Biotech's Role In Rebuilding Big Pharma's Neglected Antibiotic Pipeline
|
Antibiotic resistance has become a key market opportunity, but Big Pharma is poorly positioned to take advantage. Having all but abandoned antibiotic drug development at least a decade ago to smaller companies able to take on the risk, major drugmakers now look to those firms as a resource to revive their pipelines. But there may not be much to choose from. Industry-wide there are only about 50 small-molecule systemic antibiotic candidates in the publicly visible pipeline, and just under half of those are in the earliest stages of clinical development, Gary Noel, chief medical officer at Paratek Pharmaceuticals, told an audience at the Interscience Conference on Antimicrobial Agents and Chemotherapy Sept. 12 in Boston. All of the late-stage candidates appear to be focused on the emerging importance of methicillin-resistant Staphylococcus aureus, Noel said, adding his concern that "not a single agent in that late stage addresses the very important emerged problem of multi-drug-resistant Gram-negative bacteria." "That's where we sit, a pipeline that probably is about half of what it was a decade ago in terms of sheer number of molecules, " said Noel, who until recently was anti-infectives medical leader at Johnson & Johnson. Of greater concern is the proportion that are in early stages, because many of the drugs in the pipeline that hold promise for meeting critical medical needs are still years away from a patient's bedside, Noel said. Big Opportunity For Early Partnering While the biggest need in Big Pharma's antibiotic pipeline is for agents that can treat Gram-negative infections, even a clearly differentiated agent that can kill Gram-positive bacteria (S. aureus chief among them) would garner serious consideration, participants in a Sept. 15 panel discussion at the BioPharm America 2010 meeting, also in Boston, agreed. And, for speakers at both meetings, early partnering was not only a real possibility, it was a considered a preference of Big Pharma partners (see accompanying chart). "Whatever you have in Gram negative, Big Pharma will look at any stage, and they're going earlier because there's just nothing in the pipeline," Georg Buchner, VP of corporate business development for U.K.-based Novacta Bioscience, said. Novacta started getting interest from Big Pharma when its Clostridium difficile candidate, a peptide inhibitor of cell-wall synthesis, got animal data showing it had bested gold standard vancomycin, Buchner said. The privately held firm was founded in 2003 on assets from GlaxoSmithKline (Also see "UK Antibiotics Play Novacta Wins £13.1 million, mostly from Celtic Pharma" - Pink Sheet, 6 Jul, 2009.). "If you have animal trials, and you show that you are better in certain models, you start getting interest," he said. "Animal trials, and then talks." Before that it's too early, Buchner said.
In vivo animal activity would be enough for Peter Hammann, head of external opportunities for TSU infectious diseases at Sanofi Aventis Deutschland GmbH, a division of the French pharma. "We would get interested in discussion at that point," he said, adding that universities and start-ups might not have the capacity to conduct the kind of follow-up assays that demonstrate activity properties. However, Hammann said, "if you are including tox data we will be even more interested." Steve Projan, innovative medicines head of infectious diseases and vaccines at MedImmune, a subsidiary of AstraZeneca, was on the same Sept. 12 ICAAC panel with Noel. He advanced the early partnering argument from a different angle. "My personal preference is not to see Phase II compounds come in," Noel said. For a variety of reasons, biotechs, or their venture capital backers, in their enthusiasm to push assets forward "often don't select the best compounds," he asserted. "In my view, the sooner the better, take your money in milestones, have faith in what you do, then allow us to work with you to find the best possible compounds," Noel said, quipping that "of course we'll buy you anyway, but that's the nature of the beast." Projan also expressed a preference for working with platform companies. It's not just about working with companies that have early or Phase I or II compounds, he said. "It's about working with companies that have platforms that can help us discover that next generation of drugs." Projan recently moved from the Novartis Institute for Biomedical Research to MedImmune to spearhead the integration of vaccines and infections diseases R&D into one group with a common strategy. At MedImmune, Projan said he will be focusing on platforms for discovery of novel biologics agents "where we can have good activity against resistant bugs, maybe with a narrower spectrum."
