Although the number of complete response letters (CRLs) issued by the FDA to biopharmaceutical companies in 2017 dipped by 23 percent compared to the prior year, extensive planning and robust studies once again offered no foolproof promise of commercial glory.

Changing rules and 11th-hour safety signals created sinkholes in otherwise smooth rides to approval. This year, BioWorld reported on a total of 24 CRLs issued to companies. As of the week before Christmas, though, nearly twice as many new molecular entities (NMEs) – for a total of 46 – received approval during the year. That is a flip to 2016, which had 31 CRLs and 22 NME approvals.

Two companies met with CRLs in 2017 for Neulasta biosimilars for neutropenia, and two others for their rheumatoid arthritis therapies. Some firms suffered steep slashes in stock price. Others rebounded from 2016 CRLs, some gaining FDA approval, while others were starting new trials or resubmitting biologics license and new drug applications (BLAs and NDAs).

Coherus Biosciences Inc. watched shares (NASDAQ:CHRS) fall 24 percent, or $4.92, in June, to close at $15.73, following a CRL for CHS-1701, a biosimilar of Amgen Inc.'s Neulasta (pegfilgrastim), a $4 billion product. Analysts expected the CRL due to the lack of an FDA advisory committee (adcom), which has been required for four of the five approved biosimilars to date. The CRL follows the 2016 CRL for Sandoz Inc.'s Neulasta biosimilar, LA-EP2006, with that company aiming for a 2018 resubmission. (See BioWorld, June 13, 2017.)

In October, a second Neulasta biosimilar, MYL-1401H, from Bangalore, India-based Biocon Ltd. and partner Mylan NV, of Hertfordshire, U.K., received a CRL. As with Coherus' product, the news for MYL-1401H was unsurprising due to lack of an adcom. Biocon and Mylan had previously withdrawn a marketing authorization application in Europe due to the EMA's concerns regarding data showing product concentrations in blood. (See BioWorld, Oct. 11, 2017.)

"The Achilles heel of all the Neulasta biosimilar applications has been immunogenicity," Leerink analyst Geoffrey Porges wrote in a research note.

For Redwood City, Calif.-based Coherus, the FDA requested a reanalysis of a subset of subject samples using a revised immunogenicity assay with greater sensitivity, and it raised issues regarding manufacturing procedures. Coherus cut 30 percent of its workforce following the FDA rejection, and reported in November it will resubmit the BLA in the middle of the first quarter of 2018.

CRLs for rheumatoid arthritis therapies went to JAK1 and 2 inhibitor baricitinib and IL-6 inhibitor sirukumab. Wilmington, Del.-based Incyte Corp. and Indianapolis-based Eli Lilly and Co. received the news for baricitinib just before Easter, with the FDA calling for more clinical data to determine the most appropriate doses and safety. Lilly intends to resubmit the NDA by the end of January. Janssen Biotech Inc., a unit of New Brunswick, N.J.-based Johnson & Johnson, received a CRL for sirukumab, with the FDA requesting additional clinical data. The agency's Arthritis Advisory Committee voted 12-1 in August against approval with concerns focused on an imbalance in deaths during clinical development – 35 in the treatment arm vs. one in the placebo arm, which Janssen attributed to crossovers. Within the same week, Glaxosmithkline plc dropped its sirukumab partnership with Janssen. (See BioWorld Today, April 17, 2017, Aug. 2, 2017, and Aug. 3, 2017.)

Shares tanked 59.8 percent in October on CRL news for Redwood City, Calif.-based Acelrx Pharmaceuticals Inc.'s (NASDAQ:ACRX) NDA for Dsuvia (sufentanil) to reduce moderate to severe acute pain and dosing errors with intravenous administration. The stock closed at $2.15, losing $3.20. Reason for the CRL: insufficient safety outcomes in at least 50 patients given the maximum dose. The agency also wants changes to the directions for use, followed by validation through a human factors study. (See BioWorld, Oct. 13, 2017.)

Manufacturing, safety issues

Reasons for other CRLs in 2017 ranged from manufacturing issues to more safety issues and the need for additional clinical trials.

The months of July, August and September resulted in CRLs due to manufacturing problems for glaucoma and ocular hypertension drug latanoprostene bunod (Valeant Pharmaceuticals International Inc.), diabetes drug ITCA-650 (exenatide implant; Intarcia Therapeutics Inc.) and ocular pain drug Dextenza (Ocular Therapeutix Inc.), respectively. Dextenza also received a CRL for manufacturing issues in 2016.

