Evaluation of the Efficacy, Safety and Tolerability of SB204 4%

Once-Daily in Subjects with Moderate to Severe Acne Vulgaris

Treated Topically for Up to 52 WeeksA Hebert, J Del Rosso, M Rico, R Woolson, E de Leon, C Enloe, N Stasko

Presented by:

Adelaide A Hebert, MD

UTHealth McGovern Medical School, Houston, TX

2018 American Academy of Dermatology (AAD) Annual Meeting, San Diego, CA

February 16 – 20, 2018

Disclosures

Allergan, Inc – I (Grants/Research Funding); Amgen – I (Grants/Research Funding), SP(H); AnacorPharmaceuticals, Inc – A(H); Astellas Pharma US, Inc. – I (Grants/Research Funding); Bayer – SP(H); Cassiopia - I (Grants/Research Funding); Celgene Corporation - (Grants/Research Funding); Chugai Pharma - (Grants/Research Funding); Cutanea Life Sciences - (Grants/Research Funding); Department of DFENCE – O (Grants/Research Funding); Dermavant Sciences – I (Grants/Research Funding); Dermira – A(H), I (Grants/Research Funding); Encore Dermatology, Inc – A(H); Galderma Laboratories, LP – A(H), SP(H); GlaxoSmithKline – A(H), Data Safety Monitoring Board (H), I (Grants/Research Funding); Healthpoint – I (Grants/Research Funding); Intendis, Inc. – SP(H); Mayne Pharma Group – I (Grants/Research Funding); Medimetriks Pharmaceuticals, Inc. – I (Grants/Research Funding); Menarini Group – SP(H); Menlo Therapeutics – A(H); Merz Pharmaceuticals, LLC – I (Grants/Research Funding); NIH - (Grants/Research Funding); Novan – I (H); Novartis Pharmaceuticals Corp. – O(H); Onset Therapeutics – SP(H); Ortho Dermatologics – A(H); Pfizer Inc. – Speaker/Fucalty Education (H); Pharmaderm – A(H); PPD Inc – I (Grants/Research Funding); Prim-Med – SP(H); Promius Pharma, LLC – A(H); Promius Pharmaceuticals – A(H), I (Grants/Research Funding); Regeneron – Data Safety Monitoring Board (H); Roivant Sciences – A(H); Shionogi USA – A(IP); Sienna Biopharmaceuticals - (Grants/Research Funding); Sinclair Pharma –SP(H); Stiefel, a GSK company – A(H); TopMD – I (Grants/Research Funding); ; Valeant Pharmaceuticals International – A(H), SP(H); Vanda Pharmaceuticals Inc. – I (Grants/Research Funding);

2

Hanna-Leena Kelhälä et al. IL-17/Th17 Pathway is Activated in Acne Lesions. PLoS One. 2014;9(8): e105238.

Niedbala W et al. Regulation of Type 17 Helper T-Cell Function by Nitric Oxide During Inflammation Proc Natl Acad Sci USA. 2011;108(22):9220-9225.

Niedbala W et al. Nitric Oxide-Induced Regulatory T Cells Inhibit Th17 but Not Th1 Cell Differentiation and Function. J Immunol. 2013;191(1):164-170.

Qin M et al. Nitric Oxide Releasing Nanoparticles Prevent Propionibacterium Acnes Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial

Stimulation of the Innate Immune Response J Invest Dermatol. 2015;135(11):2723-2731.

P. acnes

Excess sebum

Inflammation

Hyper-keratinization

Keratinocyte

hyperproliferation

Bacterial colonization

(P. acnes)

