ON PERSPECTIVE THE RXPIPELINE

Understanding changes in the market and their impact.

EnvisionRx continuously monitors the drug pipeline. As treatment options change, we evaluate and share our perspective on the clinical benefits and impact in the market. Our Perspective on the Rx Pipeline reports provide ongoing insights from our team of clinical experts and considerations to protect and improve plan performance.

Included in this Edition } Clinical Pipeline } FDA Drug Approvals } New Indications } Upcoming and Recent Generic Launches } FDA Safety Update } Drug Shortages and Discontinuations

1 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market crizanlizumab SEG101 Manufacturer: Indication/Use: Dosage Form: Infusion Pipeline Stage: PDUFA 1/2020 Sickle cell disease is a debilitating genetic disorder that affects approximately 100,000 Americans.[1] Patients with sickle cell disease can suffer from vaso-occlusive crises (VOCs) that are incredibly painful and can cause irreversible tissue infarction and vasculopathy. VOCs are also associated with increased morbidity and mortality. [2] Hydroxyurea and pharmacy-grade L-glutamine are the only two FDA-approved pharmacotherapies currently available for the prevention of VOCs.[3] Crizanlizumab is a that works through selectin inhibition. P-selectin is responsible for binding to the surface of platelets and the endothelium in the blood vessels, which is a major source of pain in a VOC. Crizanlizumab is a monthly infusion to prevent VOCs and potential emergency room or hospital visits for pain management.[4] The SUSTAIN trial was a phase II, multi-center, randomized, placebo-controlled, double blind, 12-month study to assess the safety and efficacy of crizanlizumab, with or without hydroxyurea therapy, in patients with sickle cell– related pain crises. The study evaluated 198 patients with sickle cell anemia and a history of two to 10 VOCs in the previous year. Patients were randomized to a high (5 mg/kg) or low (2.5 mg/kg) dosage group. The higher dosage group had significantly reduced frequency of pain crises by 45.3% compared to placebo, regardless if the patient used hydroxyurea. Preventive infusion approximately halved the annual rate of VOCs. There was an increased percentage of patients who did not experience any VOCs versus placebo (37.5% vs. 12.2%, p=0.008) during treatment. For patients on the high dosage, the time to first pain crisis was 2.9 times longer than placebo-treated patients. The adverse effects experienced in the trial were joint pain, diarrhea, itching, chest pain and vomiting.[5] After the results of this trial, the FDA granted crizanlizumab breakthrough therapy designation, which will expedite the development and review of the drug, as this product would treat a serious or life-threatening disease and demonstrated a substantial improvement over existing therapies.[4]

Glossary BLA - Biologics License Application NDA - New Drug Application PDUFA - User Fee Act of Terms

