FDA had a slow week for approvals, but capped it with the Center for Biologics Evaluation and Research's fourth novel biologic approval of the year, for the first FDA-approved vaccine to prevent cholera.

The Center for Drug Evaluation and Research cleared a new drug application (NDA) for a new anti-hypertensive, but issued a second complete response letter (CRL) for an emergency epinephrine injection for anaphylaxis.

Headlines for CDER came from the abuse-deterrent opioid front, with advisory committee consideration of two extended-release products and a sponsor request for a review extension for another abuse-deterrent opioid. CDER also requested more data on a pending Duchenne muscular dystrophy therapy.

Vaxchora Approval Earns PaxVax A Tropical Disease Priority Review Voucher

FDA approved PaxVax Bermuda’slive, weakened oral cholera vaccine Vaxchora on June 10 for active immunization against disease caused by Vibrio cholerae serogroup O1, the predominant cause of cholera globally, in adults 18 through 64 years of age traveling to cholera-affected areas. The vaccine earned PaxVax a tropical disease priority review voucher.

Vaxchora is given as a single oral liquid dose at least 10 days before travel to a cholera-affected area.

Efficacy was shown in a randomized, placebo-controlled human challenge study and in two placebo-controlled studies of immune response the vaccine.

(See the CBER Novel Approvals chart for more information on novel products approved by FDA’s biologics center.)

KemPharm Makes Last-Minute Bid For Apadaz Abuse Deterrence Labeling

On June 9, the user fee goal date for KemPharm Inc.’s Apadaz (benzhydrocodone and acetaminophen) NDA, the sponsor announced that it had filed an “amendment request” allowing the company to submit additional information “to include in the FDA’s current review of the Apadaz NDA.”

FDA provided the company with a draft label, but “we feel that additional information could strengthen the draft, with a focus on the section relating to abuse-deterrent product labeling,” KemPharm said. “We are hopeful that we can agree on an approval pathway that includes abuse-deterrent labeling for Apadaz.”

FDA’s advisory committees were unimpressed with the NDA’s evidence of abuse deterrence, which advisory committee members referred to as “baby steps” ([A#14160505004]). Apadaz uses KemPharm’s LAT Prodrug technology that binds benzhydrocodone, a prodrug of hydrocodone, to benzoic acid and acetaminophen. The company says the technology protects against intranasal and intravenous abuse because it must be metabolized into hydrocodone in the intestinal tract.

Abuse-deterrent opioids have been a sticky issue for FDA, resulting in missed user fee goals. But two other candidates received advisory committee endorsement last week: on June 7, the committees found evidence of incremental deterrence of intranasal, I.V., and oral abuse with Teva’s Vantrela ER (hydrocodone extended-release) sufficient to recommend approval ([A#14160607005]). On June 8, the committees voted in favor of nasal and I.V. abuse deterrence claims for Pfizer’s Troxyca ER (oxycodone/naltrexone, extended release), but members were not enthusiastic and voted against recommending an oral abuse-deterrent claim ([A#14160608005]). (See also[A#00160613010]and[A#00160613016]).

(For more information on pending applications and recent FDA actions, see the User Fee Goal Dates chart on the FDA Performance Tracker. The Advisory Committees chart summarizes committee votes and issues.)

Allergan's Fixed-Dose Combo For Hypertension Finally Clears FDA

Allergan PLC plans to launch the first fixed-dose combination of a beta blocker and an angiotensin II receptor blocker, a popular pairing for treating hypertension, in the second half of the year. The nebivolol/valsartan tablets, known as Byvalson, cleared FDA June 6. The approval came later than expected, following a complete response letter at the end of 2014. FDA's Cardiovascular and Renal Drugs Advisory Committee had voted against approval, citing concerns about the efficacy data ([A#00140915008]).

The company did note in its press release that there are no controlled trials demonstrating risk reduction with Byvalson. But the approval was based on the same Phase III placebo-controlled, dose-escalating, eight-week, 4,100-patient efficacy and safety study reviewed by the advisory committee. The combo showed statistically significant reductions in blood pressure over either component alone, with similar rates of adverse events.

FDA Makes An Additional Request On Eteplirsen

Sarepta Therapeutics Inc. will be submitting additional dystrophin data "in the coming weeks" to support its eteplirsen NDA, in what might be a Hail Mary pass for the Duchenne muscular dystrophy drug.

FDA requested the additional data not long after informing the company that it was not going to complete the eteplirsen review by the May 26 user fee date ([A#00160530012]).

The agency wants to see dystrophin data measured by western blot, from biopsies already obtained from the ongoing PROMOVI confirmatory study. "The company plans to submit data from 13 patient biopsy samples, at baseline and Week 48, to the FDA over the coming weeks to facilitate a prompt decision on the NDA by the agency," the firm announced June 7. The announcement set off a new spate of speculation about whether the data request was a positive sign or was simply delaying an inevitable rejection.

FDA and its Peripheral and Central Nervous System Advisory Committee made clear there were substantial concerns about the eteplirsen data during its April review ([A#00160502007]).

While some analysts allow that the change in dystrophin levels at week 48 could yield better biomarker data, most do not expect the new data to significantly change the outlook.

FDA also missed the user fee for the other exon-skipping drug for DMD, BioMarin Pharmaceutical Inc.'s Kyndrisa (drisapersen), before issuing a complete response Also see "BioMarin's Drisapersen 'Compete Response' Shows FDA Flexibility Still Limited" - Pink Sheet, 14 January, 2016..

Adamis Receives Another CRL For Epi Injection

Adamis Pharmaceuticals Corp. has gotten a second complete response letter on its pre-filled single dose epinephrine injection for the emergency treatment of acute anaphylaxis. The first CRL was due to volume delivery issues, which the company noted have been successfully resolved ([A#00160118021]).

FDA made clear in the new CRL, issued on June 3, that "because of the improvements that were made …. in response to the FDA's original CRL dated March 27, 2015, … the company must expand its human factors study (patient usability) and reliability study (product stress testing)."

Adamis thinks it can finalize the study protocols and complete the additional testing "within a relatively short period of time at an immaterial cost," and resubmit in the second half of 2016.

Epinephine products can be tricky. Sanofi voluntarily pulled its epinephrine product Auvi-Q from the market in late 2015 due to inadequate dosing delivery. FDA first delayed action on Teva Pharmaceutical Ltd.'s generic copy of Mylan NV's EpiPen and then issued a CRL for the ANDA ([A#14160301002]).

Adamis had sold the rights to market the epinephrine PFS to Watson Laboratories Inc. (now a part of Allergan PLC, but the generic business will be transferred to Teva) for up to $32.5m, though Watson has the option to back out of the deal if the product is not approved.

(See the Complete Response Letters chart on the FDA Performance Tracker for more information on FDA action letters.)

Keeping Track: KemPharm Apadaz Delay; Cholera Vaccine Approved

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