriate use.6
A study evaluating the use of telehealth among patients with cancer during the COVID-19 pandemic showed most participating patients were satisfed with and are becoming increasingly comfortable with telehealth video visits; a majority of physicians were satisfed and likely to use it in the future.7
Telehealth is not without challenges; healthcare providers have cited several concerns, including inadequate patient interactions and acquisition of medical data, increased potential for missing signifcant clinical fndings, decreased quality of care, and potential medical liability.7 Additionally, challenges surrounding the equitable delivery of telehealth must be addressed as this modality is used moving forward. Vulnerable older, lower-income, and un- or underinsured communities may not have equal access to the technology necessary to receive this type of care.7
Oncology care has been increasingly delivered in the home setting as a response to the ongoing pandemic.8 Delaying care to reduce risk of exposure would also increase probability of death. Thus, there was a critical need to identify ways to avoid risk of exposure while continuing to provide care.8
Prior to the pandemic, in an efort to demonstrate safe oncology care delivery at home, Penn Medicine launched its Cancer Care at Home program, which was accelerated in light of the COVID-19 pandemic.9 Over a period in late March and April 2020, home infusion referrals for patients with cancer increased 700%.9 Additionally, other health systems had been working to move patients from infusion centers to home care prior to the pandemic to improve patient convenience and free up space.10 As the COVID-19 outbreak and pandemic increased the need, home care became more used where appropriate, which helped decrease exposure for already vulnerable and at-risk patients.10
There are signifcant concerns relating to home care and infusions, however. Oncologists have expressed concerns over safety issues such as urgent reactions and the potential for the spread of COVID-19 in the home setting.20 Notably, ASCO reported that it does not support the routine use of home infusion for oncology treatment, citing concerns for “increased waste and the loss of valuable patient toxicity assessment during an infusion visit in the clinic.”6
Payer management strategies will likely adjust to address the increase in use of telehealth and a shift toward home care. Moving forward, there will potentially be a shift away from delivering care in person where possible. Certain factors informing the decision to deliver care in the home setting will include capacity at sites of care, clinical considerations, drug pricing, labor and building costs, and insurer coverage and beneft design.9 Payers may strategize how to efectively include home care and telehealth options in the management of patients with cancer while ensuring patients continue receiving appropriate care. The oncology space will require strategizing and efective management in order to address the growing need stemming from a period of delayed diagnoses and care. Revisiting beneft design for patients with cancer to increase access to diferent modalities of care delivery, including telehealth and home care, can improve outcomes and help provide patients a level and setting of care that promotes additional comfort.
Certain factors informing the decision to deliver care in the home setting will include capacity at sites of care, clinical considerations, drug pricing, labor and building costs, and insurer coverage and beneft design.
References
1. Patt, Debra, et al. “Impact of COVID-19 on Cancer Care: How the Pandemic Is Delaying Cancer Diagnosis and Treatment for American Seniors.” JCO Clinical Cancer Informatics, 30 Nov. 2020, https:// ascopubs.org/doi/full/10.1200/CCI.20.00134.
2. McNulty, Rose. “Cancer Care Delays in COVID-19 Could Lead to Higher Morbidity and Mortality.” American Journal of Managed Care, 22 Oct. 2020, https://www.ajmc.com/view/cancer-care-delays-incovid-19-could-lead-to-higher-morbidity-mortality.
3. “Cancer Care During the COVID-19 Pandemic.” Pharmacy Times, 18 Dec. 2020, https://www.pharmacytimes.com/view/cancer-careduring-the-covid-19-pandemic.
4. Kaufman, Harvey, et al. “Changes in the Number of US Patients With Newly Identifed Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic.” JAMA Network Open, 2020, https:// jamanetwork.com/journals/jamanetworkopen/fullarticle/2768946.
5. Nguyen, Ryan, et al. “Telehealth Is Here to Stay: Opportunities and Challenges for Cancer Care.” OncologyLive, 29 Oct. 2020, https:// www.onclive.com/view/telehealth-is-here-to-stay-opportunitiesand-challenges-for-cancer-care.
