Pipeline Report August 2021

Home , Bamlanivimab, Hospira, Lenzilumab, Vosoritide

Pipeline Report FebruaryAugust 2021 2021

© 2021 AcariaHealth. All rights reserved. | Data is current as of 8/23/2021 Page 1 This quarterly at-a-glance publication is developed by our In other pipeline news,Pipeline the FDA Report Table of Contents Clinical Pharmacy Drug Information team to increase your approved Bylvay (odevixibat) understanding of the drug pipeline, ensuring you are equipped for the treatment of pruritusAugust 2021 with insights to prepare for shifts in pharmacy benefit associated with progressive 1 COVID-19 management. In this issue, you will learn more about further familial intrahepatic cholestasis. COVID-19 updates, endocrinology agents, CAR-T and While Bylvay is the first therapy gene therapies, and the breakthrough treatment for to be approved for pruritus Alzheimer’s disease. associated with a rare cholestatic 7 Recent Drug Approvals liver disease, it will likely not As we follow the alternating rise and fall of COVID cases, our be the last, as maralixibat is attention is drawn to recent developments in COVID vaccines following close behind with its 11 Upcoming Products and treatments. Comirnaty (Pfizer COVID-19 vaccine) is now own potential approval for pruritus associated with the first vaccine to be granted full FDA approval for a two-dose Alagille syndrome. regimen for prevention of COVID-19, for people 16 years of age 23 Biosimilars and older. Its use in adolescents 12-15 years of age, as well as The FDA review of ciltacabtagene autoleucel for relapsed use of a third dose for immunocompromised people, are still or refractory multiple myeloma should be complete by the authorized under the previous Emergency Use Authorization end of November, which would add an anti-BCMA CAR-T (EUA). Moderna has also submitted data to the FDA to therapy option other than Abecma. The regulatory pathway 25 Generic Specialty Agents support its BLA submission for full approval of mRNA 1273 for elivaldogene autotemcel (eli-cel) for the treatment of (Moderna COVID-19 vaccine) to complement its existing EUA cerebral adrenoleukodystrophy, however, has hit a bump in which was recently expanded to include use of a third dose in the road with the report that one patient in the Phase 3 ALD- 26 Glossary immunocompromised patients 18 years of age and older. All 104 study developed myelodysplastic syndrome (MDS) that is distribution of the bamlanivimab + etesevimab combination believed to likely be related to eli-cel therapy. The trial is now has been paused on a national basis due to concerns on clinical hold pending further investigation that will help to regarding resistant viral variants. REGEN-COV (casirivimab determine the ultimate fate of this cell therapy. + imdevimab), on the other hand, has seen its EUA expanded to include use as post-exposure prophylaxis for COVID-19 in To prepare this report, our team accesses a wide range of patients at high risk for progression to severe disease. The clinical resources. This information is then analyzed, resulting FDA was clear, however, that it is not to be used as pre- in updates across multiple disease states including recent exposure prophylaxis. and anticipated drug approvals, key changes in the biosimilar agent landscape, and notes on recent and anticipated generic Arguably the biggest pipeline news during the last quarter product launches. Our pipeline report is just one of many ways was the FDA’s approval of Aduhelm (aducanumab-avwa) we are committed to providing helpful tools and resources – initially for the broader population of all patients with to our clients and partners. We look forward to sharing more Alzheimer’s disease, subsequently revised to emphasize that updates with you in the months ahead. treatment should be limited to only those with milder disease. The announced cost of Aduhelm and the circumstances surrounding its FDA approval have captured the attention of news media and many stakeholders concerned with cost, quality and sustainability in healthcare. Several major health Ross Hoffman, MD systems and payors have refused to either administer or reimburse the treatment. The full impact of the FDA’s decision To provide comments, feedback or requests will be better known once CMS provides additional information for report enhancements, please email regarding national coverage determination (NCD). us at [email protected].

FDA-APPROVED AGENTS FDA Drug Name Manufacturer(s) Approval Therapeutic Class Comments Cost (WAC) Date • 10/22/2020 - FDA-approved for the treatment of adults and pediatric patients ≥ 12 years of age and weighing ≥ 40 kg requiring hospitalization for $520 for a 100 mg EUA: COVID-19 single dose vial Veklury 5/1/2020 • 5/1/2020 - Veklury is available through an FDA Emergency Use $3,120 for a 5-day remdesivir Gilead FDA Treatment - antiviral Authorization (EUA) for the treatment of COVID-19 in hospitalized pediatric course intravenous infusion Approval: patients weighing 3.5 kg to < 40 kg or aged < 12 years and weighing ≥ 3.5 kg $5,720 for a 10-day 10/22/2020 • Veklury should only be administered in a hospital or healthcare setting course capable of providing acute care comparable to inpatient hospital care AGENTS GRANTED FDA EMERGENCY USE AUTHORIZATION (EUA) EUA Drug Name Manufacturer(s) Approval Therapeutic Class Comments Cost (WAC) Date Original: • Current EUA is for the use of high titer convalescent plasma for the U.S. Dept of Convalescent plasma 8/23/2020 Treatment - blood treatment of hospitalized patients early in the disease course and to those Unknown at this Health and intravenous infusion Revised: product hospitalized patients who have impaired humoral immunity and cannot time Human Services 2/4/2021 produce an adequate antibody response • 4/16/2021 - FDA revoked the EUA for bamlanivimab when administered $1,250 single dose Original: alone LY-CoV555 infusion 11/9/2020 Treatment - bamlanivimab Eli Lilly • EUA was for the treatment of mild to moderate COVID-19 in adults and $450 Revoked: monoclonal antibody intravenous infusion pediatric patients with positive results of direct SARS-CoV-2 viral testing administration 4/16/2021 who are ≥ 12 years of age and weighing ≥ 40 kg, and who are at high risk for cost progressing to severe COVID-19 and/or hospitalization

