Keeping Track: Approvals, A Burst Of Submissions, And Some Priority Reviews

The latest drug development news and highlights from our US FDA Performance Tracker.

Here's your drug review and approval news in brief: holiday season of mass approvals has continued on, highlighted by the US FDA's backing of Novo Nordisk AS' Ozempic (semaglutide) for the treatment of type 2 diabates. The approval was No. 41 in the agency's 2017 new drug approval count.

But approvals had to share the spotlight with submissions, as Siga Technologies Inc., Amicus Therapeutics Inc. and Alnylam Pharmaceuticals Inc. each made new molecular entity (NME) filings this past week.

Bristol-Myers Squibb Co. and Merck & Co. Inc. are one step closer to tacking on additional indications to their respective programmed death receptor-1 (PD-1) inhibitors Opdivo (nivolumab) Keytruda (pembrolizumab), with each receiving a priority review.

Additionally, Pfizer Inc. got approval for its Remicade biosimilar Ixifi (infliximab-qbtx) but indicated it won't market it.

Here's your news in less brief:

FDA Inches Closer To 2015 Approval Record With Ozempic Greenlight

Novo got the FDA nod Dec. 5 for its glucagon-like peptide 1 (GLP-1) receptor agonist Ozempic, becoming new drug No. 41 approved by the agency this year as it nears its 2015 record total of 45.

A once-weekly injection, Ozempic was approved specifically as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes in 0.5 or 1 mg dosages.

Ozempic's efficacy was never in question, as it achieved sustained reductions in hemoglobin A1c in the clinical program, which included placebo- and active-controlled trials. FDA's concerns instead revolved around an increase in diabetic retinopathy complications among semaglutide-treated patients in the SUSTAIN-6 clinical trial. (Also see "Novo's Semaglutide: Retinopathy Events Will Draw US FDA Panel's Focus" - Pink Sheet, 16 Oct, 2017.)

Nevertheless, the Endocrinologic and Metabolic Drugs Advisory Committee voted in favor of approval by a 16-0 margin, with one abstention. (Also see "Semaglutide Retinopathy Risk No Bar To Approval, US Panel Says" - Pink Sheet, 18 Oct, 2017.)

As expected, Ozempic only has a standard warning in its label related to retinopathy – which notes that patients with a history of diabetic retinopathy should be monitored – rather than a boxed warning. The standard warning is not projected to dim the drug's rosy commercial prospects. (Also see "Novo's Semaglutide: Retinopathy Warning Unlikely To Dim Commercial Prospects" - Scrip, 19 Oct, 2017.)

Outside of required pediatric studies, Novo is required to conduct a medullary thyroid carcinoma registry-based case series of at least 15 years "to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Ozempic (semaglutide) into the marketplace," in the postmarketing phase. Ozempic has a boxed warning for thyroid C cell tumors, as do all GLP-1 receptor agonists.

Novo plans to launch the drug in the first quarter of 2018. The company adds that Ozempic will be priced "at parity to current market-leading weekly GLP-1 receptor agonists."

With the thumbs up, FDA has an outside shot of matching its 2015 record of new drug approvals. Merck & Co. Inc. and Pfizer Inc.'s ertugliflozin and AEterna Zentaris Inc.'s Macrilen (macimorelin) each have user fee goal dates in December 2017. But the agency has shown on several occasions this year that it is willing to approve new products with 2018 goal dates early. It would certainly look good from a public relations standpoint for the agency if it were to match 2015's total.

FDA Commissioner Scott Gottlieb acknowledged the possibility of tying the record at a Senate Committee on Health, Education, Labor and Pensions hearing earlier in December, noting that the agency "may be on track to approve the highest or second highest number of novel medicines across our combined biologics and drug centers in FDA’s entire history," in 2017. (Also see "Gene Therapy Guidances Will Focus On Specific Diseases, Gottlieb Says" - Pink Sheet, 7 Dec, 2017.)

Admelog Wins FDA Approval After Flying Under The Radar

FDA approved Sanofi's Admelog (insulin lispro injection) Dec. 11 as the first short-acting insulin approved as a follow-on through the 505(b)(2) pathway after very quietly moving through the development and regulatory review phases.

Admelog is indicated to improve control in blood sugar levels in adults and pediatric patients ages 3 and older with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. (See sidebar for related story).

The application was approved in-part based on FDA's finding of safety and efficacy for Eli Lilly & Co.'s Humalog (insulin lispro injection). Admelog-specific data included two Phase III trials with approximately 500 patients in each, according to FDA.

Gottlieb himself was featured in the agency's statement on the approval, touting FDA's backing as a step toward fostering greater competition in the Rx market.

“One of my key policy efforts is increasing competition in the market for prescription drugs and helping facilitate the entry of lower-cost alternatives," Gottlieb said. "This is particularly important for drugs like insulin that are taken by millions of Americans every day for a patient’s lifetime to manage a chronic disease."

