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MSGERC First Biennial Meeting Asilomar, California, 2016Jack Edwards

Efforts to Develop A Vaccine for Candida:

Scientific and Developmental Challenges

Disclosure

One of six scientific co-founders who hold equity and consult for NovaDigmTherapeutics, Inc.

Biotechnology company established in collaboration with the LABiomedical Research Institute at Harbor/UCLA, the NIH, the DoD, and Domain Partners specifically to develop a Candidavaccine.

“A Scientist Over the Age of 60Does More Harm Than Good.”

Thomas Huxley1825-1895

Nick Name: “Darwin’s Bulldog”

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Strong AdhesinIdentified and Gene Cloned

Initial Discovery of Candida Adhesin:Surrogate Genetics

Yue Fu

Discovery of Candida Adherence Genes

Extract andcut DNA

C. albicans

Ligate intoplasmid

TransformS. cerevisiae

Select foradherent clones

to endothelial cells

Scott Filler

Trang Phan

Ribbon model structure of rAls3 (N-terminal domain of native

Als3)

NDV-3A Vaccine Description

• Adhesin• Invasin• Biofilm Formation• Binds Ferritin

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Molecular Modeling and Structural Homology

Michael Yeaman:

Sheppard et al., J. Biol. Chem. 279 (29):

30480 (2004)

C. albicans Als3pN S. aureus adhesin

Y. pseudotuber. invasin Y. pestis invasin E. coli invasin

E. faecalis adhesin

Potential Mechanisms of Protection

NDV-3 vaccine(Als3 antigen)

Candida

Anti-Als3 antibody

Als3 antigen

Als3 antigen

Candida

inhibition of Candida adhesion to human host cells,

reducing invasion & cell damage

targeting neutrophils to recognize & kill Candida by opsonophagocytosis

Exploratory Phase 1b/2a Study in RVVC PatientsStudy Outcome Measures (Not Endpoints)

• Safety & tolerability

• Immune responses

• Signal of Efficacy:

Reduction in VVC frequency

Reduction in severity

(patient and physician scorecards)

ClinicalTrials.govIdentifier: NCT01926028

Phase 1b

Phase 2a

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“Recurrence Definition” for RVVC ImmunotherapyDoes Not Exist: No FDA Guidance for Fungal Vaccines

• Recurrence definition developed for antifungal drugs: FDA guidance 1998:

– Patient score for VVC symptoms

– Physician score for VVC signs

– Positive Candida culture from vaginal swab

• These three elements were applied to the NDV-3A exploratory vaccine/immunotherapy study

Composite score ≥3

NDV-3A Trial: Inclusion Criteria

• 18-55 age

• On birth control

• ≥3 documented VVC episodes in past 12 mos.

At least one previous episode confirmed by a positive

diagnostic lab test for Candida

• Acute episode of VVC at enrollment with signs and

symptoms composite score ≥ 3

• Positive vaginal C. albicans culture

14ClinicalTrials.gov Identifier: NCT01926028

Exploratory Phase 1b/2a Study in RVVC PatientsNDV3-A Study Design

RVVC = recurrent vulvovaginal candidiasis

Enroll adult women meeting inclusion

criteria: acute episode

Resolve acute

episode with

fluconazolePlacebo

(alum, PBS)(n = 82)

NDV-3A(300 μg Als3, alum, PBS)

(n = 88)

Immunotherapy –vaccine group

6 monthsRandomization

2 weeks

Exploratory Phase 1b/2a Study in RVVC Patients, Continued

Study Design

First unblinded evaluation of

efficacy & immune

response data

6months

12 months

End study; Final evaluation of efficacy and

immune response data

“Final” Data AnalysisPresented Today

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Patient Encounters

Office visits (physical exam, VVC scorecard,

culture)

• Seven scheduled visits

• No limit on unscheduled visits

– Patient-initiated visits based on patient

symptoms

• Multiple scheduled phone calls and follow-up of

unscheduled visits

Phase 1b/2a Study in RVVC Patients

• 20 study sites

• 188 patients vaccinated

– Last patient vaccinated on May 18, 2015

• Interim database lock and un-blinding Nov 2015

• 25% drop-out at study end (assumed 25%)

• Final database lock August 2016

Screening Observations (n=374)

• Screened women with signs/symptoms of acute vaginitis

– 62% were positive for Candida spp.