EUA Drug Name Manufacturer(s) Approval Therapeutic Class Comments Cost (WAC) Date • 7/28/2021: EUA authorizes baricitinib as monotherapy for the treatment of COVID-19 in hospitalized patients two years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) Original: • Under the revised EUA, baricitinib is no longer required to be administered $2,553 for 14-day Olumiant 11/19/2020 with remdesivir (Veklury) course baricitinib Eli Lilly Treatment - ARDS Revised: $91.17 per 2 mg oral tablet • 11/19/2020: EUA for use in combination with Gilead’s Veklury (remdesivir) 7/28/2021 for treating hospitalized patients with COVID-19 infection in patients aged tablet two years or older, with suspected or laboratory confirmed COVID-19 requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation • 4 mg once daily for 14 days or until hospital discharge • 7/30/2021: EUA was revised to authorize emergency use as post-exposure prophylaxis for COVID-19 in adults and pediatric individuals (≥ 12 years of age and weighing ≥ 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death • REGEN-COV is not authorized for pre-exposure prophylaxis to prevent COVID-19 before being exposed to the SARS-CoV-2 virus — only after exposure to the virus • 6/3/2021: Updates made to the EUA label include a change in the Original: $1,500 single dose authorized dosage (from 1,200 mg of casirivimab and 1,200 mg of REGEN-COV 11/21/2020 infusion Treatment - imdevimab to 600 mg of casirivimab and 600 mg of imdevimab), the casirivimab + imdevimab Regeneron Updated: $450 monoclonal antibody addition of a subcutaneous route of administration as an alternative to the intravenous infusion 6/3/2021, administration intravenous route, and the addition of a new REGEN-COV co-formulated 7/30/2021 cost product in a single vial • EUA is for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥ 12 years of age and weighing ≥ 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization • No cost to patients, although healthcare facilities may charge fees related to administration

EUA Drug Name Manufacturer(s) Approval Therapeutic Class Comments Cost (WAC) Date • 8/23/2021: FDA granted full FDA approval for the 2-dose regimen for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older (use in people 12-15 years of age, and use of a third dose for immunocompromised people, are still authorized under the Original EUA: previous EUA) 12/11/2020 Expanded • 8/12/2021: FDA expanded the existing EUA to include a third dose in Comirnaty EUA: certain immunocompromised people tozinameran Pfizer Vaccine $19.50 per dose* 8/12/2021 intramuscular injection • 5/10/2021: FDA expanded the existing EUA to include adolescents 12 Full FDA through 15 years of age, amending the EUA originally issued on 12/11/2020 approval: for administration in individuals 16 years of age and older 8/23/2021 • 5/7/2021: Rolling submission of BLA for full FDA approval was initiated • mRNA vaccine that expresses SARS-CoV2 spike protein • No cost to patients • 8/12/2021: FDA expanded the existing EUA to include a third dose in certain immunocompromised people

Expanded • 6/1/2021: Moderna initiated rolling submission of BLA for full FDA licensure mRNA 1273 Moderna EUA: Vaccine in individuals 18 years of age and older $15-37 per dose* intramuscular injection 8/12/2021 • 6/10/2021: Moderna filed for EUA expansion in adolescents ages 12 to 17 • mRNA vaccine that expresses SARS-CoV2 spike protein • No cost to patients *Initially, the federal government will supply the vaccine at no cost.

EUA Drug Name Manufacturer(s) Approval Therapeutic Class Comments Cost (WAC) Date • 6/25/2021: All distribution of bamlanivimab and etesevimab together and etesevimab alone (to pair with existing supply of bamlanivimab at a facility) has been paused on a national basis until further notice • The FDA recommends that health care providers nationwide use alternative authorized monoclonal antibody therapies and not use bamlanivimab and etesevimab administered together at this time; this LY-CoV555 + LY- Original: is due to certain variants proving resistant even to the combination of CoV016 2/9/2021 Treatment - bamlanivimab and etesevimab bamlanivimab + Eli Lilly N/A Paused: monoclonal antibody etesevimab • EUA is for the emergency use of bamlanivimab and etesevimab 6/25/2021 intravenous infusion administered together for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (≥ 12 years of age and weighing ≥ 40 kg) with positive results of direct SARS-CoV2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization • Outpatient only - no cost to patients, although healthcare facilities may charge fees related to administration • 7/12/2021: Warning added to the EUA that adverse event reporting suggests an increased risk of Guillain-Barré syndrome during the 42 days following vaccination

Original: • 4/23/2021: EUA Fact Sheet for Recipients and Caregivers has been updated 2/27/2021 to include information about the remote risk of blood clots Ad26.COV2-S J&J/Janssen Updated: Vaccine • Most people who developed these blood clots and low levels of platelets $10 per dose* intramuscular injection 4/23/2021, were females ages 18 through 49 years; symptoms began approximately 7/12/2021 one to two weeks following vaccination • Non-replicating adenovirus 26-vector dsDNA expressing SARS-CoV-2 spike protein • No cost to patients *Initially, the federal government will supply the vaccine at no cost.

