Keeping Track: Submissions Complete For Breakthrough Therapies From Portola And Catalyst; FDA Finally Approves Bridion, Basaglar

FDA approved two long-awaited products this week. One is the 43rd novel agent clear the Center for Drug Evaluation and Research this year; the other is the first copycat version of a long-acting insulin.

The breakthrough therapy program continued to drive review activity, with the completion of two new applications and announcements of delays in review of two other pending products.

In another highly active area, abuse-deterrent opioids, FDA received two new NDAs.

Merck's Bridion Clinches Title Of Outlier Approval Of The Year

Merck's Bridion is unique among the novel approvals in 2015. While first-cycle approvals are at record-high shares of novel approvals, Bridion took four review cycles and more than eight years from NDA submission on Oct. 31, 2007 to the drug's approval on Dec. 15, 2015. While FDA has highlighted the high percentage of novel drugs that are first approved in the US, including two-thirds of the novel agents approved by the Center for Drug Evaluation and Research in 2015, Bridion was first approved in the European Union, back in July 2008.

Bridion is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. FDA called Bridion a first-in-class approval, although the labeled indication does not specify a class. Merck describes the product as a selective relaxant binding agent.

The approval comes with an extensive list of post-marketing requirements, including studies to assess occurrence of hypersensitivity or anaphylaxis, the risk of cardiac arrhythmias, and the effect of the drug in morbidly obese patients (Also see "Merck's Bridion Approval Carries Several Post-Market Requirements" - Pink Sheet, 16 Dec, 2015.).

(The CDER Novel Approvals chart tracks new molecular entity and novel therapeutic biologic approvals for the year.)

Merck Keytruda Nabs First-Line Melanoma Indication

Merck's Keytruda (pembrolizumab) extended its use in melanoma to first-line therapy of unresectable or metastatic melanoma on Dec. 18, making it the first anti-PD-1 immunotherapy approved for previously untreated metastatic melanoma patients regardless of BRAF status.

The approval was backed by the Phase III KEYNOTE-006 trial comparing Keytruda with Bristol-Myers Squibb Co.'s immunotherapy Yervoy (ipilimumab). In the trial, 80% of patients had PD-L1 positive melanoma, 18% were PD-L1 negative, and 2% had unknown PD-L1 status. BRAF mutations were reported in 36% of patients; 46% of those patients had previously been treated with a BRAF inhibitor.

KEYNOTE-006 found a 37% reduction in the risk of death for patients receiving Keytruda 10 mg/kg every two weeks compared with Yervoy, and a 31% reduction in risk of death for Keytruda patients receiving 10 mg/kg every three weeks.

Merck also reported that FDA cleared updated labeling for Keytruda in ipilimumab-refractory metastatic melanoma patients, adding data from the Phase II KEYNOTE-002 trial of Keytruda vs. investigator's choice of chemotherapy in patients who progressed on ipilimumab. Keytruda doses of 2 mg/kg or 10 mg/kg every three weeks were superior to chemotherapy for the primary endpoint of progression-free survival, but there was no statistically significant difference between the Keytruda and chemotherapy arms in an interim overall survival analysis.

Rolling Submissions Completed For Two Breakthrough Therapies

An August 2016 user fee goal is likely for Portola Pharmaceuticals Inc.'s andexanet alfa following completion of the biologics license application (BLA) submission, announced Dec. 18. The modified human Factor Xa molecule acts as a decoy to target and sequester Factor Xa inhibitors in the blood, preventing the drugs from exerting their anticoagulant effects.

Wide use of the Factor Xa inhibitors introduced in the past few years – Bristol-Myers Squibb Co./Pfizer Inc. 's Eliquis (apixaban), Bayer AG/Johnson & Johnson's Xarelto (rivaroxaban) and Daiichi Sankyo Inc.'s Savaysa (edoxaban) – has made the development of an antidote a public health priority. Andexanet holds breakthrough therapy status with FDA, as does Boehringer Ingelheim GMBH's Praxbind, which was recently approved as a specific reversal agent for BI's Pradaxa (dabigatran), another novel oral anticoagulant that acts as a direct thrombin inhibitor (Also see "Can Praxbind Push Pradaxa Ahead?" - Pink Sheet, 16 Oct, 2015.).

Portola is aiming for approval of andexanet as a "universal reversal agent for patients anticoagulated with an oral or injectable Factor Xa inhibitor who experience a serious uncontrolled bleeding event or who require urgent or emergency surgery." The company planned to seek accelerated approval with data from Phase III trials using andexanet to reverse the effect of rivaroxaban and apixaban in healthy volunteers (Also see "Phase III Data, FDA Interactions Bode Well For Portola’s Factor Xa Antidote" - Pink Sheet, 9 Apr, 2015.).