• 98% of those were C. albicans

• Others included C. krusei, C. glabrata, C. lusitaniae

• Fluconazole resolved most VVC by vaccination day

– 99% resolved clinical signs & symptoms of VVC

No significant differences in:

• General tolerability• Injection site reactions• Systemic reactions• No serious adverse events

Phase 1b/2a and two Phase 1 Studies(252 vaccinees/136 placebos)

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NDV-3A Induces Strong B and T Cell Responses in Women with RVVC

Seru

m I

gG

Titer

Seru

m I

gA

Titer

% IF

N-γ

Responses

% IL-1

7A

R

esponders

IFN-γ

IL-17

Study Days Study Days

“Final” Data Analysis Parameters

• ITT population for NDV-3A and placebo = 174

• Per protocol population = 165

• Evaluation of recurrences starts at Study Day 18

– All patients receive fluconazole on Study Days -14, -11, -8, 1, 7 and 14

– Three half-lives for fluconazole = 3.8 days

• Censure day for K-M plot limited to 374 days (per protocol)

– Applies to 12 patients (5 NDV-3A, 7 Placebo) that exited the study later than planned

• Included all women who had not reached their 40th birthday

Protocol violations: specifics (n)Composite score <3 at screening (2) No positive culture at screening (4)Composite score >=3 on Day 0 (2) Other (1)

Recurrence Free Percentages

Kaplan-Meier Curve: time to first recurrence: patients <40 (77% of total)

Recurrences: based on patient symptom scores ≥3

Placebo

NDV-3A/placebo

hazard ratio = 0.59

Difference in curves, p = 0.026

Pro

po

rtio

n w

ho

are

re

cu

rre

nce

-fre

e

Days following single dose of NDV-3A

NDV-3A

Efficacy Data: Patient Symptom ScoresNDV-3A Extends Recurrence-Free State vs Placebo

3 months 12 months

<40 years n=122

All agesn=159

<40 years n=107

All agesn=124

Recurrence(NDV-3A)

27% 32% 58% 62%

Recurrence(Placebo)

47% 44% 78% 75%

Efficacy 43% 28% 26% 17%

Odds Ratio NDV-3A/placebo(95% CI)

0.41(0.19-0.88)

p=0.02

0.58(0.30-1.14)

p=0.11

0.39(0.16-0.92)

p=0.03

0.55(0.26–1.14)

p=0.10

Recurrence defined by patient symptom score ≥3Efficacy = (placebo recurrence rate – NDV-3A recurrence rate)/placebo recurrence rateOdds ratio = relative odds of having first recurrence by 12 months, NDV-3A/placebo

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NDV-3APts <40 yrs

Famvir1

(Novartis)Valtrex2

(GSK)GEN-0033

(Genocea)

Indication RVVC Recurrent genital herpes (HSV-2)

Administration & regimen

Single IM injection

Twice daily oral

Once daily oral

Three IM injections

Recurrence rate(treated)

58% 65% 58% 70%

Recurrence rate(placebo)

78% 93% 96% N/A

Efficacy 26% 30% 40% N/A

1) Famvir US Prescribing Information (revised 4/2013)2) Valtrex US Prescribing Information (revised 12/2013) 3) Genocea Slide Presentation, 3/31/2016

NDV-3A Compared to Treatments for Genital Herpes% Recurrence rate & efficacy at 12 months

Recurrence rates exclude recurrence-free patients that discontinued study prior to 12 monthsEfficacy = (placebo recurrence rate - treated recurrence rate)/placebo recurrence rate

12-Month Efficacy DataNDV-3A compared to genital herpes antiviral drugs

NDV-3Asingle dose

Valtrex1 gm/day

Famvir500 mgs/day

Treated Placebo Treated Placebo Treated Placebo

Recurrence free 42% 22% 42% 4% 35% 7%

Valtrex and Famvir data from US prescribing information.