2 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market lemborexant E2006 Manufacturer: Eisai Indication/Use: Insomnia disorder and irregular sleep-wake rhythm disorder (ISWRD) Dosage Form: Oral Pipeline Stage: PDUFA 12/27/19 Insomnia, defined as difficulty in falling asleep, staying asleep or returning to sleep, is the most common sleep disorder in the U.S., impacting an estimated 40 million Americans each year.[6] It can negatively impact the quality of one’s life by decreasing productivity at work or the capacity to learn, increasing the likelihood of depression, risk of anxiety disorder, drug or alcohol abuse/dependence, hypertension, diabetes, obesity, heart attack, or stroke. Multiple studies suggest that the economic burden of insomnia—including direct medical costs, such as doctor visits, hospital services and —could reach as high as billions of dollars.[7], [8] Older adults have higher occurrences of insomnia and often have limited treatment options. While some patients resolve their insomnia, it is often chronic, with studies showing persistence in 50% to 85% of individuals.[9] The American Academy of Sleep Medicine 2017 Guidelines state that psychological and behavioral interventions are effective treatments of chronic primary and secondary insomnia. Initial treatment should include at least one form of cognitive behavioral therapy (CBT-1) and short-term drug therapy should be supplemented when possible. Suggested initial pharmacological treatment may be a benzodiazepine receptor agonist (zaleplon, zolpidem, eszopiclone, triazolam, temazepam) or ramelteon, then switching products if initial treatment is ineffective or considering a sedating antidepressant (trazodone, amitriptyline, mirtazapine).[10] Lemborexant is a dual orexin receptor antagonist that suppresses wakefulness and may not shift the sleep profile, possibly allowing for more time in REM sleep.[11] Belsomra® (suvorexant) was the first orexin inhibitor approved by the FDA in 2014, but clinical studies only compared it to placebo. Two other orexin receptor antagonists are in the pipeline for approval, filorexant (Merck and Co.) and SB-649868 (GlaxoSmithKline) with PDUFA dates after lemborexant.[11] Two phase III trials, SUNRISE 1 and SUNRISE 2, were conducted by Eisai to examine the safety and efficacy of lemborexant. SUNRISE 1 consisted of 1,006 participants 55 years of age or older; with 45% over age 65.[12] Patients were randomized to lemborexant 5 mg or 10 mg, placebo, or zolpidem CR for 30 days. This is the first trial directly comparing an insomnia medication with zolpidem CR. The trial had a primary outcome of change from baseline in mean latency to persistent sleep (LPS) and secondary outcome of wake after sleep onset (WASO). It reported improvements in sleep onset and sleep maintenance compared to both placebo and zolpidem, and more improvement than zolpidem for the amount of time spent awake during the second half of the night.[13] SUNRISE 2 was a similar clinical trial analyzing data after six months, including those 18 years of age or older, and only comparing to placebo.[14] Lemborexant appears to have fewer adverse events (AE). Suvorexant reported daytime somnolence or drowsiness in 2% to 12% of patients.[15] This was also the most frequent treatment-related AE for lemborexant.[16] Safely treating insomnia is an unmet need, especially in older adults, making lemborexant and orexin inhibitors potential options for elderly patients, especially in the wake of additional black box warnings for certain medications.[17] Competitive pricing may be key to increase general prescribing and patient uptake of lemborexant versus generic products. Eisai is also pursuing clinical trials for use of lemborexant in those with mild to moderate Alzheimer’s disease who experience irregular sleep-wake rhythm disorder.[18]

3 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

lumateperone ITI-007 Manufacturer: Intracellular Therapies Indication/Use: Schizophrenia Dosage Form: Oral Pipeline Stage: PDUFA 12/27/19 Schizophrenia is a psychiatric disorder that involves both chronic and recurrent psychosis, which causes impairment in social and occupational functioning. It is one of the most disabling and economically catastrophic medical disorders according to the World Health Organization.[19] Patients with schizophrenia experience both positive and negative symptoms. Positive symptoms are being added to the psyche due to the illness and include hallucinations, delusions and suspiciousness. Negative symptoms take away and include diminished emotional expression and lack of motivation.[20] Medications target both symptoms, however, positive symptoms tend to improve more, leaving a treatment gap in improving the negative symptoms of schizophrenia. Second-generation antipsychotics treat positive symptoms, as well as some negative symptoms. While the atypical agents have less extrapyramidal side effects (EPS), other issues, such as weight gain, prolactin and glucose elevation, and sedation are observed with these medications. Lumateperone is a first-in-class medication with a hypothesized mechanism working across three neurotransmitter pathways, regulating the release, uptake and transmission of serotonin, dopamine and glutamate neurotransmitters. This novel mechanism offers the ability to manage both the positive and negative symptoms of schizophrenia, as compared to previously FDA-approved second-generation antipsychotics. The product is also in phase III trials for use in bipolar disease and Alzheimer’s.[21] In three controlled clinical trials designed to evaluate lumateperone’s efficacy for treating schizophrenia, it showed improved psychosocial function and favorable tolerability. Approximately 785 patients were given lumateperone compared to placebo. The primary endpoint was evaluating change from baseline on the Positive and Negative Syndrome total score (PANSS). Symptoms of schizophrenia assessed via the PANSS improved at the same magnitude from baseline when evaluating active drug versus placebo. Greater improvements were observed in subgroups of patients with “elevated symptomatology” (comorbid symptoms of depression and those with prominent negative symptoms), potentially favoring the impact this medication may have on treating the negative symptoms of schizophrenia. It is important to note, in the one trial where variable doses of lumateperone were compared to risperidone and placebo, neither dose of lumateperone separated from placebo when evaluating the primary endpoint.[22] Lumateperone may offer an additional treatment option for patients with schizophrenia with a potential effect on the negative symptoms of the disease as well. Another interesting use for this product may be for neurodegenerative disorders, however, the Alzheimer’s disease trial was stopped early as the primary endpoint would not be reached.[21]

