GAIN, or Generating Antibiotic Incentives Now, is a series of antibiotic drug incentives folded into the Food and Drug Administration Safety and Innovation Act. [Irochka - Fotolia.com]
While it’s hard to quantify the benefit of the new incentives intended to promote more antibiotic drug development, Rib-X Pharmaceuticals has something of an answer: $67.5 million. That’s how much the company raised in a series 2 preferred stock financing whose first of two tranches closed last month.
“I give partial credit to the more favorable environment that now exists post-passage of GAIN in being able to close that financing,” Rib-X CEO Mark Leuchtenberger, told GEN. “It really may be more dramatic than going faster. It’s the difference between going forward and not going forward.”
GAIN stands for Generating Antibiotic Incentives Now—a series of antibiotic drug incentives folded into the Food and Drug Administration Safety and Innovation Act (FDASIA)—the formal name for the fifth authorization of the Prescription Drug User Fee Act enacted in July by President Obama. Among incentives in the law is the “qualified infectious disease product” (QIDP) designation, entitling recipient drug developers to faster FDA reviews and five additional years of market exclusivity.
Rib-X was among the first companies to win QIDP status. FDA granted the designation in September for the broad spectrum fluoroquinolone delafloxacin for both acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). delafloxacin is set to enter Phase III trials for ABSSSI in 2013. The following month, Rib-X won QIDP for the oxazolidinone radezolid, for both oral and intravenous use against ABSSSI and CABP.
Since then, Durata Therapeutics achieved QIDP status for Dalbavancin, a once-weekly antibiotic drug candidate for acute bacterial skin and skin structure infections that reported preliminary Phase III results on Dec. 11. Earlier this month, Cubist won QIDP for two Phase III antibiotic candidates—CXA-201 (ceftolozane/tazobactam) for complicated intra-abdominal infections and complicated urinary tract infections caused by Pseudomonas aeruginosa and other Gram-negative bacterial infections; and CB-315 for Clostridium difficile-associated diarrhea (CDAD).
In interviews, leaders of three QIDP-winning companies praised the GAIN incentives as being just the right medicine for antibiotic drug development—namely, by boosting investor confidence that new treatments will reach the market, and sooner.
Among companies planning to pursue QIDP status is PolyMedix. Nicholas Landekic, the company’s president & CEO, told GEN his company plans to pursue QIDP status for its most advanced defensin-mimetic antibiotic in clinical development, brilacidin (formerly PMX-30063) for acute bacterial skin and skin structure infections (ABSSSI) caused by Staphylococcus aureus (including MRSA) and Streptococcus pyogenes. PolyMedix is planning a Phase IIb trial for brilacidin, incorporating direction received last month in a Type B meeting with FDA.
“If we are able to further advance them into development, we also hope to pursue QIDP status for our other defensin-mimetic compounds currently in preclinical development, such as for Gram-negative bacteria, and, with funding, potentially new programs such as tuberculosis,” Landekic said.
Much Greater Comfort
GAIN’s most valuable incentive, Durata CEO Paul Edick told GEN, was its five years of additional data exclusivity, on top of five years for new chemical exclusivity or NCE. “You now have a 10-year period where you can realize the return on all of what has been invested. That’s a huge change, and I think that’s an important change.”
“It doesn’t make development any less expensive to do,” Edick added. “You still have to get to the finish line on your own. But it does give investors much greater comfort in investing in a company that has a longer period of time with which to generate a return, and therefore shareholder value.”
Barry Eisenstein, M.D., Cubist’s senior vp, scientific affairs, told GEN another valuable component of GAIN is its provisions of FDA priority review, and “fast track” status which shortens the agency’s standard 12-month review to six months, plus the 60 days FDA gives itself for deciding whether applications may be filed.
“They give themselves an extra two month window, but you know what? That’s still great, because we get the review done by eight months rather than the 12 or 14 months. That essentially shortens a half a year on the approval process,” Dr. Eisenstein said. “We’re very confident on that basis that this is going to mean a rapid turnover. When you get a rapid turnover of review, it means that you can launch the product earlier. You can get the product out sooner, and the product has a longer lifespan to provide the return on investment.”
