December 2017

PIPELINE TRxENDS

PIPELINE TR ENDS is produced by the x 1-3 Promising New Agents 5 Industry Trends University of Massachusetts Medical School’s 4 Projected Generic Entry 5 Additional Promising Clinical Pharmacy Services division and 4 Investigational Indications New Agents distributed to our clients annually. 4 FDA Updates

In This Issue Promising New Agents

Promising New Agents Drug Name: Binimetinib/encorafenib Drug Name: Erenumab Patisiran Manufacturer: Array BioPharma Manufacturer: Amgen NDA Rolling NDA Indication: BRAF-mutant melanoma BLA Indication: Prevention of migraine submission initiated Formulation: Oral tablet/capsule Formulation: Subcutaneous injection in November 2017 Tezacaftor/ivacaftor FDA decision expected Binimetinib, a MEK inhibitor, and encorafenib, Erenumab is a monoclonal antibody targeting Feb. 28, 2018 a BRAF inhibitor, affect key protein kinases in the the calcitonin gene-related peptide (CGRP) receptor. cellular signaling pathway. The combination is being Erenumab is being studied for the prevention of Projected investigated for the treatment of BRAF-mutant migraine in patients with at least four migraine days Generic Entry advanced, unresectable, or metastatic melanoma. per month.

® Enbrel The two-part, randomized, open-label Phase The Phase III STRIVE (N=955) and ARISE (N=577) ® Lyrica III COLUMBUS trial (N=921) compared binimetinib trials evaluated the safety and efficacy of once- Remodulin® plus encorafenib to monotherapy with vemurafenib monthly treatment with erenumab compared to Sensipar® or encorafenib. In Part 1 (N=577), the median placebo in adult patients with a minimum of a progression-free survival (mPFS) was 14.9 months in one-year history of episodic migraines. In STRIVE, Investigational patients treated with binimetinib 45 mg twice daily patients in the erenumab 70 mg and 140 mg groups Indications plus encorafenib 450 mg once daily compared to 7.3 experienced 3.2-day and 3.7-day reductions in Canakinumab months in patients treated with vemurafenib 960 mg monthly migraine days (MMDs), respectively, from For the prophylaxis twice daily (hazard ratio [HR] 0.54, 95 percent CI baseline to weeks 13 to 24 compared to a 1.8-day of major adverse 0.41 to 0.71, P<0.001) and 9.6 months in patients reduction in the placebo group (P<0.001 for both). cardiovascular events treated with encorafenib 300 mg once daily (HR In addition, 43.3 percent of patients in the 70 mg 0.75, 95 percent CI 0.56 to 1.00, P=0.051). In Part group and 50.0 percent of patients in the 140 mg Obeticholic acid For the treatment 2 (N=344), the mPFS was 12.9 months in patients group experienced a 50 percent or greater reduction of non-alcoholic treated with binimetinib 45 mg twice daily plus in MMDs compared to 27 percent of patients in steatohepatitis encorafenib 300 mg once daily compared to 9.2 the placebo group (odds ratio [OR] 2.13 and 2.81, months in patients treated with encorafenib 300 mg respectively). In ARISE, patients in the erenumab 70 FDA Updates once daily (HR 0.77, 95 percent CI 0.61 to 0.97). mg group experienced a 2.9-day reduction in MMDs Baricitinib compared to a 1.8-day reduction in the placebo If approved, binimetinib plus encorafenib may Manufacturer group (P<0.001). In both trials, the frequency of provide an effective treatment option for BRAF- received complete adverse events was similar between all treatment response letter mutant advanced, unresectable, or metastatic groups. Dexamethasone melanoma. These agents are also being investigated insert in Phase II trials for the treatment of relapsed or If approved, erenumab would be the first Manufacturer refractory multiple myeloma and BRAF V600E- monoclonal antibody targeting the CGRP receptor received complete response letter mutant colorectal cancer. New Drug Applications and may offer a treatment alternative for the (NDAs) for binimetinib and encorafenib have prevention of migraines. The Biologics License Romosozumab Manufacturer been accepted for review by the Food and Drug Application (BLA) for erenumab has been accepted received complete Administration (FDA) and a decision is expected by for review by the FDA and a decision is expected by response letter June 30, 2018. May 17, 2018.