Gottlieb added that the agency will be taking additional policy steps to improve competition "in the coming months."

Sanofi, however, has said very little about the product. It does not appear that the company publicly mentioned the Admelog in a US context until it announced the tentative approval in September. Sanofi additionally brought up Admelogo in a Q3 earnings statement in November, noting that the company filed a paragraph IV certification, and that Lilly did not file a suit within the 45-day period.

Sanofi appeared to make two announcements about Admelogo in a European context, as the European Commission approved it as a biosimilar in July under the trade name Insulin lispro Sanofi. The other announcement was related to the European Union accepting the marketing authorization application for review.

A company spokesperson tells the Pink Sheet that the Sanofi will be providing more specifics on price when the product is launched in the US in early 2018.

Burst Of NME Submissions Accompany Approval Rush

The theme of November and December so far has been approvals galore. This past week, however, also featured a batch of NME filings with FDA:

• Siga's antiviral Tpoxx (tecovirimat) for the treatment of smallpox. The company filed the Tpoxx new drug application (NDA) on Dec. 8, meaning a standard review would position the drug for a Dec. 8, 2018 approval. A priority review, however, would mean a user fee date of Aug 8, 2018. The company previously signed a contract with the Department of Health and Human Services' (HHS) Biomedical Advanced Research and Development Authority (BARDA), where BARDA would provide funding for the Tpoxx's development, and the company would provide two million courses of the drug to the US government's Strategic National Stockpile. (Also see "Smallpox Discovery Prompts FDA Action Plan; Move To White Oak Unchanged" - Pink Sheet, 14 Jul, 2014.)) Siga developed Tpoxx – which would be the first smallpox drug approved in the US – under FDA's rarely used animal rule, which allows the agency to approve certain drugs developed to treat serious or life-threatening conditions based on well-controlled animal efficacy studies when human efficacy studies are not ethical and field trials are not feasible. (Also see "Flexible 'Menu' Of Antibacterial Development Options Suggested By US FDA Panel" - Pink Sheet, 18 Apr, 2017.)
• Amicus' oral precision medicine migalastat for the treatment of patients 16 and older with Fabry disease who have amenable mutations. The submission comes after a shocking reversal from FDA, which initially rejected the company's plan for accelerated approval based on kidney globotriaosylceramide (GL-3) measurements, and called for a new trial. (Also see "Amicus Eyes Broad Future Label For Migalastat After Huge Filing Setback" - Pink Sheet, 29 Nov, 2016.) However, following discussions between Amicus and the agency, FDA ultimately agreed that the company can submit its NDA based on existing data. (Also see "FDA Reversal Gives Amicus Renewed Hope For US Oral Fabry Launch" - Pink Sheet, 11 Jul, 2017.)
• Alnylam's RNA interference (RNAi) drug patisiran for the treatment of adults with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). The drugmaker announced the completion of the rolling submission Dec. 12. In the randomized, double-blind, placebo-controlled Phase III APOLLO trial, patients in the treatment arm demonstrated statistically significant lower scores the neuropathy impairment score compared with subjects in the placebo arm. Ionis Pharmaceuticals Inc. is waiting for approval for inotersen a potential competitor to patisiran. Ionis has touted the convenience of inotersen versus that of patisiran. Patisiran is administered every three weeks by infusion in a healthcare provider's office and involves pre-treatment with high doses of steroids, while Inotersen is administered at home and does not require high-dose steroids. (Also see "Keeping Track: A Massive Week Of Agency Approvals" - Pink Sheet, 12 Nov, 2017.)

FDA Accepts Lilly's Galcanezumab BLA For The Prevention Of Migraines

Lilly announced Dec. 11 that FDA accepted for review the drugmaker's biologics license application (BLA) for its preventative migraine treatment galcanezumab, as three different companies are in a race to get an anti-calcitonin gene-related peptide (anti-CGRP) to the market for the indication.

Amgen Inc. and its partner Novartis AG are first in line for an approval, as their candidate Aimovig (erenumab) has a Prescription Drug User Fee Act (PDUFA) date of May 17, 2018.

Teva Pharmaceutical Industries Ltd. was the second to file its BLA, announcing its submission of fremanezumab Oct. 17. Lilly had not submitted its BLA for galcanezumab at that point. (Also see "Keeping Track: Another Gene Therapy Approval, Several Priority Review Designations, And Many Resubmissions" - Pink Sheet, 22 Oct, 2017.) Lilly later announced in an Oct. 24 earnings call that it filed the application.

It does not appear that FDA has accepted Teva's BLA yet. Teva said the company does not currently have any updates on fremanezumab's application, noting that it hasn't reached the 60 to 74-day filing acceptance window yet.

Fremanezumab has the dosing advantage with its quarterly dosing frequency, while Aimovig and galcanezumab were each tested as monthly doses.

In the Phase III EVOLVE-1, EVOLVE-2 and REGAIN trials which evaluated 2,901 total patients, galcanezumab demonstrated a statistically significant reduction in the average number of monthly migraine headache days compared with placebo.

