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Transcript
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
• 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
• 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
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
• 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
• 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
• 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
• 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
• 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
• 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
• “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)*
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“
• 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