sign in sign up
<<
Home , Ibrexafungerp

Ibrexafungerp (formerly SCY-078) ASM Microbe 2019 San Francisco, CA June 2019

David Angulo MD Chief Medical Officer

“Committed to positively impacting the lives of patients suffering from difficult-to-treat and often life-threatening ” Disclosures

• David A. Angulo, MD is an employee and shareholder of SCYNEXIS, Inc

2 Ibrexafungerp (SCY-078) Overview

scynexis.com Ibrexafungerp A Novel Triterpenoid

Novel Glucan Synthase Inhibitor (GSI) Key Attributes

• Activity against: • Candida spp. • Aspergillus spp. • Pneumocystis spp.

• Active against -resistant and most -resistant strains Structurally distinct from other GSIs • Oral and IV formulations ()

CAS • Favorable safety profile > 500 exposed • Different enzyme-drug interaction → lower • Low risk of drug-drug Interactions impact of common FKS mutations • Oral bioavailability • Extensive tissue distribution • (Vdss > 8 L/kg)

4 Ibrexafungerp: Platform of Indications

Indications Preclinical Phase 1 Phase 2 Phase 3

Vulvovaginal Phase 3 ongoing Candidiasis

Invasive Aspergillosis Phase 2 initiated Combo

FURI (open-label, refractory IFDs, ongoing) Refractory Invasive Fungal Diseases CARES (open-label, C. auris, ongoing)

Invasive Phase 2a completed Candidiasis

Additional indications under consideration: Chronic Fungal Infections, Prophylaxis

5 Ibrexafungerp Pre-clinical Overview

scynexis.com Ibrexafungerp: in vitro Activity against Candida spp.

Ibrexafungerp exhibited fungicidal behavior against Candida spp

Scorneaux B, et al. AAC, March 2017 7 What is the percent of Candida glabrata isolates resistant to in your practice? Poll A) > 30%

B) > 15% but < 30%

C) > 5% but < 15%

D) < 5%

E) I do not know

8 What is the percent of Candida glabrata isolates resistant to at least one echinocandin in your practice?

A) > 10% Poll

B) > 5% but < 10%

C) > 1% but < 5%

D) < 1%

E) I do not know

9 Ibrexafungerp Activity against C. glabrata with Common fks Mutations

100 100 90 90 80 80 70 70 60 60 50 50 40 40

%Susceptible 30 30 % Susceptible 20 20 10 10 0 0 S629P in fks1 S663P fks2 IBX CAS MFG IBX CAS MFG

• Ibrexafungerp demonstrated activity against 78% of C. glabrata isolates with fks mutations*, including most isolates with the most commonly observed S629P (fks1) and S663P (fks2) mutations.

• Resistance to ibrexafungerp was primarily associated with deletions at position F659 in fks2¥

*Pfaller M, et al. AAC, August 2017 ¥Jimenez-Ortigosa, et.al. AAC, September 2017 10 In vitro Activity of Ibrexafungerp against C.auris

• Activity evaluated against >110 clinical isolates across two studies

CDC (N=100) CMM (N=16) IBX MIC (μg/mL) IBX MIC (μg/mL) Range 0.0625 - 2 0.5 – 2 Mode 1 1 MIC50 0.5 1 MIC90 1 1

• Ibrexafungerp activity vs. isolates with elevated echinocandin MIC

Minimum Inhibitory Concentration (μg/mL) Isolate Ibrexafungerp 1 8 1 4 1 2 16 1 4 1 3 1 16 1 1 4 2 16 2 1 5 4 0.5 0.5 0.5 6 >16 >16 >8 0.5 7 4 >16 1 1

Berkow E, et al. AAC, July 2017 11 Larkin E, et al. AAC, May 2017 In vivo Activity of Ibrexafungerp against C.auris

Efficacy of Oral Ibrexafungerp in the Treatment of Candida auris in a Murine Disseminated Model AAR-633 M. Ghannoum1*, et al. RESULTS Orally administered ibrexafungerp demonstrated potent antifungal activity against Candida auris in this model by significantly increasing survival from 20% (vehicle) to 60-70% (ibrexafungerp arms) and reducing kidney fungal burden.

Efficacy of Ibrexafungerp in the Treatment of

AAR-632 Candida auris Cutaneous Infection in a Guinea Pig Model M. Ghannoum1*, et al. RESULTS Orally administered ibrexafungerp resulted in significant reduction in skin Candida auris burden and clearance of yeast elements in skin histopathological examinations, suggesting potential role of ibrexafungerp in C.auris

For skinadditional information decolonization. contact Mahmoud A. Ghannoum, PhD at [email protected] or SCYNEXIS at [email protected].