Epidermis

Dermis

Hair

follicle

Sebocyte

hyperproliferation

IL-1, IL-17

Pathogenic Factors in Acne

NLRP3

Th17

TLR-2

IL-1R

P. acnes

bacteria

IL-17

IL-1β

X

T0

NO

XPro-IL-1β

Immunomodulatory and Antimicrobial

Activity of Nitric Oxide in Acne

Nitric oxide inhibits the NLRP3 inflammasome,

decreasing the downstream release of IL-1β and IL-17,

as well as kills P. acnes

Inflammatory

cell infiltration

Caspase

XX

Nitric Oxide and Acne

3

SB204 Study Objectives

SB204

Activating

Hydrogel

NVN1000

Alcohol Gel

SB204 is a nitric oxide-releasing topical drug candidate in

development for the treatment of acne vulgaris

SB204 4% gel has been evaluated in two replicate, multi-center,

randomized, double-blinded, vehicle-controlled, parallel group trials with

>2600 patients with moderate-to-severe acne (NI-AC301 and NI-

AC302)

The following three co-primary endpoints were assessed in the two

studies:

the absolute change in inflammatory lesions

the absolute change in non-inflammatory lesions

the proportion of patients with IGA success defined as IGA=0 or 1

and at least a two grade change

Cutaneous tolerability and safety profile has been assessed in >3,200

patients dosed to date

4

SB204 Phase 3 Patient Disposition and Study Design

NI-AC301 Study NI-AC302 Study

Pooled N = 2637

Randomized

N = 1307

ITT Population

N = 1306

SB204 4%

N = 652

Vehicle

N = 654

Excluded

N = 1

Study drug not dispensed

Inclusion Criteria

Ages 9 and up

20 - 40 inflammatory lesions on the face

25 - 70 non-inflammatory lesions on the face

IGA “moderate = 3” or “severe = 4”

3 Co-Primary Endpoints at Week 12/ET

Absolute change in inflammatory lesion counts

Absolute change in non-inflammatory lesion counts

Proportion of IGA Success (“clear = 0” or “almost clear = 1” AND

≥ two grade change)

Treatment Regimen

SB204 4%: Vehicle = 1:1

Once daily application (QD)

12 week treatment

Randomized

N = 1330

ITT Population

N = 1327

SB204 4%

N = 663

Vehicle

N = 664

Excluded

N = 3

Study drug not dispensed

Pooled SB204 Vehicle

Discontinuation 164 (12.5%) 152 (11.5%)

Adverse event 22 (1.7%) 4 (0.3%)

Lack of efficacy 0 (0.0%) 2 (0.2%)

Subject request 57 (4.3%) 56 (4.2%)

Lost to follow-up 85 (6.5%) 90 (6.8%)

5

SB204 Phase 3 Pooled Demographics and Baseline Characteristics (ITT Population)

Pooled SB204

(N = 1315)

Vehicle

(N = 1318)

Age, years

Mean (SD) 21.3 (8.4) 21.6 (8.6)

Min to max 9 – 65 9 – 73

Gender

Male504

38.3%

514

39.0%

Female811

61.7%

804

61.0%

Lesion Counts at Baseline

Inflammatory, mean (SD) 27.4 (5.6) 27.5 (5.7)

Non-Inflammatory, mean (SD) 40.2 (12.5) 39.9 (12.4)

Baseline IGA Scores

“Moderate” or a score of 31156

88.0%

1162

88.2%

“Severe” or a score of 4158

12.0%

155

11.8%

6

-20.6

-33.2

-41.7

-50.3

-20.2

-31.4

-36.9

-44.1

-55

-45

-35

-25

-15

-5

0 2 4 6 8 10 12

% C

ha

nge

fro

m B

ase

line

-15.8

-26.2

-34.8

-42.4

-14.7

-22.0

-28.3

-36.1

-55

-45

-35

-25

-15

-5

0 2 4 6 8 10 12

-17.8

-28.9

-37.6

-45.6

-17.0

-25.9

-31.8

-39.3

-55

-45

-35

-25

-15

-5

0 2 4 6 8 10 12

Inflammatory Lesions

Weeks

Non-Inflammatory Lesions

Weeks

Total Lesions

Weeks

SB204 Phase 3 Efficacy (ITT Population)

Percent Reduction in Lesions (Pooled)

Absolute change from baseline for pooled SB204 vs vehicle were: -12.48 vs -10.88 (p<0.001) for

inflammatory lesions, -15.06 vs -12.70 (p<0.001) for non-inflammatory lesions and -27.52 vs -23.75

(p<0.001) for total lesions.

