Keeping Track: Delay (For Celgene), Delay (For Allergan), Goose! (Approval For Lilly)

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

Here's your news in brief from the land of reviews and approvals: Celgene Corp. has suffered yet another setback, as the US FDA has refused to file a new drug application (NDA) for its multiple sclerosis drug ozanimod.

The agency also pushed back the Prescription Drug User Fee Action (PDUFA) date for Allergan PLC's ulipristal acetate NDA, requesting more time to evaluate the findings of a European review of potential safety signals linked to the drug.

Eli Lilly & Co. scored another approval for its kinase inhibitor Verzenio (abemaciclib), while Galera Therapeutics Inc. reeled in a breakthrough therapy designation for its severe oral mucositis candidate GC4419.

Now here's your news in less brief:

Celgene Mum On Details As FDA Refuses To File Ozanimod

FDA has refused to file Celgene's multiple sclerosis drug ozanimod, and the company did not offer much clarity on the specifics beyond that the decision was related to nonclinical and clinical pharmacology data.

The drugmaker said in a Feb. 27 statement that it would be requesting a Type A meeting with the agency to discuss the additional information that will be needed to submit the NDA for ozanimod, an oral selective sphingosine 1-phosphate 1 (S1PR1) and 5 (S1PR5) receptor modulator.

"We're going to take this step by step," Celgene CEO Mark Allen explained in a Feb. 27 investor call. "We received the Refusal to File. We wanted to inform investors. We wanted to embed this into our modeling. We will, as I said in my prepared remarks, work very aggressively and actively to meet with FDA as soon as we can. Once that meeting has happened, once we have a better sense of what information we can provide and other information we may need to provide, we would be reaching out to investors appropriately to provide updates."

Jay Backstrom, Celgene's chief medical officer, added that there is "no indication" that the company will need to conduct an additional pivotal trial. The initial NDA submission was based on the Phase III RADIANCE and SUNBEAM trials, which showed positive safety and efficacy results.  (Also see "Celgene Plots Blockbuster Course For Ozanimod" - Scrip, 30 Oct, 2017.)

A refuse to file (RTF) letter could mean only a minor delay, but multiple sclerosis drugs have seen mixed results following RTFs in the past. (Also see "Celgene Joins Troubled MS Club With Refuse To File For Ozanimod From US FDA" - Pink Sheet, 28 Feb, 2018.)

The RTF is nevertheless just the most recent setback for Celgene in recent months. For instance, it announced in October that it would discontinue development of its Chron's disease candidate mongersen after receiving results from an ulcerative colitis study. (Also see "More Bad News: Celgene Reveals Refuse-To-File Letter For Ozanimod In MS" - Scrip, 27 Feb, 2018.)

European Safety Review Of Ulipristal Pushes Back PDUFA Date

A European Medicines Agency (EMA) review of liver damage has prompted FDA to push back the PDUFA date of Allergan's uterine fibroid drug ulipristal acetate NDA by three months to August.

Allergan made the announcement in a brief statement on Feb. 28 without providing the reason for the goal date extension. In an emailed statement, however, the company pointed to an ongoing review of the selective progesterone receptor modulator by EMA's Pharmacovigilance Risk Assessment Committee (PRAC).

PRAC began a review of ulipristal acetate – marketed in the European Union under the brand name Esmya by Allergan's partner Gedeon Richter PLC – following five reports of serious liver injury, including four cases of hepatic failure needing liver transplantation. (Also see "Richter’s Uterine Fibroid Drug Esmya Hit By Liver Safety Concerns In EU" - Pink Sheet, 22 Feb, 2018.)

"As the evaluation by PRAC continues, Allergan has provided the FDA updates regarding the ongoing drug safety evaluation and provided an update in January 2018," according to the statement. "As a result, the FDA required more time and extended the NDA review."

In a Feb. 9 statement, Gedeon Richter said PRAC has recommended a series of temporary safety measures for Esmya as the review remains ongoing, including regular liver monitoring for women taking the drug for uterine fibroids. PRAC also recommended that no new patients be started on Esmya, and that no patients who have completed a course of treatment should start another one.