Non-Specialty Specialty Non-Specialty Specialty Non-Specialty Specialty Promising New Agents Promising New Agents

Drug Name: Lanadelumab years and older with type I and II HAE were well-tolerated with the most commonly- Manufacturer: Shire randomized to one of three lanadelumab reported adverse event being injection site PhaseNDA III Indication: Hereditary angioedema regimens (300 mg every two weeks, 300 pain. The HELPTM Study Extension is ongoing Formulation: Subcutaneous injection mg every four weeks, or 150 mg every four to evaluate long-term safety. weeks) or placebo. The primary efficacy If approved, lanadelumab may provide endpoint, the number of investigator- Lanadelumab is being investigated for an advantage over currently-available long- confirmed angioedema attacks during the the long-term prophylaxis of angioedema term HAE prophylactic medications due 26-week treatment period, was reduced by attacks in patients with hereditary to less frequent dosing and convenience 87 percent in the 300 mg every two weeks angioedema (HAE). Lanadelumab is a long- of administration. A BLA for lanadelumab group, 73 percent in the 300 mg every acting, fully-human monoclonal antibody is anticipated by late 2017 or early 2018. four weeks group, and 76 percent in the that binds to plasma kallikrein. The FDA has granted lanadelumab the 150 mg every four weeks group compared Orphan Drug and Breakthrough Therapy The efficacy and safety of to placebo (P<0.001). Results were found designations. lanadelumab was evaluated in the Phase to be similar regardless of baseline attack III HELPTM study (N=125). Patients ages 12 frequency. Lanadelumab was generally

Drug Name: Lasmiditan migraine. At two hours post-first dose, findings were consistent with the previous Manufacturer: Eli Lilly Phase III the percentage of patients who were Phase III trial, SAMURAI (N=2,232), which Indication: Migraine migraine pain-free was greater in the compared two doses of lasmiditan Formulation: Oral tablet lasmiditan 50 mg, 100 mg, and 200 mg (100 mg and 200 mg) to placebo. The groups compared to the placebo group (28.6 ongoing, open-label Phase III GLADIATOR percent, P=0.003; 31.4 percent, P<0.001; study will evaluate the long-term safety of Lasmiditan is a first-in-class serotonin 38.8 percent, P<0.001; and 21.3 percent, lasmiditan. (5HT) agonist targeting receptors in the 1F respectively). More patients treated with trigeminal pathway. It is being investigated If approved, lasmiditan may provide a lasmiditan 50 mg, 100 mg, and 200 mg were for the acute treatment of migraine. therapeutic alternative for the treatment also free of their migraine-associated most of migraine without the vasoconstrictor In the randomized, double-blind, bothersome symptom at two hours post- activity associated with 5HT receptor placebo-controlled Phase III SPARTAN first dose compared to patients treated 1B/1D agonists, such as triptans. An NDA trial (N=3,007), the safety and efficacy with placebo (40.8 percent, P=0.009; 44.2 submission for lasmiditan is anticipated in of three lasmiditan doses were compared percent, P<0.001; 48.7 percent, P<0.001; the second half of 2018. to placebo for the acute treatment of and 33.5 percent, respectively). These

