Elena BM Breidenstein, PhD 21 April 2018

Transcription

1 Discovery of a Novel Oral Antibiotic, DDS-01 (SMT-571), to Treat Multi-Drug Resistant Neisseria gonorrhoeae Enabled by a Proprietary Transposon Technology Elena BM Breidenstein, PhD 21 April 2018

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 preclinical trials, clinical trials, product development and regulatory filings, Summit s collaboration with Sarepta Therapeutics, Inc., 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 Sarepta and 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 forwardlooking statements, except as required by applicable law. 2

3 Approaching an Era of Untreatable Gonorrhoea Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhoea Unemo and Shafer: Clin.Rev.Micro 2014, 27(3) 3

4 Global Distribution of Resistant Gonorrhoea Isolates Estimated to be 78 million cases amongst adults worldwide (WHO 2012) Health Protection Report Advanced Access Report 29 March 2018 Incidence of gonorrhoea infection is a global problem 30% of new gonorrhoea infections are resistant to at least one drug (USA/Europe) Reported cases where dual therapy (ceftriaxone / azithromycin) failed Ceftriaxone resistance 4.4% (2013) in China 4

5 Summit s Neisseria gonorrhoeae Programme Identify and develop a novel small molecule antibiotic for front-line use Target Product Profile (TPP): o o o Oral dosing route Single dose regimen Potential for use in combination therapy with anti-chlamydia treatment Use of proprietary transposon platform to facilitate discovery and development 5

6 Discovery of a Novel Chemotype Phenotypic Screening >8K Hits 50 Hits 12 Series 4 Series 2 Series 1 Series Transposon Technology Synthesis of ~350 Analogues Aim to Nominate a Candidate for IND-Enabling Studies in H

7 Transposon Technology / Bioinformatics Platform The platform has three core areas of use: 1. Novel Targets Use of transposons, Next Generation Sequencing, bioinformatics and biological know-how to identify genes essential for bacterial survival 2. Mechanism-of- Action Use transposons to drive increases in gene expression and elucidate the Mechanism-of-Action of novel antibiotics 3. Bacterial Resistance Use transposon-mutated bacteria and sequencing to select compounds that are least susceptible to resistance development 7

8 Proprietary Transposon Technology Proprietary transposon mutagenesis / NGS based platform Tailored transposons. IP on promoter approach High-density transposon libraries Next Generation Sequencing X y Customised in-house interface Customised in-house interface Control Concentration Neisseria gonorrhoeae genome 8

9 Deciphering Mechanism-of-Action Mechanism-of- Action implicated in cell division Activation Further work on-going SMT = SMT-571 9

10 Transposon Technology Enables De-risking of Clinical Resistance Transcriptional repressor Expression of efflux pump Outcome Ctrl SMT-571 Analogue b Survival in presence of compound Substrate for efflux SMT-571 No survival in presence of compound Not substrate for efflux Efflux pump SMT-571 Analogue b SMT

11 Compound Exhibits Potent Activity Against All Neisseria gonorrhoeae Tested Novel small molecule with excellent activity across clinical isolates (WHO Panel) SMT-571 CTX ACTIVITY FA1090 WHO-M WHO-L WHO-N WHO-O WHO-G WHO-F WHO-K WHO-P WHO-X WHO-X MIC (µg/ml) No change in MIC90s across CDC 91 clinical strain panel (accessed via NIAID preclinical services) Compound MIC90 Number of Isolates SMT µg/ml 91 11

12 Low Potential for Resistance Development SMT-571 shows no cross resistance to Ceftriaxone Checkerboard assessment confirms no synergy or antagonism with current SoC SMT-571 displays very low level of resistance frequency <8.2 x 4 x MIC no resistant mutants could be isolated Rapid bactericidal profile WHO-M Clinical Isolate Log (CFU/mL) Control 16xMIC 8xMIC 4xMIC 2xMIC 1xMIC 1-16xMIC 12

13 PoC Following Multi-Parameter Optimization SMT-571 exhibits no toxicity flags and promising ADME properties PPB: 54-84% bound across species SMT-571 has an excellent oral mouse PK profile Oral bioavailability (F): 96% Low clearance (Cl) rate: 17 ml/min/kg Volume of distribution (Vd) equivalent to total body water: 0.6 L/kg Efficacy demonstrated in ex vivo cell infection assay and in vivo PoC model of Neisseria gonorrhoeae PK profile consistent for an oral single fixed dose treatment 13

14 Developing Potential New Front-line Therapies for Neisseria gonorrhoeae: Discovery Summary First-in-Class Novel series with excellent activity against MDR/XDR clinical isolates Novel Mechanism-of- Action No Pre-existing Resistance Narrow Spectrum No Collateral Damage Bactericidal profile Low resistance likelihood profile & levels of resistance frequency Excellent activity vs the Neisseria genus Oral Single Fixed Dose Orally bioavailable 100 mg/kg well tolerated Good in vitro / in vivo Correlation Efficacy in an ex vivo assay, ideal distribution to disease sites, efficacious in an in vivo model of Neisseria gonorrhoeae SMT-571 is a lead with potential to become a new front-line therapy for the treatment of all gonorrhoea infections including MDR strains. 14

15 Acknowledgements Ann E. Jerse Uniformed Services University, Bethesda, Maryland, USA (acquired by Summit) Jennifer Edwards Nationwide Children s Hospital, Ohio State University Contact Information: elena.breidenstein@summitplc.com 15