"We continue to believe that the totality of the data for Esmya supports a positive benefit-risk profile," Alergan added.

Lilly's Verzenio Rides MONARCH 3 Trial To Third Breast Cancer Indication

Lilly has worked quickly to expand the approved indications for Verzenio, the third cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor approved in the US. Verzenio received FDA clearance for its third indication in five months on Feb. 26, 2018, broadening its claims in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer to include use as initial endocrine-based therapy in combination with an aromatase inhibitor.

The NDA for the newly approved claim was submitted on Aug. 15, 2017, while Verzenio was still under review for its Sept. 28, 2017 initial approval. The original NDA supported indications for treatment of HR+, HER2- advanced or metastatic breast cancer in combination with fulvestrant for women with disease progression following endocrine therapy and as a single agent for patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The newly approved indication "is an important milestone, as it shows that Verzenio plus an aromatase inhibitor substantially reduced tumor size and delayed disease progression," Lilly said.

Verzenio received priority review for use in initial endocrine-based therapy, based on the Phase III MONARCH 3 trial. The trial compared Verzenio or placebo plus either anastrozole or letrozole in 493 postmenopausal women with HR+, HER2- breast cancer who had received no prior systemic treatment for advanced disease. Verzenio patients had a median progression-free survival (PFS) of 28.2 months compared with 14.8 months in the placebo arm. PFS was the primary endpoint of the trial, but a post-marketing commitment directs Lilly to submit overall survival (OS) data when mature.

Lilly has extensively analyzed its Verzenio data as it attempts to differentiate abemaciclib from Pfizer Inc.'s Ibrance (palbociclib) and Novartis AG's Kisqali (ribociclib) in the CDK4/6 inhibitor space. (Also see "Lilly Plumbs Data's Depths To Differentiate CDK4/6 Inhibitor Verzenio" - Scrip, 8 Dec, 2017.)

The company's announcement of Verzenio's latest approval points out that "notably, the MONARCH 3 trial included patients with certain concerning clinical characteristics, such as a pattern of disease that spread to the liver."

Galera Wins Breakthrough Designation For Oral Mucositis Candidate

Galera has picked up breakthrough therapy status for its severe oral mucositis candidate GC4419, setting its eyes on patients with head and neck cancer, the company announced Feb. 28.

A dismutase mimetic, GC4419 is specifically designed for the reduction of the duration, incidence and severity of severe oral mucositis induced by radiation therapy with or without systemic therapy. There are currently no drugs to treat or prevent severe oral mucositis in patients with head and neck cancer, the clinical-stage biotech says.

GC4419 works by converting superoxide generated by radiation therapy into hydrogen peroxide using Galera’s dismutase mimetic platform, which aims to reduce the duration, incidence and severity of radiation-induced severe oral mucositis.

Breakthrough therapy status was granted based on a 223-patient, double-blind, randomized, placebo-controlled Phase IIb trial, where the dismutase mimetic reduced the duration of severe oral mucositis from 19 days to 1.5 days. It also reduced the incidence of condition by 34% through the completion of radiation, as well as the severity by 47%.

The GC4419 designation capped off another busy month of breakthrough statuses. There were at least eight such designations publicly announced in January, along with another five in February, bringing the 2018 total to at least 13.

[Editor's note: Visit the Pink Sheet's Breakthrough Designation Therapy tracker page for the latest statistics and product listings in the category.]

Otiprio Approval Comes With Potential For Heightened Compliance, Wider Use

Otonomy Inc. has picked up its second approval for its fluoroquinolone antibiotic Otiprio (ciprofloxacin otic suspension) with an indication for the treatment of acute otitis externa (AOE), or swimmer's ear, in patients 6 months and older due to Pseudomonas aeruginosa and Staphylococcus aureus.

Otiprio has the ability to enhance compliance in subjects with AOE, as the standard of care is antibiotic ear drops that are administered multiple times a day for seven days. Conversely, Otiprio involves a single administration with its thermosensitive formulation.  (Also see "Keeping Track: Merck's Follow-On Insulin Edges Closer To Market; Braeburn Submits Another Buprenorphine Depot" - Pink Sheet, 24 Jul, 2017.)

