Disclosures Employee:

• Pfizer

Shareholder:

• GlaxoSmithKline

• Spero Therapeutics

Consultant:

• Prokaryotics

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The opinions expressed in this presentation are my own and are not necessarily

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Industry Experience with Drug Development of Anti-Infectives

John F. Tomayko, MD

ESCMID/ASM Conference on Drug Development to Meet the Challenges of

Antibiotic Resistance

September 4-7, 2018 Lisbon, Portugal

john.tomayko@pfizer.com

jftomayko@gmail.com

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Agenda

• Pearls • Phase 1 FTIH

• A chance to save time and cost

• Phase 2 • To do or not to do?

• Phase 3 • Going to the battlefield

• Public Private Partnerships • Push-incentives and trial networks

• What’s beyond--- Yikes!!

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PHASE 1

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PHASE 1-First Time in Human Studies

• FTIH studies are largely prescriptive, dose ascending studies, single ascending (SAD), followed by a multiple ascending dose (MAD) • Choose safe starting dose, based on the NOAEL of most sensitive species in

toxicology studies • Convert to Human Equivalent Dose (HED) based on body surface area • Apply safety factor, usually 10 to 20 fold lower= starting dose for single ascending dose*

• Cohort sizes vary, typically 6-8 active, 2 placebo • Staggering dosing among subjects has become standard • Sentinel patient dosing before full cohort is becoming more common • Dose escalation schemes vary

• Many now consider including multiple ascending dose in FTIH study, so that both escalations are done under one protocol • MAD start is typically midway through SAD

*Non-linear PK, irreversible toxicity, steep dose response curve, variable bioavailability requires greater safety margin

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Opportunities to Streamline FTIH Study Conduct

• Several countries have streamlined the clinical trial approval process and excel in the conduct of FTIH studies • Example 1: MHRA can approve the CTA for FTIH typically <14d

• They allow fusion of SAD and MAD and even other elements such as food effect into one study

• Several excellent UK sites can help with all aspects of the trial from regulatory submission, protocol design and execution

• Example 2: Australia uses a CTN process which is more of a notification and approved by the HREC (AUS ethics committee), this is a simple application and for straightforward programs can be approved in 5-10 days • However, if there are complexities in the program, a more detailed CTX is required and pulls

in the regulatory authorities (TGA) • Must be submitted by an AUS entity, many CROs available and similarly capable research sites • Exchange rate currently favors US$ over AUS$ further reducing costs

• Other countries (Netherlands, Germany, etc) have similar capabilities

https://www.tga.gov.au/book-page/ctn-and-ctx-schemes

http://www.richmondpharmacology.com/downloads/Publications/Richmond%20Pharmacology%20Ltd%20(2)%20(2).pdf

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PHASE 2

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Phase 2: Go or Skip? • There is controversy about the value of PH2 with properly dosed antibiotics

• Whereas ~70% of PH2 PoC trials in other TAs are unsuccessful, this doesn’t apply to antibiotic trials* • For abx, a successful PoC combines solid preclinical work, demonstrating thorough understanding

of PK/PD + Ph1 data, showing that target exposures for key pathogens can be reliably and safely achieved (good safety margin)

• Small PH2 trials often don’t reveal safety risks

• PH2 trials could be useful: • The more that you don’t know about dose, the more valuable PH2 becomes • Concerns about tolerability issues in target population, e.g. nausea, vomiting in post op pts • Dose ranging when there is room to dose higher than current MICs demand • Novelty (novel target, endpoints, delivery, etc.) • Ambiguous results regarding frequency of resistance

• PH2 trials can help discharge risk earlier, but so can adaptive PH2-3 trials when properly executed

*http://www.appliedclinicaltrialsonline.com/phase-iii-trial-failures-costly-preventable 8

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EXAMPLE:

Development Program Discontinued due to the Emergence of Resistance in PH2

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AN3365 (formerly GSK2251052) Works by Inhibiting Bacterial Leucyl tRNA Synthetase

GSK'052-A76 Adduct In Editing Site

tRNALeu

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• Mechanism of action

• LeuRS is an essential

enzyme for protein

synthesis

• GSK’052 forms an

adduct with the tRNA

in the editing site

locking LeuRS in an

unproductive state

• Mutants are editing

deficient When the 3′ end of tRNALeu binds to the editing active site, the boron crosslinks to the cis diols of its terminal ribose

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Will resistance emerge on therapy?