12 Ibrexafungerp Activity against Aspergillus spp.

Neutropenic mouse model of disseminated Ibrexafungerp aspergillosis MEC • IV inoculum, azole-resistant A. fumigatus • Treatment for 7 days, followed for 14 days MEC50 MEC90 • IBX efficacious exposure AUC0-24hr 15 - 20 μM•hr

A. fumigatus (n=134) <0.06 0.125 110 100 A. flavus (n=54) <0.06 <0.06 90 80 l

A. niger (n=27) <0.06 <0.06 a v

i 70 v r u

s 60 A. terreus (n=72) <0.06 0.125 t n

e 50 c r Other spp. (n=24) <0.06 <0.06 e VehicleF16216 - Vehicle PO q12h P 40 IBXF16216 7.5mg/kg - SCY-078 7.5mg/kg PO BIDPO q12h 30 All isolates (n=311) <0.06 0.125 IBXF16216 10mg/kg - SCY-078 10mg/kg PO BID PO q12h 20 CaspofunginF16216 - Caspofungin 5mg/kg 5mg/kg IP IPq24h QD 10 AmbisomeF16216 - AmBisome10mg/kg 10mg/kg IV IVq24h QD In vitro synergistic activity was observed when ibrexafungerp is 0 0 50 100 150 200 250 300 350 combined with , Isavuconazole or Treatment Monitoring Number of hours post-infection

Ghannoum M., et al. AAC June 2018 Barat S. et al, at TIMM 2017 13 How often do you use combination antifungal therapy for invasive aspergillosis ? Poll A) Never

B) Rarely (I have done once or twice)

C) Sometimes (< 25% of my invasive aspergillosis patients)

D) Frequently (> 25% of my invasive aspergillosis patients)

E) I do not see patients with invasive aspergillosis

14 Ibrexafungerp (SCY-078) Activity in Neutropenic Rabbit IPA Model • Neutropenic rabbit model of pulmonary aspergillosis evaluating IBX alone and in combination with Isavuconazole (ISA) • Doses: (IV) IBX 2.5, 7.5 mg/kg; (PO) ISA 40 mg/kg for 12 days • ISA 40 mg/kg in rabbits provides exposures comparable to 200 mg/day in humans • Combination therapy resulted in better efficacy vs. monotherapy for all efficacy parameters, including significantly improved survival and pulmonary infarct score

IBX + ISA

Vidmantas P, et. al. Advances Against Aspergillosis 2018 15 Ibrexafungerp Activity in Neutropenic Rabbit IPA Model – Galactomannan antigenemia

CONTROL

IBX 7.5 mg/kg ISA

IBX 7.5 + ISA

Combination therapy resulted in significant GM antigenemia suppression

Vidmantas P, et. al. Advances Against Aspergillosis 2018 16 Ibrexafungerp distribution to key tissues associated with invasive fungal disease

Spleen Estimated Volume of Distribution at Steady State Lung (human)

Drug Vdss L/kg Kidney Mean SCY-078 8.3 Caspofungin 0.15 Liver Micafungin 0.39 Anidulafungin 0.8

Salivary glands

Autoradiogram of the Radioactivity Distribution Rat at 4h Following a Single Oral Dose of [14 C]SCY-078 Felton T. et al,. Clin. Microbiol. Rev. 2014, 27(1):68. Wring S, et al. AAC 2019 17 Penetration of Ibrexafungerp (IBX) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model 2 days Tx of Micafungin vs. 2 days Tx of IBX 35 Methods: 30 MFG IBX Ibrexafungerp showed • CD1 mice infected intraperitoneally (IP) with C. g/g)

µ higher tissue concentration albicans. 25 in all liver lesion sub- • Oral IBX (30 mg/Kg single dose or 15 mg/kg, BID) or IP 20 compartments (necrotic micafungin (MFG, 5mg/kg) administered to mice for 15 single dose, 2 or 3 days (starting 3 days after core, cellular rim) 10

inoculation) ( level drug Liver tissue compared to micafungin at 5 Liver tissue drug level (mcg/g) level drug tissue Liver • Liver samples analyzed at 24, 48, and 72 h post the last undetectable all timepoints measured dose for MALDI-MSI, laser capture microdissection 0 (LCM)-directed liquid chromatography coupled tandem Core (48h) Core (72h) Core (48h) Core (72h) Cellular (48h) Cellular (72h) Cellular (48h) Cellular (72h) mass spectrometry (LC-MS/MS), for drug levels uninvolved (48h) uninvolved (72h) uninvolved (48h) uninvolved (72h) quantification and CFU assessments ** P<0.005 Ibrexafungerp showed significantly greater

CFU/g liver CFU/g reduction in fungal liver 10 burden and greater percent of tissue sterilization compared to micafungin Fungal Fungal burden Log

