The endpoint miss in phase II with a topical version for moderate to severe acute vulvovaginal candidiasis (VVC, often known as yeast infection) did not dim Cidara Therapeutics Inc.'s optimism for an intravenous (I.V.) form of the echinocandin antifungal CD101 in candidemia, though Wall Street apparently felt otherwise.

"Unfortunately, unlike outcomes from mild to systemic infections, which have a well-established track record of translation to clinical outcomes, animal models of VVC for a topical agent are less predictive, due to anatomical and chemical differences at the site of infections between rats and humans," Cidara's acting chief medical officer, Taylor Sandison, told investors during a conference call. "It's also important to point out that this is the first study in clinical trials testing the efficacy of a topical echinocandin for VVC."

Shares of San Diego-based Cidara (NASDAQ:CDTX) fell 38.5 percent, or $4.50, to close Tuesday at $7.20, on word of the RADIANT trial's fizzle. CEO Jeffrey Stein said the firm "remain[s] fully committed" to the I.V. study called STRIVE in candidemia, due to report top-line data in the fourth quarter of this year. Development of the topical form will be stopped, "even though we believe an optimized topical formulation with improved drug-release properties could produce better results and improve patient outcomes," he said.

RADIANT was a multicenter, randomized, open-label, active-controlled, dose-ranging trial that enrolled 125 patients into three treatment cohorts. In the first cohort, 50 patients were treated with CD101 gel; a second cohort of 50 patients was treated with CD101 ointment, and the third cohort comprised 25 patients treated with oral fluconazole, sold as Diflucan by New York-based Pfizer Inc. and available in generic form. The trial included women with and without a history of recurrent VVC. Data showed the clinical cure rates on the seventh day, defined as Vaginal Scoring System (VSS)=0, of 37.5 percent/40 percent/47.4 percent on CD101 gel/CD101 ointment/oral fluconazole (n=40/40/19). Cure rate at the seventh day when defined as VSS=less than 2 was 57.5 percent/62.5 percent/78.9 percent in each arm, respectively. Mycologic cure rate on day 28 was 45 percent/40 percent/57.9 percent, respectively.

Sandison said adverse events turned up "roughly equal between all three groups, and there was nothing of note that would be concerning for I.V." testing. CEO Stein added such effects were "related to the differences in the cure rates."

STRIVE, with 90 patients, will evaluate twice-weekly doses of I.V. CD101 with an optional third weekly dose (two dose cohorts: 400 mg/400 mg/optional 400 mg or 400 mg/200 mg/optional 200 mg) vs. caspofungin – sold as Cancidas by Kenilworth, N.J.-based Merck & Co. Inc. and available in generic form – at 70 mg on day one, 50 mg/day on days two to 14, and the optional 50 mg/day on days 15 to 21. Key efficacy endpoints are mycological and clinical response at day 14. Enrollment so far "has met our expectations," Stein said.

CLOUDBREAK ON THE HORIZON

H.C. Wainwright analyst Ed Arce enthused over the I.V. form in a research report last December, saying CD101 "may become the leading treatment for serious Candida infections." In the U.S., he noted, Candida is the main cause of hospital-acquired (nosocomial) bloodstream infections (BSIs), with a mortality rate of up to 47 percent. "Although echinocandins, as a class, are the preferred and recommended first-line therapy, their use is limited primarily to the hospital, because they are only available as a daily I.V. infusion," he wrote. "Thus, when patients are well enough to be discharged, they are frequently placed on an oral azole drug (i.e., fluconazole) to complete their therapy at home. As a consequence, although the azoles, as a class, are generally considered inferior to echinocandins for most BSIs, their widespread use generates over double the annual sales compared to the echinocandins, largely because the availability of an oral stepdown option allows for shorter and less costly hospital stays."

Arce hailed "key differentiating factors: a unique pharmacokinetic [PK] profile with an 80-hour half-life, [plus] a higher and earlier drug exposure (higher Cmax) that persists longer (higher AUC). In our view, this defining characteristic is crucial, as it allows CD101 to offer a full course of treatment in just two I.V. infusions, one week apart (first inpatient, second outpatient)."

Leerink analyst Paul Matteis, who wanted to know from officials on the conference call "why this [outcome with topical CD101] does not render you incrementally more cautious" about the I.V. version, seemed satisfied in a research report. "We see no read-through onto our odds of success for CD101 I.V.," he wrote, citing echinocandins' "longstanding history of being effective and safe medicines for systemic fungal infections" and, pointing, like Arce, to the PK profile. Early data have proved favorable, "underlying our 50 percent odds of success as the drug advances through phase II," he said. "With all the caveats of preclinical data, Cidara has also generated compelling results for CD101 I.V. in well-established fungal infection animal models, where the drug looks superior to once-daily echinocandin therapy."

The discontinuation of topical CD101 in VVC will let Cidara shift resources to other candidates such as the I.V. version, and accelerate the bispecific Cloudbreak immunotherapy platform, including CD201 for the treatment of infections caused by multidrug-resistant gram-negative bacteria. An IND filing for a Cloudbreak candidate in serious fungal infections is due early next year. Candidates from the platform are designed to reinvigorate white cells by simultaneously targeting them directly to the fungal mass and stimulating them to kill more effectively. In recent decades, new antifungal classes have been hard to come by, even though the mortality rate for infections is 50 percent or more in patients with immune systems attenuated by cancer therapy or purposely mitigated as part of transplant procedures. Cloudbreak is named after a popular surfing destination in the Mamanuca Islands, Fiji.