7Standard error ≤1.2 for all data points presented

SB204 Phase 3 Efficacy (ITT Population)

Investigator Global Assessments (IGA)

Baseline to Week 12

Moderate & Severe at Baseline

2 Grade Change

Severe Only at Baseline

2 Grade Change

Moderate & Severe at Baseline

IGA = 0 or 1 & 2 Grade Change

0%

10%

20%

30%

40%

50%

301 302 Pooled 301 302 Pooled

0%

10%

20%

30%

40%

50%

301 302 Pooled 301 302 Pooled

p = 0.038

Response percentages were obtained after multiple imputation (MCMC) for missing data.

0%

10%

20%

30%

40%

50%

301 302 Pooled 301 302 Pooled

663664 652654 1318 1315N = 663664 652654 1318 1315N = 6477 9478 155 158N =

Vehicle SB204 VehicleSB204Vehicle SB204

p = 0.003

p = 0.003

p = 0.002

p = 0.042

8

SB204 Phase 3 Representative Clinical Photos

Baseline Week 12

SB204 Treatment Group

9

69.1%

25.0%

5.5%

0.3%

74.3%

18.4%

4.3%

0.5%

79.6%

14.6%

2.4%

0.1%

79.5%

17.2%

3.3%

SB204 Phase 3 Pooled Tolerability

78.2%

19.5%

2.3%

80.8%

17.4%

1.5%

0.2%

83.9%

15.0%

1.0%

0.1%

84.2%

14.9%

0.7%

0.1%

Erythema

Burning / Stinging

SB204 Vehicle

Week 4 Week 12 Week 4 Week 12

Severe

Moderate

Mild

None

Week 4 Week 12 Week 4 Week 12

Severe

Moderate

Mild

None

SB204 Vehicle

Dryness

SB204 Vehicle

Severe

Moderate

Mild

None

Week 4 Week 12 Week 4 Week 12

82.1%

16.0%

1.7%

0.2%

87.6%

11.0%

0.9%

0.4%

87.6%

11.6%

0.7%

0.1%

90.0%

9.0%

0.8%

0.2%

10

SB204 Phase 3 Treatment Emergent Adverse Events (TEAEs) (Safety Population)

The most common TEAEs were application site reactions; less than 2% of patients

discontinued due to AEs. No treatment-related SAEs were reported.

NI-AC301

SB204

(N = 666)

NI-AC301

Vehicle gel

(N = 661)

NI-AC302

SB204

(N = 654)

NI-AC302

Vehicle gel

(N = 652)

Pooled

SB204

(N = 1320)

Pooled

Vehicle gel

(N = 1313)

General Disorders and

Administration-Site

Conditions

49 (7.5%) 12 (1.8%) 29 (4.4%) 11 (1.7%) 78 (5.9%) 23 (1.8%)

Application site pain 21 (3.2%) 3 (0.5%) 14 (2.1%) 4 (0.6%) 35 (2.7%) 7 (0.5%)

Application site erythema 11 (1.7%) 1 (0.2%) 10 (1.5%) 2 (0.3%) 21 (1.6%) 3 (0.2%)

Application site pruritus 16 (2.4%) 3 (0.5%) 6 (0.9%) 4 (0.6%) 22 (1.7%) 7 (0.5%)

Application site dryness 7 (1.1%) 2 (0.3%) 5 (0.8%) 1 (0.2%) 12 (0.9%) 3 (0.2%)

Other TEAEs

Nasopharyngitis 11 (1.7%) 10 (1.5%) 15 (2.3%) 18 (2.7%) 26 (2.0%) 28 (2.1%)

Headache 5 (0.8%) 1 (0.2%) 10 (1.5%) 1 (0.2%) 15 (1.1%) 2 (0.2%)

11

SB204 Long-Term Safety Design and Disposition

From AC-301

(total N = 1306)

N = 309

From AC-302

(total N = 1327)

N = 292

AC-303 (Open Label)