Anticipated Date of Drug Name Manufacturer(s) Therapeutic Class Comments Cost (WAC) EUA or FDA Approval • EUA for the treatment of COVID-19 in hospitalized patients two years of age and older who are receiving systemic corticosteroids and require Actemra $3,228 for a single Treatment - IL-6 supplemental oxygen, non-invasive or invasive mechanical ventilation, or tocilizumab Roche/Genentech 6/24/2021 infusion for a 70 kg receptor antagonist extracorporeal membrane oxygenation (ECMO) intravenous infusion patient • 8-12 mg/kg single IV infusion; one additional infusion may be administered PIPELINE AGENTS • Non-replicating chimpanzee adenovirus-vector dsDNA expressing SARS- AZD 1222 Projected $3-$4 AstraZeneca 2H 2021 Vaccine CoV-2 spike protein intramuscular injection per dose* • No cost to patients • 6/2021: NVX-CoV2373 was found to be 100% effective at protecting against moderate and severe disease, according to findings from the Phase 3 NVX-CoV2373 Projected $10-$16 Novavax 2H 2021 Vaccine PREVENT-19 trial intramuscular injection per dose* • SARS-CoV-2 spike glycoprotein nanoparticle + adjuvant vaccine • No cost to patients • Phase 2 - results showed that the percentage of outpatients who received molnupiravir Merck; Ridgeback treatment were hospitalized and/or died less frequently vs. the placebo- No projected 2H 2021 Antiviral oral therapy Therapeutics treated group pricing yet • Dose: oral twice daily for five days • Phase 2: Limited data available to date — small studies have shown virus favipiravir clearance from airway; contraindicated in pregnant women Overseas priced at Fujifilm; Others 2H 2021 Antiviral oral tablet • Dose: Loading dose twice daily on Day 1, then twice daily on $1 per tablet Days 2-7 • 7/2021: NRx presented data from a randomized Phase 2b/3 trial shows patients treated with Zyesami are less likely to experience IL-6 cytokine Zyesami No projected NRx Synthetic vasoactive rise, and have improved survival and recovery from respiratory failure, aviptadil 2H 2021 pricing yet; Pharmaceuticals intestinal peptide compared to patients receiving placebo; data have been submitted to FDA intravenous infusion for EUA support available overseas • 6/2021: EUA request resubmitted to the FDA after inital denial

Anticipated Date of Drug Name Manufacturer(s) Therapeutic Class Comments Cost (WAC) EUA or FDA Approval • 5/28/2021: EUA request submitted to the FDA lenzilumab No projected Humanigen, Inc. 2H 2021 Monoclonal antibody • Lenzilumab achieved its primary endpoint with a 54% relative intravenous infusion improvement in the likelihood of survival without ventilation compared to pricing yet placebo

Available at: AcariaHealth PANTHERx Rare Other FDA Drug Name Manufacturer(s) Indication(s) Approval Comments Cost (WAC) Date COAGULATION DISORDERS Ryplazim Congenital • First FDA-approved agent for the treatment of C-PLGD, the estimated plasminogen, Liminal BioSciences Inc plasminogen 6/4/2021 prevalence of which is ~1.6 of every 1,000,000 people Pending launch human-tvmh deficiency (C-PLGD) intravenous infusion • Projected impact: cost increase ENDOCRINOLOGY • First FDA-approved therapy for pruritus associated with PFIC • PFIC is estimated to affect between one in every 50,000 to 100,000 Bylvay Progressive familial children born worldwide and causes progressive, life-threatening liver odevixibat $385,000/year Albireo Pharma intrahepatic 7/20/2021 disease that can lead to the need for liver transplant oral capsules and oral per 18 kg patient cholestasis (PFIC) pellets • Moderate to severe pruritus is a common and problematic clinical presentation of PFIC that can severely diminish quality of life • Projected impact: cost increase • FDA-approved for the treatment of adults with moderate to severe Saphnelo Systemic lupus disease, who are receiving standard therapy anifrolumab-fnia AstraZeneca 7/30/2021 Pending launch erythematosus (SLE) • Would compete with Benlysta for the same indication intravenous infusion • Projected impact: cost replacement of existing therapies • FDA-approved for the treatment of late-onset Pompe disease — it is the second enzyme replacement therapy to be FDA-approved for Pompe Nexviazyme disease, after Lumizyme; will be launched at parity pricing to Lumizyme avalglucosidase Sanofi Genzyme Pompe disease 8/6/2021 • Prescribing Information includes black box warnings regarding severe $600,000/year alfa-ngpt hypersensitivity reactions, infusion-associated reactions, and risk of intravenous infusion acute cardiorespiratory failure in susceptible patients • Projected impact: cost replacement of existing therapies 1 Pending launch, 2 Accredo, 3Optum Frontier, 4Amber, 5U.S. Bioservices

Available at: AcariaHealth PANTHERx Rare Other FDA Drug Name Manufacturer(s) Indication(s) Approval Comments Cost (WAC) Date IMMUNOLOGY • Was studied in patients who had failed Imbruvica and Jakafi • Per NCCN guidelines on stem cell transplants and management of Rezurock GvHD, there is insufficient evidence to recommend one systemic agent Chronic graft-vs-host belumosudil Kadmon Holdings 7/16/2021 as preferred over another for steroid-refractory cGvHD $186,000/year disease (cGvHD) oral tablet • Estimated prevalence: ~14,000 people, with ~5,000 newly diagnosed each year • Projected impact: cost replacement of existing therapies NEPHROLOGY • Empaveli was FDA-approved for use in adult patients with treatment- naive PNH as well as those with past trials of Soliris or Ultomiris • A black box warning exists on the Empaveli label regarding an increased risk of meningococcal and other serious infections caused by Empaveli Paroxysmal nocturnal encapsulated bacteria that may become rapidly life threatening or fatal pegcetacoplan Apellis hemoglobinuria 5/14/2021 if not recognized and treated early $458,000/year subcutaneous (PNH) • As first-line therapy, topline results from the Phase 3 PRINCE trial injection showed superiority at Week 26 over standard of care (Soliris and Ultomiris were not included as standard of care options) • Estimated prevalence: 0.5-1.5 per one million people • Projected impact: cost replacement of existing therapies NEUROLOGY • Initially FDA-approved for all stages of disease severity, but subsequently narrowed to emphasize use only in patients with mild cognitive impairment or mild dementia Aduhelm $56,000/year aducanumab-avwa Biogen; Eisai Alzheimer's disease 6/7/2021 • CMS is currently developing a National Coverage Determination (NCD) per 74 kg patient intravenous infusion which should provide guidance to payors on coverage of Aduhelm • The majority of utilization is expected in the Medicare line of business • Projected impact: cost increase

2Accredo, 4Amber,6Biologics, 7Onco 360, 8CVS Specialty, 9OptumRx, 10Orsini Healthcare, 11Soleo Health

