Stanford University Docket

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1 Methods to improve survival from heart failure in chronic hypertension and to prevent arterial stenosis Stanford University Docket ifarm Fall 2015 Office of Technology Licensing Dr. Vandana Kaul Melanie Huttner

2 Inventors with a track record of success Dr. Daria Mochly Rosen, PhD The George D. Smith Professor in Translational Medicine, Stanford University, Chemical and Systems Biology Founder and Director, SPARK Translational Research Program that has led to founding 22 start ups, Stanford University, School of Medicine Founder & CSO, KAI Pharmaceuticals (acquired by Amgen in 2012 for $315M) Founder, ALDEA Pharmaceuticals Dr. Koichi Inagaki, MD PhD Former Mochly Rosen Postdoc fellow, Stanford University Cardiologist, Otsu Red Cross Hospital, Japan

3 VK1 Unmet DM1 medical need with global implications I Despite current therapies, patients with hypertension develop heart failure (HF) 7 out of 10 people with chronic heart failure have antecedent hypertension HF affects 5.1 million people in the US, with 50% dying within 5 years of developing HF, and over 23 million people worldwide Expected medical cost for treatment of HF in the US is $32.4B in 2015 Hospitalization rates for HF in the US Age 65+ Years Ages Years Mosterd, A.; et al. Heart, 2007, 93, Heidenreich, P. A.; et al. Circulation, 2011, 123, 933. Bui, A. L.; et al. Nat. Rev. Cardiol. 2011, 8, Mozaffarian, Dariush, et al. "Heart disease and stroke statistics 2015 update: a report from the American heart association." Circulation (2015): e29.

4 Slide 3 VK1 DM1 unmet? what about current drugs? Vandana Kaul, 11/30/2015 Despite current therapies Daria Mochly-Rosen, 12/1/2015

5 Current Standard of Care Hypertension: Diuretics, Ca2+ channel blocker, Angiotensin Receptor Blockers (ARBs) Heart Failure: ARBs and/or Angiotensin Converting Enzyme Inhibitors, Beta Blockers, Spironolactone (particularly for the elderly) Source: KOL interview w/ Dr. Grimes Challenges: Multi drug interactions Uncertainty over which patient will respond to which drug Morbidity and mortality due to hypertensioninduced HF remains high compare/

6 Solution: Highly specific PKCβII and ε Inhibitors A method for slowing or inhibiting the progression of heart failure in a mammalian subject suffering from chronic hypertension, comprising administering to the subject a therapeutically effective amount of a PKCε inhibitor wherein the inhibitor is from the V1 domain of PKCε Administration of the inhibitor in combination with olmesartan Wherein the patient will undergo a heart transplant or has undergone a heart transplant US Patent 7,741,290, 06/22/2010 Administering a therapeutically effective amount of a PKCβII inhibitor wherein the inhibitor is from the V5 domain of PKCβII or is a polypeptide having at least 80% sequence identity to the PKCβIIV5 inhibitor US Patent 8,426,364, 04/23/2013 Divisional application of US Patent 7,741,290

7 PKCβII and ε are critical for progression to HF Protein quality control Proteasome activity Protein aggregation Mast cell degranulation Release of angiotensin Release of histamine Ferreira, J. C. B.; et al. J. Mol. Cell. Cardiol. 2011, 51, 479.

8 Preclinical stage therapeutic for treating heart failure A six week treatment with selective peptide inhibitors of PKC βii and ε slow slowed heart failure progression in hypertensive rat models and delayed death. Treatment: 6 weeks at 3 mg/kg/day DRUG TREATMENT Olmesartan PKC inhibitor + Olmesartan n=12 n=13 Drug treatment Control PKC inhibitor PKC inhibitor n=13 Improved survival by ~11 weeks compared to no treatment, improved fractional shortening, and decreased cardiac parenchymal fibrosis βiipkc inhibitor (and not βipkc inhibitor) enhanced survival, improved fractional shortening, and decreased PKCβII translocation Ferreira, J. C. B.; et al. J. Mol. Cell. Cardiol. 2011, 51, 980. Inagaki, K.; et al. Hypertension, 2008, 6, 1565.

