A novel small molecule antibiotic for the treatment of Neisseria gonorrhoeae

Transcription

1 A novel small molecule antibiotic for the treatment of Neisseria gonorrhoeae

2 Forward-Looking Statements Statements in this presentation, other than statements of historical fact, constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of These forward-looking statements include statements regarding Summit s clinical trials supporting the safety and efficacy of its product candidates and the potential novelty of such product candidates as treatments for disease, plans and objectives for clinical trials, product development and regulatory filings, Summit s collaboration with Eurofarma Laboratorios SA, Summit s award from BARDA, Summit s discovery and development platform, strategies, future performance, expectations, assumptions, financial condition, liquidity and capital resources. These forward-looking statements may be preceded by, followed by or otherwise include the words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions. Actual results or events may differ materially from those expressed or implied in any forward-looking statements due to various factors, including the risks and uncertainties inherent in clinical trials and product development and commercialization, such as the uncertainty in results of clinical trials for product candidates, the uncertainty of whether the preliminary results from a clinical trial will be predictive of final results of that trial or whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, the risk of failure of the third parties upon whom Summit relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk that any third-party collaborator, including Eurofarma, terminates or fails to meet its obligations to Summit, the risk of the ability of BARDA to terminate our contract for convenience at any time, the risk that Summit s discovery and development platform may not identify new potential drug development candidates, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials and the timing, cost and design of future clinical trials and research activities, the timing of expected filings with the FDA or other regulatory agencies; and the other risks and uncertainties described in Summit s public filings with the Securities and Exchange Commission. Summit may not actually achieve the plans, intentions or expectations disclosed in its forward-looking statements, and you should not place undue reliance on its forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Summit disclaims any intent or obligation to revise or update these forward-looking statements, except as required by applicable law. 2

3 Creating a Different Antibiotic Company NEW SCIENCE NEW PHILOSOPHY NEW OPPORTUNITY New bacterial targets New drugs against those targets The right drug for the right bug Real unmet needs Innovative development plans Stewardship Beat standard of care Economic and clinical data to support premium price 3

4 Our New Mechanism Antibiotic Pipeline Phase 1 Phase 2 Phase 3 Discovery Preclinical Funding source CDI (ridinilazole) 1 BARDA Gonorrhoea (SMT-571) 1 Roche Collaboration 2 Gonorrhoea (Target #2) 1 ESKAPE Programme 1 Discuva Platform (1) We own worldwide rights to ridinilazole, outside of certain Latin American countries and Caribbean islands, and own worldwide rights to our gonorrhea and ESKAPE programmes (2) Roche holds worldwide development and commercialisation rights to these compounds and Summit is entitled to specified development, commercialisation and sales milestone payments from Roche. 4

5 Antibiotic Use and Resistance Development A major healthcare problem with an estimated 78 million cases world wide p.a. Neisseria gonorrhoeae is an urgent threat - Centers for Disease Control and Prevention (CDC) # * Ceftriaxone (CTX) is the only viable monotherapy option resistance rates 4.4% (2013) in China Reported cases of dual therapy failure (ceftriaxone / azithromycin) 5 # Centres for Disease Control and Prevention *Unemo and Shafer: Clin.Rev.Micro., 2014, 27, (3)

6 Global Healthcare Implications Infectious Disease Society of America note the following healthcare implications: Increased incidence of pelvic inflammatory disease & epididymitis Infertility in men and women Risk of ectopic pregnancy Increased HIV susceptibility and transmission Disseminated gonococcal infections WHO Model List of Essential Medicines March 2017: Urgent need to preserve ceftriaxone for the treatment of life threatening bacterial infections 6

7 Programme Goals Aim Route of Administration Co-Infection Mechanism of Action Chemotype Identify and develop a small molecule antibiotic Oral dosing route to aid compliance Potential combination with anti-chlamydia treatment Novel with no overlap to current antimicrobial classes Distinct from current antibiotic classes Resistance Low resistance likelihood & levels of resistance frequency Kill Kinetics Series should exhibit a bactericidal killing profile Spectrum of Activity Compound should ideally be microbiome sparing 7

8 Programme History Phenotypic Screening Transposon Technology SMT (SMT-571) Low molecular weight LogP = 1.46 logd = 0.36 pka = 6.3 cpsa = 77 Use of high density transposon libraries informs on mode of action and resistance liabilities Data enables the prioritisation of compounds with an improved likelihood of clinical success 8

9 Microbiology - Activity SMT-571 exhibits excellent activity across N. gonorrhoeae clinical isolates (WHO Panel) Panel captures a diverse range of resistance mechanisms to historical antibiotic classes SMT-571 CTX ACTIVITY FA1090 WHO-M WHO-L WHO-N WHO-O WHO-G WHO-F WHO-K WHO-P WHO-X MIC (µg/ml) SMT-571 demonstrates a narrow MIC range across a broad panel of clinical isolates 9

10 Microbiology Synergy/Antagonism SMT-571 is likely to be co-administered with partner antibiotics for STI coverage Azithromycin and doxycycline are current Standard of Care (SoC) for Chlamydia SMT-571 shoes no synergy or antagonism in vitro with either SoC antibiotic Drug/Drug Interaction (DDI) study currently underway 10

11 Microbiology SMT-571 shows no cross resistance with mutants raised against ceftriaxone The compound is bactericidal with a 5 Log reduction in CFU/mL after 4-8 hours Very low potential for resistance development o No spontaneous N. gonorrhoeae resistant mutants isolated in vitro Frequency of Resistance WHO-M WHO-V WHO-X <8.2 x 4 x MIC <3.1 x 4 x MIC <8.7 x 4 x MIC 11

