Rational Pricing and the Role of Generics Raymond F. Schinazi, PhD, DSc

Frances Winship Walters Professor Director, Scientific Working Group on Viral Eradication, Emory University CFAR/VAMC Center for Drug Discovery Vancouver – November 12, 2015 [email protected] Founder, Chairman & major shareholder of CoCrystal Pharma Inc. Discovery to Cure for HCV The Good News 1 2 Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989 – 2014 = 25 years to an efficient Cure

1. M. Houghton 3 4 2. Q-L Choo 3. G. Kuo 4. D. Bradley Source: Nature Medicine 6, 1082 - 1086 (2000)

The advent of the HCV replicon systems in the early 1990 transformed HCV drug discovery in industry and academia. 25 years of HCV GT 1 Therapy: from 0 to 100 %

Cornberg et al, Der Internist, 2014 Success and Challenges to HCV cure

• alfa is no longer part of the first line regimens for the treatment of HCV – Minimal on-treatment monitoring is required • may continue to be used in certain persons for 2-3 years more for severe cases • Contraindications to treatment are relatively rare but remaining challenges include: – Cirrhosis – Re-infection following HCV cure • Short duration may be highly advantageous in the real world – Increase adherence; lower toxicity, decrease cost and possibly drug resistance – Compromise in efficacy is acceptable when re-treatment options are effective and readily available • Global access to low cost HCV treatment is the primary unmet challenge – shorter treatment will make a difference especially in underdeveloped countries

Optimal antiviral regimens of the future will be simple and short

• Simple – high HCV cure rate (for most genotypes) – Minimal monitoring • Short – Minimize side effects – Improve adherence and persistence – Lower cost – Fewer health care resources required – More HCV cure per health care provider • 4 weeks = 13 patients/year • 6 weeks = 9 patients/year • 12 weeks = 4 patients/year Multiple HCV targets are available

DNA-directed RNA Entry inhibitors interference (ddRNAi) Cyclophylin Inhibitors TT-034 via Adeno-Associated Virus vector

Antisense oligonucleotides Miravirsen (miR-122) Regalus NS3/4 Protease Inhibitors (SIM) ABT-450/ (r) NS5B GS-9451 Polymerase Inhibitors Faldepravir (comeback) (nuc - SOF) GS-9669

NS5A Inhibitors IDX-21437 (nuc) (LDV) IDX-21459 (nuc) ACH-3422 (Nuc) (DCV) BMS-325 Ledipasvir (LDV) MK-8742 CC-1845 (nuc) GS-5816 () CC-31326 (NNI) Samatasvir (Merck)

ACH-3102

2015: Hepas C Virus and Curave Tx

• Oral, direct acting antiviral agents (DAA): § NS5B, Entry, Protease, NS5A, Cyclophilins, microRNA, etc. § December 2013: Sofosbuvir and Simeprivir § September 2014: Daclatasvir (Europe, Japan) § October 2014: SOF + Ledispavir (Harvoni) § December 2014: Viekira pak (FDC of 4-5 drugs) § July 2015: Harvoni (Japan) § July 2015: Daclatasvir (US) for genotype 3 § July 2015: Technivie (ombitasvir//ritonavir) • Nucleoside Analog Inhibitors (NAI) are Best in Class: – High potency – no drug-drug interactions – Pan-genotypic – High barrier to resistance – Low pill burden and orally bioavailable General Characteristics of Direct-Acting Antiviral Agents

NS5B NS5A NS5B PI, PI, NS5A Inhibitors Non- Inhibitors Nucleoside 1st Generation 2nd Generation 2nd Generation Nucleoside 1st Generation Inhibitors Inhibitors

Efficacy

Resistance Profile

Pangenotypic Efficacy Adverse events Drug-drug interactions

Good profile Average profile Least favorable profile

Schinazi, R.F., Halfon, P., Marcellin, P., and Asselah, T. HCV direct-acng anviral agents: the best interferon-free combinaons. Liver Int., 34 Suppl 1:69-78, 2014 Priorities for Direct-Acting Antiviral Agents

Potency Genotype Coverage Highest Importance Resistance Barrier Safety/Tolerability

Treatment Duration Half life & Pills burden

Drug-drug Interaction Secondary Priorities

Cost

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014 HCV Treatment Expansion: Generic Manufacturing for Developing Countries • Gilead has signed agreements with 11 Indian companies: (Aurobindo Pharma Ltd., Biocon Limited, Cadila Healthcare Ltd., Cipla Ltd., Hetero Labs Ltd., Laurus Labs Pvt. Ltd., Mylan Laboratories Ltd., Natco Pharma Ltd., Ranbaxy Laboratories Ltd., Sequent ScientiÄc Ltd. And Strides Arcolab Ltd.) • To manufacture generic HCV medicines for 91 developing countries:

