Clinical Studies….?

Clinical research in the midst of an Ebola outbreak

Peter Horby Brisbane, 1-2 June 2015 Acknowledgements

Stephen Kennedy (PIRE, Liberia) Foday Sahr (DoD, Sierra Leone) Mohamed Samai (COMAHS, Sierra Leone) Jake Dunning, Trudie Lang, Jen Groves, Mandy Rojek, Gail Carson and many others at Oxford Annick Antierens and others at MSF Fiona Gannon and others at GOAL Tim Brooks (Public Health England) John Whitehead (Lancaster, Trial Statistician) Chimerix Inc. / Tekmira Pharmaceuticals Inc. The RAPIDE trial teams The ISARIC, PREPARE and The Global Health Network Teams in Oxford The MSF and MoH teams in country The Ebola Patients

Sponsor: University of Oxford Funder: Wellcome Trust  Background  The therapies  The trials  The challenges  Lessons learned & next steps

13th August 2014

“investigators have a moral duty to evaluate these interventions in the best possible clinical studies that can be conducted under the circumstances of the epidemic.” The therapies Promising candidates

Product What is it? Evidence ZMapp Ebola antibody cocktail Solid protection in monkeys TKM-Ebola RNA inhibitor Solid protection in monkeys Brincidofovir Small molecule with Antiviral activity in broad antiviral activity cell lines Favipiravir RNA polymerase Solid protection in inhibitor mice. Antiviral in monkeys Convalescent Antibodies from Failed in monkeys plasma recovered patients

Repurposed therapies

Product – Primary Comment Azithromycin (Zithromax) Widely used in critically ill pts Sertraline (Zoloft) Large safety db – healthy pts Chloroquine Large safety db – healthy pts Amiodarone (Cordorone) Clinical data in Ebola pts Erlotinib / Sunitinib Combination rx with phase 3 data Product - Secondary Comment Cepharanthine “Anti-inflammatory” licensed in Japan Interferon products Systemic reactogenicity Toremifene (Fareston) Black box warning - hypokalemia 9 TKM-Ebola The Favipiravir trials Convalescent plasma

ZMapp Brincidofovir Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola RAPIDE Objective

Rapidly assess and triage a number of potential Ebola treatments in Phase 2 studies.

Survival Conclusion Outcome (a) 80% Very effective Maximize benefits (b) 67% Promising Justification for RCT (c) 50% Ineffective Minimize wasted effort RAPIDE trial design

Cooper B et al. PLoS Med. 2015 Apr 14;12(4):e1001815. Probabilities of reaching each conclusion for the phase II trial of treatment

Exact probabilities for Phase 2 with 140 cases p = true probability of surviving for 14 days

p description Probability of reaching conclusion:

(a) (b) (c) 0.800 very effective 0.908 0.092 0.000 0.667 promising 0.034 0.950 0.016 0.500 ineffective 0.000 0.100 0.900 Maximum sample size = 140 24 straight successes  (a) 12 straight failures (c) Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola

Brincidofovir trial Scientific Title Open-label, non-randomised single arm trial to investigate the efficacy of Brincidofovir compared to historic controls or Ebolavirus Disease in an outbreak setting in West Africa Clinical Phase 2 Trial Design Open-label, non-randomised, single arm trial Trial Participants Patients with confirmed Ebolavirus disease attending the participating treatment centre Planned Sample Size Up to 140 adult participants, paediatric enrolment according to presentation over the same recruitment period

Investigational Brincidofovir (BCV) Medicinal Product Formulation, Dose, Patients ≥50 kg: 200 mg initial dose, then 100 mg twice weekly Route of for 4 doses Administration Patients <50 kg: 4mg/kg initial dose, then 2 mg/kg twice weekly for 4 doses Treatment duration 2 weeks Follow up duration 30 days follow-up Objectives Outcome Measures

