An advantage specific among obese patients seen in the first phase III trial with Baxdela (delafloxacin) "didn't pan out in the second" experiment, Melinta Therapeutics Inc. CEO Eugene Sun told BioWorld Today, "but what we did end up with is a very robust study in very challenging patients, so I think we have a rich dataset now to convince physicians that Baxdela is an ideal drug" across a wide sample of subjects with acute bacterial skin and skin structure infections (ABSSSIs).
New Haven, Conn.-based Melinta's bigger, confirmatory study was "enriched for obese patients and the co-morbidities that they would carry with them," Sun said. "If you look at who gets hospitalized with serious skin infections, in fact it is disproportionately obese patients and patients with underlying chronic conditions. We felt we had a good position in that segment of the population. We thought there was a possibility [that the particularly strong showing in the first trial could hold in the second], but it's quite difficult to show statistical superiority in antibiotic trials."
The second trial was different in another way, including not just the intravenous (I.V.) form, but the I.V. accompanied by a stepdown to the oral version. In the first study, patients were given all-I.V. Baxdela for five to 14 days. In the second, they got three days of I.V. drug and finished therapy with the oral form. "It's always preferable to be able to leave the hospital earlier, and to be able to leave the hospital on the same therapy that you started, so you don't introduce the additional risk of a new medication – new side effects and so on," Sun noted. "If you or I showed up in the emergency room with one of these big, nasty-looking lesions and a fever, and maybe we had underlying diabetes or some kind of chronic conditions, the decision to admit the patient is one of conservatism, where they want to make sure the patient doesn't go downhill, but they also want to make sure the patient gets enough drug in them. The I.V. route is typically chosen, certainly for the very first day," though patients "can very rapidly go to oral therapy," he said.
John Temperato, chief operating officer (COO), said the versatility of Baxdela gives hospitals options. The label could allow doctors to initiate with both forms, or start with I.V. and transition to the oral, and thus "give the hospital the ability to 'treat and street' as quickly as possible." Baxdela is "very appropriately positioned," he added, telling BioWorld Today that the company estimates as much as $800 million per year in maximum sales. Vancomycin currently takes 40 percent of the share of the market, quinolones 20 percent. "We don't need half of that volume to be successful," he said. "We can get to an $800 million drug in skin [infections] with single-digit market share at peak year." Another plus is that "we're not the seventh proton pump inhibitor or the fifth calcium channel blocker," he said. "You get to realize or monetize the opportunity with a very focused effort. About 1,800 hospitals represent 80 percent of the skin and skin structure infection" market, he said.
CEO Sun said that "covering the waterfront" with a monotherapy – and a quinolone that, uniquely, hits methicillin-resistant Staphylococcus aureus (MRSA) – means a strong advantage over the standard-of-care pair, both of which are I.V.-delivered. "Neither of those actually covers all the pathogens that you can encounter," he said. "Vancomycin, while used fairly frequently first-line, only covers gram-positive organisms, and that's not sufficient in a lot of these patients with more complex lesions and more serious underlying disease."
CAPTISOL CURTAIN CALL
Baxdela had already proved its broad-spectrum activity against gram-positive and gram-negative bacteria, including MRSA, and was tested again in the most recent experiment as compared to vancomycin plus aztreonam. In the intent-to-treat (ITT) population, Baxdela proved its noninferiority (10 percent margin) at the early clinical response at 48-72 hours after initiation of therapy (83.7 percent) compared to standard of care (80.6 percent). The 95 percent confidence interval for the treatment difference had lower and upper bounds of -2 percent and 8.3 percent, respectively. Baxdela also met the EMA's required endpoint of statistical noninferiority (57.7 percent) compared to vancomycin plus aztreonam (59.7 percent) based on the investigator's assessment of complete cure (resolution of all baseline signs and symptoms) at the follow-up visit in the ITT population. Lower and upper bounds of the confidence interval for the treatment difference were -8.6 percent and 4.6 percent, respectively. Baxdela turned up comparable to vancomycin plus aztreonam in achieving treatment success at follow-up (cure or improved, with no further antibiotics needed), with the trial showing success rates of 87.2 percent vs. 84.8 percent, respectively. I.V./oral Baxdela monotherapy successfully eradicated gram-positive pathogens, including MRSA, and gram-negative pathogens at rates comparable to I.V. vancomycin/aztreonam combination treatment, the company said, and both forms of the drug were well tolerated.
Overall adverse event rates were similar between treatment arms, the most common on Baxdela being diarrhea and nausea, generally mild and not leading to dropouts. The oral form evidenced no increase in gastrointestinal events compared to the I.V. Only 1.2 percent of Baxdela-treated patients in all discontinued due to treatment-related adverse events. Obese patients (body mass index ≥ 30kg/m2) constituted 50 percent of the enrolled population, and as expected had a higher prevalence of co-morbidities such as diabetes and cardiovascular disease than other subjects. CEO Sun said that between the two phase III studies, enrolling 740 patients, only 0.8 percent had a side effect that caused them to discontinue.
A new drug application will be filed in the second half of this year with an eight-month review, since Baxdela has been designated a qualified infectious disease product by the FDA. "We're looking for a partner in Europe," Sun said, and will "proceed together with them to register the compound" there. COO Temperato said Melinta will "absolutely be ready to launch this by ourselves [in the U.S.] next year."
Meanwhile, a phase III trial in pneumonia is enrolling about 850 patients, with data due around the first part of 2018, depending to some extent on the severity of the flu season. A phase II trial in urinary tract infections is expected to start by the end of this year. Although he declined to speculate about off-label use if the drug is cleared in ABSSSIs, Temperato said that physician discretionary use of recently launched antibiotics ranges 5 percent to 20 percent.
Sun said approval of Baxdela would be an important milestone for the company. "This will bring us into the commercial realm and provide us with revenue to keep funding the R&D engine, and hopefully we'll have a continual stream of antibiotics coming out of this company," he said.
Melinta used Captisol technology from Ligand Pharmaceuticals Inc., of San Diego, in formulating Baxdela for ABSSSI. Captisol is a chemically modified cyclodextrin, pioneered at the University of Kansas and designed to optimize the solubility and stability of drugs. It has enabled six FDA-approved products, including the likes of Thousand Oaks, Calif.-based Amgen Inc.'s Kyprolis (carfilzomib) for multiple myeloma, Deerfield, Ill.-based Baxter International Corp.'s Nexterone (amiodarone) for ventricular fibrillation and hemodynamically unstable ventricular tachycardia, and Kenilworth, N.J.-based Merck & Co. Inc.'s antifungal Noxafil (posaconazole). More than 30 Captisol-enabled products are moving through pipelines.
As an excipient, Captisol "reduces the irritation when the drug is given I.V.," Sun said. "Some drugs can produce a burning sensation when delivered," and Ligand's technology relieves the problem in exchange for a small royalty. "It's really more of a bystander that helps the drug get into the system," he said.