Drug Name: Omadacycline omadacycline or moxifloxacin for 7 to trials of adults with ABSSSI, treatment Manufacturer: Paratek 14 days. Clinically stable patients in with omadacycline was non-inferior Phase III Indication: ABSSSI, CABP both treatment arms transitioned to to linezolid at the ECR, defined as ≥20 Formulation: Oral, intravenous omadacycline 300 mg or moxifloxacin percent reduction in lesion size at 400 mg orally once daily after a minimum 48 to 72 hours post-first dose. of three days of intravenous therapy. The Omadacycline is a first-in-class Omadacycline received the Qualified primary endpoint of non-inferiority to aminomethylcycline with broad-spectrum Infectious Disease Product and Fast Track moxifloxacin at the early clinical response activity against gram-positive, gram- designations from the FDA and may offer (ECR) was defined as an improvement negative, and atypical bacteria. It is a treatment option for patients with in ≥2 of 4 symptoms at 72 to 120 hours. being studied for the treatment of acute ABSSSI or CABP who are not candidates Treatment with omadacycline was non- bacterial skin and skin structure infection for standard antibiotic therapy. inferior to moxifloxacin, with 81.1 and 82.7 (ABSSSI) and community-acquired bacterial Omadacycline is also being studied for percent of patients, respectively, achieving pneumonia (CABP). the treatment of uncomplicated urinary an ECR (treatment difference -1.6, tract infection. NDA submissions are In the Phase III OPTIC trial (N=774), 95 percent CI -7.1 to 3.8). In the Phase anticipated in early 2018. adults with CABP were randomized to III OASIS-1 (N=645) and OASIS-2 (N=735)

UMass Medical School’s Clinical Pharmacy Services 2 Non-Specialty Specialty Promising New Agents

Drug Name: Ozanimod orally once daily to Avonex® (interferon treatment with ozanimod did not achieve Manufacturer: Celgene [IFN] beta-1a) intramuscularly once weekly statistical significance in the time to three- Phase III Indication: Relapsing MS for the treatment of RMS. In SUNBEAMTM, month confirmed disability progression. Formulation: Oral capsule patients receiving ozanimod 1 mg and Both trials reported no episodes of second 0.5 mg achieved a greater reduction in or third degree atrioventricular block, annualized relapse rate (ARR) compared to similar infection rates between groups, Ozanimod is an oral, selective patients receiving IFN beta-1a (ARR=0.18, and that most alanine aminotransferase sphingosine 1-phosphate receptor P<0.0001; ARR=0.24, P=0.0013; and increases that occurred were self-limiting. (S1PR) 1 and 5 modulator currently ARR=0.35, respectively). In RADIANCETM being investigated for the treatment of If approved, ozanimod may provide Part B, patients receiving ozanimod 1 mg relapsing multiple sclerosis (RMS). an effective oral treatment option for RMS and 0.5 mg achieved a greater reduction with a more favorable side effect profile The randomized, double-blind in ARR compared to patients receiving IFN than the currently available non-selective Phase III SUNBEAMTM (N=1,346) and beta-1a (ARR=0.17, P<0.0001; ARR=0.22, S1PR modulator. An NDA submission is RADIANCETM Part B (N=1,320) trials P=0.0167; and ARR=0.28, respectively). In a anticipated by the end of 2017. compared ozanimod (1 mg and 0.5 mg) pre-specified pooled analysis of both trials,

Drug Name: Patisiran with hATTR amyloidosis and polyneuropathy. increase (worsening) with placebo (mean NDA Manufacturer: Alnylam The primary endpoint was the between- difference 21.1 points, P=1.10 x 10-10). Indication: hATTR amyloidosis group difference in mean change in modified Peripheral edema and infusion-related Formulation: Intravenous infusion Neuropathy Impairment Score (mNIS+7) reactions occurred more frequently in the from baseline at 18 months. Patients patisiran group than in the placebo group. receiving patisiran achieved a mean 6.0- Patisiran, a small interfering If approved, patisiran will be the first point reduction (improvement) in mNIS+7 ribonucleic acid (siRNA), targets a specific RNA interference (RNAi) therapeutic, a score from baseline at 18 months compared sequence of messenger RNA (mRNA) to new class of medications, and the first to a mean 28.0-point increase (worsening) reduce serum levels of transthyretin FDA-approved agent for the treatment of with placebo (mean difference 34.0 points, (TTR) protein. Patisiran is currently being hATTR amyloidosis. The FDA has granted P=9.26 x 10-24). Patients receiving patisiran studied for the treatment of hereditary patisiran the Orphan Drug and Fast Track achieved a mean 6.7-point reduction amyloidogenic TTR (hATTR) amyloidosis. designations. A rolling NDA submission was (improvement) in Norfolk-Quality of Life- initiated in November 2017. The Phase III APOLLO trial (N=225) Diabetic Neuropathy score from baseline at compared patisiran to placebo in adults 18 months compared to a mean 14.4-point