Available at: AcariaHealth PANTHERx Rare Other FDA Drug Name Manufacturer(s) Indication(s) Approval Comments Cost (WAC) Date ONCOLOGY • Is the first FDA-approved agent for the treatment of NSCLC with EGFR exon 20 insertion mutations, which comprise ~1-2% of patients with Rybrevant Non-small cell lung NSCLC amivantamab-vmjw Janssen 5/21/2021 $233,000/year cancer (NSCLC) • Current EGFR tyrosine kinase inhibitors and chemotherapy provide intravenous infusion limited benefit for these patients • Projected impact: cost increase • Approved for the treatment of KRAS G12C-mutated locally advanced or Lumakras metastatic NSCLC, following at least one prior systemic therapy sotorasib Amgen NSCLC 5/28/2021 • Approximately 13% of U.S. patients with NSCLC adenocarcinoma harbor $218,000/year oral tablet the KRAS G12C mutation • Projected impact: cost increase • Approved for use as second-line treatment of advanced or metastatic Truseltiq disease with FGFR2 genetic aberrations; FGFR2 genetic aberrations are infigratinib BridgeBio Pharma, Inc. Cholangiocarcinoma 5/28/2021 present in approximately 15% to 20% of people who have this disease $129,000/year oral capsules • Currently Pemazyre is the only other FDA-approved agent • Projected impact: cost replacement of existing therapies Rylaze • Approved for use as a component of a multi-agent chemotherapeutic asparaginase Acute lymphoblastic regimen in patients who have developed hypersensitivity to E. coli- $1.2 million/6- erwinia chrysanthemi leukemia (ALL) derived asparaginase Jazz Pharmaceuticals 6/30/2021 month course of (recombinant)-rywn and lymphoblastic • Is a recombinant formulation of Erwinaze, which is FDA-approved for the therapy intramuscular lymphoma (LBL) same ALL indication, but which has been in short supply since 2016 injection • Projected impact: cost replacement of existing therapies

6 Biologics, 12 Open distribution, 13 Buy and bill

Available at: AcariaHealth PANTHERx Rare Other FDA Drug Name Manufacturer(s) Indication(s) Approval Comments Cost (WAC) Date • Approved for the treatment VHL- associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery • The Welireg Prescribing Information includes a black box warning Welireg Von Hippel Lindau regarding embryo-fetal toxicity belzutifan Merck (VHL)-associated 8/13/2021 • Patients with VHL disease are at risk for benign blood vessel tumors as Pending launch oral tablet tumors well as several cancers • Estimated prevalence: 1 in 36,000 people (~10,000 cases in the U.S.) • As many as 70% of people with VHL disease develop RCC • Projected impact: cost replacement of existing therapies

1 Pending launch

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date CARDIOVASCULAR DISEASE • Proposed for use in secondary prevention Atherosclerotic patients with ASCVD; is dosed by subcutaneous cardiovascular injection administered in the doctor's office as a Leqvio disease (ASCVD) PCSK9 synthesis single dose every six months after an initial two inclisiran Alnylam; Novartis $6,000/year 1/1/2022 and familial inhibitor doses given three months apart intravenous infusion hypercholesterolemia • Would compete with Repatha and Praluent for (FH) patients who are already on maximized statin therapy • Proposed for use in left ventricular systolic dysfunction; would be reserved for use in patients who had failed multiple other therapies • In the Phase III DREAM-HF trial, Revascor failed Revascor* to meet the primary endpoint of reduction in $500,000/ rexlemestrocel-L Mesoblast Chronic heart failure Stem cell therapy recurrent hospitalization relative to placebo one-time 1H 2022 intramyocardial injection —it did, however, meet the secondary endpoint treatment of reduction in ischemic major cardiac adverse events, defined as a stroke or a heart attack; Revascor reduced these ischemic events by 60% relative to placebo (p=0.002) COAGULATION DISORDERS • On August 19, 2020, BioMarin received a Complete Response Letter for its BLA for Roctavian* valoctocogene roxaparvovec $2 million/ valoctocogene roxaparvovec BioMarin Hemophilia A Gene therapy • The FDA recommended two years of data from one-time 4Q 2022 intravenous infusion the Company's ongoing Phase 3 trial in order to treatment provide substantial evidence of a durable effect • BLA resubmission is anticipated in 2Q 2022 *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • For the treatment of adults with severe disease • Current standard of care is factor IX replacement therapy • Recent data from the Phase 3 HOPE-B study showed continued durable, sustained increases in FIX activity at 52 weeks post-infusion with a mean FIX activity of 41.5% of normal • During the 52-week period, a single dose AMT-061* $1-2 million/ Uniqure; CSL significantly reduced the annualized rate of etranacogene dezaparvovec Hemophilia B Gene therapy one-time 2H 2022 Behring bleeding requiring treatment by 80% intravenous infusion treatment • The annualized rate of spontaneous bleeding requiring treatment was also significantly reduced by 85% during the 52-week period • Usage of FIX replacement therapy in all patients declined 96%, with 52 of 54 patients successfully discontinuing their prophylactic infusions • Estimated prevalence of hemophilia B: ~6,300 people; ~40% have severe disease • Proposed for the treatment of adults with severe disease (~60% of the total hemophilia A population) • Current standard of care is factor VIII replacement therapy or Hemlibra $1-2 million/ SPK-8011* • In the ongoing Ph I/II trial, factor VIII expression Spark; Roche Hemophilia A Gene therapy one-time 2023 intravenous infusion was sustained in 16 of 18 participants with up to treatment four years of follow-up • Across all dose cohorts, there was a 91.2% reduction in annualized bleed rate • There were no deaths and no FVIII inhibitor development in the four years *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • For the treatment of adults with severe disease SB-525* Sangamo (~60% of the total hemophilia A population) $1-2 million/ giroctocogene fitelparvovec BioSciences, Inc; Hemophilia A Gene therapy one-time 2023 intravenous infusion Pfizer • Current standard of care is factor VIII treatment replacement therapy or Hemlibra DERMATOLOGY PF-04965842 • Proposed for the treatment of moderate to Janus kinase 1 abrocitinib Pfizer Atopic dermatitis severe disease in patients 12 years of age and $45,000/year 4Q 2021 (JAK1) inhibitor oral tablet older • Proposed for the treatment of the cutaneous Filsuvez Keratinocyte manifestations of junctional and dystrophic EB, Epidermolysis bullosa $100,000/ oleogel-S10 Amryt migration which is a rare genetic skin disorder that can 11/30/2021 (EB) year topical ointment promoter cause skin to blister and tear from the slightest friction or trauma ENDOCRINOLOGY • Proposed for the treatment of patients one year Apical sodium- SHP625 Cholestatic pruritus in of age and older Mirum dependent bile $250,000/ maralixibat patients with Alagille 9/29/2021 Pharmaceuticals acid transporter • There are currently ~2,000 to 2,500 children year oral therapy syndrome (ALGS) inhibitor with ALGS in the U.S. who would be eligible for treatment with maralixibat • Was studied in patients with impaired awareness of hypoglycemia and severe hypoglycemic Lantidra* Allogeneic $500,000/ Brittle Type 1 diabetes events despite medical treatment donislecel CellTrans islet cell one-time 3Q 2021 mellitus (T1D) intra-portal vein infusion transplantation • Experts have opined that this therapy will likely treatment only benefit a select few patients given advances in diabetes care that are available today *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Once daily injection proposed for use in children whose growth plates are still open • The worldwide incidence rate of achondroplasia BMN 111 C-type is about one in 25,000 live births $250,000/ vosoritide BioMarin Achondroplasia Natriuretic 11/20/2021 year subcutaneous injection Peptide analog • There are no FDA-approved agents for achondroplasia • Injectable growth hormone products have been used off-label • Proposed for the treatment of hyperphagia and LV-101 Prader-Willi syndrome behavioral distress associated with PWS $250,000/ carbetocin Levo Therapeutics Oxytocin analog 12/1/2021 (PWS) year intranasal spray • Would be the first FDA-approved therapy for these PWS-related symptoms • Racemic ketoconazole is already used off-label for the treatment of Cushing's syndrome, but Recorlev Strongbridge Cortisol synthesis levoketoconazole is claimed to have improved $250,000/ levoketoconazole Cushing's syndrome 1/1/2022 Biopharma inhibitor efficacy, as it may inhibit hydroxylases more year oral tablet potently and reaches 3-fold higher plasma levels in humans • Proposed for the treatment of polyneuropathy of hATTR amyloidosis in adults ALN-TTRsc02 Transthyretin- TTR-targeting $400,000/ vutrisiran Alnylam mediated (hATTR) RNA interference • Would compete with Onpattro (IV infusions every 4/14/2022 year subcutaneous infusion amyloidosis agent three weeks) and Tegsedi (weekly subcutaneous injections) for the same indication, with quarterly subcutaneous infusions

