MRx Clinical Alert - September 2020 by Prime/Magellan Rx

SEPTEMBER 2020

CLINICAL

ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS

EDITORIAL STAFF EDITOR IN CHIEF Maryam Tabatabai PharmD

TRENDING TOPICS

BIOSIMILAR CORNER

COVID-19 UPDATE

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

PIPELINE NEWS

RECENT FDA APPROVALS

EXECUTIVE EDITOR Anna Schreck Bird PharmD DEPUTY EDITORS Jessica Czechowski PharmD Lara Frick PharmD, BCPS, BCPP Carole Kerzic RPh Leslie Pittman PharmD

TRENDING TOPICS HOT TOPIC: FIRST ORAL DRUG FOR SMA The United States (US) Food and Drug Administration (FDA) approved Genentech’s oral treatment for spinal muscular atrophy (SMA), risdiplam (Evrysdi™), marking the third therapy and first oral agent approved for SMA. Risdiplam received Orphan Drug designation and a Rare Pediatric Disease Priority Review Voucher. Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier indicated for the treatment of SMA in patients ≥ 2 months of age. SMA is a group of inherited neuromuscular disorders that leads to progressive muscle weakness and muscle atrophy. The severity and age of onset is dependent on the subtype of SMA. Risdiplam is supplied as a powder for constitution into a 0.75 mg/mL oral solution; constitution is required by a pharmacist before dispensing. The once daily oral dose is given at approximately the same time every day after a meal. The recommended dose is based on the patient’s age and body weight: 0.2 mg/kg for 2 months to < 2 years, 0.25 mg/kg for ≥ 2 years who weigh < 20 kg, and 5 mg for patients ≥ 2 years, weighing ≥ 20 kg. Approval was based on studies conducted in patients with infantile-onset and later-onset SMA. The open-label infantile-onset (Type 1 SMA) trial was conducted in 21 infants with a median age of 6.7 months and demonstrated that after 12 months of therapy, 41% of infants were able to sit independently for ≥ 5 seconds, and following ≥ 23 months of therapy, 81% of patients remained alive and did not require permanent ventilation. A randomized, double-blind, placebo-controlled study assessed non-ambulatory patients with later-onset SMA (Type 2 or Type 3) between the ages of 2 and 25 years (n=180). The primary endpoint assessed motor function at 1 year compared to baseline and was increased by 1.36% in patients receiving risdiplam compared to a 0.19% decrease in patients on placebo (p=0.0156).

2 | SEPTEMBER 2020

Risdiplam does not have any contraindications to use nor does it carry any warnings/precautions. The most common adverse reactions in later-onset SMA, occurring in ≥ 10% of risdiplam-treated patients, were fever, diarrhea, and rash. In infantile-onset SMA, similar adverse reactions occurred as well as upper respiratory tract infection, pneumonia, constipation, and vomiting. The other 2 FDA-approved therapies for SMA are nusinersen (Spinraza®), an SMN2-directed antisense oligonucleotide given intrathecally with maintenance dosing of once every 4 months following the initial 4 loading doses, and onasemnogene abeparvovec-xioi (Zolgensma®), an adeno-associated virus vector-based gene therapy given as a single-dose intravenous (IV) infusion. Nusinersen is indicated for the treatment of SMA in pediatric and adult patients, whereas onasemnogene abeparvovec-xioi is indicated for the treatment of pediatric patients < 2 years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

ICER REPORT ON NASH WITH FIBROSIS The Institute for Clinical and Economic Review (ICER) has released an evidence report on obeticholic acid (Ocaliva®) for the treatment of nonalcoholic steatohepatitis (NASH) with fibrosis. There are no medications currently FDA-approved for NASH; weight loss is recommended to treat the condition. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist that has an Accelerated Approval for the treatment of adults with primary biliary cholangitis (PBC) either in combination with ursodeoxycholic acid (UDCA) in those with an inadequate response to UDCA, or as monotherapy in those unable to tolerate UDCA. OCA was undergoing FDA review for the additional indication of treatment of fibrosis due to NASH. However, the FDA issued a complete response letter (CRL) in June 2020 stating the drug’s efficacy and safety data were inadequate to grant approval for this indication. As a