6. Bennett, Christina. COVID 1 Inspires Recommendations to Improve Cancer Care and Research.” Cancer Therapy Advisor, 21 Dec. 2020, https://www.cancertherapyadvisor.com/home/cancertopics/general-oncology/asco-covid19-coronavirus-cancer-careimprovements-guidelines/.
7. Darcourt, Jorge, et al. “Analysis of the Implementation of Telehealth Visits for Care of Patients with Cancer in Houston During the COVID-19 Pandemic.” JCO Oncology Practice, 7 Oct. 2020, https:// ascopubs.org/doi/full/10.1200/OP.20.00572.
8. Chakraborty, Mainak, et al. “Caring for cancer patients in the Covid pandemic: choosing between the devil and deep sea.” World Journal of Surgical Oncology, 22 Aug. 2020, https://wjso. biomedcentral.com/articles/10.1186/s12957-020-02002-7.
9. Laughlin, Amy, et al. “Accelerating the Delivery of Cancer Care at Home During the Covid-19 Pandemic.” NEJM Catalyst, 7 July 2020, https://catalyst.nejm.org/doi/full/10.1056/cat.20.0258.
10. “At-Home Cancer Care, Infusions Widespread Amid Pandemic.” Clinical Oncology News, 14 Dec. 2020, https://www.clinicaloncology. com/Community-Oncology/Article/12-20/At-Home-Cancer-CareInfusions-Widespread-Amid-Pandemic-/61420.
This
But
Working
So that someday HIV is no more.
coagulation factor VIIa (recombinant)-jncw (SEVENFACT®) Hema Pharmaceuticals
15-valent pneumococcal conjugate vaccine Merck
narsoplimab Omeros
hemophilia A and B (prevention of bleeding related to surgery or invasive procedure)
pneumococcal disease
thrombotic microangiopathy
odevixibat Albireo Pharma progressive familial intrahepatic cholestasisrelated pruritus
retifanlimab Incyte anal cancer (squamous cell, locally advanced/ metastatic, failed on/ intolerant to platinumbased chemotherapy)
sulopenem etzadroxil/probenecidIterum Therapeutics uncomplicated UTI (quinolone-resistant)
(UPTRAVI®) Janssen Pharmaceuticals
levonorgestrel 52 mg intrauterine device (Mirena®) Bayer
duration up to 6 years
(Xeljanz®/Xeljanz XR®) Pfzer
upadacitinib (RINVOQ™) AbbVie
encephalitis vaccine Pfzer
Medac
dermatitis (moderate-severe, ages >12 years)
encephalitisIM
topiramate oral solution Azurity Pharmaceuticalspartial seizures
sodium oxybate (XYWAV™)Jazz Pharmaceuticals idiopathic hypersomniaoral
sotorasib (LUMAKRAS™) Amgen
enfortumab vedotin-ejfv (PADCEV™) Astellas Pharma
NSCLC (KRAS G12 mutation, locally advanced/metastatic, >1 prior systemic therapy)
bladder cancer (locally advanced/metastatic, after PD-1/L1 inhibitor therapy, cisplatin ineligible)
oportuzumab monatox Sesen Bio
cancer (BCG-unresponsive, nonmuscle-invasive)
dextromethorphan/bupropionAxsome Therapeutics MDD
difelikefalin Cara Therapeutics
lenvatinib (LENVIMA®) Eisai
505(b)(2) NDA; breakthrough therapy;
(hemodialysisrelated)
RCC frst line, in combination with pembrolizumab)
pembrolizumab (KEYTRUDA®)Merck RCC frst line, in combination with lenvatinib) IV
rivaroxaban (XARELTO®) Janssen Pharmaceuticals peripheral arterial disease (post-recent lower-extremity revascularization)
belumosudil Kadmon
adalimumab (biosimilar to HUMIRA®) Alvotech
(chronic)
RA; AS; PsO; PsA; JIA; CD; UC SQ BLA September 2021
ivosidenib (TIBSOVO®) Les Laboratoires Servier biliary tract cancer (previously treated, IDH1 mutated)