Primary To evaluate the impact of Mortality at Day 14 BCV treatment on early mortality in EVD Secondary 1. To evaluate the impact of 1. BCV treatment of adults and a) Time to meeting EVD treatment children on: center discharge criteria. b) Mortality at Day 30 after first dose a) Time to recovery of study treatment b) Late mortality c) Day 4 viral load c) Viral load d) Presence and duration of d) EVD symptoms symptoms (Days 1-14) e) EVD antibody response e) Convalescent anti-Ebolavirus IgG titer (Day 30) 2. To assess the safety of BCV 2. Incidence of SARs and key adverse treatment of adults and events (Days 1-14) children Rapid Assessment of Potential RAPIDE Interventions & Drugs for Ebola

TKM-Ebola-Guinea Trial Tekmira’s Lipid Nanoparticle Platform

Components:

Amino Lipid

Structural Lipid

PEG - Lipid

Nucleic Acid

40-140 nm diameter Jeffs et al. Pharm. Res. 2005. siRNA Proof-of-Concept non-Human Primates

Geisbert et al, Lancet 2010; 375: 1896-905

20 Ebolavirus Zaire Outbreak in Guinea, March 2014 Guinea Variant Is Divergent From Kikwit, Original Target of TKM-100802 siRNA

+ 99 Sierra Leone sequence entries Jun-Jul 2014

Phylogenetic analysis suggests single clade distinct from outbreaks in central Africa

Baize et al, NEJM Apr 16 2014 Product details: TKM-130803

• siRNA cocktail adjusted to Guinea strain • Wet formulation • IV once daily infusion over two hours • Seven days treatment • 100 treatment courses Simple, pragmatic trials

. Consecutive enrollment & analysis

. Dead or alive on day 14

. Max 100-140 patients

. What could possibly go wrong?

★

★ Challenges to research: PEARLS

POLITICAL ETHICAL ADMIN

REGULATORY LOGISTICAL SOCIETAL PEARLS - Political PEARLS - Ethical so long as standard requirements for human research ethics are met, all scientifically recognized methodologies and study designs should be considered as ethically acceptable— whether they are placebo controlled randomized trials or trials that don’t involve randomization to choosing the trial design that will control groups. both answer the question at issue and also be ethically and practically acceptable to the community in Pregnancy / children which the research is to be conducted.

PEARLS - Administrative

Grant awarded DM system Protocol Drug Selected Contracts Ethics -- Oxford Ethics - Liberia Import license Export drug Final agreements First Patient 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 Sept Oct Nov Dec Jan PEARLS - Regulatory This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues, clients or customers visit http://www.djreprints.com. http://www.wsj.com/articles/chimerix-scraps-testing-of-experimental-ebola-drug-in-liberia-1422739087

BUSINESS Chimerix Scraps Testing of Experimental Ebola Drug in Liberia Declining Ebola Infection Rat e Contributed to Company’s Decision

By PETER LOFTUS Jan. 31, 2015 4:18 p .m. ET

Chim er ix I nc. scr apped t est ing of it s exper im ent al ant ivir al in Ebola pat ient s in Liber ia, saying t he num ber of infect ions had dr opped in r ecent w eeks, and t hat only a handful of pat ient s had been enr olled in t he Liber ian s t udy.

The abr upt r ever sal in Chimerix ’s plans could r aise questions about whet her t he declining number of Ebola infections in W est Afr ica could be a pr oblem for o t her exper im ent al dr ugs and vaccines cur r ent ly under g oing t est ing in t he r egion for safet y and efficacy. The Wor ld H ealt h Or ganizat ion said t his w eek t he incidence of t he deadly disease cont inues t o fall in t he t hr ee count r ies t hat w er e har dest hit last year —Guinea, Liber ia and Sier r a Leone.

M or e t han 22,000 people had been infect ed wit h Ebola and m or e t han 8 ,800 had died as of Jan. 25, pr im ar ily in t he t hr ee W est African countries, accor ding t o WH O.