TRENDING TOPICS continued result, ICER determined they would not be conducting the previously planned August 2020 Midwest Comparative Effectiveness Public Advisory Council (CEPAC) meeting to discuss findings from the ICER evidence report. The report found that OCA-treated patients with NASH with fibrosis experienced a reduction in fibrosis progression and a regression of fibrosis compared to those who received placebo. However, uncertainty exists regarding the long-term implications of these changes. ICER concluded that OCA would likely decrease progression to cirrhosis and therefore is expected to have beneficial effects on long-term, specific patient outcomes. However, the size of the potential benefit is unknown. ICER stated the long-term effects of OCA on health and quality of life in NASH patients with F2/F3 fibrosis are not certain. They determined the evidence for OCA in NASH with F2 fibrosis was insufficient (“I” rating), and for patients with F3 fibrosis, evidence for OCA was promising but inconclusive (“P/I” rating). Cardiovascular (CV) death is the leading cause of death in these patients, and as OCA increases low-density lipoprotein cholesterol (LDL-C) levels, it is uncertain whether OCA can improve overall outcomes. The diabetes drug pioglitazone (Actos™) showed less evidence for effectiveness at improving fibrosis compared to OCA, but the size of the treatment benefit seemed to be comparable to that of OCA. Although pioglitazone may potentially decrease CV events in type 2 diabetes mellitus (T2DM) patients, it carries the potential for heart failure and weight gain; therefore, the long-term benefit versus risk for NASH patients is unknown. As a result, ICER concluded that pioglitazone for NASH was determined to be promising but inconclusive (“P/I” rating). ICER found the evidence to be insufficient (“I” rating) for a comparison of OCA to pioglitazone for NASH.

BIOSIMILAR CORNER: PURPLE BOOK The FDA’s Purple Book Database of Licensed Biological Products has been updated to add information on products regulated by the Center for Biologics Evaluation and Research (CBER), including FDA-licensed allergenic, cellular and gene therapy, hematologic, and vaccine products. Additional updates include exclusivity details as well as a glossary providing information about terminology. Due to the update, the previously available portable document format (PDF) of CBER’s list of biological products will no longer be updated. To access the Purple Book Database, visit: https://purplebooksearch.fda.gov/.

Word count: 742

COVID-19: NOTABLE DEVELOPMENTS The FDA has released an update of the Coronavirus Treatment Acceleration Program (CTAP), created to support the development of potential therapies for the novel coronavirus infection (COVID-19). There are currently more than 570 drug development programs in the pre-investigational new drug (preIND) stages, and the FDA has reviewed more than 270 trials as safe to proceed INDs. Both single agent treatments (e.g., antivirals, cell and gene therapies, immunomodulators, neutralizing antibodies) and combination therapies are being evaluated. Of note, the CTAP data does not include vaccine development. Gilead, the manufacturer of the investigational antiviral drug remdesivir, has announced the submission of a New Drug Application (NDA) for the treatment of patients with COVID-19. The rolling NDA submission was started on April 8, 2020. Remdesivir is currently available under an Emergency Use Authorization (EUA) for the treatment of patients hospitalized with COVID-19. The completed application includes data from 2 randomized, open-label, multi-center, phase 3 manufacturer conducted clinical studies and the randomized, placebo-controlled, phase 3 study conducted by the National Institutes of Health (NIH). Trial data have demonstrated that treatment with remdesivir resulted in faster recovery than placebo. Notably, a 5-day or 10-day treatment course resulted in comparable clinical improvement. Remdesivir was found to be well-tolerated overall. The NIH has updated the COVID-19 treatment guidelines regarding the use of remdesivir to address the patient’s supplemental oxygen requirements as well as the method for oxygen delivery. The guidelines previously recommended using remdesivir for patients on high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); however, this has been updated due to uncertainty of benefit for initiating remdesivir in these patients. For more resources on COVID-19, visit the Magellan Rx Coronavirus Update webpage. For the most current information, visit the FDA, the Centers for Disease Control and Prevention (CDC), the NIH, and the World Health Organization (WHO) websites. State and local health departments also provide valuable information regarding management in local communities.