Bristol Eyes Springtime Opdivo, Yervoy Approval For RCC Indication

Bristol has snagged a priority review for its Opdivo and Yervoy (ipilimumab) combination for the treatment of intermediate- and poor-risk patients with advanced renal cell carcinoma (RCC), with a user fee goal date of April 16, 2018.

In the randomized, open label Phase III CheckMate 214 trial, the combination met the co-primary endpoints of improved overall survival and objective response rate compared with Pfizer Inc.'s Sutent (sunitinib). Bristol stopped the study early with the recommendation of an independent data monitoring committee, following an interim analysis of overall survival. The overall survival data, could ultimately save the combination, which previously failed to achieve statistical significance in the progression-free survival (PFS) endpoint. (Also see "Another Opdivo Disappointment For BMS, This Time In Kidney Cancer" - Scrip, 15 Aug, 2017.)

Bristol also announced that the combination previously received a breakthrough therapy designation for the treatment of RCC. The Opdivo/Yervoy combination is currently approved for the treatment of patients with unresectable or metastatic melanoma, which received accelerated approval based on PFS.

In the RCC arena, Opdivo is currently approved as a monotherapy for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, as well as a slew of other indications. A PD-1 inhibitor, Opdivo recently scored an approval for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Bayer AG's Nexavar (sorafenib). (Also see "FDA Approval Round Up: Keytruda, Opdivo Add Claims" - Pink Sheet, 24 Sep, 2017.)

Keytruda Gets Priority Review For PMBCL Indication

Speaking of PD-1 inhibitors, Merck & Co. Inc.'s Keytruda also won a priority review, picking up the designation for the treatment of adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) who have relapsed after two or more prior lines of therapy, the company announced Dec. 11.

An approval would mark Keytruda's first non-Hodgkin lymphoma indication and its eleventh overall.

In the PMBCL cohort of the Phase II KEYNOTE-170 trial, KEYTRUDA demonstrated an overall response rate (ORR) of 41%, including a 24% complete response rate and a 17% partial response rate.

FDA has assigned Keytruda a PDUFA date of April 3, 2018. The PD-1 inhibitor previously received a breakthrough therapy designation for the PMBCL indication. (Also see "Keeping Track: A Blizzard Of Submissions And A Small Flurry Of Approvals" - Pink Sheet, 5 Feb, 2017.)

Keytruda most recently garnered accelerated approval for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 with disease progression on or after two or more prior lines of therapy. (Also see "FDA Approval Round Up: Keytruda, Opdivo Add Claims" - Pink Sheet, 24 Sep, 2017.) In March, FDA approved Keytruda for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma who have relapsed after three or more prior lines of therapy.

Nucala sBLA Wins FDA Approval For First EGPA Treatment

Continuing what has been a busy fourth quarter of approvals, GlaxoSmithKline PLC's nabbed FDA's blessing to a Nucala (mepolizumab) supplemental biologics license application (sBLA) Dec. 12 for the treatment of adults with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease.

It is the first agency-approved treatment for EGPA, which causes inflammation in the wall of blood vessels. The inflammation can then affect the lungs, gastrointestinal tract, skin, heart and nervous system.

An interleukin-5 (IL-5) antagonist, Nucala met its co-primary endpoints of accrued time in remission and the proportion of patients achieving remission at weeks 36 and 48 in the placebo-controlled, 136-patient Phase III MIRRA trial.

"The expanded indication of Nucala meets a critical, unmet need for EGPA patients," Badrul Chowdhury, director of FDA's Division of Pulmonary, Allergy and Rheumatology Products, said in a statement. "It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

Nucala was first approved in November 2015 as an add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. In November, GSK filed Nucala for the treatment of chronic obstructive pulmonary disease (COPD) in 2017, despite a missed primary endpoint in one Phase III study and no significant improvement in clinical outcomes. (Also see "Glaxo Set To File Nucala In COPD, Despite Mixed Phase III Results" - Pink Sheet, 12 Sep, 2017.)

Pfizer Won't Launch Remicade Biosimilar Following Approval

Pfizer will have its Remicade biosimilar Ixifi in its back pocket following FDA's Dec. 13 approval as the drugmaker will not launch its copycat in the US amid its partnership with Celltrion Inc.

The company currently markets Celltrion's Remicade biosimilar Inflectra (infliximab-dyyb) in the US, and says it remains committed to doing so. Pfizer now has Ixifi as an option for flexibility in case of changes in its partnership with Celltrion. (Also see "Pfizer's Infliximab Biosimilar Approved In US But Won't Launch Against Inflectra" - Scrip, 14 Dec, 2017.)

Pfizer obtained commercialization rights to Inflectra as part of its acquisition of Hospira Inc., when Pfizer's biosimilar was in Phase III development. (Also see "Where's the value in Pfizer's $17bn Hospira buy?" - Scrip, 6 Feb, 2015.)