Coherus Biosciences Inc.'s CHS-1701 has become the latest biosimilar candidate for Neulasta (pegfilgrastim) to hit a regulatory snag, earning a complete response letter (CRL) that is expected to delay for at least a year approval of its version of Amgen Inc.'s long-acting G-CSF drug.

Shares of the Redwood City, Calif.-based firm (NASDAQ:CHRS) fell 24 percent, or $4.92, to close Monday at $15.73, though analysts had been bracing for a potential CRL given the lack of an FDA advisory committee for CHS-1701. Adcoms so far have been required for four of the five biosimilars approved to date; the only exception was the recently approved Renflexis (infliximab-abda), a biosimilar of Remicade (Johnson & Johnson) from Samsung Bioepis Co. Ltd. (See BioWorld Today, April 25, 2017.)

And while the FDA has approved a biosimilar to Neupogen (filgrastim, Amgen Inc.) – Sandoz Inc.'s Zarxio, which marked the first FDA approval under the new biosimilars pathway – the pegylated version of filgrastim, in which the protein is bound to polyethylene glycol to allow for less frequent dosing, has proved much tougher to get through regulatory channels, likely to due to its effect on immunogenicity. (See BioWorld Today, March 9, 2015.)

Last year, Sandoz's Neulasta biosimilar, LA-EP2006, received a CRL. While details were scant, the company, a unit of Basel, Switzerland-based Novartis AG, said it planned to work with the FDA to address the outstanding issues. The latest update shows Sandoz aiming for a resubmission in 2018. And Apotex Inc., which filed for approval via the 351(k) biosimilar pathway for its Neulasta biosimilar in 2014, is still awaiting an FDA decision.

An application for MYL-1401H, from Mylan NV and Biocon Ltd., has been accepted for filing. The FDA set a BsUFA date for Oct. 9, though Mylan has previously guided a launch for late 2018 or early 2019.

Even in Europe, where biosimilars are more entrenched in the market – the first biosimilar gained approval well over a decade ago and the first Neupogen biosimilars won approval in 2008 – biosimilars for Neulasta also have failed to clear regulatory hurdles. Gedeon Richter plc, of Budapest, yanked its marketing authorization application (MAA) late last year after the EMA's Committee for Medicinal Products for Human Use indicated the data were not sufficient for demonstrating a positive benefit-risk assessment. Following its FDA rejection, Sandoz withdrew its MAA for LA-EP2006 early this year, stating that the EMA had expressed concern regarding data showing concentrations of product in the blood. It has indicated plans to resubmit this year.

An MAA for Mylan and Biocon's MYL-1401H was accepted by the EMA in mid-2016 and is pending review, as is Coherus' application for CHRS-1701, accepted by the EMA in November. Whether those applications clear approval on the first pass remains to be seen.

"The Achilles heel of all the Neulasta biosimilar applications has been immunogenicity," Leerink analyst Geoffrey Porges wrote in a research note. Coherus' CRL suggests that firm has "fallen foul of the same heightened sensitivity to this issue for this molecule that resulted in disappointment for Sandoz and Apotex's applications."

n the CRL issued to Coherus, the FDA requested a reanalysis of a subset of subject samples using a revised immunogenicity assay that offered greater sensitivity, Chairman and CEO Denny Lanfear said during an early Monday conference call. The use of highly sensitive assays to look for potential antidrug antibodies and the presence of neutralizing antibodies is particularly important in development of biosimilars, and "we believed we had met that bar," with study CHRS-1701-04 in 303 healthy subjects.

Data from that study, reported in early 2016, showed that it met both pre-specified immunogenicity endpoints, detecting no neutralizing antibodies and showing a percent difference in antidrug antibody response within the pre-specified biosimilarity criteria, when compared to Neulasta.

To address the FDA's request, Lanfear said Coherus will develop an assay consistent with the agency's recommendations, rerun samples with that assay and perform analyses on those data as requested.

Lisa Bell, senior vice president of global regulatory affairs, added that only a subset of patient samples were required for testing, which "we feel is addressable within the context of the data we have."

Lanfear also noted that the FDA did not ask for an additional study involving oncology patients and did not suggest that Coherus' study was inadequate.

In April, potential competitor Apotex filed a Citizen Petition asking the FDA to require all biosimilars makers working on Neulasta biosimilar candidates to conduct comparative efficacy studies in at least one intended patient population, apparently taking aim at Coherus' application based on a healthy subject trial. In response, Coherus argued that biosimilarity was demonstrated using sensitive analytical methods in comparison to the reference product and that testing in healthy volunteers reduces the potential for variability in pharmacokinetic and pharmacodynamic results.

The CRL also raised issues regarding manufacturing procedures, which Lanfear said appear to be "fully addressable with our existing data" and should be resolved more quickly than the additional immunogenicity data. "We would categorize these requests as standard and consistent with expectations at this point in the review," he said of the manufacturing questions.

Providing a rough timeline going forward, Lanfear said he expects a type 1 meeting with the FDA, which usually takes 30 days. "I believe we can generate responses to the CRL in six months," though he cautioned that interactions with the agency occur on its schedule. After that, the agency can take up to six months to evaluate the resubmission.

In the meantime, the company is conserving its cash. As of March 31, Coherus had $174.8 million, having spent $73 million in the first quarter, primarily to prepare for the anticipated launch of CHRS-1701. A revised plan for the second half of this year anticipates an average use of cash at about $40 million per quarter, Lanfear said, followed by a $30 million to $35 million per-quarter spend for the first half of 2018. "We believe we can operate at this rate into the second half of 2018," he said, with sufficient resources to resubmit the CHRS-1701 BLA and to submit a BLA for CHRS-1420, its Humira (adalimumab, Abbvie Inc.) biosimilar.

The delay of Coherus' CHRS-1701 offers a slight reprieve for Thousand Oaks, Calif.-based Amgen, postponing the biosimilar threat to Neulasta, a roughly $4-billion product, until mid-2018 or later, noted Leerink's Porges. However, he added, that "windfall is offset by today's biosimilar decision from the Supreme Court that effectively eliminates the widely referenced six-month delay associated with notification." (See the story in this issue.)

Shares of Amgen (NASDAQ:AMGN) closed Monday at $164.88, up 82 cents.