Corbus Pharmaceuticals : Presentation

Targeting CB1 and CB2 for

Human Therapeutics

NYAS Targeting the Endocannabinoid System for

Treatment of Human Diseases

Barbara White, MD

Chief Medical Officer and Head of Research

	27 JAN 2021	NASDAQ: CRBP
@corbuspharma
	www.corbuspharma.com

Barbara White Disclosures

• Corbus Pharmaceuticals, Inc. - employee, stock owner
• Will discuss investigational agents that are not approved for human therapeutic use in any disease by any regulatory agency

2

CB1 Agonists

3

Some approved therapeutic uses of CB1 agonists and cannabidiol

Dronabinol (synthetic THC)

Supportive

Care

• Anorexia, weight loss (HIV/AIDS)

• Nausea and

Nabilone (synthetic THC-like)vomiting from chemotherapy

Nervous

System

Diseases

• Muscle spasticity from multiple sclerosis
• Rare childhood epilepsy (Lennox- Gastaut syndrome or Dravet syndrome)

Nambiximols (plant-based

THC/CBD)

Genetic

Diseases

• Tuberous sclerosis complex

Cannabidiol (plant-based)

4

CB1 Antagonists/Inverse Agonists

5

Some reported potential therapeutic uses of CB1 antagonists/inverse agonists

Rimonabant (CB1 inverse agonist, withdrawn 2008)

Metabolic

Fibrotic

Other diseases

diseases diseases

•	Weight-loss (previous	•	Lung fibrosis5	•	Ascites9
	approval)	•	Cardiac fibrosis6	•	Cognitive defects10
•	Diabetes1	•	Renal fibrosis7	•	Prader-Willi
•	Diabetic nephropathy1	•	Liver fibrosis8		syndrome11
•	Diabetic retinopathy2			•	Smoking cessation12

• Metabolic syndrome3
• NASH4

1 Nam, Endocrinology 2012:153:1387; 2 El-Remessy, Diabetologia 2011;54:1567; 3 Hirsh and Tam, Toxins (Basel) 2019;11:275; 4 Chen, Immun Inflamm Dis 2020;8:544; 5 Cinar, JCI Insight 2017;20:e92281; 6 Lin, J Biol Chem 2003;85:249; 67Dao J Cell Mol Med 2019;23:7279; 8 Kunos, J Med Chem 2017, 60:1126; 9 Domencicali, Gastroenterology 2009; 137:341; 10 Navarro-Romero, Neurobiol Dis 2019;125:92; 11 Knani, Mol Meta 2016;5:1187; 12 Robinson Addiction Biology 2018;23:291

6

Novel Corbus CB1 inverse agonists with limited blood-brain barrier penetration

• Inhibit CB1 which regulates metabolism, inflammation, and fibrosis
• Must limit brain exposure because of on-target AEs of anxiety and suicidality

µg./mL or µg/g

Plasma and brain levels of rimonabant 30 minutes post 20 mg/kg IP injection. Han, FASEB J 2018; 33:4314

Plasma Brain

Plasma levels

Cmpd A

Cmpd B

Cmpd C

Cmpd D

Cmpd E

Brain levels

Mice received single 10 mg/kg dose orally, n = 3 per time point

Some novel CB1 inverse agonists have low brain:plasma ratios

7

Corbus CB1 inverse agonists are active in diet-induced obesity model

Body Weight change (%)

Vehicle 2

110	Pioglitazone 30 mg/kg QD

Rimonabant 10 mg/kg QD

100

90

80						**
0	2	4	6	8	10	12	14	16	18	20
					Time (day)

					Vehicle 1
		(%)	110		Cmpd C 5 mg/kg BID
				Cmpd C 10 mg/kg BID
		change			Cmpd D 5 mg/kg BID
		100		Cmpd D 10 mg/kg BID
		Weight	90
		Body			*				**
			80						**
22	24
	0	2	4	6	8	10	12	14	16	18	20	22	24

* P ≤ 0.05, ** P ≤ 0.01

Time (day)

Mice received a high fat diet for 28 days to induce obesity and glucose intolerance, then continued to receive high fat diet plus received oral compounds for 21 days, n = 3 per time point. Day 0 = start of investigational compounds. Note that 1 hour after last dose, the brain:plasma ratio for Cmpd C was 0.04 (5 mg/kg) and 0.022 (10 mg/kg) and for Cmpd D was 0.04 for both doses. Overall Cmpd D gave exposures that were ~7-12 fold lower than exposures for the same dose of Cmpd D.