DRUG INFORMATION

HAPPENINGS & HIGHLIGHTS • The FDA has approved a prescription to over-thecounter (OTC) switch for olopatadine hydrochloride (HCl) 0.7% ophthalmic solution (Pazeo®) to Pataday® Once Daily Relief Extra Strength 0.7%. The OTC product is used as 1 drop in the affected eye(s) once daily for temporary relief of itchy eyes due to pollen, ragweed, grass, animal hair and dander. • In March 2020, the “Coronavirus Aid, Relief, and Economic Security Act” (“CARES Act”) was signed into law which modernizes the OTC Drug Review process, also known as the OTC monograph. The OTC monograph contains requirements for therapeutic categories and testing for an OTC medication to be deemed safe and effective. Prior to the CARES Act, modifying these monographs required the tedious practice of notice-and-comment rulemaking. The CARES Act allows for replacement of the rulemaking with a streamlined approach to enhance efficiency and speed. Additionally, it allows for the collection of user fees by the FDA from manufacturers of OTC monograph drugs; the fees will help support and maintain these policy updates. Visit the FDA website for more information on the CARES Act monograph reform.

• Ferring issued a voluntary recall of all lots of desmopressin acetate (DDAVP®) nasal spray 10 mcg/0.1 mL (6 lots), desmopressin acetate nasal spray 10 mcg/0.1 mL (16 lots), and desmopressin acetate (Stimate®) nasal spray 1.5 mg/mL (15 lots) to the consumer level due to amounts of desmopressin higher than specified found during routine testing. The potential risks from elevated levels of desmopressin are related to hyponatremia which could lead to seizure, coma, and death. • The FDA has released a drug safety communication recommending healthcare providers (HCPs) consider and discuss naloxone use with all patients at the time of prescribing opioid pain relievers and opioid use disorder (OUD) treatments (e.g., buprenorphine, methadone, naltrexone). When therapy with opioid analgesics or OUD agents is started or renewed, the FDA advises HCPs to assess the need for a naloxone prescription. For patients that are not receiving a prescription for an opioid pain medication or OUD treatment, consideration should be given to prescribing naloxone if the patient is at higher risk for opioid overdose (e.g., current/prior OUD or prior opioid overdose). For additional details, view the Drug Safety Communication.

DI HAPPENINGS • The American Urological Association (AUA), in collaboration with the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) with panel representation from the American Society of Clinical Oncology (ASCO), have published extensive guidance on the management of advanced prostate cancer. Visit the AUA website to view the executive summary. • The American Thoracic Society (ATS) has published a new practice guideline on tobacco dependence treatment in adults; it provides recommendations on starting pharmacologic therapy and is available here. • The ATS, European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) issued a clinical practice guideline providing an update on the treatment of nontuberculous mycobacterial pulmonary disease in adults. View the full guideline here. • The American College of Cardiology (ACC) has released Expert Consensus Decision Pathways on Novel Therapies for CV Risk Reduction in Patients with Type 2 Diabetes and on the Management of Bleeding in Patients on Oral Anticoagulants. The decision pathways are available on the ACC website. 4 | SEPTEMBER 2020

PIPELINE

NEWS

UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES DRUG NAME MANUFACTURER

FORMULATION THERAPEUTIC CLASS

PROPOSED CLINICAL USE

ANTICIPATED FDA APPROVAL

HIV therapeutic vaccine Immune Response

• IM • therapeutic vaccine

Human immunodeficiency virus-1 (HIV-1) infection treatment (pediatrics)

Sep – Dec 2020

terlipressin Mallinckrodt

• IV • vasopressin agonist

Hepatorenal syndrome type 1

09/12/2020

cefiderocol (Fetroja®) Shionogi

• IV • cephalosporin antibiotic

Healthcare-associated pneumonia

09/25/2020

diazepam film Aquestive

• Oral transmucosal • benzodiazepine

Seizure clusters

09/27/2020

hydrocortisone granule Eton

• Oral • glucocorticosteroid

Adrenal insufficiency (ages birth to < 17 years)

09/29/2020

tramadol Fortress

• IV • opioid agonist

Postsurgical pain

10/09/2020

IM = intramuscular; IV = intravenous; SC = subcutaneous

RECENT FDA

APPROVALS DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs budesonide/ glycopyrrolate/ formoterol fumarate (Breztri Aerosphere™) AstraZeneca