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date HEMATOLOGY • Current therapies for ANCA-associated vasculitis Anti-neutrophil typically include broad immunosuppression CCX168 C5a complement cytoplasmic antibody with daily doses of glucocorticoids such as $200,000/ avacopan ChemoCentryx protein receptor 10/7/2021 (ANCA)-associated prednisone or methylprednisone year oral therapy inhibitor vasculitis (AAV) • Estimated prevalence: 55,000 people; ~15% have relapsed disease • The estimated prevalence of clinically diagnosed PK deficiency is ~3.2-8.5 per million in Western populations • Transfusion-dependent patients account for 15- 20% of those with PKD • The Phase 3 ACTIVATE-T trial (n=27) in regularly transfused adults demonstrated a statistically significant and clinically meaningful reduction in AG-348 Agios Pyruvate kinase Pyruvate kinase transfusion burden $250,000/ mitapivat 2/21/2022 Pharmaceuticals deficiency (PKD) stimulator year oral therapy • In the 24-week fixed dose period, 37% achieved a ≥ 33% reduction in transfusion burden compared to individual historical transfusion burden, and 22% were transfusion-free • In the Phase 3 ACTIVATE trial in adults who do not receive regular transfusions, 40% of patients randomized to mitapivat achieved a hemoglobin response compared to zero patients who received placebo • Proposed for use in both dialysis- and non- Vafseo dialysis-dependent CKD vadadustat Akebia; Vifor Anemia of CKD HIF-PHI ~$13,000/year 3/9/2022 oral tablet • Would compete with erythropoietin stimulating agents (ESAs, e.g., Procrit, Aranesp)

