® RxOutlook 3rd Quarter 2021 optum.com/optumrx a RxOutlook 3rd Quarter 2021 In this edition of RxOutlook, we highlight 12 key pipeline drugs with an expected FDA decision by the end of 2021. Of the products discussed below, one has already been approved by the FDA – AstraZeneca’s Saphnelo® (anifrolumab) for the treatment of systemic lupus erythematosus (SLE). Saphnelo is one of the few novel therapies approved for SLE over the last several decades and it would provide an additional treatment option in patients that have failed standard therapy (eg, hydroxychloroquine). Bimekizumab, an injectable interleukin (IL)-17 monoclonal antibody, is the first of a series of novel drugs that could potentially be approved in the next 18 months for plaque psoriasis. While this is already a highly competitive therapeutic category, bimekizumab demonstrated superiority in head-to-head trials vs. several biologic treatment options for the condition. Plinabulin is a first-in-class treatment for chemotherapy-induced neutropenia (CIN) and would potentially be the first change in the treatment paradigm for management of CIN since the development of granulocyte colony stimulating factors (eg, Neulasta®, Neupogen®). Consistent with recent pipeline trends, a significant proportion of drugs remaining this year have been granted orphan drug designation and would be used for rare conditions. Of the 12 drugs discussed below, 7 have an orphan drug designation. In some cases, these treatments will represent the first FDA approved therapies for their conditions. This includes narsoplimab for transplant-associated thrombotic microangiopathy and vosoritide for achondroplasia. Other orphan drugs included will be entering more competitive landscapes where alternative treatment options are available, but they may provide advantages in certain subsets of patients (pacritinib in patients with myelofibrosis and severe thrombocytopenia). Overall, individual orphan drugs are unlikely to be significantly impactful from a budgetary perspective for payers; however, collectively they pose a challenge as they represent an increasingly larger proportion of overall drug spend. Approval decisions for other key novel therapies are expected in the second half of 2021 but are not reviewed in this report because they were covered in previous editions of RxOutlook. These include: abrocitinib and topical ruxolitinib for atopic dermatitis; atogepant for migraine prophylaxis; maralixibat for Alagille syndrome; and avacopan for ANCA-associated vasculitis. Key pipeline drugs with FDA approval decisions expected by end of the 4th 2021 Expected FDA Drug Name Manufacturer Indication/Use Decision Date Saphnelo® AstraZeneca Systemic lupus erythematosus 7/30/2021 (anifrolumab) (Approved) Dextromethorphan/ Axsome Therapeutics Major depressive disorder 4Q 2021 bupropion Bimekizumab UCB Plaque psoriasis 10/15/2021 Varenicline Oyster Point Pharma Dry eye disease 10/17/2021 (nasal spray) Narsoplimab Omeros Hematopoietic stem cell transplant-associated 10/17/2021 thrombotic microangiopathy* Mobocertinib Takeda Non-small cell lung cancer* 10/26/2021 Ropeginterferon PharmaEssentia Polycythemia vera* 11/13/2021 alfa-2b optum.com/optumrx b RxOutlook 3rd Quarter 2021 Expected FDA Drug Name Manufacturer Indication/Use Decision Date Vosoritide BioMarin Achondroplasia* 11/20/2021 Ciltacabtagene Janssen/ Legend Biotech Multiple myeloma* 11/29/2021 autoleucel Plinabulin BeyondSpring Chemotherapy-induced neutropenia 11/30/2021 Pacritinib CTI BioPharma Myelofibrosis* 11/30/2021 Efgartigimod Argenx Generalized myasthenia gravis* 12/17/2021 * Orphan Drug Designation optum.com/optumrx c RxOutlook 3rd Quarter 2021 OptumRx closely monitors and evaluates the drug development pipeline to identify noteworthy upcoming drug approvals and reports the essential findings here in RxOutlook. The report is organized in the following manner: Detailed Drug Insights This section reviews the important characteristics (eg, therapeutic use, clinical profile, competitive environment and regulatory timeline) for key pipeline drugs with potential FDA approvals by the end of the 4th Quarter 2021. Read more Extended Generic Pipeline Forecast This section provides a summary of upcoming first-time generic drugs and biosimilars that may be approved in the upcoming two years. Read more Extended Brand Pipeline Forecast This supplemental table provides a summary of developmental drugs, including both traditional and specialty medications that may be approved in the upcoming two years. Read more Key Pending Indication Forecast This supplemental table provides a