Afghanistan Chad Guatemala Maldives Papua New Guinea Swaziland Angola Comoros Guinea Mali Rwanda Tajikistan Antigua and Congo, DR Guinea-Bissau Mauritania Samoa Tanzania Barbuda Congo, Rep. Guyana Mauritius Sao Tome & Pr. Timor Leste Bangladesh Cote d’Ivoire Haiti Mongolia Senegal Togo Benin Cuba Honduras Moz am bique Seychelles Tonga Bhutan Djibouti India Myanm ar Sierra Leone Turkmenistan Bolivia Dominica Indonesia Namibia Solomon Islands Tuvalu Botswana Egypt Kenya Nauru Somalia Uganda Burkina Faso Equatorial Guinea Kiribati Nepal South Africa Uzbekistan Burundi Eritrea Kyrgyz Republic Nicaragua South Sudan Vanuatu Cambodia Ethiopia Lao PDR Niger Sri Lanka Vietnam Cameroon Fiji Lesotho Nigeria St. Vincent and the Zambia Cape Verde Gabon Liberia North Korea Grenadines Zimbabwe Central African Gambia Madagas c ar Pakistan Sudan Republic Ghana Malawi Palau Suriname • Provide access of HCV drugs to 7 million people living with HCV • Price for generic Sovaldi (sofosbuvir) = $567 for full 12 week treatment course (which is still up to 20 % of the average annual income in India). Cost of pan-oral DAAs is onerous

• Adversely affecting treatment access and drug compliance • Encouraged drug counterfeiting which could create substantial public health hazards and cause safety concerns Jayasekera CR, et al. NEJM 2014;370:1869-71. McCarthy M. BMJ 2015;350:h2137. Attaran A. Am J Trop Med Hyg 2015;92:127-32. Correlation between HCV drug prices and gross national income – High income countries Correlation between HCV drug prices and gross national income – Low and middle income countries

I. Andrieux-Meyer et al, Disparity in market prices for HCV direct acting agents. Lancet – in press 2015 New drivers towards generics

Médecins Sans Frontières/Doctors Without Borders (MSF) is in the process of starting to treat HCV+ individuals in at least 9 countries; therefore there is a need for affordable access to DAAs.

Australian Society of HIV/HBV/HCV Medicine (ASHM) have joined forces with NSW Health to issue “Importation of Generic HCV Drugs” policy which allows for individuals to import up to 3 months of for their use under the Commonwealth Government’s Personal Importation Scheme.

http://fixhepc.com/blog/item/18-ashm-position-statement-on-hcv-generics.html

Arguments “for” HCV Generics

• Generics account for 78% of all US prescriptions1 • Ontario Drug Benefit Program reports > 88% generics dispensed within 2 months of availability 2 • Same FDA approvals required (USP), to meet public standards of same quality, strength and purity3 • According to Canadian Family Physician (CFP) review, “generic are bioequivalent and produce similar clinical outcomes to brand-name medications”4 • Numerous reports of equivalent efficacy and safety of generic compared to brand for other life-threatening conditions5,6 • Adherence rates reportedly remained similar between generic and brand users7 or more likely to adhere and have lower rate of a composite clinical outcome8 • For HCV, non-incestuous FDC can be manufactured (e.g., DAC + SOF)

1 R Manning and R Smith. Brand-Name Versus Generic drugs. Health Affairs, 30, no. 10, 2011. 2 Fraser et al., Patterns of use for brand-name versus generic oral bisphosphonate drugs in Ontario over a 13-year period: a descriptive study. CMAJ Open. 2015 ,3(1):E91-6. 3 Generic drugs versus brand names: switching could save money. Generic drugs have to go through the same FDA approvals as brand names, so they have the same quality. Harv Womens Health Watch. 2013; 11:3. 4J McCormack and J. T. Chmeliceck. Generic versus brand name: the other drug war. Canadian Family Physician. 2014 , Vol. 60. 5 Ting, et al, Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilespsy: a field test of the FDA bioequivalence standard. Epilepsia. 2015, 56(9): 1415-24. 6Panahi, et al., Efficacy and safety of Dorocontin® versus Sustac® in the treatment of stable angina pectoris: a randomized, double-blind comparative trial. Sci Pharm. 2014, 82 (4): 815-24. 7O’Brien et al., Patient adherence to generic versus brand statin therapy after acute myocardial infarction: insights from the Can Rapid Stratifcation of Unstable Angina Patients suppress Adverse Outcomes with Early Implementation of the American College of Cariodlogy/American Heart Association Guidelines Registry. Am Heart J. 2015; 170 (1): 55-61. 8Gagne et al., Comparative effectiveness of generic and brand-name statins on patient outcomes: a cohort study. Ann Intern Med. 2014. 161(6): 400 -7. Arguments “against” HCV Generics