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Demonstrated ability to dramatically decrease or terminate the need for chronic blood LentiGlobin* Transfusion- transfusions $1-2 million/ betibeglogene autotemcel bluebird bio dependent beta- Gene therapy • Twenty-five of 29 patients (86%) in a Phase 3 one-time 1H 2022 intravenous infusion thalassemia (TDT) trial demonstrated transfusion independence treatment (TI) after treatment, with a median ongoing TI duration of 26.3 months (min-max: 13.1 – 39.4) IMMUNOLOGY • Intended for use once per lifetime • In the absence of treatment, children born RVT-802* Tissue-based $1-2 million/ Complete DiGeorge with congenital athymia have no ability to fight allogeneic thymic tissue Enzyvant regenerative one-time 10/8/2021 Syndrome (cDGS) infections and typically die within the first 24 injection therapy treatment months of life • Estimated prevalence: ~1 in 300,000 infants • Proposed for the treatment of patients with high-risk disease, specifically those patients Hematopoietic stem who have persistent TMA despite modification of OMS721 cell transplant- Anti-MASP-2 $250,000/ Omeros immunosuppressive therapy narsoplimab associated thrombotic monoclonal course of 10/17/2021 Corporation intravenous infusion microangiopathy antibody • Approximately 20,000 HSCT procedures are therapy (HSCT-TMA) performed in the U.S. annually, and TMA is reported to occur in approximately 10 to 25% of HSCT patients INFECTIOUS DISEASE SHP620 Post-transplant Viral DNA • Proposed for the treatment of both solid $150,000/ maribavir Takeda cytomegalovirus synthesis organ transplant and hematopoietic stem cell 10/26/2021 year oral tablet (CMV) infection inhibitor transplant recipients *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date MUSCULOSKELETAL CONDITIONS • One-time treatment • Is the first DMD gene therapy candidate to start PF-06939926* $1-2 million/ Duchenne muscular dosing in a Phase 3 trial fordadistrogene movaparvovec Pfizer Gene therapy one-time 2023 dystrophy (DMD) intravenous infusion • Has become the DMD gene therapy front- treatment runner since SRP-9001 failed to demonstrate a functional benefit in a pivotal trial • Would compete with SRP-9001 gene therapy for GALGT2* those with mutations between exons 18 and 58 $1-2 million/ Sarepta AAVrh74.MHCK.GALGT2 DMD Gene therapy one-time 2023 Therapeutics • SRP-9001 is further along in the pipeline intra-arterial injection process, but comparative safety and efficacy are treatment undetermined • Targets exons 18 through 58 (~60-75% of DMD patients have mutations in these exons) SRP-9001* $1-2 million/ Sarepta • Topline results from a Phase 2 trial showed delandistrogene moxeparvovec DMD Gene therapy one-time 2023 Therapeutics benefit on the biological endpoint of micro- intravenous infusion dystrophin protein expression, but a treatment functional benefit relative to placebo was not demonstrated • The FDA's previous clinical holds on the IGNITE- DMD trial have been lifted $1-2 million/ SGT-001* Solid Biosciences DMD Gene therapy • Interim data recently released suggest a benefit one-time 2023 intravenous infusion on functional outcomes such as ambulation and treatment lung function 12-24 months after administration of SGT-001 NEPHROLOGY • Proposed for the treatment of moderate- Korsuva Peripheral kappa Uremic pruritus in to-severe uremic pruritus in CKD patients $100,000/ difelikefalin Cara Therapeutics opioid receptor 8/23/2021 CKD undergoing hemodialysis year intravenous infusion blocker • Administered at the end of each dialysis session *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Proposed for the treatment of CKD caused by Alport syndrome RTA 402 • Estimated prevalence of Alport syndrome: Reata CKD in Alport $150,000/ bardoxolone methyl Nrf2 activator ~30,000 to 60,000 people 2/25/2022 Pharmaceuticals syndrome year oral capsule • Alport syndrome is estimated to account for 3% of children with CKD and 0.2% of adults with end-stage renal disease in the U.S. NEUROLOGY • Would compete with several other available ARGX-113 Generalized therapies currently in use for gMG, such $250,000/ efgartigimod argenx myasthenia gravis Anti-IgG antibody as cholineserase inhibitors, steroids, 12/17/2021 year intravenous infusion (gMG) immunosuppressants, plasmapheresis, IVIG, Rituxan, Soliris

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Currently, the only therapeutic option for patients with cALD is allogeneic hematopoietic stem cell transplant (HSCT) • Beneficial effect has been reported if performed early in the course of cALD progression • On August 9, 2021, bluebird bio announced that one patient in the ALD-104 clinical trial had developed myelodysplastic syndrome, and that it was likely related to Lenti-D therapy; the Lenti-D* Cerebral ALD-104 trial has been placed on clinical hold $1-2 million/ elivaldogene autotemcel bluebird bio drenoleukodystrophy Gene therapy pending further investigation into this case one-time Mid-2022 intravenous infusion (cALD) • In the U.S., newborn screening for ALD has been treatment added to the Recommended Universal Screening Panel and is currently active in 20 states, accounting for ~60% of U.S. newborns • The worldwide incidence of ALD is ~1 in 5,000 to one in 17,000 newborns (both male and female), and ~1 in 20,000 to one in 30,000 newborn males • cALD develops in approximately 40% of affected boys and in a smaller number of adult men • There are no approved therapies for the treatment of AADC deficiency • Estimated prevalence: ~5,000 patients GT-AADC* Aromatic L-amino $1-2 million/ worldwide, with a live-birth incidence of eladocagene exuparvovec PTC Therapeutics acid decarboxylase Gene therapy one-time 2022 approximately one in 40,000 worldwide intraputamenal injection (AADC) deficiency treatment • While several diagnostic tests for AADC deficiency are available, the condition remains largely misdiagnosed or undiagnosed *Expected to cost > $500,000 per member.

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date ONCOLOGY • NEW INDICATION FOR AN EXISTING THERAPY: Tecartus is currently FDA-approved for the treatment of mantle cell lymphoma Tecartus Acute lymphoblastic CAR-T cell • The new proposed indication is for the treatment $373,000/ brexucabtagene autoleucel Gilead 10/1/2021 leukemia (ALL) therapy of adults with relapsed or refractory B-cell year intravenous infusion precursor ALL • Kymriah is similarly FDA-approved for ALL, but only for patients up to 25 years of age Humax TF • Proposed for the treatment of patients with Antibody-drug $200,000/ tisotumab vedotin Genmab; Seagen Cervical cancer recurrent or metastatic cervical cancer with 10/10/2021 conjugate year intravenous infusion disease progression on or after chemotherapy • Proposed for the treatment of adults with epidermal growth factor receptor (EGFR) Exon 20 insertion mutation-positive metastatic TAK-788 NSCLC who have received prior platinum-based EGFR and HER2 $250,000/ mobocertinib Takeda NSCLC chemotherapy 10/26/2021 exon 20 inhibitor year oral therapy • Rybrevant is now FDA-approved for the same indication, with a higher overall response rate and overall tolerability, albeit with an intravenous route of administration