• 505(b)(2) NDA approval 07/23/2020 • Indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the relief of acute bronchospasm or for treating asthma • Combination of an inhaled corticosteroid (ICS), an anticholinergic, and a long-acting beta2-adrenergic agonist (LABA) • Inhalation aerosol: 160 mcg budesonide, 9 mcg glycopyrrolate, and 4.8 mcg formoterol fumarate per inhalation in a pressurized metered dose inhaler (MDI) • Recommended dosage is 2 oral inhalations twice daily

abametapir (Xeglyze™) Dr. Reddy’s

• NDA approval 07/24/2020 • Indicated for the topical treatment of head lice infestation in patients ≥ 6 months old • Pediculicide, a metalloproteinase inhibitor • Lotion: 0.74% w/w in a glass bottle of 200 g (210 mL) • Recommended dosage is to apply to dry hair thoroughly to coat hair and scalp; massage into the scalp and hair; leave on for 10 minutes, then rinse off • Recommended to be used as part of an overall lice management program that includes washing (with hot water) or dry-cleaning recently worn clothing, hats, used bedding, and towels; washing items (e.g., combs, brushes, hair clips) in hot water; using a fine-tooth comb for removing lice and nits

brexucabtagene autoleucel (Tecartus™) Kite

• BLA approval 07/24/2020; Accelerated Approval, Breakthrough Therapy, Orphan Drug, Priority Review • Indicated for adults with relapsed or refractory mantle cell lymphoma (MCL); continued approval may require demonstration of benefit in confirmatory clinical trials • CD19-directed genetically modified autologous T cell immunotherapy • Cell suspension infusion: 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells/kg of body weight for a maximum of 2 x 108 CAR-positive viable T cells in 68 mL • Recommended dosage is a patient-specific infusion over 30 minutes at a certified healthcare facility; patient should be pre-treated with IV cyclophosphamide and IV fludarabine on the 5th, 4th, and 3rd days prior to the Tecartus infusion; premedicate with acetaminophen and diphenhydramine (or another H1-antihistamine) about 30 to 60 minutes prior; avoid use of prophylactic systemic corticosteroids • Boxed warning for cytokine release syndrome (CRS) and neurologic toxicities • Available only through a Risk Evaluation and Mitigation Strategy (REMS) program

ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; H = Half; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

6 | SEPTEMBER 2020

RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued tafasitamab-cxix (Monjuvi®) Morphosys

• BLA approval 07/31/2020; Accelerated Approval, Assessment Aid, Breakthrough Therapy, Orphan Drug, Priority Review • Indicated in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from low grade lymphoma, and in those who are not eligible for autologous stem cell transplant (ASCT); continued approval may require demonstration of benefit in confirmatory clinical trials • CD19-directed cytolytic antibody • Injection: 200 mg lyophilized powder in a single-dose vial (SDV) for reconstitution • Recommended dosage is 12 mg/kg IV infusion according to the dosing schedule below administered by an HCP with immediate access to emergency equipment and medical support for managing infusion-related reactions (IRRs); pre-medications should be administered 30 minutes to 2 hours before initiating the infusion due to the potential for IRRs » Cycle 1: days 1, 4, 8, 15, and 22 of the 28-day cycle » Cycles 2 and 3: days 1, 8, 15, and 22 of each 28-day cycle » Cycle 4 and beyond: days 1 and 15 of each 28-day cycle • Administer in combination with lenalidomide for up to 12 cycles, then continue tafasitamab-cxix as monotherapy until disease progression or unacceptable toxicity

enzalutamide (Xtandi®) Astellas

• NDA approval 08/04/2020 • Indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) or metastatic castration-sensitive prostate cancer (mCSPC) • Androgen receptor inhibitor • Tablet: 40 mg, 80 mg; already approved as 40 mg capsule • Recommended dosage is 160 mg (two 80 mg or four 40 mg tablets or capsules) orally once daily without regard to food • Patients should also receive a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy

belantamab mafodotinblmf (Blenrep) GlaxoSmithKline

• BLA approval 08/05/2020; Accelerated Approval, Breakthrough Therapy, Orphan Drug • Indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received ≥ 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent; continued approval may require demonstration of benefit in confirmatory clinical trials • B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate • Injection: 100 mg lyophilized powder in a SDV for reconstitution • Recommended dosage is 2.5 mg/kg as an IV infusion over 30 minutes every 3 weeks • Boxed warning for ocular toxicity; ophthalmic exam should be conducted before starting and during therapy; patients should use preservative-free lubricant eye drops and avoid contact lenses, unless directed otherwise by an ophthalmologist • Available only through a REMS program

RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued nifurtimox (Lampit®) Bayer