• Differences in shape, color, taste, and name can lead to patient (and even clinician) confusion1 • Confusion can lead to non-persistent use • Generics can contain different “fillers” which may not be tolerated • No quality assurances in certain countries (e.g., Egypt) • Metal levels may be higher leading to mental issues • Subtle difference in bioavailability may limit optimal treatment2 • Misuse by subjects obtaining drugs over the counter (e.g., monotherapy)

1 J. McCormack and J. T. Chmelicek, Generic versus brand name: the other drug war. Canadian Family Physician. 2014, Vol 60. 2 S. M. Jankovic and R. D. Ignjatovic, Is bioavailability altered in generic versus brand anticonvulsants? Expert Opin Drug Metabl Toxicol. 2015, 11(3): 329 -32. Counterfeit drugs vs. Generic DAA

It’s important to remember that if the drugs were affordable for individuals and countries in the first place, true counterfeit drugs wouldn't be profitable as an enterprise, at all. Genotype 1: good SVR rates for treatment-naïve subjects in clinical trials

GT-1, treatment-naïve These studies are not head-to-head comparison ION 22 PEARL-III3 Study 040 (GT-1b)4 SOF + LDV ± RBV OBV/PTV/r + DSV DCV + SOF ± RBV

100 100 100% 100% 100% 100% 95% 100 100

80 80 60 60 40 40 SVR12 (%) 20 108 110 20 109 111 0 SOF + SOF + 0 LDV LDV SOF Lead-In+DCV (24 wk) + RBV •C DCV+SOF (24-wk) 24-week treatment DCV+SOF+RBV (24 wk) DCV+SOF (12 wk) DCV+SOF+RBV (12 wk) • 3D, peritaprevir/ritonavir + ombitasvir + dasabuvir; ASV, asunaprevir; DCV, daclatasvir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; Missing data* SVR, sustained virologic response.

1. Gane EJ, et al. N Engl J Med 2013;368:34–44; 2. Afdhal N, et al. N Engl J Med 2014;370:1483–1493; 3. Ferenci P et al. CROI 2014; 4. Sulkowski et al. N Engl J Med 2014;370:211–21. HCV therapy with Sofosbuvir Inial Poor results for genotype 3 Many studies conducted in the last 6 years including Astral studies

Asselah et al 2014

• Valence trials: 91% SVR12 in SOF/RBV for 24 weeks for non-cirrhoc GT 3a paents

19 Truncation of therapy possible & is advantageous

Short duration may be highly advantageous in the real world – reduce cost and simplify Tx § Increase adherence; decrease cost; less tox and resistance (dead viruses don’t mutate) § Make curative treatment regimens more accessible and affordable § Curtail the massive use of counterfeit medicine, which could be potentially harmful § Use the most potent and safest DAA together § Plan scenario in case of failure like we do for HIV (need markers for success or failure and when to stop therapy) – treat longer based on Response-Guided Therapy (RGT) Previous attempt-Pan-Oral DAAs 4 and 6 wks for non-cirrhotic GT1 CHC

Duration 6 weeks 4 weeks

Company Gilead Gilead MSD

Regimen SOF+LDV SOF+LDV SOF+LDV+ SOF+LDV+ SOF+LDV+ + +RBV +GS-9669 GS-9451 GS-9451 GS-9451+ +SOF GS-9699

Genotype 1 1 1 1 1 1

SVR12/8* 68% 95% 100% 40% 20% 37%*

Author Gane1 Kohli2 Kattakuzhy3 Lawitz4

1. Gane EJ, et al. Gastroenterology. 2014:146:736-43. 2. Kohli et al, Lancet 2015, 385: 1107-1113 3. Sarah Kattakuzhy EASL 2015 4. Lawitz et al. C-Swift study 2015 Response-guided therapy leads to complete cure after three weeks of all-oral triple-direct acting antiviral regimens in non-cirrhotic chronic genotype 1b Chinese subjects (SODAPI study)

AASLD 2015 Late Breaker (LB23 , p1394A) Monday, Nov 16, 2015

1b strain accounts for about 22% of all HCV infections globally SODAPI STUDY (3 x 3)

• Divided the 26 Naïve genotype 1b subjects into three groups. A “rapid virologic response” (RVR), defined as plasma viral RNA less than 500 IU/ml by day two, was achieved in 18 persons (Response Guided Therapy).