4 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

™ Accrufer ferric maltol Manufacturer: Shield Therapeutics Indication/Use: Iron deficiency Dosage Form: Oral Traditional or Specialty: Traditional On July 25, 2019, the FDA approved Accrufer™ for iron deficiency in adults. While it was granted a broader indication, the three studies used for the FDA approval of Accrufer—AEGIS 1, AEGIS 2 and AEGIS 3—focused on those with concurrent diseases, such as ulcerative colitis, Crohn’s disease and chronic kidney disease. Injectable iron is the standard of care for this studied populations.[23] Oral Accrufer, consisting of a ferric maltol formulation, is hypothesized to have a more tolerable gastrointestinal profile and, therefore, may lead to greater adherence. An additional study, AEGIS H2H, examined Accrufer compared to intravenous IV for iron deficient anemia, examining the capability of the oral medication to raise hemoglobin levels. Accrufer was within 9% of the response seen with the IV iron formulation and statistically non-inferior after 12 weeks of therapy.[24] For more information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212320Orig1s000lbl.pdf

™ Nourianz istradefylline Manufacturer: Kyowa Kirin, Inc. Indication/Use: Parkinson’s disease “off episodes” Dosage Form: Oral Traditional or Specialty: Traditional The FDA approved Nourianz™, an adenosine A2A receptor antagonist on August 27, 2019. It provides a novel mechanism of action for the treatment of “off episodes” in Parkinson’s patients.[25] “Off episodes” are the occurrence of worsening symptoms, such as muscle stiffening and difficulty with voluntary and involuntary movements, between doses of levodopa/carbidopa for the treatment of the disease. These episodes occur most commonly in patients who have been taking levodopa/carbidopa for several years. A 2001 literature review stated the median “off symptom” frequency was near 40% when patients were taking levodopa for four to six years.[26] Nourianz joins other products, such as MAO-B inhibitors (selegiline, rasagiline, safinamide), COMT inhibitors (entacopone, tolcapone) and dopamine antagonist (ropinirole, pramipexol, rotigotine).[27] Nourianz is taken daily, unlike Apokyn (apomorphine) or Inbrija™ (levodopa), which are taken on an as-needed basis.

For more information: https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug- treat-episodes-adults-parkinsons-disease

5 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

Rinvoq™ upadacitinib Manufacturer: AbbVie Indication/Use: Rheumatoid arthritis Dosage Form: Oral Traditional or Specialty: Specialty Rinvoq™ was approved by the FDA on August 16, 2019, for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. In clinical trials, 71% of patients treated with Rinvoq plus methotrexate achieved an ACR 20 (composite measure that captures at least a 20% improvement in RA) compared to 36% treated with placebo plus methotrexate at 12 weeks. Rinvoq adds another oral option to the management of RA. For more information: https://www.rinvoq.com/

Rozlytrek™ entrectinib Manufacturer: Genentech/Roche Indication/Use: Metastatic non-small cell lung cancer (NSCLC) or metastatic solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusion Dosage Form: Oral Traditional or Specialty: Specialty On August 15, 2019, the FDA approved Rozlytrek™, an oncology medication indicated for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive and those 12 years of age and older with metastatic solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation and have progressed following prior treatment. Rozlytrek is the second NTRK gene fusion-positive tumor treatment, as Vitrakvi® was approved by the FDA in November 2018. A limitation for the NTRK gene fusion positive solid tumor treatment drugs is a lack of a non-standardized diagnostic test, however, Roche states that they are working to create a companion diagnostic for Rozlytrek that would identify ROS1 and NTRK gene fusions.[28] For more information: https://www.fda.gov/news-events/press-announcements/fda-approves-third-oncology- drug-targets-key-genetic-driver-cancer-rather-specific-type-tumor

6 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

® Rybelsus semaglutide Manufacturer: Novo Nordisk Indication/Use: Type 2 diabetes Dosage Form: Oral Traditional or Specialty: Traditional On September 20, 2019, the FDA approved Rybelsus®, the first oral glucagon-like polypeptide (GLP-1) agonist to be approved in the United States. In head-to-head trials, Rybelsus was compared with injectable GLP-1 liraglutide oral dipeptidyl peptidase-4 (DPP-4) sitagliptin and oral sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin. Rybelsus produced reductions in hemoglobin A1c (HbA1c) and was found non-inferior to existing therapies. Similar to the injectable GLP-1s, Rybelsus also led to a reduction in body weight of up to 4.4 kg (9.7 lbs). For more information: https://www.rybelsuspro.com/