Due to the economic turndown, option deals have emerged as a broader industry trend in the last two years, as Big Pharma looked for risk-sharing strategies and mid-range data lost its predictive value (Also see "Dealmaking When Pharma's the Only Game in Town" - In Vivo, 1 Sep, 2009.). A Crying Need For Something New The downside of Big Pharma's willingness to deal is the dearth of novel anti-infectives available. Looking around at ICAAC, where researchers annually showcase the latest developments in anti-infective technology, executives looking to license were not excited. "My socks are still on," Projan exclaimed. The BioPharm America panelists agreed. "There was nothing new to see there," Novacta's Buchner said. The most interesting compound, said Sanofi's Hammann, was an early stage antibiotic from Anacor Pharmaceuticals' boron-based small molecule platform. The antibiotic, AN3365, was featured among a handful of early stage candidates spotlighted by ICAAC organizers as most like to become drugs. Importantly, the inhibitor of t-RNA synthesis is active against Gram-negative bacteria. GlaxoSmithKline tied up a handful of the Palo Alto, Calif., biotech's anti-infective candidates in a 2007 option deal, then exercised its option on AN3365 in July ("GSK Options Several Boron Drug Candidates From Anacor." Elsevier's Strategic Transactions Database, October 2007, with updates). But the rest of even the brightest stars at the meeting were derivatives of known antibiotics. The problem with changes in antibiotics is the uphill battle against resistance, Hammann said. "The resistance is there, and the bug has seen it before." Another company on the ICAAC Featured Compounds list, however, has a platform of synthetic tetracyclines it believes can take back the spectrum that drug class once had. Tetraphase Pharmaceuticals' lead candidate TP-434 is a broad-spectrum antibiotic headed into Phase II studies. It has the ability to combat antibiotic-resistant Gram-negative bacteria, with the exception of Pseudomonas aeruginosa. Among the Gram-negative pathogens, the highly adaptive P. aeruginosa is considered the toughest to hit and therefore the ultimate target in antibiotic development. But with the exception of cystic fibrosis patients, who are plagued by the strain, the bacteria is uncommon enough in the general population to make an asset effective against everything else on the Gram-negative list a good bet, the company reasons. Tetraphase, in Watertown, Mass., has venture backing enough to carry '434 and two other candidates through mid-2012, according to CEO Guy Macdonald. At that point the lead compound will be at the Phase II partnering inflection point, but Tetraphase is poised to take it through to commercialization if a partner doesn't step forward, the CEO said (Also see "Tetraphase's Broad-Spectrum Antibiotic Candidate Makes A Good Showing At ICAAC" - Pink Sheet, 14 Sep, 2010.). [This paragraph was updated Oct. 5.] Cubist Pharmaceuticals, which made its fortune quite literally by developing an antibiotic candidate it salvaged from Eli Lilly through to commercialization, is working on a combination antibiotic that hits all the Gram-negatives, including P. aeruginosa. Gained through its 2009 acquisition of Calixa Therapeutics, CXA-201 combines a novel broad spectrum cephalosporin with tazobactam, a component of Pfizer/Wyeth's beta-lactase inhibitor Zosyn (piperacillin/tazobactam). The combination antibiotic is in Phase II development ("Cubist Touts Activity Of Its Broad-Spectrum Antibiotic Candidate Against High Value Gram-Negative Targets." "The Pink Sheet" DAILY, Sept. 21, 2010). Broken Pipeline, Lost Opportunities A revised model may be evolving, in which a small company develops an antibiotic asset to the point where traditionally it would have been partnered in some fashion, but a partner doesn't appear. So, the biotech either abandons the asset or takes it forward on its own with alternate financing in hopes of attracting a partner at a later stage – creating yet another inflection point in an already discontinuous, disjointed model, Paratek's Noel proposed. As of the third quarter of 2010, about 10% of the molecules in the industry pipeline have Big Pharma backing in Phase I and Phase II, Noel said. Of the few in Phase III, only a quarter are backed by Big Pharma, so companies that are considered small pharma have taken them into Phase III, he said. The issue is continuity, Noel stated. At a time when there are few enough candidates in the pipeline, the system is poorly designed to encourage late-stage development. Noel proposed encouraging early partnerships in order to create an end-to-end drug development continuum from discovery to launch. In that way, he said, drug candidates would have better scientific profiles that meet commercial expectations. Speakers at both meetings pointed to the sad fact that only three new antibiotic drug classes have been discovered in the last 45 or so years, two in the last decade, and each of those has only one marketed product to represent it. They are cyclic lipopeptides, represented by daptomycin (Cubist's Cubicin); oxyzolidones, represented by linezolid (Pfizer's Zyvox); and glycylcyclines, represented by Pfizer/Wyeth's tigecycline (Tygacil). |