Factors

Do at least 90% of strains tested have a low/moderate Frequency of Resistance? Low: ≤9 x 10-9 Moderate: 1 x 10-8 to 4 x 10-8 High = ≥5 x 10-8

Is it likely the exposure in patients can “cover” the MIC of the mutants?

Is there a fitness cost in the mutants?

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AN3365/(‘052) : Pre-Clinical Knowledge Regarding Resistance

• FOR was considered moderate-to-high, ranging 10-7-10-8

• Laboratory generated mutants resistant to AN3365/(‘052) contain mutations in leuS and were determined to be incapable of editing

• AN3365/(‘052) MICs of resistant mutants range from 32->512 mcg/mL

Given a novel target and the extremely broad GN spectrum of AN3365 (‘052), and a false sense that the mutants would be unfit, PH2 studies in cUTI and cIAI were started

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Both studies were suspended when the rapid emergence of resistance was detected in four subjects in the cUTI study, emerging after the 1st day of therapy

cUTI: (20 patients recruited) cIAI: (15 patients recruited)

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PHASE 3

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Phase 3 Trial Development

• Phase 3 studies are typically randomized, controlled, double-blinded, non-inferiority, multicenter trials of large patient numbers intended to support a regulatory submission

• Comparison of the test drug to a drug considered to be the “gold standard” for treatment of the disease under study

• Make sure you have the capabilities in place before you embark on a Phase 3 trial

• You must have a clear protocol that can be feasibly executed • Consider obtaining input from high recruiting site investigators or study coordinators

• Build in protocol flexibility where possible to avoid amendments

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Non-inferiority vs. Superiority* • Why are new antibiotics mainly developed using non-

inferiority (NI) trials vs. existing SoC agents • New antibiotic trials must (usually) be designed to avoid superiority

• MDR/XDR are rare (we hope) & require customized comparators (BAT)

• Must NOT enroll if resistance is known/likely to TEST or comparator.

• Highly unlikely to see superiority over a fully dosed modern comparator when pathogen is susceptible to same

• Very hard to win on toxicity

• Superiority is a high-stakes gamble for a novel agent • If your primary aim is to show superiority and you fail on this, you cannot

retreat to a claim of non-inferiority

• But if you see superiority in a NI study, you can claim that result

• Once you show superiority you have a new SoC therapy, harder for next agent to demonstrate superiority

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*Modern Non-inferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance Link: https://doi.org/10.1093/cid/cix246

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Phase 3 Antibiotic Pivotal Trials

• Should have selected the proper dose for body site infection under study • Very important for lung infection

• If you have chosen the proper dose, biggest remaining risk is safety risk • Remember the “Rule of 3”– 1/100 risk will be detected in 300 pt. exposures…

• Select qualified, experienced sites • Make sure they are collaborative, and help them define a referral network • Site engagement throughout study is crucial

• Sponsor’s designated medical monitor should follow up with PI on all SAEs • A robust narrative, following the work-up and course of each SAE is essential

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Challenges of Pivotal Trials of Antibiotics

• Patients are urgently started on empiric therapy to reduce mortality and morbidity which may obscure the effect of an abx under study • Imprecise diagnosis of infection under study can weaken the conclusion of a

NI analysis

• Uncertainty of bacterial pathogen can lead to additional abx coverage with overlapping spectrum with abx under study

• The severity of the acute illness can make obtaining informed consent and completing enrollment procedures challenging

• Hospital policies often encourage early discharge increasing the operational challenges of studying IV only antibiotics

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Challenges (cont.)

• Start-up timelines can be delayed, particularly for inpatient studies, if site-specific issues are not understood • Contracting with sites is time consuming, sometimes need multiple contracts

(e.g. PI, hospital, pharmacy)

• Often several review committees, that may not meet every week

• Sites may require sponsors to provide ancillary supplies for infusions, and sometimes ancillary equipment, IV pumps, refrigerators, etc. Its important to learn early

• Understand patient flow, communications or alert systems in hospitals so that patients can be enrolled quickly

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Microbiologically Evaluable Population (ME cohort)

Challenges • Obtaining quality specimen

• Transport

• Central Lab vs. Local

• Protocol adherence

• Microbiological technique and identification

• Consistent results reporting

• Storage of isolates

• Real time review of culture results

• AST (frozen; dried; MIC; disk; eTESTS; CLSI; EUCAST???)