9 Mechanism of action Selective inhibition of PKCβII attenuates post myocardial infarction HF Candidate drug βiiv5 3, a selective inhibitor of PKC Carrier peptide TAT47 57, vehicle control Particulate fraction Selective loss of activated PKCβII from the particulate fraction of failed hearts treated with βiiv5 3 Treatment with PKC inhibitor IMPROVES cardiac functions; fractional shortening increased from 21% to 35%. Collagen deposition: 150% decrease n= 3 No HF, TAT Post MI HF, TAT Post MI HF, βiiv5 3 Two fold decrease in inflammation Palaniyandi, S. S.; et al. J. Cell. Mol. Med. 2011, 8, Ferreira, J. C.; et al. PLoS One, 2012, 7, e33175 Mast cell degranulation: 30% reduction

10 Opportunity for new IP I Combination therapy Additive benefit when combined with antihypertensive therapeutic (Inagaki et al. Hypertension, 2008, 51, 1565 and Ferreira et al. J. Mol. Cell. Cardiol. 2011, 51, 479) Method of delivery Patch, subcutaneous implant, pump for localized delivery to heart Maximize patient compliance and convenience

11 Interviews and Key findings Category # of Interviewees Licensing Associates 1 VCs/Investors 2 Physicians 2 Inventors 1 Regulatory affairs 2 Research Scientists 1

12 Interviews and Key findings Category Positives Concerns Future directions Research Scientist Unmet need for highly specific intracellular inhibitors Need to identify what dose needs to reach target before deciding on delivery method Determine the max tolerated dose and minimum efficacious dose Has animal models to complete studies but requires funding

13 Interviews and Key findings Category Positives Concerns Future directions VCs/Investors High specificity good candidate Peptide therapeutic for a chronic indication; delivery Some data for treatment in humans necessary for VC to invest Small molecule would decrease company s risk in pursuing this project Lower hurdle for rare/orphan disease

14 Interviews and Key findings Category Positives Concerns Future directions Physicians Good drug candidate because peptide does not have interactions with other drugs/ does not need processing in body Delivery of therapeutic May prevent protective ischemic preconditioning Competing with current SOC Narrow target population based on their biopsies or genomic data, endstage disease, etc. Additional animal models/studies needed

15 Interviews and Key findings Category Positives Concerns Future directions Regulatory advisor/ Clinical Development Consultant Application of this therapeutic to orphan diseases FDA concerned with gamesmanship (approving for orphan, then expanding treatment population) Opening conversations with companies pursuing treatments for population subsets Resources from advocacy groups and grants for Ph I or II Get clear answers from companies on what type of preclinical studies they are looking for Look for early development group in a large company Look for a small company willing to develop a peptidomimetic

16 Companies for potential licensing with active CVD pipeline Companies good fit for our technology Company CVD drugs in pipeline Recent CVD success (2015) Amgen 3 Corlanor, Repatha Daichii Sankyo 8 Savaysa Gilead 4 Bayer 12 Regeneron 2 Eli Lilly 2 Pfizer 8 Novartis 2 Entresto

17 Companies for potential licensing with active CVD pipeline Company Amgen Daichii Sankyo Gilead Bayer Regeneron Eli Lilly Companies contacted Acknowledged , awaiting feedback Not interested Pfizer Companies we will contact next: Novartis Raptor Concerns over safety/off target effects Targeting a chronic disease Need animal toxicity studies Need to address delivery

18 Potential Indications: (rare) diseases with unmet medical needs Carcinoid syndrome HF Chemotherapy induced cardiomyopathy Peripartum cardiomyopathy Chagas heart disease Aortic stenosis Stage 4 heart failure Patients with HF awaiting Heart transplant Diabetes induced cardiomyopathy

19 Example Indication I Clinical trials for βpkc inhibition in diabetesinduced cardiomyopathy Eli Lilly also conducted clinical trials for ruboxistaurin mesylate (RBX), a βpkc inhibitor, for complications of diabetes such non proliferative diabetic retinopathy. Program was abandoned in 2011; the FDA asked for additional clinical trials and Lilly decided that it would not be commercially and clinically feasible. Lilly s inhibitor was not selective for βiipkc. In comparison, our inhibitor is highly specific for βiipkc. References: Ruboxistaurin: PKC beta inhibition for complications of diabetes. Danis RP, Sheetz MJ. Expert opin Pharmacother Dec;10(17): doi: / may be able prevent diabetic kidney disease

20 Summary Positive Outlooks: Potential to address several unmet medical needs Long patent life & potential for new IP Highly selective drug with promising in vivo results Major Hurdles: Bridging the gap between academia and industry Method of delivery Need to generate more preclinical data Future plans: Conduct in depth research to identify which indication(s) are most applicable for this technology Meeting next week with inventor and research scientist to discuss future preclinical studies Need to come up with funding source

21 Thanks to I Mentors Tom Lenk (tjlenk@comcast.net) Linda Molnar (lindakmolnar@gmail.com) Inventors Dr. DariaMochly Rosen (mochly@stanford.edu) Dr. Koichi Inagaki (kinagaki circ@umin.net) Stanford Office of Technology Licensing Associate Sara Nakashima (laughter@stanford.edu) Grant Schoonover (grant.schoonover@stanford.edu)