The BLA includes data from those Phase III studies, but the "clinical basis for the BLA" will be formed by "data from a small number of patients from ANNEXA-4," an ongoing Phase IV trial, Portola said. ANNEXA-4 is a single-arm, open-label confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low molecular weight heparin and indirect Factor Xa inhibitor) who present with an acute major bleed.

Catalyst Pharmaceutical Partners Inc. completed the NDA submission for Firdapse (amifampridine phosphate) by year-end, as the company predicted when it announced the start of the rolling NDA in July 2015 (Also see "Keeping Track: FDA Clears Big Batch Of Products; 'Breakthrough' For Bristol HIV Drug" - Pink Sheet, 27 Jul, 2015.). If FDA grants Catalyst's request for priority review – a likely event, given Firdapse's breakthrough therapy designation – the user fee goal would fall on Aug. 17, 2016 or earlier.

The completed NDA contains two indications. In addition to treatment of Lambert Eaton Myasthenic Syndrome (LEMS), the orphan autoimmune neuromuscular disease for which Firdapse holds breakthrough status, the NDA also seeks approval for congenital myasthenic syndrome (CMS), another orphan neuromuscular disease.

(See the 'Breakthrough Therapy' chart on the FDA Performance Tracker for detailed information on products receiving the designation.)

Review Delays For Two Breakthrough Therapies

FDA will not act on the NDAs for breakthrough-designated products from Clovis Oncology Inc. and BioMarin Pharmaceutical Inc. before the products' original user fee goals.

FDA extended the user fee goal for Clovis' rociletinib, an irreversible mutant-selective epidermal growth factor receptor (EGFR) inhibitor for EGFR T790 mutant-positive non-small cell lung cancer, from March 30, 2016 to June 28, 2016, the company announced Dec. 15. Clovis submitted a major amendment on Nov. 16 "in response to the FDA’s request for additional clinical data for both the 500 mg and 625 mg BID dose patient groups," the company said.

Concerns have centered on the number of confirmed responses in the updated dataset submitted in early October, which were dramatically lower than early data including unconfirmed responses (Also see "AstraZeneca Scores Lung Cancer Touchdown, While Clovis Fumbles" - Pink Sheet, 16 Nov, 2015.).

BioMarin's Dec. 18 announcement that FDA would not meet the Dec. 27 user fee goal for its Duchenne muscular dystrophy therapy Kyndrisa (drisapersen) was not unexpected after a Nov. 24 advisory committee questioned the strength of the clinical data (Also see "BioMarin May Have To Find Subgroups For Drisapersen Efficacy" - Pink Sheet, 24 Nov, 2015.). BioMarin predicted FDA action in early January 2016.

(The FDA Performance Tracker's Advisory Committees In 2015 chart summarizes advisory committee recommendations and FDA’s eventual actions.)

PaxVax Quest For Priority Review Voucher Advances

PaxVax Inc.'s BLA for its single-dose oral cholera vaccine Vaxchora has been accepted by FDA with priority review status, setting a June 15, 2016 user fee goal date. Priority status is "a critical step in the process of being awarded a Priority Review Voucher," PaxVax said. "The potential of being granted a voucher has been an important incentive for PaxVax and our decision to bring this vaccine to the US market."

FDA has identified cholera as a neglected tropical disease, making anti-cholera products eligible for the priority review voucher program. The US market for the vaccine would largely be travelers, a space also targeted by PaxVax' approved typhoid fever vaccine Vivotif.

Vaxchora uses a cholera strain that PaxVax licensed from the University of Maryland in 2010, the CVD 103-HgR strain. The vaccine was tested in Phase III trials in the US and Australia that enrolled 3,000 subjects.

Egalet, Kempharm Abuse-Deterrent Opioids Target Different Ends Of Pain Market

Egalet Corp. is seeking broad labeling for abuse deterrence in its NDA for its extended-release tablet formulation of morphine, Arymo ER, for round-the-clock treatment of severe chronic pain. The Egalet product could be one of the first abuse-deterrent opioids to be approved with all three categories of evidence defined by FDA's April 2015 final guidance on abuse-deterrent opioids: lab-based in vitro manipulation and extraction studies, pharmacokinetic studies, and clinical abuse-potential studies.

Arymo ER uses Egalet's Guardian polymer matrix tablet technology to deter abuse by I.V. injection, snorting, and oral routes. Egalet uses a plastic injection process to manufacture tablets "with controlled-release properties as well as physical and chemical features that have been demonstrated to resist both common and rigorous methods of manipulation," the company said. The tablets are "extremely hard, very difficult to chew, resistant to particle size reduction, and inhibit/block attempts at chemical extraction of the active pharmaceutical ingredient. In addition, the technology results in a viscous hydrogel on contact with liquid, making syringeability very difficult."