Drug Name: Tezacaftor/ivacaftor The Phase III EVOLVE trial (N=477) mean absolute improvements of 6.8 and Manufacturer: Vertex compared tezacaftor 100 mg once daily in 2.1 percentage points in ppFEV compared NDA 1 Indication: Cystic fibrosis combination with ivacaftor 150 mg twice to placebo and ivacaftor monotherapy, Formulation: Oral tablet daily to placebo in patients with two copies respectively, from baseline to the average of the F508del mutation. Treatment with of the week four and eight measurements tezacaftor/ivacaftor resulted in a mean (P<0.0001). Tezacaftor/ivacaftor is a combination absolute improvement in percent predicted product that includes an FDA-approved If approved, tezacaftor/ivacaftor forced expiratory volume in one second cystic fibrosis (CF) transmembrane may provide a more effective option for (ppFEV ) of 4.0 percentage points from conductance regulator (CFTR) potentiator, 1 patients with specific combinations of baseline to 24 weeks compared to placebo ivacaftor, and an investigational CFTR F508del mutations. Tezacaftor/ivacaftor (P<0.0001). The Phase III EXPAND trial corrector, tezacaftor. Tezacaftor/ivacaftor was granted the Breakthrough Therapy (N=235) evaluated tezacaftor/ivacaftor is being studied for the treatment of designation and Priority Review status by and ivacaftor monotherapy in patients patients ages 12 and older with CF and the FDA, with a decision expected by with one copy of the F508del mutation and two copies of the F508del mutation or Feb. 28, 2018. one residual function mutation. Treatment one copy of the F508del mutation and one with tezacaftor/ivacaftor resulted in residual function mutation.

UMass Medical School’s Clinical Pharmacy Services 3 * Projected Generic Entry Investigational Indications

• Treximet® (sumatriptan/naproxen) • Aloxi® (palonosetron injection) Ilaris® (canakinumab) 2/2018 9/2018 The Phase III CANTOS trial (N=10,061) compared canakinumab 300 mg, 150 mg, and 50 mg every three • Factive® (gemifloxacin tablet) • Cialis® (tadalafil) months to placebo in adults with a previous myocardial 3/2018 9/2018 infarction (MI) and elevated high-sensitivity C-reactive

protein. The incidence rate of nonfatal stroke, nonfatal • Sensipar® (cinacalcet tablet) • Staxyn® (vardenafil orally MI, or cardiovascular (CV) death per 100-person years 3/2018 disintegrating tablet) was 3.90, 3.86, and 4.11 for the canakinumab 300 mg, 10/2018 150 mg, and 50 mg groups, respectively, compared • Enbrel® (etanercept) to 4.50 for the placebo group (P=0.031, P=0.021, and 4/2018 • Vesicare® (solifenacin P=0.30, respectively). The incidence of CV death was succinate) not significantly lower for any of the canakinumab • Lexiva® (fosamprenavir tablet) 10/2018 groups compared to placebo. A supplemental BLA 6/2018 submission is expected by the end of 2017. • Finacea® (azelaic acid gel) • Remodulin® (treprostinil injection) 11/2018 Ocaliva® (obeticholic acid) 6/2018 The Phase IIb FLINT trial (N=283) compared treatment • Fortesta® (testosterone gel) with obeticholic acid (OCA) 25 mg daily to placebo for • Acanya® (benzoyl peroxide/ 11/2018 72 weeks in patients with non-cirrhotic, non-alcoholic clindamycin phosphate 2.5%/1.2%) steatohepatitis (NASH). A greater proportion of patients 7/2018 • Lyrica® (pregabalin) treated with OCA achieved improved liver histology 12/2018 compared to the placebo group (45 versus 21 percent, Production Staff • Ampyra® (dalfampridine extended- P=0.0002). A retrospective analysis of the FLINT study release tablet ) • Rapaflo® (silodosin) found that 57 percent of patients with type 2 diabetes 7/2018 12/2018 who were treated with OCA achieved improved liver