™ Turalio pexidartinib Manufacturer: Daiichi-Sankyo Indication/Use: Tenosynovial giant cell tumor (TGCT) Dosage Form: Oral Traditional or Specialty: Specialty The FDA approved the tyrosine kinase inhibitor Turalio™ for symptomatic tenosynovial giant cell tumor (TGCT) on August 2, 2019. TCGT is a rare condition where benign (non-cancerous) tumors develop in the synovium, bursae and tendon sheath of the patient.[29] Growth of the tumors can damage surrounding areas and lead to pain, swelling and movement limitations. Surgery is the first line treatment for TCGT, but there was an unmet pharmacological need for those with recurrent TCGT or those unable to be treated with surgery. In the ENLIVEN study, 15% of patients treated with Turalio reached a complete response and 23% achieved a partial response, compared to 0% with the placebo.[30] Turalio has a boxed warning for potentially fatal liver injury and requires a risk evaluation and mitigation strategy (REMS) program that must be followed. For more information: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare- joint-tumor

7 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

® Wakix pitolisant hydrochloride Manufacturer: Harmony Biosciences Indication/Use: Narcolepsy Dosage Form: Oral Traditional or Specialty: Traditional Wakix® was approved by the FDA on August 14, 2019. This medication provides a novel mechanism of action for the treatment excessive daytime sleepiness (EDS) in narcolepsy patients. Wakix is the first and only treatment approved for patients with narcolepsy that is not scheduled as a controlled substance by the DEA. This product joins recently approved Sunosi™, another product indicated for narcolepsy. For more information: https://wakix.com/

8 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals - Biosimilars

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

Reference Drug Biosimilar Earliest Manufacturer Indication 2017 Sales Approved Launch Date

Avastin® Mvasi Allergan Metastatic colorectal cancer (mCRC), Launched (bevacizumab) 09/14/2017 metastatic non-squamous non-small $3,038M cell lung cancer (NSCLC), glioblastoma, metastatic renal cell carcinoma (mRCC), Zirabev Pfizer persistent/recurrent/metastatic 4Q2019 06/27/2019 cervical cancer

Enbrel® Erelzi Sandoz Plaque psoriasis, rheumatoid arthritis, 1H2020 (etanercept) 08/2016 ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis $7,967M Eticovo Samsun Bioepsis 04/2019 Epogen® Retacrit Hospira Anemia due to kidney disease, zidovudine Launched (epoetin alfa) 5/15/2018 chemotherapy, reduction of allogenic red $1,543M blood cell transfusions in surgery

Ogivri Mylan HER2-overexpressing breast cancer, 2H2019 12/2017 HER2-overexpressing metastatic gastric or gastroesophageal junction Herzuma Roche/Genetech adenocarcinoma. 2H2019 12/2018

Herceptin® Ontruzant Roche/Genetech 2H2020 (trastuzumab) 01/2019 $3,127M

Trazimera Pfizer 2H2019 03/2019 Kanjinti Amgen, Allergan Launched 06/13/2019 Amjevita Amgen Rheumatoid arthritis, ankylosing 01/21/2023 09/2016 spondylitis, Crohn’s disease, juvenile idiopathic arthritis, plaque psoriasis, Cyltezo Boehringer Ingelheim psoriatic arthritis, ulcerative colitis 08/2022 Humira® 8/25/2017 () Hadlima Samsung Bioepis, 08/2022 $18,078M 07/23/2019 Merck & Co, Biogen

Hryrimoz Sandoz 08/2022 10/30/2018

Neulasta® Fuphila Mylan Febrile neutropenia (pegfilgrastim) 06/2018 $1,610M Launched Udenyca Amgen Neutropenia associated with 11/2018 myelosuppresive chemotherapy

9 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Drug Approvals - Biosimilars

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

Reference Drug Biosimilar Earliest Manufacturer Indication 2017 Sales Approved Launch Date

Granix Teva 8/29/2012 Reduce duration of neutropenia

Zarxio Hospira Acute myeloid leukemia patients receiving Neupogen® 3/6/2015 induction or consolidation chemotherapy, (filgagrastim) Launched cancer patients receiving bone marrow $283M Nivestym Hospira transplant or myelosuppressive 7/20/18 chemotherapy, patients undergoing peripheral blood progenitor cell collection and therapy, severe chronic neutropenia. Remicade® Inflectra Pfizer () 11/2016 Crohn’s disease, ulcerative colitis, $5,228M psoriatic arthritis, plaque psoriasis, Launched Renflexis Merck rheumatoid arthritis, ankylosing spondylitis 07/2017

