FDA approval count fell last year, despite a steady regulatory filing rate.

Asher Mullard

After 2 years of sky-high approval numbers, the class of 2016 FDA approvals is smaller than average. The agency’s Center for Drug Evaluation and Research approved 22 drugs in 2016 (TABLE 1), down from the 19-year high of 45 in 2015 (FIG. 1).
This makes the class size below the 5-year and 10-year averages (35 and 29, respectively). But,rather than indicating a new crisis in pharmaceutical productivity, the FDA’s outgoing Director of the Office of New Drugs John Jenkins urged analysts to look at these approvals from beyond the context of a single calendar year. “The numbers are down this year for approvals, but I don’t think that’s the best metric for the success of either the FDA or industry,” saysJenkins, who retired from the FDA in January (see Nat. Rev. Drug Discov. 16, 80–81; 2017). “Some of this is just a timing issue of when things were submitted and when their goal dates were.”For example, the agency approved five drugs in 2015 that actually had approval action dates in 2016: had the agency acted on the scheduled Prescription Drug User Fee Act (PDUFA) dates, the gap between last year’s high and this year’s low would be narrower. The number of drugs submitted for review at the FDA is also stable, he points out. As of mid-December, pharmaceutical and biotech companies had filed 36 new drug applications (NDAs) and biologics licence applications (BLAs) with the agency. Companies submitted 40 and 41 submissions over the full year in 2015 and 2014, respectively. A key driver of the low 2016 approval count, instead, was an
increase in the number of drugs that the agency rejected. Whereas the FDA issued only 2 complete response letters in 2016, it issued 14 in 2016 (TABLE 2). A key reason for many of these rejections was sponsors’ failure to comply with good manufacturing practice regulations. The EMA also approved fewer drugs in 2016 than in previous years (see Nat. Rev. Drug Discov. 16, 77; 2017).  Reflecting the decreased approval count, analysts expect the class of 2016 to deliver lower cumulative commercial punch than previous years. The new approvals should earn
US$35 billion in peak aggregate sales, just half the $69 billion expected by 2015’s approvals, shows an analysis by Boston Consulting Group (see Nat. Rev. Drug Discov. 16, 78; 2017). Nevertheless, the cohort includes 11 (50%) products that analysts have pegged as blockbuster contenders (FIG. 2). The class of 2015 had 16
(36%) potential blockbusters, and the class of 2014 had 12 (29%). Sales forecasting is notoriously unreliable, however, and most of the time it misses actual peak sales by more than 40% (Nat. Rev. Drug Discov. 12, 737–738; 2013).

The 2016 cohort also included a higher proportion of breakthrough therapy designees: 7 (32%) in 2016, compared with 10 (22%) in 2015 and 9 (22%) in 2014. The agency has now granted breakthrough therapy designation to more than 141 approved and experimental products, prompting Jenkins to question whether the agency set the bar for this designation too low (see Nat. Rev. Drug Discov. 16, 80–81; 2017). The FDA approved 9 (41%) products with orphan designation, in line with recent interest in rare diseases. It approved 21 (47%)orphan designees in 2015 and
17 (41%) in 2014. Cancer shares top slot Cancer products did not, for a
change, dominate the approval list (FIG. 3). The agency approved 4 (18%) oncology drugs in 2016, down from 14 (31%) in 2015, 9 (22%) in 2014 and 9 (33%) in 2013 (Nat. Rev. Drug Discov. 15, 73–76; 2016). This may only be a temporary blip. Around a third of new filings in 2016 — many of which will be acted on this year — were submitted to the Office of Hematology and Oncology. “There is almost a herd mentality right now to move towards oncology, immunotherapies and the rare disease drugs, leaving behind a lot of diseases that still need better treatments,” says Jenkins. “That’s a concern that I have about where the industry is going.” Of the new oncology approvals, analysts expect only two of these to achieve sales of more than $2 billion. There are high hopes for Genentech’s atezolizumab, the first programmed cell death protein 1 ligand 1 (PDL1)-targeting antibody 