CB1 inverse agonists preferentially limited to peripheral tissues have weight loss activity

8

Corbus CB1 inverse agonists improve glucose tolerance

		Vehicle 1
	300	Cmpd C 5 mg/kg BID
mg/dL	Cmpd C 10 mg/kg BID	mg/dL	300
	Cmpd D 5 mg/kg BID
	200	Cmpd D 10 mg/kg BID		200
Glucose,		Glucose,
*
*
	*		*
	100	*
	*		100

Vehicle 2

Pioglitazone 30 mg/kg QD Rimonabant 10 mg/kg QD

Basal	30	60	90	120
		Time, Minutes

Basal

30

60

90

120

Time, Minutes

* P ≤ 0.05 vs Vehicle 1, ** P ≤ 0.01 vs Vehicle 1, ## P ≤ 0.01 vs Vehicle 2

Mice received a high fat diet for 28 days to induce obesity and glucose intolerance, then continued to receive high fat diet plus received oral compounds for 21 days. Oral glucose challenge was done on Day 21, N = 3 per time point

CB1 inverse agonists preferentially limited to the periphery improve glucose tolerance

9

CB2 Agonists

10

Some reported potential therapeutic uses of CB2 agonists

Autoimmune

Fibrotic

Cancer

CNS

Other

Diseases

Diseases

Diseases

•

Systemic sclerosis1

•

Skin fibrosis

•

Anti-tumor activity

•

ALS

•

Cystic fibrosis

•

Dermatomyositis2

•

Lung fibrosis

•

Anti-metastasis

•

Multiple sclerosis

•

Atopic dermatitis

•

Rheumatoid

•

Liver fibrosis

•

Chemo-induced

•

Alzheimer's

•

Interstitial cystitis

arthritis

•

Renal fibrosis

cardiomyopathy

disease

•

Acute pancreatitis,

•

Inflammatory

•

Heart fibrosis

•

Chemo-induced

chronic

bowel disease

•

Myocardial

ototoxicity

pancreatitis

•

Idiopathic

infarction

•

Ischemic

thrombocytopenia

reperfusion injury

purpura

•

Traumatic brain

injury

•

Acute lung injury

•

Osteoporosis

11

CB2 agonists may provide therapeutic options to immunosuppressive treatments for chronic inflammatory and fibrotic diseases

• CB2 are expressed on activated immune cells and fibroblasts
• CB2 agonists reduce production of pro- inflammatory mediators and activate resolution of inflammation
• CB2 agonists reduce production of pro-fibrotic growth factors, myofibroblast transformation, and collagen production
• Lenabasum is a synthetic, selective CB2 agonist

IN SILICO BINDING OF

LENABASUM (PURPLE)

TO CB2

12

Systemic sclerosis is a rare, debilitating and life-threatening autoimmune disease characterized by inflammation & fibrosis

Patient images provided by the Scleroderma Foundation

13

CB2 knock-out mice develop systemic sclerosis-like disease

CB2-/- mice exposed to hypochlorite, which generates oxygen radicals, fail to resolve innate immune response with persistent inflammation, autoimmunity (anti-DNA topoisomerase I antibodies), increased fibroblast proliferation, and excessive skin and lung fibrosis1

Lung

Skin

CB2+/+

CB2-/-

CB2+/+

CB2-/-

CB2+/+ HOCI

CB2-/- HOCI

CB2+/+ HOCI

CB2-/- HOCI

1 Servettaz et al. Am J Pathol 2010;177:187-96

14

Lenabasum, a CB2 agonist, reduced fibrosis in an animal model of

systemic sclerosis lung disease

Control		Bleomycin

		Bleo + Lenabasum 5 mg/kg
Bleo + Lenabasum 1 mg/kg

Lung fibrosis induced with bleomycin

• Lung fibrosis is induced with bleomycin
• Lenabasum, whether started prophylactically before bleomycin or therapeutically 1 week after bleomycin, reduced lung inflammation and fibrosis
• Lung histology is shown for Day 14 post- bleomycin, when lenabasum was starting therapeutically at Day 8