N = 601

SB204 experienced: 296

SB204 naïve: 305

Completed

N = 448

SB204 experienced: 232

SB204 naïve: 216

Treatment Regimen

SB204 4%

Once Daily Application (QD)

40 week treatment

Efficacy Endpoints

Change in inflammatory lesions

Change in non-inflammatory lesions

Tolerability and Safety

Primary Reason for Study Discontinuation

• Adverse events: 9

• Withdrawal by patients: 76

• Physician decision: 1

• Protocol violation: 1

• Lost to follow-up: 61

• Pregnancy: 2

• Other: 3 (non-compliance with taking study drug and

duplicate patients)

12

SB204 Long-Term Safety (Safety Population)

Overall

Other Events

Nasopharyngitis 19 (3.2%)

Headache 8 (1.3%)

Influenza 7 (1.2%)

Upper respiratory tract infection 6 (1.0%)

Bronchitis 3 (0.5%)

Migraine 3 (0.5%)

Nausea 3 (0.5%)

Tooth impacted 3 (0.5%)

Back pain 3 (0.5%)

Anxiety 3 (0.5%)

Cough 3 (0.5%)

Overall

N = 601

General Disorders and Administrative Site

Conditions26 (4.3%)

Application site dryness 9 (1.5%)

Application site pruritus 9 (1.5%)

Application site pain 6 (1.0%)

Application site erythema 4 (0.7%)

Application site exfoliation 3 (0.5%)

Application site pyrexia 3 (0.5%)

Any TEAE: n = 112 (18.6%)

Treatment-related TEAE: n = 23 (3.8%)

Discontinuation due to AE: n = 9 (1.5%) (1.3% - application site reactions)

No deaths

SAE: 6 patients (1%) (none of them were considered by the Investigator to be related to study treatment)

Two pregnancies: Early discontinuation (One delivered a healthy baby girl, no complications with the pregnancy.

One had a spontaneous abortion.)

13

-53.8

-74.5

-75

-65

-55

-45

-35

-25

-15

-5

0 10 20 30 40 50

% C

ha

nge

fro

m B

ase

line

-44.3

-70.5

-75

-65

-55

-45

-35

-25

-15

-5

0 10 20 30 40 50

-48.0

-72.0

-75

-65

-55

-45

-35

-25

-15

-5

0 10 20 30 40 50

Inflammatory Lesions

Weeks

Non-Inflammatory Lesions

Weeks

Total Lesions

Weeks

SB204 Long-Term Safety Efficacy (52 Weeks)

Percent Reduction in Lesions (SB204 Experienced Only)

Overall, a 75% reduction in inflammatory lesion counts was observed over 52 weeks of treatment,

showing a long-term benefit of continuous treatment with SB204.

14

0 2 4 8 12 16 24 36 48 52 0 2 4 8 12 16 24 36 48 52 0 2 4 8 12 16 24 36 48 52

Standard error ≤2.2 for all data points presented

Summary

In a pooled analysis from two Phase 3 trials (NI-AC301 and NI-AC302):

At Week 12, SB204 had statistically significant greater reduction over vehicle in:

inflammatory lesions (-50.3% vs -44.1%)

non-inflammatory lesions 12 (-42.4% vs -36.1%)

total lesions (-45.6% vs -39.3%)

Among patients in the severe group (IGA = 4), the percent of respondents with at least a 2 grade

improvement in IGA was approximately two times higher for SB204 than vehicle.

The most frequent adverse events were application site reactions, but mostly in the mild category.

Overall, less than 2% of patients discontinues due to AEs.

In the long-term safety study:

Continuous treatment with SB204 showed further benefit.

The 40 week safety profile was consistent with the 12 week trial. Application site reaction (4.3%) and

nasopharyngitis (3.2%) were the most frequent adverse events.

A separate study (NI-AC101) showed no measurable systemic exposure when treating 17% BSA of 18

patients with moderate-to-severe acne.

15

SB204 has shown evidence of efficacy in treating acne vulgaris with a favorable long-term

safety profile.