Rituxan® Truxima Roche/Biogen/ Non-Hodgkin’s lymphoma (NHL) 2H2019 (rituximab) 11/2018 Genetech $4,291M Ruxience Pfizer Non-Hodgkin’s lymphoma (NHL), chronic 2H2019 07/23/2019 lymphocytic leukemia (CLL), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA)

* Recent FDA Approvals

10 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 New Indications

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

® Descovy emtricitabine and tenofovir alafenamide Manufacturer: Gilead Indication/Use: HIV, Pre-Exposure Prophylaxis (PrEP) Dosage Form: Oral Traditional or Specialty: Traditional Date of Original Approval: April 4, 2016 Descovy was approved for the expanded indication of pre-exposure prophylaxis (PrEP) on October 3, 2019. Descovy is indicated for HIV prevention in adults and adolescents weighing at least 35 kg who are HIV-negative and at-risk for sexually acquired HIV, excluding individuals at-risk from receptive vaginal sex. Descovy is the second product approved for by the FDA for PrEP in the United States. For more information: https://www.descovy.com/

® Invokana canagliflozin Manufacturer: Janssen Indication/Use: Type 2 diabetes Dosage Form: Oral Traditional or Specialty: Traditional Date of Original Approval: March 29, 2013 On September 27, 2019, the FDA approved an expanded indication for Invokana® to treat diabetic kidney disease (DKD) and reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and DKD. Invokana is now the only diabetes medication that is indicated to treat or reduce risk for both of these complications of the disease. For more information: https://www.invokana.com/splash-home

11 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 New Indications

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

® Ofev nintedanib Manufacturer: Boehringer Ingelheim Pharmaceuticals, Inc. Indication/Use: Idiopathic pulmonary fibrosis and sclerosis-associated interstitial lung disease (SSc-ILD) Dosage Form: Oral Traditional or Specialty: Specialty Date of Original Approval: October 15, 2014 Ofev® received FDA approval for a second indication to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) on September 6, 2019. SSc-ILD is a serious complication of systemic sclerosis or scleroderma, a connective tissue disease causing organs to thicken and scar. SSc-ILD standard of care currently is treatment with immunosuppressant therapy.[31] Notably, SSc-ILD is a systemic disease, whereas idiopathic pulmonary fibrosis (IPF) is limited to lung disease. For more information: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment- patients-rare-type-lung-disease

® Rituxan rituximab Manufacturer: Genentech, Inc. Indication/Use: Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (GPA) or Wegener’s Granulomatosis, microscopic polyangiitis (MPA), pemphigus vulgaris Dosage Form: Intravenous injection Traditional or Specialty: Specialty Date of Original Approval: November 26, 1997 On September 27, 2019, Rituxan® was granted a label expansion to include granulomatosis with polyangiitis (GPA) or Wegener’s Granulomatosis and microscopic polyangiitis (MPA) in pediatric patients two years of age and older. GPA and MPA are inflammatory blood vessel diseases that reduce the flow of blood to tissue and organs, and can possibly lead to organ damage.[32] Previously Rituxan was approved for GPA and MPA in adults only. For more information: https://www.rituxanforgpampa.com/

12 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 New Indications

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

® Taltz Manufacturer: Eli Lilly and Company Indication/Use: Plaque psoriasis, psoriatic arthritis and active ankylosing spondylitis (AS) Dosage Form: Subcutaneous injection Traditional or Specialty: Specialty Date of Original Approval: March 22, 2016 Taltz® was approved for treatment of adults with active ankylosing spondylitis (AS) on August 23, 2019. Previously, Taltz was approved for adults with moderate-to-severe plaque psoriasis and active psoriatic arthritis. The 2019 AS guidelines recommend continuous non-steroidal anti-inflammatory treatment initially.[33] Taltz will most likely find its place in therapy after a patient has tried and failed, has an intolerance to or a contraindication to a TNF inhibitor, such as Humira®, Remicade® or Enbrel®. For more information: https://www.taltz.com/ankylosing-spondylitis

13 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Upcoming and Recent Generic Launches

PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market

# of Manufacturer Anticipated Brand Name Generic Name Indication Entrants Launch Date

Aczone® 7.5% dapsone 1 Acne vulgaris 2H2019

Afinitor® Breast cancer, neuroendocrine tumors, everolimus 1 4Q2019 (2.5, 5, 7.5 mg) renal cell carcinoma

Emend (150 mg Prevention of chemotherapy induced nausea fosaprepitant 5 Launched injection) and vomiting

Evzio® naloxone hydrochloride 1 Emergency treatment of opioid overdose 2019

Chronic iron overload due to blood Jadenu® deferasirox 3 transfusion or treatment and non- 4Q2019 transfusion-dependent thalassemia

Prophylaxis of invasive Aspergillus and Noxafil® (tablet) posaconazole 1 Candida infections, treatment of oropharyngeal Launched Candida infections

Orfadin® (capsule) nitisinone 1 Hereditary tyrosinemia type 1 Launched

sodium phosphate, dibasic, anhydrous; Cleansing of the colon as a preparation OsmoPrep® 1 11/16/2019 sodium phosphate, for colonoscopy monobasic,monohydrate

Samsca® tolvaptan 1 Hyponatremia 2019

Travatan Z® travoprost 5+ Ocular hypertension and open angle-glaucoma 2019

14 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 FDA Safety Updates Drug Safety Communication

FDA Review Finds No Increased Risk of Prostate Cancer with Parkinson’s Disease Medicines Containing Entacapone (Comtan®, Stalevo®) The FDA released positive data on August 13, 2019, that entacapone, a medication used to treat dose wearing (“off episodes”) in levodopa/carbidopa treatment for Parkinson’s disease, did not increase the risk of prostate cancer. In 2010, the FDA stated that a clinical trial may have shown an increased likelihood of prostate cancer with entacapone treatment, and subsequently required Novartis to conduct further studies. Based on Novartis’s study and data from a review of the Department of Veterans Affairs healthcare system, the correlation between entacapone and prostate cancer was found not to be of concern.[34] For more information: https://www.fda.gov/drugs/drug-safety-and-availability/fda-review-finds-no-increased-risk- prostate-cancer-parkinsons-disease-medicines-containing

FDA Warns About Rare Occurrence of Serious Liver Injury with Use of Hepatitis C Medicines Mavyret™, Zepatier® and Vosevi® in Some Patients On August 28, 2019, the FDA reported that certain medications used to treat chronic hepatitis C (Mavyret, Zepatier and Vosevi) resulted in worsening liver function or even liver failure in those patients with moderate to severe liver dysfunction (Child-Pugh B or C, or other serious liver conditions). Some patients also had pre-existing factors, such as alcohol abuse, liver cancer and serious illness resulting in liver complications. Liver failure most often occurred within the first four weeks of starting treatment. It is important to note that these medications are not indicated to be used in patients with moderate to severe liver dysfunction. Prescriber adherence to FDA-approved guidance when selecting patients who qualify for Mavyret, Zepatier and Vosevi treatment should continue. Any patient treated with antivirals for chronic hepatitis C should contact their prescriber if signs of liver injury occur, such as yellow eyes or skin, fatigue, weakness, loss of appetite, nausea or vomiting. For more information: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence- serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and

Rare but Severe Lung Inflammation Possible with Certain Breast Cancer Medications The FDA recently issued a warning that Ibrance®, Kisqali® and Verzenio® may cause severe lung inflammation. These CDK 4/6 inhibitors are hormone therapies indicated for advanced or metastatic (HR)-positive, (HER2)-negative breast cancer. The FDA did state that the drug class still shows an overall benefit that outweighs the risk when used appropriately. If a patient is taking a CDK4/6 inhibitor and experiences difficulty breathing or shortness of breath with limited or no physical exertion, they should talk to their healthcare professional. For more information: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung- inflammation-ibrance-kisqali-and-verzenio-breast-cancer

Drug Shortages and Discontinuations Immune Globulin On August 12, 2019, the FDA issued information about the shortage of immune globulin (IG) products, such as intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), which they attribute largely to an increased demand for the products. The FDA is attempting to mitigate shortages and work with the manufacturer industry to improve IG manufacturing and yields. To date, the FDA has approved new IG products: Xembify®, Asceniv™ and Cutaquig®. For more information on drug shortages: https://www.fda.gov/vaccines-blood-biologics/safety-availability- biologics/information-about-immune-globulin-human-product-shortage