Egalet has been expanding its commercial operations in anticipation of Arymo ER (Also see "Egalet Ramps Up Commercial Ahead Of Abuse-Deterrent Pain Drug Filing" - Pink Sheet, 22 Oct, 2015.).

While most abuse-deterrent opioids, like Arymo ER, target the chronic use segment of the severe pain market, KemPharm Inc. is hoping to introduce the first abuse-deterrent immediate-release hydrocodone combination product for acute pain. KemPharm announced the submission of an NDA for KP201, its prodrug of hydrocodone, and acetaminophen (APAP) on Dec. 15. KemPharm is requesting priority review.

KemPharm used its LAT Prodrug technology to develop KP201. The hydrocodone prodrug remains inactive when subjected to physical or chemical manipulation, reducing the prospect of abuse, the company explained. The NDA contains in vitro and PK evidence of abuse deterrence, and "potentially" could support category 3 (clinical abuse-potential studies) labeling as well, KemPharm said.

Marketed hydrocodone/APAP products are listed on the Drug Enforcement Agency's restrictive Schedule II, but KemPharm has requested less-restrictive Schedule III status because of the reduced abuse potential.

(See the User Fee Goals chart on the FDA Performance Tracker for information on pending and recently approved applications.)

Lilly/Boehringer Ingelheim 'Follow-On' Insulin Glargine Basaglar Officially Clears FDA

FDA formally approved Eli Lilly & Co. and Boehringer Ingelheim GMBH's Basaglar (insulin glargine) on Dec. 16, 2015, two years after tentatively approving the long-acting insulin analog, a copycat of Sanofi's Lantus, in August 2014. The approval clears the way for a mid-December launch of Basaglar, as agreed to by the sponsors and Sanofi in a settlement reached in September 2015 (Also see "FDA Makes It Official With Basaglar Approval For Diabetes" - Pink Sheet, 16 Dec, 2015.).

"Basaglar is the first insulin product approved through an abbreviated approval pathway," FDA said. The 505(b)(2) NDA referenced Lantus approval data, the agency noted, while demonstrating that Basaglar was "sufficiently similar to Lantus to scientifically justify reliance." Lilly and BI also provided Basaglar-specific data, included two clinical trials enrolling a total of over 1,200 patients.

Basaglar is indicated to improve glycemic control in adult and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes.

Teligent Transformation Accelerates With Cefotan Approval

The approval of an sNDA for the injectable cephalosporin antibiotic Cefotan (cefotetan) is a major step forward in Teligent Inc.'s transformation from a contract manufacturer and developer of topical generic products into a more broadly focused specialty generics company.

Teligent, which was known as IGI Laboratories until Oct. 23, 2015, acquired Cefotan and 17 other discontinued and withdrawn products from AstraZeneca PLC in September 2014. FDA approved a new manufacturer for Cefotan under an sNDA approved Dec. 9, 2015. Teligent says it is working with its manufacturing partner to launch Cefotan in early 2016.

Cefotan will be the third injectable antibiotic, and the fourth injectable overall, to be marketed by Teligent. The company acquired the approved injectable antibiotics Fortaz (ceftazidime) and Zinacef (cefuroxime), as well as an injectable Zantac (ranitidine), from Concordia Pharmaceuticals Inc. in October 2015. The company believes the hospital-administered injectable anti-infective market "is best served by a portfolio approach."

Zavante Broad-Spectrum Antibiotic Gets Broad QIDP Designation

Zavante Therapeutics Inc. expects to start the first pivotal study of its broad-spectrum antibiotic candidate ZTI-01 in the first quarter of 2016, the company announced Dec. 16. In addition to clearing the Phase III study, FDA also broadened ZTI-01's Qualified Infectious Disease Product designation, Zavante reported.

The pivotal trial will pit ZTI-01, a broad-spectrum bactericidal antibiotic with activity against both Gram-negative and Gram-positive bacteria, against piperacillin/tazobactam in hospitalized adult patients with complicated urinary tract infections (cUTI), including acute pyelonephritis. The cUTI setting earned ZTI-01 its first QIDP designation, in September 2014.

The December expansion of the antibiotic's QIDP status added designations for complicated intra-abdominal infections (cIAI), hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP), and acute bacterial skin and skin structure infections (ABSSSI).

(See the Qualified Infectious Disease Product Designations chart on the FDA Performance Tracker for more information.)