Solutions • Clear Protocols

• Involve Clinical Microbiologists; not just the Investigator

• Training for investigator site staff

• Training for laboratorians/specimen collectors

• Follow-up during study

• If CRO involved; ensure high quality clinical microbiology support

• Invest in expertise for real time review of culture results.

Clinical Microbiologist = Indispensable role on the Clinical and Project team

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Public/Private Partnership to Overcome Challenges

• “Push incentives” have had a tremendously positive impact on our field

• COMBACTE projects generate clinical epidemiology and microbiology data from several observational studies • supporting greater disease understanding and informed clinical trial design and conduct

• BARDA SMEs and COMBACTE academic leads providing advice as integrated members of the pharma team – real time advice leading to clinically relevant protocols

• Clinical Trial Networks and Platform Trials could reduce costs and expedite recruitment (Wellcome Trust, BARDA)*

Clin Infect Dis. 2016 Aug 15; 63(Suppl 2): S57–S59 * 20

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Safety and Efficacy of ZTI-01 (IV Fosfomycin) vs Piperacillin/Tazobactam for Treatment cUTI/AP Infections (ZEUS)

Sponsor: Zavante Therapeutics Collaborator: Medpace, Inc.

Study Type : Interventional (Clinical Trial) Actual Enrollment : 465 participants

Allocation: Randomized Intervention Model: Parallel Assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment Official Title: Randomized, Double-Blind, Comparative Study to

Evaluate the Safety and Efficacy of ZTI-01 vs Piperacillin/Tazobactam in the Treatment of cUTI/AP Infection in Hospitalized Adults

Actual Study Start Date : April 2016 Actual Primary Completion Date : January 12, 2017

Actual Study Completion Date : May 30, 2017

465 pts. recruited in <7 months

Recent Clinical Trial Highlights the Value of a Clinical Trial Network

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Aztreonam/Avibactam a Unique Collaboration

BARDA Ph3

• All non EU sites (LA/AP/US)

• Support for drug supply and microbiology

• Resistant pathogen study

• Clin Pharm studies

• Pediatric PK

COMBACTE-CARE Ph2

• ARO in place of CRO 1st time

• EU sites (Clin Net) in Spain/France/Germany • Spain recruited ~90% pts.

Ph3

• Academic partners provided pragmatic relevance to protocol improving feasibility

• Clin Net sites in EU

• Global clinical leadership

Pfizer Ph1

• SAD/MAD

Ph 2 and 3

• Overall management and governance

• Clinical Management

• Regulatory

• Safety

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What About Narrow-Spectrum Agents? • There is clear recognition that narrow or single spectrum agents vs. P.

aeruginosa, A. baumannii, etc. could be therapeutically useful

• Tier C development was outlined to develop narrow spectrum agents when a “Tier B” non-inferiority study not feasible

• Regulations must still be met

• Substantial evidence of effectiveness • Adequate safety data to support benefit/risk

FDA workshop on narrow spectrum agents: https://www.fda.gov/drugs/newsevents/ucm497650.htm FDA workshop: Animal models of serious infections https://www.fda.gov/Drugs/NewsEvents/ucm534031.htm AMDAC: “Developing Antibacterial Therapies Targeting a Single Bacterial Species“

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM551632.pdf

*Duke Margolis: “Understanding the Development Challenges Associated with Emerging Non-Traditional Antibiotics”

https://healthpolicy.duke.edu/events/understanding-development-challenges-associated-emerging-non-traditional-antibiotics

*FDA workshop: Developing non-traditional therapies for bacterial infections https://www.fda.gov/Drugs/NewsEvents/ucm606052.htm

23 *Many of these “non-traditional therapies” would need to be studied as adjunctive to antibiotics

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Parting Comments…

• Following the regulatory guidance can yield an approvable file…

…obtaining ROI means you need a reimbursable file

• Make sure your investors understand the risks (not easy)

• Get expert help early in the process, experienced help is critical to success

• Don’t forget CMC!!

• Regulators want you to succeed, they are on your team! ENGAGE THEM

• Small Companies who intend to commercialize their newly approved products should build resource to support regulatory approvals in regional markets, and recognize the perpetual challenges of supporting a marketing license

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Acknowlegements

• Linda A. Miller, PhD (GSK retired, Independent Consultant)

• Nicole Scangarella-Oman (GSK)

• Joseph Chow, MD (Pfizer)

• Juliet McQuillan, MSc (Pfizer)

• Seamus O’Brien, PhD (GARDP)

• Brian Murphy, MD (Medpace)

john.tomayko@pfizer.com jftomayko@gmail.com

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