Vulvovaginal Candidiasis

Ibrexafungerp for Vulvovaginal Candidiasis

Ibrexafungerp for Vulvovaginal Candidiasis

Ibrexafungerp (formerly SCY-078), if approved, may represent an optimal therapy for the treatment of acute vulvovaginal candidiasis (VVC) and for prevention of recurrence. Ibrexafungerp is orally administered and is extensively distributed into vaginal tissues. It is also fungicidal, with a broad spectrum of activity and enhanced activity in the acidic pH at the site of infection.

Acute VVC and recurrent VVC are serious conditions with significant morbidity and with very limited oral treatment options. No product is approved for the prevention of recurrent VVC, and current treatment alternatives have significant limitations, particularly in patients with other comorbidities and those who are taking certain concomitant medications, are pregnant or are experiencing episodes caused by an azole-resistant micro-organism.

What is Vulvovaginal Candidiasis?

VVC, commonly known as a "vaginal yeast infection," is the second most common cause of vaginitis and is usually caused by Candida spp. It affects approximately 70-75% of women at least once in their lifetime, with 40-50% of these women experiencing more than one episode. The majority of VVC episodes are uncomplicated cases with sporadic mild-to-moderate infections. The remaining complicated cases are severe and/or recurring infections.

Market Need

VVC can be associated with substantial morbidity, including significant genital discomfort, reduced sexual pleasure, psychological distress and loss of productivity. Diagnosis and treatment, combined with lost productivity, are estimated to cost $1.0 billion per year in the U.S. Current treatments for VVC include over-the-counter (OTC) topical azole antifungals and the prescription oral azole antifungal, fluconazole.

  • Fluconazole is the only orally-administered antifungal currently approved for VVC in the U.S., with a reported therapeutic cure rate of 55%.
  • Management of VVC during pregnancy and treatment of moderate-to-severe VVC, recurrent VVC and VVC caused by fluconazole-resistant Candida are not fully addressed by oral fluconazole.
  • There are no oral alternatives for VVC patients who do not respond to or tolerate fluconazole, and there are no FDA-approved products for the treatment of recurrent VVC.

We believe that ibrexafungerp, if approved for the treatment of VVC, may provide a significant benefit for patients not satisfied with existing therapies

~70-75% of women of reproductive age will have at least one episode of VVC during their lifetime
~40-45% of women will experience two or more episodes of VVC
~650K patients suffer from recurrent complicated VVC (at least four episodes during a 12-month period)

*Data on File (2015 IMS Consulting Group study, commissioned by SCYNEXIS).

Ibrexafungerp (formerly SCY-078) could provide a first-line therapy for recurrent VVC, for which there is currently no FDA-approved treatment, and be the only oral, non-azole, fungicidal treatment for moderate and severe cases of VVC.

  • Ibrexafungerp's broad spectrum activity (including against fluconazole-resistant strains), enhanced activity at acidic pH and high penetration in the vaginal tissue may allow ibrexafungerp to address the current unmet needs in this indication and improve the quality-of-life of these patients.
  • Ibrexafungerp is fungicidal against most Candida isolates, in contrast with fluconazole, which is fungistatic. Ibrexafungerp's "cidal" activity (i.e., killing the pathogen) may provide an advantage in preventing recurrences.

“Many of the unresolved clinical issues in managing women with recurrent VVC would disappear if truly fungicidal drugs and regimens were available.”

- Dr. Jack D. Sobel
Current Infectious Disease Reports 2006,8:481–486

Clinical Trial Results

Clinical experience to date has shown promising evidence of the antifungal activity of Ibrexafungerp (formerly SCY-078) in patients with Candida infections.

Identified 600 mg dose as having optimal combination of activity and tolerability - plan to move this into Phase 3.