12 Discuva Platform Elucidate Mechanism of Action and Optimise Against Resistance Our libraries of mutant bacteria have increased, decreased or disrupted gene expression levels In the presence of an antibiotic, the mutant libraries help us to rapidly elucidate mechanisms of action and optimise against potential resistance mechanisms Library of mutant engineered bacteria + Drug of interest Next-generation sequencing Genome map of mutation insertions 12

13 Discuva Platform Establishing the Mechanism of Action Transposon mutant libraries established in WHO-M strain of N. gonorrhoeae o In the absence of compound no transposon insertions are observed in this region of the genome o Under the selection pressure of SMT-571, surviving bacteria have transposons upstream of genes associated with cell division o Upregulation of gene products involved in cell division have conferred an advantage to the surviving bacteria o Further cytological and macromolecular profiling currently ongoing 13

14 In vitro ADMET Profiling SMT-571 exhibits no in vitro toxicity flags and ADME properties suitable for oral dosing RBC Cytotox Mitotox GSH (50 µm) Ames (25 µm) herg (IC 50 ) %PPB (m/r/h/d) human Hep Stability (µl/min/10 6 cells) >200 µm >100 µm Negative Negative Negative >25 µm 78 / 54 / 84 / % SMT-571 shows no polypharmacology in a CEREP safety panel 100% % Inhibition 0% CEREP spectrum assay (168 targets) further confirmed no off-target binding 14

15 In vitro Metabolism SMT-571 displayed no inhibition against all major cytochrome P450 isoforms Isoform CYP3A4 CYP2C8 CYP2C9 CYP2B6 CYP2D6 CYP1A2 CYP2C19 IC 50 >25 µm >25 µm >25 µm >25 µm >25 µm >25 µm >25 µm The compound exhibits very low metabolism with negligible metabolite formation ID % MS Profile Rat Dog Human SMT Metabolite 1 1 <1 <1 Metabolite 2 <1 <1 <1 Metabolite 3 <1 ND ND Metabolite 4 <1 ND ND Metabolite 5 <1 <1 ND Rat & dog confirmed as suitable species for preclinical toxicity evaluation 15

16 Pharmacokinetic (PK) Summary Pharmacokinetics guided selection of lead candidate SMT-571 PK data 1 mg/kg IV and 10 mg/kg PO in fasted male CD-1 mice Species %F Cl (ml/min/kg) Vd (L/kg) T 1/2 (h) (IV) T 1/2 (h) (PO) C max (PO) (ng/ml) CD-1 Mouse SMT-571 has an oral PK profile suitable for daily dosing; o o o High oral bioavailability (F) Low clearance (Cl) rate Volume of distribution (Vd) equivalent to total body water Cervical tissue concentrations in excess of MIC at 8h following oral dose of 30 mg/kg (Mouse) 16

17 In vivo Data Pharmacokinetic/Pharmacodynamic Indices Total vs Free Blood Levels Concentration (ng/ml) MIC = 86 ng/ml Time (h) 60mg/kg Total 60mg/kg Free Species PO Dose (mg/kg) T>MIC (h) PO Cmax (ng/ml) C max /MIC PO AUC 0-last (ng/ml) AUC/MIC (fauc/mic) Mouse (233) 17

18 Preliminary Efficacy Studies Activity against intracellular and extracellular infection determined in primary cervical cells Dose dependent reduction in colonies in line with ceftriaxone (24h) SMT Ceftriaxone Dr Jennifer Edwards, Nationwide Children s Hospital, Ohio State University Early efficacy demonstrated in a murine model of N. gonorrhoeae infection Prof Ann Jerse Further PK/PD and dose optimisation studies to run in parallel 18

19 Programme Goals - Reviewed Aim Identify and develop a small molecule antibiotic Route of Administration Oral dosing route to aid compliance Co-Infection Potential combination with anti-chlamydia treatment Mechanism of Action Novel with no overlap to current antimicrobial classes Chemotype Distinct from current antibiotic classes Resistance Low resistance likelihood & levels of resistance frequency Kill Kinetics Series should exhibit a bactericidal killing profile Spectrum of Activity Compound should ideally be microbiome sparing 19

20 Current Preclinical Development Physicochemical Characterisation & Form selection X-ray crystallography, salt screen and dissolution studies concluded parent was preferred form Polymorph studies Non-polymorphic under a range of conditions Manufacture/route development Current single step synthesis high yield and purity Method development underway for a 3 step synthesis to meet regulatory guidelines Toxicology Maximum Tolerated Dose (MTD) studies initiated Repeat dose studies to complete before end 2018 Quantitative Whole Body Autoradiography (QWBA) / Excretion Mass Balance 14 C labelled material currently being synthesised 20

21 Planned Milestones Sept 2018 Nominated SMT-571 as lead candidate H Phase 1 clinical trial initiation H Phase 1 clinical trial top-line data; Phase 2 clinical trial initiation H Phase 2 clinical trial top-line data 21

22 Acknowledgements Dr Jennifer Edwards Nationwide Children s Hospital, Ohio State University, USA Prof. Ann E. Jerse Uniformed Services University, Bethesda, Maryland, USA 22

23 Contact Details Dr Paul Meo Associate Director, Anti-infective Research Merrifield Centre Rosemary Lane Cambridge CB1 3LQ UK 23