paliperidone palmitate 6-month injectable Janssen Pharmaceuticalsschizophrenia IM NDA 09/02/2021
Lenvatinib (LENVIMA®) Eisai
endometrial carcinoma (advanced, in combination with pembrolizumab)
nivolumab (OPDIVO®) Bristol Myers Squibb
cancer (adjuvant, high-risk muscle-invasive)
pembrolizumab (KEYTRUDA®)Merck endometrial carcinoma (advanced, in combination with lenvatinib)
mesylateImpel NeuroPharma
pembrolizumab (KEYTRUDA®)Merck squamous cell carcinoma (locally advanced)
daratumumab hyaluronidase fhj (Darzalex Faspro™) Janssen Pharmaceuticals
myeloma (relapsed/refractory, in combination with pomalidomide and dexamethasone)
belzutifan Merck RCC
budesonide (long-acting) Calliditas Therapeutics IgA nephropathy (Berger’s disease)
risperidone long-acting
udenafl Dong-A Socio Holdings single-ventricle heart defects (post-Fontan operation)
reltecimod Atox Bio
organ dysfunction/failure (ages >12 years)
ranibizumab (biosimilar Lucentis®)Biogen/Samsung wet AMD
maralixibat Mirum PharmaceuticalsAlagille syndromeoral
RVT-802 (cultured human thymus tissue) Enzyvant DiGeorge syndrome (congenital athymia)
tisotumab vedotin Seagen
cancer (recurrent, metastatic)
sodium oxybate Avadel Pharmaceuticals narcolepsy-related excessive daytime sleepiness and cataplexy
SeptemberOctober 2021
NDA; orphan drug10/15/2021
varenicline Oyster Point Pharma dry-eye syndromeintranasal505(b)(2) NDA 10/18/2021
zanubrutinib (BRUKINSA®) BeiGene
dupilumab (DUPIXENT®) Sanof
macroglobulinemia
(moderatesevere, adjunct, ages 6-11 years)
andexanet alfa (Andexxa®) Alexion Pharmaceuticals acute intracranial hemorrhage while taking an oral Factor Xa inhibitor, including edoxaban and enoxaparin
dexamethasone insert (DEXTENZA®) Ocular Therapeutix
(PROGRAF®) Astellas
abemaciclib (Verzenio®) Eli Lilly and Company breast cancer (highrisk HR+, HER2-, early disease) oral sNDA
amivantamab Janssen Pharmaceuticals
OctoberDecember 2021
NSCLC (EGFR exon 20 insertion mutations, progressed on or after platinum-based chemotherapy) IV BLA; breakthrough therapy OctoberDecember 2021
AMD = age-related macular degeneration; ANCA = antineutrophil cytoplasmic antibody; AS = ankylosing spondylitis; BCG = Bacillus Calmette-Guerin; BLA = biologics license application; CD = Crohn’s disease; GVHD = graft versus host disease; HSCT = hematopoietic stem cell transplantation; IDH1 = isocitrate dehydrogenase 1; IgA = immunoglobulin A; IM = intramuscular; IU = intrauterine; IV = intravenous; JIA = juvenile idiopathic arthritis; MDD = major depressive disorder; NDA = new drug application; NSCLC = non-small cell lung cancer; NSTI = necrotizing soft-tissue infections; PAH = pulmonary arterial hypertension; PsA = psoriatic arthritis; PsO = psoriasis; RA = rheumatoid arthritis; RCC = renal cell carcinoma; sBLA = supplemental biologics license application; sNDA = supplemental new drug application; SQ = subcutaneous; T1DM = Type 1 diabetes mellitus; UC = ulcerative colitis; UTI = urinary tract infection
This information is up to date as of July 9, 2021.
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Today, MTPC group companies are focused on driving scienti c discovery in many areas, including amyotrophic lateral sclerosis (ALS).