Given the frets of an advisory committee (adcom), the FDA’s complete response letter (CRL) to Cempra Inc. for ketolide antibiotic solithromycin (soli) wasn’t much of a surprise – but a request by the agency for a pre-approval safety study that would enroll about 9,000 patients was, and Wall Street reacted accordingly.

Shares of Chapel Hill, N.C.-based Cempra (NASDAQ:CEMP) closed Thursday down 57.4 percent, or $3.50, to $2.60 on word of the CRL regarding the NDAs related to oral and intravenous soli as a treatment for community-acquired bacterial pneumonia (CABP) in adults. Last month, the adcom split 7-6 in a vote that favored the drug’s risk/benefit profile only narrowly. (See BioWorld Today, Nov. 7, 2016.)

“We’re going to need to meet with the FDA to review the requirements that they see of the clinical trial, and after that meeting we will determine the size, the timing and the cost of the study,” acting CEO David Zaccardelli told investors during a conference call. The magnitude of the experiment specified in the CRL, noted Raymond James analyst Christopher Raymond, “would seem to be a significant financial burden for the company to manage, even with a current cash position of about $225 million.” He added in a research report that he was “more cautious” about soli’s prospects as a result of the latest news.

Specifically, the FDA said the risk of hepatotoxicity had not been adequately characterized and pointed out that the safety database is limited to 920 patients who received soli at the proposed dose and duration – too few, according to the agency. The proposed study in about 9,000 patients exposed to the treatment would be designed to exclude serious drug-induced liver injury (DILI) events occurring at a rate of about one in 3,000 with a 95 percent probability. The CRL also said that, while the agency typically reserves comment on the proposed labeling until NDAs are otherwise adequate, even in the absence of a case of Hy’s Law or another form of serious DILI in future studies, labeling for soli will need to include adequate information about the liver risk, limiting use to those patients with fewer therapeutic options while specifying duration of therapy. A plan for postmarketing safety assessment, including an enhanced pharmacovigilance program, would also be required. Regarding manufacturing, regulators said that the FDA field investigator found deficiencies during the inspections of the Wockhardt Ltd. and Hospira Inc. facilities, though the CRL provided no details.

ANY 'SCENARIO WHERE IT MAKES SENSE'?

Cowen and Co. analyst Ritu Baral asked on the conference call about the size of the comparator arm in the proposed safety trial. “Does that mean that could be an 18,000 patient study with an active comparator? Also, how much should we be looking to the Ketek safety study as potential precedent for what you’re going to be talking to FDA about?” Her reference was to Paris-based Sanofi SA’s telithromycin, the first ketolide antibiotic approved for CABP in 2004 but withdrawn from the market two years later, after a boxed warning and restricted label were added. The subject of Ketek had come up before, as part of briefing documents before the adcom meeting. (See BioWorld Today, Oct. 30, 2006, and Nov. 3, 2016.)

“We’ll be reviewing those details with the agency, but I think that as a comparative study, we’ll have another arm in the trial,” Zaccardelli said. “Its size and the treatment of that arm have not been determined. We’ll be discussing that with the agency.”

Baral speculated in a research report that the trial could include 12,000 patients or more and may resemble the Ketek safety study, which involved 24,000 patients. “While that trial enrolled incredibly rapidly (in less than 12 months), study conduct issues and data fraud confounded the final data,” she wrote, adding that she has “grave concerns” around the feasibility of a Ketek-like trial.

J.P. Morgan analyst Jessica Fye wasn’t hopeful, either. “While the company plans to request a meeting with the FDA as soon as possible to discuss these concerns, given the consistency of these recommendations [with] the briefing documents and adcom, we continue to see liver toxicity as a risk to ultimate approval and see limited commercial potential even in the case of eventual approval,” she wrote in a report, also citing the $225 million cash balance. She called the move in Cempra’s share price “a justified reaction.”

Gabelli & Co. analyst Kevin Kedra put the matter starkly on the call. “The FDA is asking for a 9,000-or-so-patient study, and it sounds like even if that came back clean, they’d still have concerns, and [would] want to have restrictive labeling for the product,” he said. “Is there really a path forward here in CABP? Can you foresee a scenario where it makes sense to do such an arduous study, and still bring your product to market with a very restrictive label?” Zaccardelli said such questions can’t be answered until the company meets with the FDA.

Adding to investor concerns after the November adcom was the December retirement of Cempra CEO Prabha Fernandes, now serving as scientific consultant.

“Was this expected? Yes and no,” said James’ Raymond at the time. “Since the disclosure of manufacturing issues associated with the soli regulatory submission and the FDA advisory committee meeting, many investors we have spoken with have speculated about what Fernandes’ role with the company would look like going forward,” he wrote in a report. “Given her role in its founding and extended tenure as Cempra’s CEO, we had a hard time envisioning new leadership at the helm. Bottom line, while some may have speculated, we think few were anticipating this development.”

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