Lucatelli, Respir Res. 2016;17:49

Lenabasum inhibited lung fibrosis

15

Lenabasum, a CB2 agonist, reduced fibrosis in an animal model of SSc

lung disease

Control		Bleomycin

		Bleo + Lenabasum 5 mg/kg
Bleo + Lenabasum 1 mg/kg

Lung fibrosis induced with bleomycin

• Lung fibrosis is induced with bleomycin (bleomycin versus control)
• Lenabasum, whether started prophylactically before bleomycin or therapeutically 1 week after bleomycin, reduced lung inflammation and fibrosis
• Lung histology is shown for Day 14 post- bleomycin, when lenabasum was starting therapeutically at Day 8

Lucatelli, Respir Res. 2016;17:49

Lenabasum inhibits lung fibrosis

16

SSc Phase 2

Lenabasum, a CB2 agonist, improved inflammation and fibrosis in skin biopsies from SSc patients in a Phase 2 study

				Inflammation		Fibrosis
		P = 0.006 Fisher's exact probability test	P = 0.05 Fisher's exact probability -test
	Biopsies	100%
	15%	43%
• More improvement or			15%								15%
stability of histological		80%									Improved
Skin										48%
findings of inflammation											38%
of	60%
and fibrosis in paired	%
Baseline,												39%
weeks treatment with										Stable
skin biopsies after 12		40%
			69%	43%
	from
lenabasum versus											46%
Change	20%									Worsened
placebo
	0%				13%							13%
			Placebo	Lenabasum		Placebo	Lenabasum

Analyses are of paired skin biopsies at baseline and Week 12, N = 23 lenabasum and N = 13 placebo.

Note: Primary efficacy endpoint in Phase 2 study was met

17

RESOLVE-1 Phase 3

Systemic sclerosis subjects treated with lenabasum 20 mg BID added

to immunosuppressants > 2 years duration had stable lung function

			100								Nominal P = 0.048 at Week 52, 2-samplet-test
		(SEM)	75
•	RESOLVE-1 Phase 3	50
	25
	study	mean	0													N = 38
•	Primary efficacy	-25
	-50
	endpoint (ACR CRISS
	mL,	-75
	score) was not met
	-100
• Post-hoc analysis:	FVC,	-125
-150
	Subjects treated with														N = 26
	in	-175
	lenabasum 20 mg BID
	-200
	Change
	added to established	-225	Lenabasum 20 mg BID
	immunosuppressive		-250
	therapies had stable		-275	Placebo
	FVC, mL over 1 year		-300
			0	4	8	12	16	20	24	28	32	36	40	44	48	52
									Weeks
		IST = immunosuppressant therapies. Post-hoc analyses, per protocol population of subjects who completed study
		drug and Week 52, LOCF for any missing values. Subjects were receiving at least 1 background IST for greater

than 2 years treatment duration at baseline, and any mycophenolate treatment must be > 2 years duration

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Acceptable lenabasum safety profile in Phase 3 RESOLVE-1 study

RESOLVE-1 Phase 3

• Lenabasum's safety profile was favorable, with numerically lower percentage of subjects with serious and severe AEs in lenabasum groups compared to placebo
• Lenabasum was well- tolerated with no probably- or definitely- related adverse event leading to study drug discontinuation

Treatment-emergent Adverse Events	Placebo	Lenabasum	Lenabasum
			5 mg	20 mg
(TEAE)
N = 123, n (%)	N = 120, n (%)	N = 120, n (%)
Any TEAE	106 ( 86.2)	110 ( 90.2)	110 ( 91.7)
Any Serious TEAE	18 ( 14.6)	10 (	8.2)	11 (	9.2)
Any TEAE by Maximum Severity
Mild	44	( 35.8)	47	( 38.5)	55	( 45.8)
Moderate	46	( 37.4)	59	( 48.4)	48	( 40.0)
Severe	16 ( 13.0)	4 (	3.3)	7 (	5.8)
Any TEAE by Strongest Relationship
Unrelated	41	( 33.3)	35	( 28.7)	36	( 30.0)
Unlikely	30 ( 24.4)	34 ( 27.9)	27 ( 22.5)
Possible	33	( 26.8)	36	( 29.5)	42	( 35.0)
Probable			2	(	1.6)	5	(	4.1)	4	(	3.3)
Definite					0			0	1	(	0.8)
Any TEAE Leading to Study Drug	7	(	5.7)	2	(	1.6)	5	(	4.2)
Discontinuation
Potentially Related TEAEs Leading to Study	1	(	0.8)			0			0
Drug Discontinuation
Any TEAE Leading to Death	1 (	0.8)			0	1 (	0.8)

Safety population of 365 subjects receiving at least 1 dose of study drug. Deaths during active treatment were unrelated to study drug. Death in the placebo group was from rapidly progressing SSc with respiratory and renal failure. Death in the lenabasum 20 mg group was from myocarditis leading to heart and respiratory failure.