Annie Lee, et al. ASMmicrobe 2019, Poster AAR-696 18 Ibrexafungerp Drug-Drug Interactions studies • Ibrexafungerp (IBX) has low potential for DDIs

• IBX is a substrate of CYP3A4 – (strong inhibitor) increases IBX AUC0-inf ~5.7 fold – Diltiazem (moderate inhibitor), mild effect in IBX AUC (<3 fold)

• IBX does not induce CYP3A

• In vitro, IBX is an inhibitor of CYP2C8 – But no significant effect observed in a clinical trial with rosiglitazone (CYP2C8 substrate) at clinically relevant plasma concentrations

• Co-administration of IBX resulted in a mild increase in Tacrolimus exposure (AUC ~1.4 fold)

19 Ibrexafungerp Clinical Trials

scynexis.com What is your most common problem when prescribing antifungal agents for invasive fungal disease? Poll A) Lack of tolerance or toxicity, including drug interactions

B) Fungal disease not responding to the selected antifungal

C) Limited oral options for adequate oral step-down therapy

D) Concerns about the rate of resistance in your practice (limiting your therapeutic options)

E) I rarely (or never) see patients with invasive fungal disease

21 FURI Study: Design and Interim Analysis

• Open-Label, orally administered First interim look Ibrexafungerp (ongoing) # of patients 20 Mean Days of Therapy 36.4 (7-90) • Subjects with invasive or severe Primary Underlying Disease mucocutaneous Candida spp. • Esophageal Candidiasis 6

infections • Intra-abdominal Candidiasis 5

• Oropharyngeal Candidiasis 2 • Refractory or intolerant to standard of care antifungal agents • Spondylodiscitis 2 • Other Candida infections (mediastinitis, • Sites open in US, Germany, UK, candidemia/endocarditis, 5 hepatosplenic, subcutaneous, Spain, Austria, Netherlands chronic mucocutaneous)

22 FURI Study: Global Outcome per Data Review Committee Twenty patients included in the first analysis 17 (85%) patients had complete, partial or stable responses

Complete/ Progression of Stable Disease Indeterminate Partial Response Disease

11 (55%) 6 (30%) 2 (10%) 1 (5%)

Most common Candida species were glabrata (11), krusei (4), albicans (3)

Interim Analysis of a Phase 3 Open-label Study to Evaluate the Poster Efficacy and Safety of CIV-166 Oral Ibrexafungerp in Patients with Refractory or Intolerant Fungal Diseases (FURI)

OA Cornely1, L Ostrosky-Zeichner2, R Miller3, A Spec4, GR Thompson5, TJ Walsh6, R Rautemaa-Richardson7, R Krause8, KM Mullane9, PG Pappas10, CG Morse11, JW Sanders11, G Weiss12, O Witzke13, J Vazquez14, MH Miceli15, TF Patterson16, M Hoenigl8,17, BD Alexander3, DA Angulo18

23 CARES Study: Design and Case Reports

• Open-Label, orally administered Two cases of C.auris candidemia recently presented* Ibrexafungerp (ongoing) A 58-year-old male with diabetes mellitus, aspiration pneumonia and septic shock. • Developed C. auris candidemia received fluconazole • Subjects with documented and switched to micafungin • Clinical improvement was observed but blood cultures Candida auris infections remained positive • Received oral Ibrexafungerp for 17 days achieving complete response • Treatment naïve or refractory or intolerant to standard of care A 64 year-old female with diabetes mellitus, renal failure, antifungal agents hemodialysis presented with fever and hypotension • Diagnosed with C. auris candidemia and Ibrexafungerp was initiated (naïve to antifungal therapy) • Available in US and India • Blood cultures became negative and the patient improved, completed 22 days of ibrexafungerp with complete response

* Juneja D, et al. ECCMID 2019 24 SCYNERGIA Study: Combination therapy in Invasive Aspergillosis Screening Double-blind, randomized DX Confirmation (ongoing) Population: Baseline Randomization – Pulmonary invasive Aspergillosis – Hematological malignancy Voriconazole Voriconazole – Positive Galactomannan test in blood (IV or Oral) (IV or Oral) (GMI) + + Endpoints include: Oral Ibrexafungerp Oral Placebo – Survival – Global response End of Treatment – GMI profile Approximately 60 subjects from ~30 sites in US and EU Survival Follow up

25 VANISH and CANDLE Studies in VVC

VANISH (1 and 2): • TWO, randomized double blind, Phase 3 studies in patients with ACUTE VVC • Oral ibrexafungerp: One day treatment • Ongoing in US and EU

CANDLE: • ONE randomized, double blind, Phase 3 study in patients with RECURENT VVC • Oral ibrexafungerp: One day treatment every month for 6 months • Start up activities the US and EU.

26 Thank you