Solithromycin Proves Safe, Makes Cempra A Deal Target

The antibiotic showed promising results in a late-stage study of the oral formulation, setting the company up as a potential target for acquirers and partnering opportunities – though for now it is signaling its intent to go it alone.

Cempra Inc.’s antibiotic solithromycin exhibited strong Phase III data – particularly in the area of liver safety – putting the biotech in prime position to find a partner or get acquired as antibiotic development re-emerges as a viable therapeutic area.

Solithromycin, a fourth-generation macrolide antibiotic in the fluoroketolide family, is in Phase III testing for community-acquired bacterial pneumonia (CABP) in adults. Topline results from the Solitaire-Oral trial, announced Jan. 4, showed that solithromycin was not inferior to moxifloxacin in the treatment of patients with CABP.

The Phase III study included 860 intent-to-treat (ITT) patients, those that had certain microbial isolates as determined by several different diagnostic tests. Cempra said the study was the first to be completed under FDA’s draft guidance on CABP, which allows for assessment of the primary endpoint of early clinical response in the pooled ITT population across two similar Phase III trials, utilizing a 12.5% non-inferiority margin (Also see "Panel Gives Mixed Reviews To Using Single Trial For Community-Acquired Pneumonia" - Pink Sheet, 14 Nov, 2011.).

Cempra is following this model and will pool data from Solitaire-Oral with the ongoing Solitaire-IV for an NDA submission, though no timeline was given. Solitaire-IV, which was initiated in December 2013, is comparing the intravenous form of solithromycin with moxifloxacin in 800 patients with CABP.

Microbiological confirmation was an important issue for the advisory committee that reviewed the draft guidance, and Senior VP-Clinical Research David Oldach told a Jan. 5 analyst call on the results that the company got lots of praise from “academic advisors and partners in the study … because of the efforts we went to establish microbiological diagnosis.”

“FDA has clearly indicated that they will support use of molecular diagnostic testing for establishment of the mITT population. So, we have taken that opportunity and used several innovative tests to enhance our ability to make a diagnosis,” he said, adding that the firm was “quite pleased” with the 53.6% rate of pathogen confirmation in the mITT population “and we look forward to discussing the data with the FDA in the future.”

Patients in the Solitaire-Oral trial either received an 800 mg starting dose of oral solithromycin, followed by 400 mg once daily for five days, or a 400 mg oral dose of moxifloxacin for seven days. Patients were evaluated for improvement in cough, sputum production, shortness of breath and chest pain at 72 hours into treatment and five to 10 days after treatment.

After 72 hours of treatment, patients in the solithromycin group had a 78.2% clinical response rate compared with 77.9% in the moxifloxacin group. While the results were consistent across patients, a higher rate of response was seen in patients over 75 years of age with solithromycin – something the company considers a win since patients in this group are more likely to die from pneumonia.

Cempra CEO Prabhavathi Fernandes noted that the solithromycin group had more patients that were diagnosed with severe pneumonia than in the moxifloxacin group. “These are the people who are at risk of dying and we did so much better,” he said. He later added that despite the randomization, the solithromycin group had more patients with the higher severity scores than the moxifloxacin arm, “so we've got more severely sick patients and we actually did numerically better.”

Further results from the study will be published in a major medical journal and presented at an upcoming medical meeting, the company said.

Firm Dismisses ALT Elevations

Results from the Solitaire-Oral trial showed that there were no serious adverse events. Two patients in the moxifloxacin arm experienced C. difficile related diarrhea, a problem seen with this drug. There was no incidence of the issue in patients on solithromycin.

Asymptomatic, reversible alanine transaminase (ALT) elevation was observed in both treatment arms. Grade 3 ALT elevation occurred in 2.1% of moxifloxacin patients and 4.6% of solithromycin patients; the higher Grade 4 ALT elevation occurred in 1.2% of moxifloxacin patients and 0.5% of solithromycin patients.

“You must remember that ALT elevations alone don't mean a whole lot, especially when it's non-symptomatic and is reversible,” said Fernandes. “All of these were reversible. We certainly would have preferred not to see it, I guarantee you that. But on the other hand, we are not surprised. We expected that. We didn't see any bilirubin increase in the same patients. And so of course, they don't really last long. You probably know that if you eat a couple of hamburgers, you can get ALTs to go up like that,” he added.

Follow-up testing of patients in the study was done and showed that ALT level returned to normal, said the company.

The ALT reading can be indicative of liver toxicity and is therefore closely scrutinized by regulators since macrolides are processed first through the liver. There has been a history of macrolides causing severe liver toxicity – Sanofi’s Ketek (telithromycin) was slapped with a black box warning by FDA in 2007, three years after its initial approval, and two of its previously approved indications were rescinded due to the safety issue (Also see "Ketek Is Emerging As Lens For Wider Hill Scrutiny Of Clinical Trial Integrity" - Pink Sheet, 18 Feb, 2008.).

All of this is good news for Cempra – the data is likely to make the company a target for acquirers, as well as partners. Antibiotic development deals have seen an uptick in recent months as more antibiotics continue to get approved under the Generating Antibiotic Incentives Now (GAIN) Act, a program introduced under the 2012 FDA Safety and Innovation Act to provide incentives to drug makers in hopes of overcoming a drought of antibiotic development (Also see "The Regulatory Pendulum Swings In Favor Of Antibiotics, But Will Investments Follow?" - Scrip, 27 Feb, 2013.). There were four novel antibiotics approved in 2014 under the regulatory program (Also see "Cubist’s Zerbaxa Challenge Will Be Lack Of Superiority Claim" - Pink Sheet, 5 Jan, 2015.).

With plenty of incentives, big pharma has begun jumping into the deal fray. Merck & Co. Inc. announced at the beginning of December that it intends to acquire antibiotic drug developer Cubist Pharmaceuticals Inc. for $9.5 billion (Also see "Under Pressure: Can Merck Show Cubist Is Worth $9.5 Billion Without Cubicin?" - Pink Sheet, 15 Dec, 2014.).

Yet, Cempra might not be so eager to be acquired. Fernandes remarked during the company’s Jan. 5 call with investors that the biotech is not looking for a partner and is planning to launch solithromycin on its own.

The specialty role of novel antibiotics has meant commercialization is feasible for smaller companies, but with larger firms interested, that might prove an attractive route for a fledgling sponsor.

The firm is “not out there looking for partners. If some partner wants to talk to us, we will meet them and keep them informed,” he said. “Our biggest value is to submit the NDA and get that approved,” the exec added.

In 2013, Cempra earned $58 million in potential funding for solithromycin from the U.S. Biomedical Advanced Research and Development Authority (BARDA). Under the agreement with BARDA, Cempra also will attempt to develop the antibiotic as a pediatric oral suspension, oral capsule and intravenous formulation for CABP. The North Carolina-based biotech is guaranteed at least $17.7 million over the first two years of the contract, with decisions on further extensions to be based on the progress of the work (Also see "BARDA To Fund Pediatric Development Of Cempra’s Solithromycin" - Pink Sheet, 30 May, 2013.).