Recurrence for NDV-3A defined by patient symptom score ≥3

% Recurrence free at 12 months, excluding unknowns

NDV-3APts <40 yrs

Bezlotoxumab(Merck)1

VGX-3100(Inovio)2

Indication RVVCRecurrentC. difficile

HPV cervical dysplasia

Administration& regimen

Single IM injectionSingle IV infusion

Three IM injections

Time to endpoint

3 months 12 months 3 months 9 months

Event rate(treated)

27% 58% 17% 50%

Event rate(placebo)

47% 78% 27% 69%

Efficacy 43% 26% 37% 28%

NDV-3A Efficacy Compared to ID Immunotherapies

Efficacy = (placebo recurrence rate - treated recurrence rate)/placebo recurrence rate

1) Merck Bezlotoxumab FDA Advisory Committee Briefing Document 6/9/2016 (event rate is recurrent CDI)2) Trimble et al, Lancet, 2015, 2078 (event rate is no decrease in CIN2/3 severity)

Perspectives: 1b/2a Study ResultsImmunotherapy with NDV-3A for RVVC patients

• Single dose is safe and well tolerated

• Robust antibody and T-cell responses

• Efficacy demonstrated over 12-month period

• Higher efficacy in women < age 40

– Vaccine significantly delays time to first recurrence

• Candida culture results do not differentiate the vaccinated from the placebo arms (commensal and no antibiotics)

• To our knowledge first fungal vaccine showing a statistically significant signal of efficacy in a placebo controlled human trial

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• Use multiple doses of NDV-3A rather than single dose

• Refinement and focus on patient self-reported assessments

• Assess additional microbiological methods to explore “hard”

microbiological endpoint. May not be required

– Multiple hyphae-specific genes can be used to assess yeast & hyphae

forms (e.g., PCR, q-PCR, nanostring, gene expression)

• Limit to patients under 40 years of age

• Multiple antigens

Considerations for Future RVVC Studies

• Job’s Patients at NIH Clinical Center (CHI)

• DoD Military Recruits Fort Benning, Sept. 2017

• Collaboration with CDC on C. auris

• Detailed Evaluation of Multiple Antigens (HYR1,

SAP2, ALS3) Alone and Combined

• Healthcare-Associated (Nosocomial) Study (MSG)

Other Plans

“Progress always involves risk.

You can’t steal second base

and keep your foot on first.”

Frederick B. Wilcox

Three Rules for Successful InvestigatorsFrank DeSantis Circa 1990

1. Get the Money

2. Get the Money

3. Get the Money

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Acknowledgements

John P. Hennessey, Jr.*Clint S. Schmidt*

Terry CochraneMichael M. Schwartz* Erica MarchusMary Lizakowski

Elizabeth Ann DeMontignyJesse Hoeg

Tim Cooke*

Tuomas Holmberg*Holly JorudFred HaneySavery Nash

Will JosephAl JosephGordon Douglas

Hugh GeorgeJoe GerstnerPatrice DuboisFlorian Schodel

Jo WhiteEric Brass

Study Investigators

Dennis Dixon*

Rory Duncan*

Jim BlairTodd BradyPartners

Michael Augenbraun Khadra Osman

Liesl Bredeson Smith Rovena Reagan

Michael Drusano Allen Silanee

Lance Edwards Jack Sobel

Charles Eubank Valerie Sorkin-Well

Mark Jacobs Steven Sussman

Susan Jeanfreau Andrew Wagner

Helena Kirkpatrick Richard Wyatt

Stephen McCann Edward Zbella

Paul Nyirjesy Keila Hoover

Ashraf S. Ibrahim*Michael R. Yeaman

Scott G. Filler*Yue FuBrad Spellberg