A novel small molecule of Neisseria gonorrhoeae · Neisseria gonorrhoeae - A Global Disease • A...

A novel small moleculeantibiotic for the treatment of Neisseria gonorrhoeaeNovember 2018

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 1995. 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 EurofarmaLaboratorios 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.

November 2018Antimicrobial Drug Discovery2

Creating a Different Antibiotic Company

November 2018Antimicrobial Drug Discovery

New bacterial targets

New drugs against those targets

NEW SCIENCE

The right drug for the right bug

Real unmet needs

Innovative development plans

Stewardship

NEW PHILOSOPHY

Beat standard of care

Economic and clinical data tosupport premium price

NEW OPPORTUNITY

3

Our New Mechanism Antibiotic Pipeline


CDI(ridinilazole)1

Gonorrhoea(SMT-571)1

Gonorrhoea(Target #2)1

RocheCollaboration2

ESKAPE Programme1

Phase 1 Phase 2 Phase 3Discovery Preclinical Funding source

BARDA

Discuva Platform

4

(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, commercialisationand sales milestone payments from Roche.

Neisseria gonorrhoeae - A Global Disease

• 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)


Antibiotic Use and Resistance Development

#Centres for Disease Control and Prevention*Unemo and Shafer: Clin.Rev.Micro., 2014, 27, (3)

*#


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


Global Healthcare Implications



Programme Goals

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


• 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


Programme History

Transposon Technology

Phenotypic Screening

SMT026571 (SMT-571)

• Low molecular weight• LogP = 1.46• logD = 0.36• pKa = 6.3• cPSA = 77


• 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 demonstrates a narrow MIC range across a broad panel of clinical isolates


Microbiology - Activity

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) 0.08 0.09 0.09 0.09 0.09 0.09 0.09 0.09 0.09 0.09 2.8


• 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


Microbiology – Synergy/Antagonism


• SMT-571 shows no cross resistance with mutants raised against ceftriaxone

• The compound is bactericidal witha 5 Log reduction in CFU/mL after 4-8 hours

• Very low potential for resistance developmento No spontaneous N. gonorrhoeae resistant mutants isolated in vitro


Microbiology

Frequency of Resistance

WHO-M <8.2 x 10-10 @ 4 x MIC

WHO-V <3.1 x 10-10 @ 4 x MIC

WHO-X <8.7 x 10-10 @ 4 x MIC



Library of mutantengineered bacteria

Next-generationsequencing

Genome map of mutation insertions

12

+ Drug of interest

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



Discuva Platform – Establishing the Mechanism of Action

o In the absence of compound no transposoninsertions are observed in this region of the genome

o Under the selection pressure of SMT-571,surviving bacteria have transposons upstreamof genes associated with cell division

o Upregulation of gene products involved in celldivision have conferred an advantage to the surviving bacteria

o Further cytological and macromolecular profiling currently ongoing

• Transposon mutant libraries established in WHO-M strain of N. gonorrhoeae


• SMT-571 exhibits no in vitro toxicity flags and ADME properties suitable for oral dosing

• SMT-571 shows no polypharmacology in a CEREP safety panel

• CEREP spectrum assay (168 targets) further confirmed no off-target binding


In vitro ADMET Profiling

RBC Cytotox Mitotox GSH(50 µM)

Ames(25 µM)

hERG(IC50)

%PPB(m/r/h/d)

human Hep Stability(µL/min/106 cells)

>200 µM >100 µM Negative Negative Negative >25 µM 78 / 54 / 84 / 632.9

86% remain @120min

0%

100%

% In

hibi

tion


• SMT-571 displayed no inhibition against all major cytochrome P450 isoforms

• The compound exhibits very low metabolism with negligible metabolite formation

• Rat & dog confirmed as suitable species for preclinical toxicity evaluation


In vitro Metabolism

Isoform CYP3A4 CYP2C8 CYP2C9 CYP2B6 CYP2D6 CYP1A2 CYP2C19

IC50 >25 µM >25 µM >25 µM >25 µM >25 µM >25 µM >25 µM

ID% MS Profile

Rat Dog Human

SMT-571 98 100 100

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


• Pharmacokinetics guided selection of lead candidate• SMT-571 PK data established @ 1 mg/kg IV and 10 mg/kg PO in fasted male CD-1 mice

• SMT-571 has an oral PK profile suitable for daily dosing;o High oral bioavailability (F)o Low clearance (Cl) rate o 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)


Pharmacokinetic (PK) Summary

Species %F Cl(mL/min/kg)

Vd(L/kg)

T1/2 (h)(IV)

T1/2 (h)(PO)

Cmax (PO)(ng/mL)

CD-1

Mouse96 17 0.6 0.5 2.0 3017



In vivo Data – Pharmacokinetic/Pharmacodynamic Indices

Species PO Dose(mg/kg)

T>MIC(h)

PO Cmax(ng/ml) Cmax/MIC PO AUC0-last

(ng/ml)AUC/MIC(fAUC/MIC)

Mouse 60 24 10577 123 90967 1058 (233)

1

10

100

1000

10000

0 5 10 15 20 25

Con

cent

ratio

n (n

g/m

L)

Time (h)

Total vs Free Blood Levels

60mg/kg Total 60mg/kg Free

MIC = 86 ng/mL


• 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


Preliminary Efficacy Studies

SMT Ceftriaxone

• Activity against intracellular and extracellular infection determined in primary cervical cells

• Dose dependent reduction in coloniesin line with ceftriaxone (24h)

Dr Jennifer Edwards, Nationwide Children’s Hospital, Ohio State University



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


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• 14C labelled material currently being synthesised


Current Preclinical Development



Planned Milestones

H2 2019 Phase 1 clinical

trial initiation

H2 2020Phase 1 clinical

trial top-line data; Phase 2 clinical

trial initiation

Sept 2018Nominated

SMT-571 as lead candidate

H2 2021Phase 2 clinical trial top-line data

Acknowledgements


Prof. Ann E. JerseUniformed Services University, Bethesda, Maryland, USA

Dr Jennifer EdwardsNationwide Children’s Hospital,Ohio State University, USA

Contact Details

Dr Paul MeoAssociate Director, Anti-infective [email protected]

Twitter: @summitplc

Merrifield CentreRosemary LaneCambridgeCB1 3LQUK


mailto:[email protected]

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