15 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Sources

[1] Centers for Disease Control and Prevention. Sickle Cell Disease. https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed 11 October 2019. [2] Gutsaeva D, Parkerson J, Yerigenahally S, et al. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood. 2011;117(2):727-735. [3] McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015;14(11):1749. Epub 2015 Sep 14. [4] SEG 101 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-investigational-therapy-crizanlizumab-seg101- receives-fda-breakthrough-therapy-designation-prevention-vaso-occlusive-crises-sickle-cell-disease Accessed 11 October 2019. [5] Ataga, K, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. New England Journal of Medicine. https://www.nejm.org/doi/10.1056/ NEJMoa1611770. Accessed 14 October 2019. {6} National Sleep Foundation. What is Insomnia? https://www.sleepfoundation.org/insomnia/what-insomnia. Accessed 14 October 2019 [7] Colten, H., Altevogt, B., Research, I. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. https://www.ncbi.nlm.nih.gov/books/ NBK19948/#a2000f7efddd00033. Accessed 14 October 2019. [8] Daily, M., Morin, C., LeBlanc, M. The Economic Burden of Insomnia: Direct and Indirect Costs for Individuals with Insomnia Syndrome, Insomnia Symptoms, and Good Sleepers. Sleep, 32(1), 55–64. doi: 10.5665/sleep/32.1.55. [9] Morin, C., LeBlanc, M., Daley, M., Gregoire, J., Merette, C. Epidemiology of insomnia: Prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Medicine, 7(2), 123-130. doi: 10.1016/j.sleep.2005.08.008. [10] Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med, 13(2), 307–349. https://aasm.org/resources/clinicalguidelines/040515.pdf. Accessed 14 October 2019. [11] Janto, K., Prichard R., Pusalavidyasagar, S. An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. J Clin Sleep Med, 14(8),1399–1408. http://jcsm.aasm.org/ViewAbstract.aspx?pid=31355. Accessed 14 October 2019. [12] Eisai to Present New 12-month Safety & Effectiveness Data from Phase 3 Lemborexant SUNRISE 2 Study and New Patient and Cohabitant Insights about Insomnia and Toll on Next-Day Functioning at World Sleep Congress. http://eisai.mediaroom.com/2019-09-19-Eisai-to-Present-New-12-month-Safety-Effectiveness-Data-from- Phase-3-Lemborexant-SUNRISE-2-Study-and-New-Patient-and-Cohabitant-Insights-about-Insomnia-and-Toll-on-Next-Day-Functioning-at-World-Sleep-Congress. Accessed 14 October 2019. [13] Zammit, G., Mayleben, D., Kumar, D., Murphy, P., Moline, M. Efficacy of lemborexant compared with zolpidem extended release and placebo in elderly subjects with insomnia:results from a phase 3 study (SUNRISE 1). The American Journal Of Geriatric Psychiatry, 27(3), S195-S196. doi: 10.1016/j.jagp.2019.01.108. [14] Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2). NCT02952820 ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02952820. Accessed 14 October 2019. [15] Belsomra (suvorexant) [prescribing information]. Whitehouse Station, NJ: Merck, Sharpe & Dohme Corp.; July 2018. [16] Moline, M., et al. 0368 Efficacy and Tolerability of Lemborexant in Female and Male Subjects with Insomnia. Sleep, 42(Supplement_1), A150-A150. doi: 10.1093/ sleep/zsz067.367. [17] Federal Drug Administration. FDA requires stronger warnings about rare but serious incidents related to certain prescription insomnia medicines. https://www.fda. gov/news-events/press-announcements/fda-requires-stronger-warnings-about-rare-serious-incidents-related-certain-prescription-insomnia. Accessed 14 October 2019. [18] Eisai presents new data on lemborexant for the treatment of irregular sleep-wake rhtym disorder in patients with Alzheimer’s disease at the 11th clinical trials in Alzheimer’s disease conference. News Release：2018 | Eisai Co., Ltd. https://www.eisai.com/news/2018/news201893.html. Accessed 14 October 2019. [19] World Health Organization. The Global Burden of Disease: 2004 Update, WHO Press, Geneva 2008. [20] Buchanan RW, et al. Schizophrenia Patient Outcomes Research Team (PORT). The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71. Epub 2009 Dec 2. [21] DISORDERS, A. (2019). Lumateperone | Intracellular Therapies. https://www.intracellulartherapies.com/products-and-technology/lumateperone/. Accessed 9 October 2019. [22] Vanover, K., et al. 30 Lumateperone (ITI-007) for the Treatment of Schizophrenia: Overview of Placebo-Controlled Clinical Trials and an Open-label Safety Switching Study. CNS Spectrums, 24(1), 190-191. doi: 10.1017/s1092852919000245. [23] Short M., Domagalski J. Iron Deficiency Anemia: Evaluation and Management. Am Fam Physician, 87(2), 98-104. [24] Positive results for Feraccru® in AEGIS-H2H non-inferiority study. https://www.shieldtherapeutics.com/wp-content/uploads/2019/03/STX-AEGIS-H2H-study-results. pdf. Accessed 14 October 2019. [25] Nourianz. [package insert] Kyowa Kirin: Bedminster, NJ. September 2019. [26] Ahlskog J., Muenter M. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.(2001) Mov Disord, 16 (3), 448–458. [27] Zhou C. et al. Comparison for Efficacy and Tolerability among Ten Drugs for Treatment of Parkinson’s Disease: A Network Meta-Analysis. (2017). Sci Rep. 7, 45865. doi: 0.1038/srep45865 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379205/ [28] FDA approves Roche’s Rozlytrek (entrectinib) for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours. (2019). Retrieved 14 October 2019, from https://www.roche.com/media/releases/med-cor-2019-08-16.htm [29] Scharschmidt, T. Tenosynovial Giant Cell Tumor - NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/tenosynovial-giant-cell- tumor/. Accessed 14 October 2019. [30] Tap, W., et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. The Lancet, 394(10197), 478-487. doi: 10.1016/s0140-6736(19)30764-0. [31] Cappelli, S., et al. Interstitial lung disease in systemic sclerosis: where do we stand?. European Respiratory Review, 24(137), 411-419. doi: 10.1183/16000617.00002915.