histology (P<0.01). The Phase III pivotal REGENERATE trial is currently ongoing. *Dates are estimates, current as of 12/1/17, and are subject to change due to any patent litigation or additional patents.

fFDA Updates

Baricitinib DextenzaTM (dexamethasone insert) EvenityTM (romosozumab) On April 14, 2017, Eli Lilly and Company On July 11, 2017, Ocular TherapeutixTM, Inc. On July 16, 2017, Amgen and UCB announced and Incyte Corporation announced that the announced that the FDA issued a second that the FDA issued a CRL declining FDA issued a complete response letter (CRL) CRL for Dextenza TM (dexamethasone insert) approval of Evenity™ (romosozumab), a regarding the NDA for baricitinib, a Janus for the intracanalicular treatment of ocular subcutaneously-administered, bone-forming kinase (JAK) inhibitor being studied for the pain due to ophthalmic surgery. The CRL monoclonal antibody targeting sclerostin that treatment of moderate-to-severe rheumatoid cited deficiencies in manufacturing and is being investigated for the treatment of arthritis. The FDA requested additional data analytical testing. Citations from an FDA postmenopausal women with osteoporosis. to determine the most appropriate doses and reinspection in May 2017 prompted the Although no increased CV risk was observed to characterize the risk-benefit profile given company to submit an amendment in July in the FRAME clinical trial data that was the thromboembolic events that occurred in 2017; however, the FDA did not review this included in the BLA, the FDA has requested clinical trials. The manufacturers announced information prior to issuing the CRL. The CRL data from the subsequent BRIDGE and ARCH in August 2017 that a new clinical trial would indicated that resolution of the deficiencies trials after increased CV risk was observed in not be necessary. The NDA resubmission, is required before approval, but applicable the ARCH trial. The manufacturers are pooling which will include new safety and efficacy sections of the amendment may be included the requested data and plan to resubmit the data, is planned for January 2018. in future submissions. BLA as an extension of the current review.

Due to the frequent emergence of new information related to topics presented, this informational resource includes data publicly available to the production staff prior to the publication date. This publication is intended for informational use only and should not be used for making patient care decisions. References furnished upon request. 4 Industry Trends Additional Promising New Agents Agents in Clinical Development Drug Name Manufacturer Indication Product Timeline Phase III Phase I: 37.9% RPE65-mediated LuxturnaTM (voretigene Phase II: 43.3% Spark Therapeutics inherited retinal PDUFA date 1/12/2018 Phase I neparvovec) (subretinal)* Phase III: 18.8% dystrophy Advanced Lutathera® (lutetium Lu Phase II Accelerator Neuroendocrine tumors PDUFA date 1/27/2018 177 dotatate) (IV)* Applications

CNS AndexXa® Portola Factor Xa inhibitor Leading Indications with Agents PDUFA date 2/2/2018 in Late-Stage Development (andexanet alfa) (IV) Pharmaceuticals antidote

