Biologics took center stage at FDA last week. The Center for Drug Evaluation and Research accepted another biosimilar application, while the Center for Biologics Evaluation and Research approved a novel agent – CSL Behring's Afstyla – and extended the age range and number of strains covered by the first cell culture flu vaccine.

FDA also approved Titan Pharmaceuticals Inc. and Braeburn Pharmaceuticals SPRL's Probuphine, a new implantable formulation of the partial opioid agonist buprenorphine, for use in medication-assisted treatment of opioid dependence – one of FDA's top public health priorities.

The news was less positive for AstraZeneca PLC and Sarepta Therapeutics Inc. AZ's hyperkalemia drug ZS-9 received a complete response letter, and Sarepta announced that FDA's review of its Duchenne muscular dystrophy therapy eteplirsen would continue past the user fee goal.

Afstyla Is Third Long-Acting Clotting Factor To Clear CBER This Year

With the approval of Afstyla on May 25, CBER has approved three new biologics license applications (BLAs) in 2016, and all three are long-acting "biobetter" formulations of coagulation factors (see the CBER Novel Approvals chart on the FDA Performance Tracker for a full listing of approvals).

CSL is a long-time player in the hemophilia market, but the company has only recently entered the long-acting biobetter space. CSL Behring's Idelvion for hemophilia B was approved March 4 ([A#00160314013]).

Idelvion and Afstyla use different technologies to ensure longer activity, however: Idelvion fuses albumin to recombinant Factor IX, while Afstyla uses "a covalent bond that forms one structural entity, a single polypeptide-chain, to improve the stability of factor VIII and provide longer-lasting factor VIII activity," the company explained.

Afstyla is approved for use in children and adults with hemophilia A for on-demand control of bleeding episodes, routine prophylaxis, and perioperative management of bleeding. The product is dosed two to three times weekly.

CSL expects Aftsyla to be available "early this summer."

Seqirus Extends Flucelvax With Pediatric Claim, Quadrivalent Formulation

On May 24, the day before the Afstyla approval, FDA approved pediatric use and a quadrivalent formulation of the seasonal influenza vaccine Flucelvax. The sponsor is Seqirus, the name CSL gave its influenza vaccine business after acquiring Novartis AG's flu portfolio in 2015 ([A#00150727001]).

Both the new quadrivalent and older trivalent formulations are now indicated for use in people ages 4 years and up. Flucelvax, the first flu vaccine derived from cell culture, was initially approved in 2012 as a trivalent vaccine for use in people 18 and older.

FDA required studies of Flucelvax in children and adolescents from age 4 to up to18 years old with the original approval. The pediatric supplemental BLA was submitted Nov. 20, 2014, but received a complete response letter on Sept. 17, 2015 because the submission did not support effectiveness in the 4 to 8 year old age group for one strain. At a meeting a month later, CBER told the sponsor that the 4 to 18 year old cohort could be pursued under accelerated approval; Seqirus requested approval under AA regs on Jan. 20, 2016.

(Track submissions and approvals with the User Fee Goal Dates chart on the FDA Performance Tracker.)

Samsung Bioepis' First 351(k) Submission Would Be Second Infliximab Biosimilar

Samsung Bioepis Co. Ltd.'s SB2, a biosimilar version of Johnson & Johnson's tumor necrosis factor (TNF) inhibitor Remicade (infliximab), has been accepted for review by FDA, the Samsung BioLogics/Biogen Inc. joint venture announced May 24.

The 351(k) BLA was submitted in March, giving it a January 2017 user fee goal. Merck & Co. Inc. will handle US marketing and distribution of SB2 under a 2013 agreement.

FDA has already approved one infliximab biosimilar, Celltrion Inc./Pfizer Inc.'s Inflectra (infliximab-dyyb). Like Celltrion, Samsung Bioepis is banking on extrapolation of clinical data in arthritic indications to support approval of its biosimilar candidate for treatment of inflammatory bowel diseases as well ([A#14160524001]).