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Designed for administration once every two weeks, or once every four weeks during long- term maintenance • PV is a cancer originating from a disease- p1101 initiating stem cell in the bone marrow, PharmaEssentia Polycythemia vera Monopegylated $150,000/ ropeginterferon alfa-2b-njft estimated to affect more than 160,000 people 11/13/2021 Corporation (PV) proline interferon year subcutaneous injection in the U.S., who have progressively burdensome symptoms • Without proper management, the disease progresses into malignancies including myelofibrosis and acute myeloid leukemia • Proposed for the treatment of relapsed/ refractory disease after at least three prior lines JNJ-68284528 of therapy $450,000/ Anti-BCMA ciltacabtagene autoleucel Janssen Multiple myeloma one-time 11/29/2021 CAR-T therapy • Demonstrated a 97% overall response rate and intravenous infusion 67% achieved a stringent complete response at treatment a median follow-up of 12.4 months in the Phase I/ II CARTITUDE-1 trial AGEN2034 Programmed • Proposed for the treatment of patients with balstilimab Agenus Inc. Cervical cancer death-1 (PD-1) recurrent or metastatic disease with progression $175,000/year 12/16/2021 intravenous infusion inhibitor on or after chemotherapy Immunoglobulin Tyvyt • Proposed for use in combination with G4 (IgG4) sintilimab Eli Lilly NSCLC pemetrexed and platinum chemotherapy for $175,000/year 3/18/2022 monoclonal intravenous infusion first-line treatment of nonsquamous NSCLC antibody • Proposed for use in combination with umbralisib Chronic lymphocytic TG-1101 Anti-CD20 (Ukoniq) leukemia (CLL) and $125,000/ ublituximab TG Therapeutics monoclonal 3/25/2022 small lymphocytic • It is estimated that there are approximately year intravenous infusion antibody leukemia (SLL) 20,000 new cases of CLL diagnosed each year in the United States

Anticipated Mechanism(s) Anticipated Drug Name Manufacturer(s) Indication(s) Comments Approval of Action Cost Date • Proposed for the treatment of advanced and HMPL-012 Hutchison China Neuroendocrine Tyrosine kinase progressive pancreatic and extra-pancreatic $200,000/ surufatinib 4/30/2022 MediTech Limited tumors (NETs) inhibitor NETs in patients who are not amenable for year oral therapy surgery RESPIRATORY • Proposed for the treatment of severe uncontrolled asthma in adults and adolescents Anti-thymic • Would compete with Dupixent, Cinqair, Nucala, stromal AMG157 Fasenra; all of these, however, except Dupixent, AstraZeneca; lymphopoietin tezepelumab Asthma are only approved for the eosinophilic subtype $42,000/year 1/7/2022 Amgen (TSLP) subcutaneous injection monoclonal • Dupixent is also approved for those who are oral antibody corticosteroid-dependent • Non-eosinophilic disease accounts for around half of severe asthma cases

Biosimilar Reference Status/Estimated Biosimilar Currently Drug Name Manufacturer(s) Indication(s) Comments Drug Approval Launched? ENDOCRINOLOGY • First insulin biosimilar product to be granted interchangeable status by the FDA • The interchangeable Semglee product will be differentiated from the currently available Semglee Semglee Yes - original Semglee FDA-approved: with new NDCs and a new insulin glargine-yfgn Mylan/Viatris Lantus Diabetes mellitus formulation without 7/28/2021 interchangeable label subcutaneous injection interchangeable status • Launch of the interchangeable product is anticipated over the next few months • The currently available Semglee product is technically not interchangeable • First insulin aspart MYL-1601D biosimilar application after BLA is under FDA review insulin aspart Mylan; Biocon Novolog Diabetes mellitus No reclassification of insulin (BsUFA date: 3Q 2021) subcutaneous injection products as biologic agents HEMATOLOGY

MSB11455 • Another biosimilar to BLA is under FDA review Yes - Fulphila, Udenyca, pegfilgrastim Fresenius Kabi Neulasta Neutropenia Neulasta, after Fulphila, (BsUFA date: 3Q 2021) Ziextenzo subcutaneous injection Udenyca, and Ziextenzo

Lupifil-P • Another biosimilar to Lupin BLA is under FDA review Yes - Fulphila, Udenyca, adalimumab Neulasta Neutropenia Neulasta, after Fulphila, Pharmaceuticals (BsUFA date: 2/2/2022) Ziextenzo subcutaneous injection Udenyca, and Ziextenzo

Biosimilar Reference Status/Estimated Biosimilar Currently Drug Name Manufacturer(s) Indication(s) Comments Drug Approval Launched? IMMUNOLOGY • Another biosimilar to AVT02 BLA is under FDA review Humira, after Abrilada, adalimumab Alvotech Humira Rheumatoid arthritis No (BsUFA date: 9/1/2021) Amjevita, Cyltezo, subcutaneous injection Hadlima, Hulio, Hyrimoz • Another biosimilar to Humira, after Abrilada, Amjevita, Cyltezo, Hadlima, Hulio, Hyrimoz CHS-1420 Coherus BLA is under FDA review adalimumab Humira Rheumatoid arthritis No • If approved, Coherus plans BioSciences (BsUFA date: 12/1/2021) subcutaneous injection to launch this product in the U.S. on or after July 1, 2023, per the terms of an agreement with Humira manufacturer AbbVie ONCOLOGY Colorectal; Non-small BAT1706 • Another biosimilar to Bio-Thera cell lung; Cervical BLA is under FDA review bevacizumab Avastin Yes - Mvasi, Zirabev Avastin, after Mvasi and Solutions, Inc. cancers; Glioblastoma; (BsUFA date: 11/27/2021) intravenous infusion Zirabev Renal cell carcinoma MYL-1402O • Another biosimilar to BLA is under FDA review bevacizumab Mylan; Biocon Avastin Breast cancer Yes - Mvasi, Zirabev Avastin, after Mvasi and (BsUFA date: 2H 2021) intravenous infusion Zirabev Colorectal; Non-small Alymsys • Another biosimilar to Amneal cell lung; Cervical BLA is under FDA review bevacizumab Avastin Yes - Mvasi, Zirabev Avastin, after Mvasi and Pharmaceuticals cancers; Glioblastoma; (BsUFA date: 4/15/2022) intravenous infusion Zirabev Renal cell carcinoma OPHTHALMOLOGY SB11 Macular degeneration; BLA is under FDA review • Would be the first Lucentis ranibizumab Samsung Bioepis Lucentis No Macular edema (BsUFA date: 9/18/2021) biosimilar agent intraocular injection