• 505(b)(2) NDA approval 08/06/2020; Accelerated Approval, Orphan Drug, Priority Review • Indicated in all pediatric patients (term newborn to < 18 years old) weighing ≥ 2.5 kg for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi; continued approval may require demonstration of benefit in confirmatory clinical trials • Nitrofuran antiprotozoal • Tablets: 30 mg, 120 mg (both functionally scored) • Recommended dosage is weight-based and should be administered orally 3 times daily with food for 60 days » Body weight ≥ 2.5 kg to < 40 kg: 10 to 20 mg/kg total daily dose » Body weight ≥ 40 kg: 8 to 10 mg/kg total daily dose

oliceridine (Olinvyk™) Trevena

• NDA approval 08/07/2020 • Indicated for use in adults for the management of acute pain severe enough to require an IV opioid analgesic and for whom alternative treatments are inadequate; due to the risks of addiction, abuse, and misuse, reserve use for patients in whom alternative options have not been tolerated and not provided sufficient analgesia • Opioid agonist • Injection: 1 mg/mL and 2 mg/2 mL (1 mg/mL) in SDVs; 30 mg/30 mL (1 mg/mL) in single patient-use vial for patient-controlled analgesia (PCA) use only • Recommended dosage is the lowest effective dose for the shortest amount of time; safety of use for > 48 hours has not been evaluated in controlled trials » IV: initiate with a 1.5 mg dose administered by an HCP; individualize dose based on pain severity, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse » PCA: recommended demand dose is 0.35 mg, with a 6-minute lock-out; 0.5 mg demand dose may be considered » Cumulative total daily dose should not exceed 27 mg due to risk for QTc interval prolongation • Boxed warning for addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; and risks from concomitant use with benzodiazepines or other central nervous system (CNS) depressants • Product availability is expected 4Q 2020

risdiplam (Evrysdi™) Genentech

• NDA approval 08/07/2020; Orphan Drug, Priority Review • Indicated for the treatment of SMA in patients ≥ 2 months old • Survival of motor neuron 2 (SMN2) splicing modifier • Oral solution: 60 mg powder for constitution to a 0.75 mg/mL solution • Recommended dosage is weight-based and based on the patient’s age, administered orally once daily after a meal » 2 months to < 2 years: 0.2 mg/kg daily » ≥ 2 years and < 20 kg: 0.25 mg/kg daily » ≥ 2 years and ≥ 20 kg: 5 mg daily

8 | SEPTEMBER 2020

RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued viltolarsen (Viltepso™) NS Pharma

• NDA approval 08/12/2020; Accelerated Approval, Orphan Drug, Priority Review • Indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping; continued approval may require demonstration of benefit in confirmatory clinical trials • Antisense oligonucleotide • Injection: 250 mg/5 mL (50 mg/mL) in a SDV • Recommended dosage is 80 mg/kg once weekly as an IV infusion over 60 minutes by an HCP; option for home infusion administered by a trained HCP

satralizumab-mwge (Enspryng™) Genentech

• BLA approval 08/14/2020; Orphan Drug • Indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive • Interleukin-6 (IL-6) receptor antagonist • Injection: 120 mg/mL solution in a single-dose prefilled syringe • Recommended dosage is 120 mg SC loading doses for the first 3 doses at weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg SC every 4 weeks; following proper training, patients can self-inject or the patient’s caregiver can administer, if the HCP determines it is appropriate

cysteamine ophthalmic solution (Cystadrops®) Recordati Rare

• 505(b)(2) NDA approval 08/19/2020 • Indicated for the treatment of corneal cystine crystal deposits in adults and children with cystinosis • Cystine-depleting agent • Ophthalmic solution: 3.8 mg/mL of cysteamine (0.37%) in a glass bottle • Recommended dosage is 1 drop in each eye, 4 times a day during waking hours

ofatumumab (Kesimpta®) Novartis

• sBLA approval 08/20/2020; new indication and new formulation for ofatumumab as well as a corresponding new brand name • Indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults • CD20-directed cytolytic antibody • Injection: 20 mg/0.4 mL solution in a single-dose prefilled syringe and Sensoready® pen • Recommended dosage is an initial dose of 20 mg by SC injection at week 0, 1, and 2, followed by subsequent dosing of 20 mg by SC injection once monthly starting at week 4; it is intended for patient self-administration; however, the 1st injection should be given under the supervision of an HCP; if injection-related reactions occur, symptomatic treatment should be given • Product availability is expected in early September

References:

fda.gov

gilead.com

icer-review.org

nih.gov