SB2 is the first product to reach FDA from the Samsung Bioepis joint venture, but it is not likely to be the last. The company reports that it has 13 biosimilar candidates in its pipeline, including two more late-stage immunology antibodies. SB4 is a biosimilar Enbrel (etanercept) and SB5 is a biosimilar Humira (adalimumab).

(Follow the progress of 351(k) applications on the FDA Performance Tracker's Pending Biosimilars chart.)

Braeburn/Titan Probuphine Approved With Extensive Risk Management Strategy

Titan Pharmaceuticals and its marketing partner Braeburn received FDA approval for the first implantable formulation of buprenorphine, Probuphine, for maintenance treatment of opioid dependence on May 26, 2016, after two advisory committee reviews and a 2013 complete response letter from FDA.

The indication is limited to patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).

FDA required a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh its risks. The REMS requires all healthcare providers to successfully complete a live training program on insertion and removal procedures and become certified before performing insertions or prescribing Probuphine implants.

Braeburn President and CEO Benshad Sheldon said 2,200 physicians already have signed up for training sessions over the next six weeks ([A#14160527005]).

Probuphine uses Titan's ProNeura continuous drug delivery system to formulate buprenorphine. The commercial product consists of four, one-inch-long rods that are implanted under the skin of the upper arm to provide treatment for six months.

Labeling specifies that Probuphine is not appropriate for new entrants to treatment and patients who have not achieved and sustained prolonged clinical stability. Probuphine implants are intended to be in place for six months and once removed new implants may be inserted in the other arm. The labeling states that after one insertion in each arm, most patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment.

AstraZeneca's ZS-9 Tripped Up By Manufacturing

FDA's complete response letter for hyperkalemia therapy ZS-9 (sodium zirconium cyclosilicate) "refers to observations arising from a pre-approval manufacturing inspection," AstraZeneca announced May 27, 2016. The inspection covered a facility in Coppell, Texas ([A#14160527003]). The letter does not require the company to generate new clinical data.

"FDA also acknowledged receipt of recently-submitted data which it has yet to review," AstraZeneca reported. The insoluble, non-absorbed compound is structured to preferentially trap potassium ions.

ZS-9 was the centerpiece of AstraZeneca's $2.7bn acquisition of ZS Pharma Inc. in late 2015 ([A#14151105005]).

The companies expect ZS-9 to have cleaner, less complex labeling than Relypsa Inc.'s Veltassa (patiromer), an organic polymer potassium binder approved for hyperkalemia in October 2015. Veltassa has complicated dosing and distribution due to its potential to bind to other medications ([A#14151022004]). ZS-9 is more selective, and binds to potassium ions "even in the presence of other competing ions," AstraZeneca said.

(For more information on products that have received action letters from FDA, see the Complete Response Letters chart.)

FDA Review Of Sarepta DMD Drug Eteplirsen To Continue Beyond Goal Date

FDA is "continuing their review and internal discussions" regarding Sarepta's Duchenne muscular dystrophy therapy eteplirsen, and "will not be able to complete their work" by the exon-skipping drug's May 26, 2016, user fee goal, the company reported May 25.

A company spokesman told the Pink Sheet that FDA did not provide any additional details on the timing of a decision ([A#14160525002]).

The lack of a set extension of the goal date suggests FDA has not received additional data or other information that would have constituted a major amendment to the application and triggered a three-month extension of the review goal. The goal date was already extended once due to submission of data that FDA considered to be a major amendment.

Exon-skipping Duchenne muscular dystrophy (DMD) therapies have proven a particular challenge for FDA, which now rarely misses user fee goal dates. FDA missed the user fee goal for the first exon-skipping DMD submission BioMarin Pharmaceutical Inc.'s Kyndrisa (drisapersen) before issuing a complete response letter Also see "BioMarin's Drisapersen 'Compete Response' Shows FDA Flexibility Still Limited" - Pink Sheet, 14 January, 2016..

Keeping Track: A Good Week For Biologics And Probuphine, Less So For Eteplirsen And ZS-9

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