Amesh Adalja, of the University of Pittsburgh School of Medicine, told BioWorld Today that, although too early to tell for sure about toxicity, it’s “an encouraging sign” that Nabriva Therapeutics AG has chosen to develop lefamulin, a new antibiotic in the mushroom-derived pleuromutilin class that has shown a clean profile in phase II trials against skin infections.
“Other drug classes that may have been known for a while [should start] being commercially developed,” Adalja said, as drugmakers “start looking for things that might be on the shelf or other classes, really aggressively going after some of the other candidates that they haven’t pursued in the past.”
Companies have been more focused on chronic and lifestyle therapies because “a drug that someone is going to be on for the rest of their life is a lot more attractive to them than antibiotics,” Adalja added. Meanwhile, resistance grows.
Liver toxicity worries in last week’s FDA advisory panel on Cempra Inc.’s solithromycin added more weight to the optimism around the pleuromutilin candidate from Nabriva, of Vienna. The FDA’s Antimicrobial Drugs Advisory Committee evaluated Chapel Hill, N.C.-based Cempra’s oral and injectable forms of solithromycin and voted 13-0 in favor of efficacy in community-acquired bacterial pneumonia (CABP), but the panel split on the benefit/risk profile question, balloting 7-6. In briefing documents and during the panel meeting itself, solithromycin – in the macrolide class and ketolide subclass – was haunted by Ketek (telithromycin), the first ketolide antibiotic approved (in 2004) for CABP, which Sanofi SA, of Paris, pulled from the market after a boxed warning and restricted label were added. (See BioWorld Today, Oct. 30, 2006, Nov. 3, 2016, and Nov. 7, 2016.)
PDUFA dates are Dec. 27 and Dec. 28 for the two forms of Cempra’s solithromycin.
Nabriva’s compound has shown in vitro activity against the most common pathogens associated with CABP, including multidrug-resistant strains. With a special protocol assessment from the FDA in hand, Nabriva began its two-trial phase III program with lefamulin, being tested as an intravenous (I.V.) and oral therapy. RBC Capital Markets analyst Adnan Butt about a year ago noted that lefamulin has been shown noninferior to vancomycin in patients with acute bacterial skin and skin structure infections, proving effective while turning up no safety signals such as QTc interval prolongation. He started coverage with an “outperform” rating and a $21 price target. Nabriva, which said Friday it was in the process of raising capital through a rights offering, closed Tuesday (NASDAQ:NBRV) at $4.44, down 54 cents, or 10.8 percent.
Lefamulin is derived from the fungi Pleuro mutilis, and works by inhibiting bacterial protein synthesis at two unique binding sites on the ribosome, thus yielding early stage efficacy against pathogens that have evolved resistance to widely used classes of antibiotics such as macrolides, quinolones and tetracyclines. London-based Glaxosmithkline plc in 2007 won approval of a topical antibiotic in the class for impetigo, Altabax (retapamulin), but no systemic pleuromutilin has been cleared for marketing.
STAVING OFF A CRISIS
In a research report after the Cempra panel meeting, RBC’s Butt acknowledged phase II studies with lefamulin in the skin infections turned up “isolated increases in alanine and aspartate aminotransferases; however, they were comparable among treatment groups, which included low- and high-dose lefamulin and vancomycin.” For the “entirely new mechanism from a new drug class, liver-damage concerns do not appear to be an issue at this time.” Overall, he said, “The value proposition for Nabriva’s lefamulin is at least as attractive as if not better than Cempra’s solithromycin. While Cempra’s phase III program in CABP (less severe patients) is completed, Nabriva’s phase III trials still have to read out,” and shares of the latter may be due for a boost when they do, he said.
Leerink analyst Paul Matteis likes lefamulin’s odds, too. LEAP1, the phase III I.V.-to-oral CABP study, already underway, has been amended upon an agreement with the FDA reached in April. The change means regulators will now allow for a 12.5 percent noninferiority margin (compared to moxifloxacin ± linezolid) as opposed to the original 10 percent margin, along with treatment to seven days as opposed to five days, “both reflecting FDA recognition of the difficulty of performing I.V.-to-oral studies and the severity of the patients treated. With the amendment, LEAP1 can enroll a minimum of 550 patients with 90 percent power to hit the FDA endpoint of early clinical response and the EMA endpoint retains 80 percent powering for test of cure.” An interim analysis due in the fourth quarter of this year “will assess if statistical assumptions remain valid,” he said.
The LEAP2 trial, begun in April, is testing an oral-only lefamulin regimen and will enroll 740 patients with a 10 percent noninferiority margin (compared to moxifloxacin) for the primary efficacy endpoint, reflecting the fact that patients will be less severe than those recruited to LEAP1.
“Any new antibiotic in this situation is a major advance, because we are in dire straits with regard to antibiotic-resistant bacteria,” Adalja said. “We are really scrambling to find new antibiotic solutions” in order to “stave off what really is going to be a crisis.”
Nabriva was incorporated as a spin-off from Sandoz GmbH (now part of Basel, Switzerland-based Novartis AG) and started operating in February 2006. Backers include Vivo Capital, HBM Healthcare Investments, Orbimed Healthcare Fund Management, Phase4 Partners, Omega Funds, Wellcome Trust, Ecor1 Capital, Novartis Venture Fund and Boxer Capital. The firm also has an office in King of Prussia, Pa.