Recent Approvals GENERIC NAME BRAND NAME MANUFACTURER(S) MARKET LAUNCH DATE rufinamide Banzel (200 mg, 400 mg tablets) Hikma 5/30/2021 lopinavir/ritonavir Kaletra (tablets) Hetero 6/7/2021 etravirine Intelence Amneal 6/16/2021 Pipeline Agents GENERIC NAME BRAND NAME MANUFACTURER(S) ANTICIPATED LAUNCH DATE apremilast Otezla (tablet) Sandoz; Zydus 9/21/2021 sunitinib malate Sutent Mylan/Viatris 3Q 2021 ibrutinib Imbruvica (tablet) Alvogen/Natco Pharma 3Q 2021 Vifor Pharma; American Regent; Daiichi ferric carboxymaltose Injectafer 11/10/2021 Sankyo; Lutipold fingolimod Gilenya (0.25 mg, 0.5 mg) Teva 4Q 2021 vasopressin Vasostrict Par/Endo 2H 2021 mifepristone Korlym Teva 2021 ritonavir Norvir (capsules) Hikma; Mylan/Viatris 2021 posaconazole Noxafil (oral suspension) Par/Endo; Roxane/Hikma; Sandoz 2021 maraviroc Selzentry (tablet) Hetero 2/7/2022 lenalidomide Revlimid (2.5, 5, 10, 15,20, 25 mg) Dr. Reddy's; Teva; Natco Pharma 3/1/2022 paclitaxel Abraxane Dr. Reddy's; Teva; Natco Pharma 3/31/2022 Apotex; Fresenius; Pharmascience; Hetero; bortezomib Velcade 5/1/2022 Aurobindo; Teva; Zydus; Amneal Teva; Amneal; Accord; Hospira; Apotex; pemetrexed disodium Alimta (100, 500, 750, 1,000 mg) Wockhardt; Sandoz; Dr. Reddy's; Fresenius; 5/25/2022 Glenmark; Biocon; Sun; Zydus gefitinib Iressa Apotex; Cipla; Natco Pharma; Synthon 7/13/2022

Term Definition Term Definition Term Definition aromatic L-amino acid AADC cDGS complete DiGeorge Syndrome EB epidermolysis bullosa decarboxylase

ALGS Alagille syndrome CGRP calcitonin gene-related peptide EUA Emergency Use Authorization

ALL acute lymphoblastic leukemia cGvHD chronic graft-vs-host disease FDA Food and Drug Administration

anti-neutrophil cytoplasmic ANCA-AAV CKD chronic kidney disease FGFR2 fibroblast growth factor receptor 2 antibody-associated vasculitis

atherosclerotic cardiovascular ASCVD CLL chronic lymphocytic leukemia FH familial hypercholesterolemia disease

BCG Bacille Calmette-Guerin CMV cytomegalovirus FOP fibrodysplasia ossificans progressiva

BCMA B-cell maturation antigen COVID-19 coronavirus disease 2019 gMG generalized myasthenia gravis

BLA biologics license application C-PLGD congenital plasminogen deficiency HAT human African trypanosomiasis

BsUFA Biosimilar User Fee Act DLBCL diffuse large B-cell lymphoma hATTR hereditary transthyretin-mediated

hypoxia-inducible factor prolyl cALD cerebral adrenoleukodystrophy DMD Duchenne muscular dystrophy HIF-PHI hydroxylase inhibitor

hematopoietic stem cell CAR-T cell chimeric antigen receptor T-cell dsDNA double-stranded DNA HSCT-TMA transplant-associated thrombotic microangiopathy

Term Definition Term Definition Term Definition

transfusion-dependent beta- IgG4 immunoglobulin G4 PD-1 Programmed death-1 TDT thalassemia

progressive familial intrahepatic JAK1 Janus kinase 1 PFIC TI transfusion independence cholestasis

LBL lymphoblastic lymphoma PKD pyruvate kinase deficiency TSLP thymic stromal lymphopoietin

paroxysmal nocturnal NCD National Coverage Determination PNH VHL von Hippel-Lindau hemoglobinuria

NET neuroendocrine tumor PWS Prader-Willi syndrome VKC vernal keratoconjunctivitis

NMIBC non-muscle invasive bladder cancer PV polycythemia vera VVC vulvovaginal candidiasis

Nrf2 nuclear factor erythroid 2 RCC renal cell carcinoma WAC Wholesale Acquisition Cost

severe acute respiratory syndrome NSCLC non-small cell lung cancer SARS-CoV-2 coronavirus 2

obstructive hypertrophic cardiomy- oHCM SLL small lymphocytic leukemia opathy

P2X3 P2X purinoceptor 3 T1D Type 1 diabetes

proprotein convertase subtilisin/ PCSK9 T2D Type 2 diabetes kexin type 9

© 2021 AcariaHealth. All rights reserved. | Data is current as of 8/23/2021 Page 27 AcariaHealth, an Envolve Pharmacy Solution, is a national comprehensive specialty pharmacyPipeline focused Reporton improving care and outcomes for patients livingAugust with 2021complex conditions, such as hepatitis C, multiple sclerosis, oncology, rheumatoid arthritis, hemophilia, cystic fibrosis and other conditions. Offering specialized care management services in these disease states, AcariaHealth is dedicated to enhancing the patient care offering, collaborating with providers and capturing relevant data to measure patient outcomes.

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