Chim er ix, of Dur ham , N.C., said in a news r elease issued lat e Fr iday t hat aft er discussions wit h t he U.S. Food and Dr ug Adm inist r at ion, t he com pan y “ is ceasing further participation in all current and future clinical s tudies of brincidofovir ” for Ebola vir us disease. This includes a st udy in Liber ia sponsor ed b y t he U.K.’s Univer sit y of Oxfor d, which began in J anuar y.

Pet er H or by, an Oxfor d r esear cher who w as helping t o r un t he st udy, said t he decision t o halt it “ ar ose fr om bilat er al discussions bet ween Chim er ix and t he FD A.” H e said he wasn’t awar e of any r easons for t he decision beyond declining case num ber s. An FDA r epr esent at ive couldn’t im m ediat ely be r eached.

The com pany said t he num ber of new cases of conf ir m ed Ebola vir us disease in Liber ia “ has decr eased signif icant ly, wit h only a handful of pat ient s enr olled t o dat e” in t he PEARLS - Logistical

Ebola, AIDS Manufactur ed by Western Pharmaceuticals, US D oD? | The Liber ian Obser ver 08/12/2014 09:31

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Scientists allege deadly diseases such as Ebola and AIDS are bio weapons being tested on Africans. Other reports have linked the Ebola virus outbreak to an attempt to reduce Africa’s population. Liberia happens to be the continents’s fastest growing population.

Popullar Sttor iies Ebola, AIDS Manufact ured By W est ern 1. Where Did US$14m Go? Pharmaceut icals, US DoD? 2. Montserrado Still Focal Point Tue, 09/09/2014 - 09:59 admin 3. ‘Delay Tactics’? Scientists Allege 4. Ellen withdraws Davis-Russell’s Nomination By: Dr. Cyril Broderick, Professor of Plant Pathology 5. Ebola, AIDS Manufactured by Western Dear World Citizens: Pharmaceuticals, US DoD? I have read a number of articles from your Internet outreach as well as articles from other sources about the casualties in Liberia and other West African countries about the human devastation caused by the Ebola virus. About a week ago, I read an article published in the Internet news summary publication of the Friends of Liberia that said that there was an agreement that the initiation of the Ebola outbreak in West Africa was due to the contact of a two-year old child with bats that had flown in from the Congo. That report made me disconcerted with the reporting about Ebola, and it stimulated a response to the “Friends of Liberia,” saying that African people are not ignorant and gullible, as is being implicated. A response from Dr. Verlon Stone said that the article was not theirs, and that “Friends of Liberia” was simply providing a service. He then asked if he could publish my letter in their Internet forum. I gave my permission, but I have not seen it published. Because of the widespread loss of life, fear, physiological trauma, and despair among Liberians and other West African citizens, it is incumbent that I make a contribution to the resolution of this devastating situation, which may continue to recur, if it is not properly and adequately confronted. I will address the situation in five (5) points:

1. EBOLA IS A GENETICALLY MODIFIED ORGANISM (GMO)

Horowitz (1998) was deliberate and unambiguous when he explained the threat of new diseases in his text, PEARLS - SocietalEmerging Viruses: AIDS and Ebola - Nature, Accident or Intentional. In his interview with Dr. Robert Strecker http://www.liberianobserver.com/security/ebola-aids-manufactur ed-wester n-pharmaceuticals-us-dod Page 1 of 11 What have I learned? Money, protocol, and ethics – can be fast-tracked

BCV Grant award opened

- 3.5 months BCV TKM - 39 days closed opened Operations – can be solved

People – can be found Unfinished pipelines are a bottleneck and a risk

Product Status Issues Brincidofovir (CMX001) Trial initiated New data arising Terminated TKM-100802 Trial initiated (TKM- Clinical trial lot not available 130803) until November 2014 AVI-7537 Not available - ZMapp Trial initiated Clinical trial lot not available until late 2014 Convalescent plasma Trial initiated Lead time to produce plasma Diverse organizational goals, cultures, & experience are the greatest challenge