In a 262-patient pivotal Phase III trial, Otiprio met the primary endpoint of showing a statistically significant increase in clinical cure rate by day 8.  (Also see "Otonomy To Challenge Multi-Dose Ear Drops With Otiprio Expansion Plans" - Scrip, 6 Jan, 2017.)

The drugmaker also touted the wider reach of the drug as a result of the approval. Otonomy CEO David Weber said in a March 2 statement that Otiprio's new indication includes roughly 4 million episodes of AOE per year in the US, and that it "broadens the target physician population beyond otolaryngologists to pediatricians and primary care physicians who treat the vast majority of AOE cases."

FDA first approved Otiprio in 2015 for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement.

Sanofi, Regeneron's Dupixent Could Enter Asthma Market This Year

Sanofi and Regeneron Pharmaceuticals Inc.'s interleukin-4 and IL-13 inhibitor Dupixent (dupilumab) is already expected to become a blockbuster in its approved atopic dermatitis indication, but the companies are targeting an even larger market with the latest submission for the biologic: asthma.

The supplemental biologic license application (sBLA) for Dupixent as add-on maintenance treatment for moderate-to-severe asthma will receive a standard review from FDA, with a user fee goal date of Oct. 20, 2018. The sBLA covers use in adults and adolescents aged 12 years and older.

The three pivotal trials in the LIBERTY ASTHMA clinical program for dupilumab enrolled 2,888 patients. Initial results of the LIBERTY ASTHMA QUEST trial, released in autumn 2017, found reductions on both of its primary endpoints, severe asthma attacks (exacerbations) and improved lung function, but the companies also highlighted dupilumab's greater efficacy in patients with baseline eosinophil counts, which are generally thought to be associated with worse asthma control. (Also see "Sanofi and Regeneron Hit Asthma Phase III Endpoints With Dupixent" - Scrip, 11 Sep, 2017.)

Dupixent is administered every two weeks for asthma, a more frequent regimen than that approved for that anti-IL5 antibodies that are expected to be its major rivals. Dupixent, however, could have a broader label than anti-IL5s like GlaxoSmithKline PLC's Nucala (mepolizumab), AstraZeneca PLC's Fasenra (benralizumab) and Teva Pharmaceutical Industries Ltd.'s Cinqair (reslizumab). Those antibodies are approved by FDA only for severe asthma patients with elevated eosinophil levels. (Also see "Dupixent FDA Asthma Review Bolsters Sanofi And Regeneron" - Scrip, 2 Mar, 2018.)

Shire Looks Forward To Busy Year-End After FDA Accepts Calaspargase Pegol BLA

FDA assigned a Dec. 22, 2018 user fee goal to Shire PLC's biologics license application (BLA) for calaspargase pegol (Cal-PEG), a successor to the company's Oncaspar (pegaspargase) for first-line treatment of acute lymphoblastic leukemia, the company announced Feb. 28. Like Oncaspar, the new pegylated asparaginase would be indicated for use as a part of a multi-agent chemotherapeutic regimen for treatment of ALL.

"Asparagine depletion remains a cornerstone of ALL treatment regimens," Shire said. Cal-PEG, like Oncaspar, is thought to exert its effect through plasma L-arginine depletion, but the newer enzyme product, also known as SHP663, "has an extended shelf life beyond that of the current pegylated asparagnise treatment, helping to ensure availability to patients," Shire said.

Calaspargase pegol is the second novel agent from Shire recently accepted for review by FDA: the company's he breakthrough-designated lanadelumab for prevention of hereditary angioedema (HAE) attacks received a priority review user fee goal date of Aug. 26, 2018.  (Also see "Keeping Track: Apadaz Approved Without Abuse-Deterrent Label, FDA Denies Translarna Appeal, And Some Priority Reviews " - Pink Sheet, 25 Feb, 2018.)

Both of the novel agents under review by FDA came to Shire as part of the company's aggressive acquisition and in-licensing activity. Shire acquired calaspargase pegol and the Oncospar portfolio from Sigma-Tau Finanziaria S.p.A. in July 2015; lanadelumab (also known as SHP643 and DX-2930) came with Shire's acquisition of Dyax Corp. in January 2016.