FDA approved line extensions and new indications in the past week, but continued the spate of negative news on the new molecular entity approval front with its second Refuse to File letter this month.

The Refuse to File action for PTC Therapeutics Inc.'s Translarna (ataluren) comes a week after an RTF letter for Firdapse was announced Also see "Keeping Track: FDA Approves Briviact, Refuses To File Firdapse, Rejects Remune" - Pink Sheet, 22 February, 2016..

Third Try Is Not The Charm In Duchenne Muscular Dystrophy

PTC Therapeutics became the third of three companies to face setbacks in getting a Duchenne muscular dystrophy drug through FDA when it announced a Refuse to File letter for ataluren, its first-in-class protein restoration therapy for treatment of nonsense mutation DMD, on Feb. 23, 2016.

FDA found the new drug application "not sufficiently complete to permit a substantive review," PTC said ([A#14160223004]).

While the company declined to elaborate on the issues in the letter, Translarna's efficacy could be an issue. In October, the company reported that the Phase III ACT DMD trial failed to meet its primary endpoint; the NDA likely draws on benefit seen on secondary and tertiary endpoints.

FDA appears to be being strict in its review of the new wave of DMD therapies, despite patient and advocacy group pressure Also see "Sarepta's Eteplirsen Is Centerpiece Of Senate Hearing On Expanded Access" - Pink Sheet, 26 February, 2016.. The agency issued a complete response letter for BioMarin Pharmaceutical Inc.'s Kyndrisa (drisapersen) in January calling for a new clinical trial.

Briefing materials for an advisory committee review of Sarepta Therapeutics Inc.'s eteplirsen showed agency concerns with efficacy data, but the committee meeting was cancelled due to snow and Sarepta submitted additional information, extending the review deadline.

Spectrum Submits EOquin NDA While Learning Lessons From Ongoing Phase III

Spectrum Pharmaceuticals Inc. expects its non-muscle invasive bladder cancer (NMIBC) therapy EOquin (apaziquone) will be reviewed by an FDA advisory committee before its Dec. 11, 2016 user fee goal.

EOquin, a tumor-activated prodrug of an alkylating agent, is administered as one or two intravesical instillations immediately following transurethral resection of bladder tumors (TURBT) procedures – a setting with no currently approved drug therapy.

The NDA is based on pooled data from Phase III studies in 1,615 patients that "showed a statistically significant reduction in the two-year recurrence rate and strong safety data," Spectrum said.

The company is already looking past those trials, however. In October, Spectrum initiated another Phase III study, under a special protocol assessment with FDA, that is "specifically designed to address important lessons learned from the previous apaziquone Phase 3 studies, as well as recommendations from the FDA that improve chances of a successful study outcome."

The additional Phase III will randomize patients with Ta, G1-G2 NMIBC to one or two instillations of apaziquone or placebo. The primary endpoint is time to recurrence. "Since apaziquone is known to be inactivated in the presence of blood, the new protocol requires the dosing … in a 30-90 minute window post-TURBT," Spectrum said.

FDA Approvals

FDA approvals during the week included two supplemental indications and two new formulations.

On Feb. 26, FDA approved a new indication for Novartis AG 's mTOR inhibitor Afinitor (everolimus) for treatment of adult patients with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. In the pivotal trial for the indication, median progression-free survival was 11 months in the everolimus arm and 3.9 months for placebo.
On Feb. 26 FDA also approved the second indication for Roche /Genentech Inc.'s anti-CD20 monoclonal antibody Gazyva (obinutuzumab). The new claim is for use in combination with bendamustine followed by Gazyva alone in follicular lymphoma patients who relapsed after or did not respond to a regimen containing rituximab. The follicular lymphoma claim is based on PFS data from the Phase III GADOLIN trial, which found a 52% reduction in the risk of disease worsening or death compared with bendamustine alone.
After two complete response letters, FDA finally approved a single-dose, preservative-free formulation of Lumara Health Inc.'s Makena (hydroxyprogesterone) on Feb. 19. Both CR letters cited manufacturing issues ([A#00151123011]). The treatment to reduce risk of preterm birth in women pregnant with one baby who have a history of preterm delivery was previously available in a multi-dose vial containing five weekly injections. Lumara plans to launch the preservative-free, single-dose formulation in the second quarter of 2016.
On Feb. 23, FDA cleared a new once-daily formulation of Pfizer Inc.'s JAK inhibitor Xeljanz (tofacitinib). The 11 mg extended-release tablet, called Xeljanz XR, is indicated for adults with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to methotrexate.

REMS Changes Lead To Review Extension For Probuphine

FDA requested changes to the proposed Risk Evaluation and Mitigation Strategy (REMS) for Braeburn Pharmaceuticals SPRL and Titan Pharmaceuticals Inc.'s Probuphine (buprenorphine implant) after a Jan. 12, 2016 advisory committee voted 12-5 in favor of approval for a population of opioid-dependent patients previously stable on a regimen of sublingual buprenorphine, the companies said.

The changes were submitted, resulting in a three-month extension of the Probuphine user fee goal date to May 27.

Keeping Track: Gazyva, Afinitor Get New Indications; PTC's Translarna Gets Refuse To File

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