to enter the increasingly competitive PD1/PDL1 immunotherapy fray (Nat. Rev. Drug Discov. 15, 235–247; 2016). AbbVie’s venetoclax, the other multiblockbuster oncology candidate, is a first-in-class B cell lymphoma 2 (BCL-2) inhibitor that prevents cancer cells from evading apoptotic cell death (Nat. Rev. Drug Discov. 15, 147–149; 2016). It is also the first small-molecule protein–protein interaction inhibitor to make it to market (Nat. Rev. Drug Discov. 15, 533–550; 2016). Infectious diseases and neurology each notched up 4 (18%) approvals last year. Among the infectious disease approvals, Gilead Science’s hepatitis C virus (HCV) combination therapy Epclusa is expected to become the most profitable approval of 2016. The drug combines the nucleotide analogue NS5B polymerase inhibitor sofosbuvir and the HCV NS5A inhibitor velpatasvir, and has efficacy in all six HCV genotypes. Gilead hopes that the drug’s efficacy in genotypes 2 and 3 in particular — which are least well served by currently available anti-HCV drugs — will provide an edge in this increasingly competitive market. The agency also approved Merck & Co.’s bezlotoxumab, a pioneering toxin-targeting antibacterial antibody for preventing the recurrence of Clostridium difficile infection (Nat. Rev. Drug Discov. 14, 737–738; 2015). Among neurology approvals, the agency granted a controversial green light to Sarepta Therapeutics’ eteplirsen for Duchenne muscular dystrophy (DMD). DMD is a muscle-wasting disease that is caused by defects in the dystrophin gene. Eteplirsen is an antisense oligonucleotide that forces the exclusion of exon 51 during dystrophin translation, in an attempt to sidestep the

consequences of genetic defects. The approval drew criticism from some FDA staff and from drug safety watchdogs in part because it was based on results from an inconclusive 12-patient phase II study (Nat. Biotechnol. 34, 1078; 2016). Jenkins, a vocal critic of the approval, said that this approval will not set a lower approval precedent for other agents (see Nat. Rev. Drug Discov. 16, 80–81; 2017). The agency also approved another splice-modifying, antisense oligonucleotide: Biogen and Ionis Pharmaceuticals’ nusinersen, for spinal muscular atrophy (SMA). SMA is a muscle-wasting disease that can be caused by loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Nusinersen modifies the translational splicing of the related SMN2 gene to compensate for mutations in SMN1. Splice-modifying technologies could
eventually provide new treatment options for various other indications (Nat. Rev. Drug Discov., published online on 22 July 2016). Acadia’s pimavanserin gained the first approval for hallucinations and delusions associated with psychosis in Parkinson
disease, which affects as many as 50% of Parkinson patients. Although the FDA counts Biogen’s interleukin 2 (IL-2)-targeting monoclonal antibody (mAb) daclizumab for multiple sclerosis as a novel approval, the agency approved the same antibody for kidney transplant rejection in 1997. Roche, who owned rights to the drug in this indication, withdrew it from the market in 2009 because of lack of demand.

The approval of Intercept Pharmaceuticals’ obeticholic acid for primary biliary cholangitis provides validation of this farnesoid X receptor (FXR) agonist. But the true prize for this drug will be an approval in non-alcoholic steatohepatitis (NASH), an unmet drug development opportunity with a potential total market size of more than
$15 billion (Nat. Rev. Drug Discov. 15, 745–746; 2016). The Center for Drug Evaluation and Research did not approve any cardiology or rheumatology products in 2016. The Center for Biologics Evaluation and Research made a few notable approvals last year (TABLE 3). And three newly approved biosimilars are set to provide competition to lucrative mAbs and a fusion protein (TABLE 4). 2017 could see several novel introductions into the pharmaceutical armamentarium (TABLE 5). Roche’s anti-CD20 mAb ocrelizumab could provide a much needed new treatment for primary progressive multiple sclerosis (Nature 540, S7–S9; 2016). And Amgen’s first-in-class anti-sclerostin mAb romosozumab could at long last decouple bone formation from bone resorption in osteoporosis treatment (Nat. Rev. Drug Discov. 15, 445–446; 2016). Some of the applications that the FDA rejected in 2016 have been resubmitted for approval in 2017, including Teva’s deutetrabenazine, the lead deuterated drug.

Fonte Revista Nature FEBRUARY 2017 | VOLUME 16

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