16 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Sources Continued

[32] Granulomatosis with Polyangitis (Wegner’s). https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Granulomatosis-with-Polyangitis- Wegners. Accessed 14 October 2019. [33] Ward, M, et al. Update of American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis & Rheumatology, 7(10), 1599-1613 DOI 10.1002/ art41042. https://www.rheumatology.org/Portals/0/Files/AxialSpA-Guideline-2019.pdf. [34] Korhonen P., Haukka J., Kuoppamaki M., Ellmen J., Aho V., Vahteristo M. The risk of developing prostate cancer in entacapone and levodopa/DDCI users compared to levodopa/DDCI users without entacapone – A nation-wide retrospective register-based study. (2013). EPID Research Oy, Tekniikantie, Finland.

Clinical efficacy and safety, balanced with a drug’s value, are always at the forefront in the EnvisionRx formulary decisions and pipeline planning. The rationale for those decisions may go beyond the use of the FDA’s labeled indication. Our clinical reviews may utilize, but are not limited to, recognized consensus guidelines, the Institute for Clinical and Economic Review (ICER), and compendium such as the National Comprehensive Cancer Network (NCCN Guidelines®) and DRUGDEX®. EnvisionRx monitors FDA updates and safety announcements daily, as well as follows guidance from the Center of Disease Control and prevention (CDC) and the US Preventive Service Task Force (USPSTF®).

17 | PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Our Clinical Steering Committee

The Envision Clinical Steering Committee brings together leaders from across our national pharmacy care company to monitor the drug landscape, provide recommendations on how to address changes, and to ensure our clients and patients are prepared—in advance.

With any new development, we partner with our Pharmacy & Therapeutics (P&T) Committee and consult with our best-in-class specialty pharmacy, to provide a balanced perspective on the clinical effectiveness of all available options, the cost impact to our plan sponsors and patients, and the impact on the overall patient experience.

Kel Riley, MD Chief Medical Officer

Learn more ways to improve patient and plan outcomes visiblydifferent.envisionrx.com

ABOUT ENVISIONRX | ENVISIONRX.COM EnvisionRx is a Pharmacy Benefit Manager (PBM), providing affordable and effective prescription drug coverage for employers and health plans. Using its proprietary EnvisionCare model, EnvisionRx optimizes all aspects of the pharmacy care experience to consistently achieve better patient and plan outcomes.

© 2019 EnvisionRxOptions All Rights Reserved. 19-3738