summary of key new indications that are currently under review by the FDA and may be approved in the upcoming 12 months. Read more Past and future reviews Please note that RxOutlook highlights select near-term approvals. Some drugs may not appear in this issue because they have been reviewed in previous editions of RxOutlook. Drugs of interest that are earlier in development or with expected approvals beyond 4th quarter 2021 may appear in future reports; however, for those who need an initial look at the full pipeline, please refer to the Brand Pipeline Forecast Table found later in this report. optum.com/optumrx d RxOutlook 3rd Quarter 2021 Getting acquainted with pipeline forecast terms Clinical trial phases Phase I trials Researchers test an experimental drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase II trials The experimental study drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. Phase III trials The experimental study drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. Phase IV trials Post marketing studies delineate additional information including the drug’s risks, benefits, and optimal use. Pipeline acronyms ANDA Abbreviated New Drug Application BLA Biologic License Application CRL Complete Response Letter FDA Food and Drug Administration MOA Mechanism of Action NME New Molecular Entity NDA New Drug Application sBLA Supplemental Biologic License Application sNDA Supplemental New Drug Application OTC Drugs Over-the-Counter Drugs PDUFA Prescription Drug User Fee Act REMS Risk Evaluation and Mitigation Strategy optum.com/optumrx e 3rd Quarter 2021 Detailed insights on key drugs optum.com/optumrx RxOutlook 3rd Quarter 2021 Anifrolumab-fnia (Brand Name: Saphnelo®) Manufacturer: AstraZeneca Regulatory designations: Fast Track Approval decision: 7/30/2021 Therapeutic use • Treatment of adult patients with moderate to severe Anifrolumab is was approved for the treatment of adult patients with moderate to severe SLE, who are receiving systemic lupus erythematosus (SLE), who are receiving standard therapy. standard therapy SLE is a chronic, autoimmune disorder that can affect different organs in the body. Common symptoms include fatigue, skin rashes, fevers, and pain or swelling in the joints. Causes of premature death associated by SLE are mainly active disease, organ failure (eg, kidneys), infection, or cardiovascular disease from accelerated atherosclerosis. The prevalence of SLE varies widely due to differences in case definitions and study methods. A conservative estimate on prevalence from the Center for Disease Control and Prevention (CDC) is 161,000 with definite SLE and 322,000 with definite or probable SLE. Clinical profile • Monoclonal antibody targeting type 1 IFN Anifrolumab is human monoclonal antibody that binds to subunit 1 of the type I interferon receptors (IFN) receptor, blocking the activity of all type I interferons including IFN-alpha, IFN-beta and IFN-omega. Type I interferons are cytokines involved in the inflammatory pathways. • IV formulation Between 60% and 80% of adults with SLE have an increased type I interferon gene • For efficacy results, refer to signature. the complete pivotal trial Pivotal trial data: data The safety and efficacy of anifrolumab were evaluated in three randomized, double-blind, • Common AEs: placebo-controlled studies. All patients had moderate to severe disease despite receiving Nasopharyngitis, upper standard therapy. Efficacy of anifrolumab was established based on assessment of clinical respiratory tract infections, response using the composite endpoints, the British Isles Lupus Assessment Group based bronchitis, infusion related Composite Lupus Assessment (BICLA) and the SLE Responder Index (SRI-4). reactions, herpes zoster, cough Study 1 randomized 305 patients. The primary endpoint was a combined assessment of the SRI-4 and the sustained reduction in oral corticosteroids (OCS). SRI-4 response was • Dosing: Every 4 weeks 62.8% in the anifrolumab treated patients vs. 38.8% in placebo patients (treatment difference: 24.0; 95% CI: 10.9, 37.2). Consistent trends in favor of anifrolumab vs. placebo, on effect of reduction of OCS use, were observed, but the difference was not statistically significant. Study 2 randomized 457 patients. The primary endpoint was improvement in disease activity evaluated at 52 weeks, measured by SRI-4. SRI-4 response was 49% in the anifrolumab treated patients vs. 43% in placebo patients (treatment difference: 6.0; 95% CI: -4.2, 16.2). This was not a statistically significant improvement. Study 3 randomized 362 patients. The primary endpoint was