PK/Efficacy
  • High clinical and mycological activity vs. Candida
  • Sustained clinical response over time
    • Data suggests improved sustained benefit relative to the standard of care
  • Clinical data consistent with pre-clinical evaluations of SCY-078’s attributes:
    • Fungicidal vs. Candida
    • High vaginal tissue penetration
    • Enhanced activity at the low pH characteristic of the vaginal environment
Safety/Tolerability
  • Safe and well-tolerated
    • No serious AEs or discontinuations
    • Gastrointestinal (GI) events were mild to moderate and of short-duration

Phase 2b Dose-Finding Study (DOVE)

(ClinicalTrials.gov Identifier: NCT03253094)

  • Goal: Identify optimal oral dose of SCY-078 for Phase 3
  • Design: Randomized, multi-center, double-blind, active-controlled, dose-finding study
  • Enrollment:
    • 186 female patients with moderate-to-severe acute VVC (S&S ≥7)*
    • 153 patients in the modified Intent-To-Treat (mITT = culture-confirmed infection)
Treatment Groups
Total Dose in mg
Reginmen ITT / mITT
(# of patients)
600mg SCY-078 300mg BID for 1 day 30 / 27
750mg SCY-078 750mg QD for 1 day 32 / 26
900mg SCY-078 450mg BID for 1 day 28 / 21
900mg SCY-078 150mg BID for 3 days 32 / 29
1080mg SCY-078 300mg BID for 3 days 32 / 26
150mg Fluconazole 150mg QD for 1 day 32 / 24
  • Primary efficacy endpoint: Clinical cure: Resolution of all signs and symptoms (all scores = 0) without further antifungal treatment at Test-of-Cure (TOC) visit (Day 10)
  • Secondary efficacy parameters:
    • Clinical outcome at Follow-Up (FU) visit (Day 25)
    • Mycological eradication (negative culture) at Days 10 and 25
  • Use of antifungal rescue therapy and changes from baseline signs and symptoms score also evaluated
  • Signs and symptoms:
    • By investigator: Edema (swelling of tissue), Erythema (redness), Excoriation (fissures)
    • By patient: Burning, Itching, Irritation
    • Scoring scale: 0 (absent), 1 (mild), 2 (moderate), 3 (severe)
    • Score range on scale: 0-18

Results based on mITT population | * No rescue antifungal use.

Signs and Symptoms [S&S] score defined as a composite endpoint of the subject’s reported symptoms (burning, itching and irritation) and the investigator’s assessed signs (swelling, redness and excoriations). Each sign and symptom can be absent, mild, moderate or severe, with a corresponding score from 0 to 3. The total composite scale goes from 0 to 18 points.

Results based on mITT population.

Mean signs and symptoms score based on 0-18 scale.

P value based on change from baseline score mean difference between SCY-078 600mg and FLU.

Phase 2a Proof-Of-Concept (POC) VVC Study

SCY-078 Phase 2 Study in Moderate and Severe Vulvovaginal Candidiasis (VVC)

Randomized, multicenter, active controlled, evaluator-blinded study of oral SCY-078 compared to oral fluconazole in adult female patients with acute vulvovaginal candidiasis (VVC). A total of 96 patients with an acute moderate to severe, symptomatic episode of VVC were randomized in a 1:1:1 ratio to receive either three daily doses or five daily doses of SCY-078 or oral fluconazole, at the labeled dose regimen of 150mg single dose. Efficacy was evaluated based on the proportion of patients achieving clinical cure (resolution of all signs and symptoms, score=0 and 1) mycological eradication and therapeutic cure (combination of both clinical cure and mycological eradication) at day 24 (+/-3) after initiation treatment, in line with draft guidelines from the FDA.

(ClinicalTrials.gov Identifier: NCT02679456)

The Phase 2a POC VVC Study and the Phase 2b DOVE study showed comparable efficacy results, providing reassurance of reliability of findings across studies.

  • Using the definition of clinical response from the POC VVC study (signs and symptoms composite score of 0 or 1 at Day 25), the clinical response in the SCY-078 600mg dose arm of the DOVE study was 81% compared to 76% observed for SCY-078 in the prior POC VVC study. In addition, the clinical response in the fluconazole arms were similar in both studies (58% in the DOVE study and 65% in the prior POC VVC study).

Clinical Development Plan

SCYNEXIS anticipates that the dose regimen selected from the DOVE study will be subsequently evaluated in Phase 3 studies following an End-of-Phase 2 meeting with the FDA. SCYNEXIS expects to initiate the Phase 3 clinical program in the fourth quarter of 2018 and file a New Drug Application (NDA) for acute VVC in 2020.

Indication

2018

2019

2020-2021

Acute Vulvovaginal Candidasis

Two Phase 3 Acute VVC Studies

Recurrent Vulvovaginal Candidasis

One Phase 3 Rucurrent VVC Study

Sources

Preliminary assessment (to be further validated). SCYNEXIS Primary HCPs and Payers Market Research.

CDC: Vaginal Candidiasis.