• sofosbuvir, ledipasvir, asunaprevir (Harvoni, Sunvepra); RVR in 6/12 • sofosbuvir, daclatasvir, simeprevir (Sovaldi, Daklinza, Olysio); RVR in 6/6 • sofosbuvir, daclatasvir, asunaprevir (Sovaldi, Daklinza, Sunvepra); RVR in 6/8

• All subjects (100%) followed achieved SVR12, including those that took drugs only for 3 weeks

• To be presented at AASLD as a Late Breaker – Not funded by pharma Efficacy and Safety Assessments

Week Day 0 2 4 7 14 21 Week 4 12

Baseline Treatment period Post-treatment follow-up

Vrial kinetics 0,1,2,4,8,24,48 hours

ü HCV RNA ü HCV RNA ü HCV ü HCV RNA ü LFT genotyping ü LFT ü RFT ü IL28B ü RFT ü CBP ü IFNL4 ü CBP ü Fibroscan (Day 21) ü RAVs ü Fibroscan (Week 12) ü LFT ü Ultrosound (Day 21) ü Ultrosound (Week 12) ü RFT ü AE record ü CBP ü Fibroscan ü Ultrosound ü CT ü ECG Treatment Response (ITT)

100 100 100 100 100 100 100 100 100 100 100 100 100 SOF+LDV+ASV (Group 1)

90 83.3 83.3 SOF+DCV+SMV (Group 2) 80 SOF+DCV+ASV (Group 3) 66.7 70

60

50

40 33.3 33.3 33.3 30

20 16.7 0 0 patients with HCV RNA < LLOQ (ITT) LLOQ < RNA patients with HCV 10 2/6 2/6 4/6 6/6 6/6 6/6 6/6 1/6 6/6 2/6 6/6 5/6 6/6 6/6 6/6 6/6 6/6 6/6 % 0/6 5/6 0/6 0 Day 2 Day 4 Day 7 Week 2 Week 3 Fu_Week 4 Fu_Week 12 Cost-effectiveness • Evaluation (assuming retail price) – Decision analytic Markov model – Uncertainty was tested by probabilistic sensitivity analysis using second Monte Carlo simulation • Compared to 8-12 weeks SOF-based dual therapy, 3-weeks triple therapy is cost-saving with é QALYs and ê cost per person

Base-case results

Treatment regimens QALYs QALY gained Costs (US$) Cost saved (US$)

SOF+DCV (12 week) 11.196 181,696 SOF+DCV+SMV (3 week) 11.222 0.026 74,651 107,045 SOF+DCV+ASV (3 week) 11.222 0.026 71,273 110,423

SOF+LDV (8 week) 11.207 85,046 SOF+LDV+ASV (3 week) 11.222 0.015 47,592 37,454 • In this proof-of-concept study, all (100%) non-cirrhotic CHC GT1b Chinese treated with triple-DAAs

• With RVR by D2 achieve SVR12 • Excellent tolerability

• Multi-scale model – predicts no subjects had < 1 virus in the body extracellular water at EOT

• Further studies investigating shorter durations of therapy are warranted – Pharmacokinetic and immunological – Use of DAAs with high potency and non-overlapping resistance profiles tailored to specific characteristics of the subjects and viruses Funding support • Hong Kong (George Lau and Team) – Humanity and Health Medical Group

• US (Raymond Schinazi, Alan Perelson and Team) – National Institute of Health • NIH grants 5P30-AI-50409 (to RFS) • NIH grants R01-AI028433, R01-AI078881 (to AP) – Department of Veterans Affairs to (RFS) – Department of Energy (to AP) – National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) R01-OD011095 (to AP)

As of October 2015, only about 600,000 individuals have been cured of HCV worldwide with DAAs

Problem in the US will persist until 2036

SODAPI approach could be applied in China where the predominant genotype is 1b (40 million people infected)

HCV Approach: 4+ Direct-acting antiviral agents for shorter modalities

Pan-genotypic All oral HCV De-risked NS5B Nuc near-term regimen approach Pan-genotypic creating NS5B NNI multiple “shots on goal” Pan-genotypic NS5A Inhibitor

Pan-genotypic Helicase Inhibitor From Z-Pak to C-Pak?

Schinazivir®

The best is yet to come The game is NOT over! Schinazi’s Lab of Biochemical Pharmacology – Emory University/VA

Raymond F. Schinazi (PI), Leda C. Bassit, many others

Supported by NIH, CFAR, and the Department of Veterans Affairs COI: I am the Founder, Chairman & major shareholder of CoCrystal Pharma Inc.