Cubist now markets CUBICIN® (daptomycin for injection) for complicated skin and skin structure infections caused by some strains of Gram-positive microorganisms, including MRSA; and ENTEREG® (alvimopan), a peripherally-acting µ-opioid receptor antagonist for accelerating gastrointestinal recovery after partial large or small bowel resection surgery with primary anastomosis.
The company discovered CXA-315 internally, but created CXA-201 from the original P. aeruginosa compound CXA-101 of Calixa Therapeutics—which Cubist acquired in 2010—by adding to it the beta-lactamase inhibitor tazobactam, a component of the antibiotic Zosyn®. “We’re starting to lose effectiveness of our present antibiotics against pseudomonas. So having that drug in that late-stage development, we think it is extraordinarily important addition to the armamentarium of physicians in practice,” Dr. Eisenstein said.
Over time, the executives said, their companies and others will pursue new indications for approved drugs. Durata, for example, is looking to expand dalbavancin to osteomyelitis, reasoning that its once-weekly dosing regimen will prove attractive to patients undergoing the four to eight weeks of treatment required by the bone infection.
“We have advantages to the patient in that it’s certainly much more convenient. And the doctors feel good about it because they’re guaranteed to get compliance over that timeframe,” Michael W. Dunne, M.D., the company’s chief medical officer, told GEN.
QIDP status, he said, will likely nudge drug developers to revive some compounds now languishing on the proverbial back burner.
“There will be large pharmas, for example, that have a portfolio that they’ve been watching, that now may be able to go back and justify bringing some of these compounds back into development. I think that would be good for patients overall,” Dr. Dunne said. “For dalbavancin in the short term, I’m not sure that it’s going to change the competitive landscape. But over time, I think, there may be opportunities for more compounds to come out into the market than there might have been without having the QIDP option available.”
Antibiotic drug development is unlikely to see soon the competition among companies that has emerged in, say, hepatitis C. Developers are unlikely to dramatically expand internal R&D when the rest of the biopharma industry is scrambling to cut development costs.
Developing antibiotics, as with most drugs, runs from hundreds of millions on up. While biopharmas can recoup development costs with high prices for many indications—especially rare diseases, where treatments have long enjoyed development incentives—they cannot do the same with antibacterial drugs. Their markets are often developing countries, where patients and governments lack the ability to pay for the medicines.
“If you have a diabetes compound, or a heart disease related compound, those returns can be quite high, in many billions. For anti-infectives, the typical return for a compound could be between $500 million and $1 billion. That would be what you would target,” Edick said. “There are blockbusters in antibacterials, no question about it. But the frequency of those is much less. And now, it’s taking longer, with more risk, to get to that point. So when companies look at their whole portfolio, the antibacterial area started to look less attractive. That’s why they backed out.”
FDA rules intended to reduce risk, such as requiring more extensive trials, added to development costs. After FDA’s 2010 withdrawal of guidance on ABSSSI, Rib-X’s Leuchtenberger said, “there definitely was a very chilling effect, and that indecision and the lack of clarity definitely played a part in the market’s attitude toward antibiotic development. Contrast that now with the clarity FDA has shown on these GAIN guidelines.”
In the meantime, antibiotic drug discovery has been left largely to niche companies like the QIDP status winners to date. If GAIN is as attractive as the companies say, then big biopharma will return to antibiotics, whether by launching its own antibiotics, or more likely, by snapping up successful smaller companies.
Also to be decided: What pathogens should qualify drug developers for QIDP? FDA held a hearing on the topic Tuesday, taking testimony from agency officials, Rib-X executives, and others on how to apply—and whether to add to—four criteria already set in FDASIA: impact on the public health due to drug-resistant organisms in humans; growth rate of drug-resistant organisms in humans; increase in resistance rates in humans; and morbidity and mortality in humans.