19

Lenabasum reduced PEx rates in post-hoc analyses in subjects with similar baseline lung function (FEV1 40-<90% predicted) and CFTR-modulator use

CF Phase 2b

• Phase 2b study in subjects with CF and high risk of pulmonary exacerbations (PEx)
• Primary efficacy endpoint (rate of PEx per subject per 28 Weeks) was not met
• Post-hocsubset analysis was done of subjects with similar baseline FEV1 and use of CFTR modulators, excluding 5 Eastern European countries with unusually low PEx rates
• Numerically lower PEx rate in lenabasum versus placebo cohorts for multiple comparisons, especially in lenabasum 5 mg BID group

				PEx rate per Subject per 28 Weeks (relative reduction vs PBO)
				Primary PEX	Primary PEX	Secondary	Secondary
		CFTR		definition	definition	PEX definition	PEX definition
		Modu-			IV ABx		IV ABx
Treatment	N	lators
			FEV1 % predicted ≥ 40 to < 90%
Placebo	111		1.10	0.58	1.31	0.65
Lenabasum 5 mg	55		0.75 (19%)	0.51	0.96 (26%)	0.48 (16%)
Lenabasum 20 mg	104		1.02	0.50	1.23	0.60
Placebo	78		1.09	0.57	1.32	0.64
Lenabasum 5 mg	42	No	0.93 (15%)	0.55	1.03 (22%)	0.60
Lenabasum 20 mg	68		1.00	0.48 (16%)	1.22	0.57
Placebo	33		1.11	0.59	1.27	0.68
Lenabasum 5 mg	13	Yes	0.76 (31%)	0.38 (35%)	0.76 (40%)	0.38 (44%)
Lenabasum 20 mg	36		1.06	0.54	1.24	0.67
Per protocol population.	Relative reduction is shown only if ≥ 15% reduction

20

Some potential activities of CB2 agonists in cancer

• Anti-proliferativeeffects1, block cell cycle progression2
• Pro-apoptoticeffects on tumor cells3
• Reduce EGF/EGFR and GF-I/IGF-IR pathways4
• Reduce Akt pathways5
• Attenuate downstream functions of CXCR46 or Her27 , which form heterodimers with CB2
• Attenuate bone-cancer-induced pain and bone loss8
• Reduce fibrosis9
• Reduce angiogenesis10 and tumor metastasis2

1. Olea-Herrero,Br J Cancer 2009;101:940. 2 Caffarel, Cancer Res 2006;66:6615. 3 Morales. J Med Chem 2015;58:2256. 4 Elbaz, Oncotarget 2017:8:29668. 5 Rao, Biol Direct 2019;14:9. 6 Coke, J Biol Chem 2016;291,9991. 7 Blasco-Benito. Proc Natl Acad Sci USA 2019;116:3863.

1. Lozano-Ondoua. Life Sci 2010; 8:646. 9 Spiera Arthritis Rheumatology 2020:72,1350. 10 Vidinsky, 2012 Folia Biol 2012;58:75.

21

Novel Corbus CB2/CB1 agonists inhibit breast cancer cell growth

IC50 µM concentrations that cause 50% inhibition of breast cancer cell growth

		Triple negative
Cmpd
MD-		MDA-	MDA-
	MB-468	MB-231	MB-436
AA	3.1		5.4	4.5
BB	3.6		8.1	10.7
CC	2.9		6.7	2.6
DD	3.6		8.4	4.0
EE	3.8		11.3	4.1
FF	6.2		11.6	9.0
GG	6.0		6.8	6.6

		Her2+
Cmpd
BT-474	HCC19	SKBR3
	54
AA	5.1	3.5	5.2
BB	5.4	5.2	6.1
CC	7.2	7.7	11.3
DD	7.9	6.4	10.5
EE	13.5	6.1	16.2
FF	10.2	7.2	12.9
GG	10.2	6.5	11.9

		ER+
Cmpd
T-47D	MCF-7
AA	5.4		> 10
BB	5.7		> 10
CC	11.7
DD	10.4
EE	8.5		> 10
FF	12.1
GG	8.8

The human cancer cell lines were cultured ± compounds from 0 μM to 10 or 20 μM. After 3 days, number of viable cells was determined using the CellTiter-

Glo luminescence assay, and then IC50 concentrations were determined. Compounds were not toxic at these doses.