In terms of safety, the agency expressed concern that Xyosted (testosterone enanthate, Antares Pharma Inc.) increases blood pressure and causes depression and suicidal thoughts. It requested more data for Intellipharmaceutics International Inc.'s pain drug Rexista (oxycodone), specifically from category 2 and 3 studies to determine the abuse-deterrent properties of the drug, and it asked for an additional efficacy trial for PTC Therapeutics Inc.'s Translarna (ataluren) to treat nonsense mutation dystrophinopathies.

Vernalis plc, of Winnersh, U.K., received CRLs in April for CCP-07 and in August for CCP-08, both for cough and cold indications, citing undisclosed outstanding items that needed to be addressed, but no issues with the formulation or pharmacokinetic profiles.

Another disappointing CRL for the year arrived on the doorsteps of Brussels, Belgium-based UCB SA and Thousand Oaks, Calif.-based Amgen in July for osteoporosis drug Evenity (romosozumab). A few months earlier, the phase III Arch trial unearthed a potential cardiovascular safety signal not previously seen, prompting the FDA to look deeper. (See BioWorld, July 18, 2017.)

"Approval still seems likely, although potentially in [a] narrower population," wrote Jefferies analyst Peter Welford.

Changing rules seemed to affect Boca Raton, Fla.-based Therapeuticsmd Inc.'s Yuvvexy (TX-004HR), which received a CRL in May for its NDA to treat moderate to severe vaginal pain during sex. The company's stock (NYSE MKT:TXMD) dropped 10.5 percent to close at $4.18 that day, with the agency pointing to the lack of 12-month endometrial safety data. CEO and co-founder Robert Finizio said at the time that the FDA "did not once tell us to perform a 12-month endometrial safety study, or tell us that our 12-week trial design was inadequate to support approval" during discussions of safety and efficacy design. Other therapies, such as Evamist, Divigel and Elestrin, have received approval based on 12-week safety data, he said. Therapeuticsmd resubmitted the NDA in late November, and the stock is now trading at more than $6, higher than it was before the CRL. (See BioWorld Today, May 9, 2017.)

Rebounding from CRLs

Although a CRL – especially those requiring additional clinical studies – can be a death blow, as it was in 2016 for Duchenne muscular dystrophy drug Kyndrisa (Biomarin Pharmaceuticals Inc.), some companies and products rebound with stronger packages.

A year after receiving a CRL in November 2016, Berkeley, Calif.-based Dynavax Technologies Corp. won FDA approval for Heplisav-B to treat hepatitis B virus after addressing questions of a numerical imbalance and cardiac events. Its shares (NASDAQ:DVAX) fell 64.7 percent ($7.50) to close at $4.10 upon announcement of the CRL, but rose through the year, closing at $20.25 following the approval. (See BioWorld Today, Nov. 15, 2016, and Nov. 13, 2017.)

An even shorter turnaround occurred for Amgen's Parsabiv (etelcalcetide) for secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis. The company received its CRL in August 2016, its stock (NASDAQ:AMGN) largely unaffected, and it gained FDA approval six months later. The CRL was due to the need for more time to finalize prescribing information, an Amgen spokesperson said. (See BioWorld Today, Feb. 9, 2017.)

Waltham, Mass.-based Chiasma Inc. began in November a third phase III trial of its acromegaly drug Mycapssa (octreotide capsules), following a CRL in April 2016. Unlike Dynavax, its stock (NASDAQ:CHMA) has declined steadily, having lost 63 percent of its value, closing at $6.42, upon receiving the CRL, and most recently closing at $1.74.

Portola Pharmaceutical Inc., of South San Francisco, resubmitted its BLA in August for Andexxa (andexanet alfa) for use as a reversal of blood thinners, following its August 2016 CRL due to manufacturing issues.

And within six months of 2017, Sunovion Pharmaceuticals Inc. received a CRL, resubmitted its NDA and won FDA approval for its chronic obstructive pulmonary disease therapy SUN-101 (glycopyrrolate) and the Eflow nebulizer, with the trade name Lonhala Magnair. The CRL did not require new clinical studies so the NDA was resubmitted within a month, and approval came in early December. (See BioWorld Today, May 31, 2017.)