Bictegravir/emtricitabine/ Gilead Sciences HIV-1 PDUFA date 2/12/2018 1. Breast cancer tenofovir alafenamide 2. Non-small cell lung cancer Makena® auto-injector 3. Colorectal cancer AMAG Prevention of (hydroxyprogesterone PDUFA date 2/14/2018 Pharmaceuticals preterm birth 4. Pancreatic cancer caproate) (SC) 5. Type 2 diabetes mellitus Aerie Glaucoma, ocular 6. Ovarian cancer Netarsudil (opthalmic) PDUFA date 2/28/2018 7. Alzheimer’s disease Pharmaceuticals hypertension 8. Rheumatoid arthritis Multidrug-resistant Ibalizumab (IV)* Theratechnologies PDUFA date 4/3/2018 9. Prostate cancer HIV-1 10. Brain cancer Ultragenyx, Kyowa X-linked Burosumab (SC)* PDUFA date 4/17/2018 Hakko Kirin hypophosphatemia Production Staff

BioMarin Editor-in-Chief Pegvaliase (SC)* PKU PDUFA date 6/29/2018 Nicole M. Trask, PharmD Pharmaceuticals Clinical Consultant Pharmacist Familial Clinical Pharmacy Services Volanesorsen (SC)* Akcea Therapeutics chylomicronemia PDUFA date 8/30/2018 Managing Editor syndrome Sage Bagwell, PharmD Clinical Pharmacy Resident BAY94-9027 (IV)* Bayer Hemophilia A BLA accepted 10/2017 Clinical Pharmacy Services

Editorial Advisory Board Timothy Cummins, MBA, RPh Fremanezumab (SC)* Teva Pharmaceuticals Migraine prevention BLA submitted 10/2017 Executive Director Clinical Pharmacy Services Elagolix AbbVie Endometriosis NDA accepted 10/2017 Additional Contributors Bonnie Greenwood, PharmD, BCPS Clinical Program Director Sunovion Dasotraline ADHD NDA accepted 11/2017 Clinical Pharmacy Services Pharmaceuticals Mylissa Price, MPH, RPh Clinical Account Management Director Epidiolex® (cannabidiol)* GW Pharmaceuticals LGS, Dravet syndrome NDA submitted 10/2017 Clinical Pharmacy Services

Hind Douiki, PharmD Moderate-to-severe Tasmina Hydery, MBA, PharmD OlinvoTM (oliceridine) (IV) Trevena NDA submitted 11/2017 Neha Kashalikar, PharmD acute pain Pavel Lavitas, PharmD, BCPS Thomas Pomfret, MPH, PharmD, BCPS Table Abbreviations: ADHD=attention-deficit hyperactivity disorder, Karen Stevens, PharmD BLA=Biologics License Application, HIV=human immunodeficiency virus, Stephanie Tran, PharmD IV=intravenous, LGS=Lennox-Gastaut syndrome, NDA=New Drug Appli- Clinical Consultant Pharmacists cation, PDUFA=Prescription Drug User Fee Act, PKU=phenylketonuria, Clinical Pharmacy Services SC=subcutaneous

Acknowledgements Note: All agents are administered orally unless otherwise indicated. Ashley Thrasher, PharmD Candidate *Designates specialty drug.

UMass Medical School’s Clinical Pharmacy Services 5 Who We Are and What We Do

The University of Massachusetts Medical School’s Clinical Pharmacy Services is a national leader in clinical pharmacy support. Established in 1999 to provide drug utilization review services for the Massachusetts Medicaid program, Clinical Pharmacy Services now provides clinical and operational support, consulting , and service delivery in a broad range of areas such as evidence-based pharmaceutical care management, medication therapy management, patient-centered medical homes, pharmacy analytics, pharmacoeconomic analysis, and patient/prescriber outreach. We have assembled a team with exceptional depth and experience in multiple fields. Our clients include state Medicaid agencies, pharmacy benefit managers and managed care plans. PIPELINE TRxENDS is produced annually to provide our clients with critical information about drugs in development.

Contact: Timothy Cummins, MBA, RPh Executive Director UMass Medical School Clinical Pharmacy Services University of Massachusetts Medical School 333 South Street Tel: 774-455-3440 Clinical Pharmacy Services Shrewsbury, MA 01545 Fax: 877-208-7428 Website: commed.umassmed.edu/cps Email: [email protected]

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