22

CB2 agonists provide dose-dependent and time-dependent inhibition of

growth of triple negative breast cancer cell line MDA-MB-468

Luminescence (RLU)

6×10	5
4×10	5
2×10	5
0

Cmpd AA	0 uM
1.25 uM
	2.5 uM
	5 uM

0	20	40	60	80
		Time (h)

Luminesce (RLU)nce

6×10	5
4×10	5
2×10	5
0

Cmpd BB

0

20

40

60

80

0 uM 1.25 uM 2.5 uM 5 uM

Time (h)

Luminescence (RLU)

6×10	5
4×10	5
2×10	5
0

Cmpd DD	0 uM
1.25 uM
	2.5 uM
	5 uM

0	20	40	60	80
		Time (h)

(RLU)	6×105		Cmpd EE
cenceLumines	4×105
2×105
0
0	20	40	60	80

Time (h)

0 uM

1.25 uM

2.5 uM

5 uM

Human triple negative breast cancer cell line MDA-MD-468 was cultured ± CB2 agonists in different concentrations, for different times. Number of viable cells was determined using the CellTiter-Glo luminescence system, and luminescence is shown. Compounds were not toxic at these doses.

23

A CB2 agonist inhibits Her2 phosphorylation and Her2+ tumor cell growth in a xenograft model

Compound DD inhibited HER2 phosphorylation

in HCC1954 breast cancer cells

	0.25
HER/Her2-p	0.20
0.15
	0.10
	0.05
	0.00

DMSO 4h

6h

8h 24h

HCC1954 Her2+ breast cancer cells were cultured with vehicle (DMSO) or compound DD for different times. Densitometric analysis of the relative expression of the phosphorylated Her2 vs. total Her2 protein was determined. Compound DD suppressed both HER2 (shown) and Akt phosphorylation in HCC1954 cells.

Tumor Volume (mm3)

1400	Vehicle
1200	Cmpd DD 5 mg/kg BID								**
Cmpd DD 10 mg/kg BID							*
	BKM-120 35 mg/kg QD
1000											**
800										**
								**
						*
								**
600					*	**	**	**	**
400					*
200
							* P ≤ 0.05	**p ≤ 0.01
	2	4	6	8	10	12	14	16	18	20

Days post dosing

Female Balb/c mice nude mice were injected in the flank with HCC1954 Her2+ breast cancer cells. Pharmacological treatments for 21 days were started when tumors reached 90-180 mm3 were cultured with vehicle or compound DD for different times, with compound BKM-129 serving as the positive control. Tumor size was measured using a caliper and tumor volume was calculated.

24

CB2 agonists also inhibit lung cancer and glioblastoma cell growth

IC50 µM concentrations that cause 50% inhibition of cancer cell growth

Non-small cell lung cancer cells

Cmpd	SW1573	A549	HCC827
AA	4.5	7.1	6.4
BB	8.6	9.0	7.8
CC	3.3	8.4	13.3
DD	4.6	12.6	13.0
EE	6.2	8.4	13.2
FF	10.8	14.2	10.4
GG	5.7	5.9	11.2

Glioblastoma cells

Cmpd	U251	SF216
AA	3.8	9.0
BB	5.9	14.0
CC	3.6	10.5
DD	3.5	18.5
EE	4.3	18.3
FF	7.0	14.8
GG	4.6	9.0

Image from John Hopkins Medicine

The human cancer cell lines were cultured ± compounds from 0 μM to 10 or 20 μM. After 3 days, number of viable cells was determined using the CellTiter-Glo luminescence assay, and then IC50 concentrations were determined. Compounds were not toxic at these doses.

25

Summary and conclusions

• CB1 agonists have already been approved for treatment of anorexia, weight loss, nausea, vomiting, muscle spasticity, rare seizures, and tuberous sclerosis
• Novel CB1 inverse agonists with low brain:plasma ratios have been identified, and some have activity in animal models of metabolic disease
• Novel CB2 agonists that inhibit growth of tumor cells have been identified, with early evidence of activity in a xenograft model

CB1 and CB2 may be involved in disease pathogenesis of multiple human

diseases, providing potential targets for new therapeutics

26