Request For Proposal
A Phase 1, Open-Label, Study to Investigate Pharmacokinetics, Effect of Food and Safety of a New Immediate-Release Formulation of Zoliflodacin and Optional Single Dose Study to Assess Pharmacokinetics, Safety and Tolerability of Zoliflodacin in Healthy Subjects
Dated: May 15th 2018
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Table of Contents
1 PURPOSE ...... 3 2 RFP INSTRUCTIONS ...... 3 2.1 General information ...... 3 2.2 Timelines ...... 4 2.3 RFP processes and contact information ...... 5 2.3.1 Instructions...... 5 2.3.2 Confirmation of Intent ...... 5 2.4 Format and content of the proposal ...... 6 3 GARDP STI PROGRAM OVERVIEW ...... 7 4 SCOPE OF WORK ...... 7 4.1 Phase I FIH Clinical trial: Key data ...... 7 4.2 Short presentation of Zoliflodacin ...... 8 4.3 General Information on the Phase studies ...... 8 4.3.1 Inclusion criteria...... 8 4.3.2 Exclusion criteria ...... 9 4.4 List of activities to be performed ...... 11 4.5 Expected reporting ...... 12 5 CRITERIA FOR SELECTING SERVICE PROVIDERS ...... 12 5.1 Technical criteria ...... 12 5.2 Capacity to deliver ...... 13 5.3 Financial criteria ...... 13 6 PROPOSAL REQUIREMENTS, DELIVERABLES & TIMELINES ...... 13 6.1 Proposal requirements ...... 13 6.2 Deliverables ...... 14 6.3 Timelines ...... 14 7 ANNEXES ...... 14
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1 PURPOSE
GARDP is a not-for-profit research and development organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavoring to ensure sustainable access. Initiated and incubated through close collaboration between WHO and Drugs for Neglected Diseases initiative (DNDi), GARDP’s mission is to work in partnership with the public and private sectors, to develop and deliver new treatments for bacterial infections where drug resistance is present or emerging, or for which adequate treatments do not exist. GARDP is currently hosted and facilitated by DNDi, which provides the scientific environment, necessary personnel, and infrastructure to ensure an effective start- up phase. For more information, please visit GARDP website: https://www.gardp.org/ The evaluation is requested by GARDP. GARDP would like to conduct in United States of America a phase 1 open-label, food-effects study to investigate pharmacokinetics of a new immediate-release formulation of Zoliflodacin. This Request for Proposal (RFP) is also for an optional single dose study to assess pharmacokinetics, safety and tolerability of Zoliflodacin in healthy subjects. Both studies are covered by this RFP and the Service Provider is kindly requested to provide two separate cost evaluations.
2 RFP INSTRUCTIONS
2.1 General information
GARDP invites you as a Service Provider to submit a proposal in regards of this RFP for conducting both studies. This entire RFP and all the related discussions, meetings, information exchanges and subsequent negotiations that may occur are subject to the confidentiality terms and conditions of the Intent to Participate letter attached as Annex 1. All bidders are required to complete and send in return the Intent to Participate letter. The issuance of this current RFP in no way commits GARDP to make an award. GARDP is under no obligation to justify the reasons of its service provider’s choice following the competitive bidding. GARDP could choose not to justify its business decision to the participants of the RFP. GARDP reserves the right to: Reject any proposal without any obligation or liability to the potential service provider. Withdraw this RFP at any time before or after the submission of bids without any advance notice, explanation or reasons. Modify the evaluation procedure described in this RFP Accept other proposal than the lowest one
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Award a contract on the basis of initial proposals received without discussions for best and final offers Award all services to only one service provider or allocate them to different service providers according to what GARDP will consider necessary.
Late submission proposals are subject to rejection.
GARDP reserves the right to request additional data, information, discussions or presentations to support their proposal. All bidders must be available to discuss about details of their proposal during the RFP process.
All offers should be submitted in an electronic format.
A proposed time plan set out below indicates the process GARDP intends to follow. If there are changes to these timelines, GARDP will notify the bidders in writing.
2.2 Timelines
Process steps Responsible party Timelines
Launch RFP GARDP 15 May 2018
Send back the Intent to Participate letter Service Provider 17May 2018
Send the study synopsis to Service Provider GARDP 18May 2018
Q&A sent to GARDP Service Provider 23 May 2018
GARDP responses to Q&A GARDP 25 May 2018
Reception of proposals GARDP 1 June2018
Notification to Preselected bidders GARDP 8 June 2018
GARDP / Service Bid Defence Meetings Provider 14-15 June 2018
Project award GARDP 21 June 2018
Project Start Service Provider 4 July 2018
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2.3 RFP processes and contact information
2.3.1 Instructions
All bidders may request further clarifications in regards of this current RFP, by addressing questions in writing to the dedicated key contacts identified below. These questions should be submitted to GARDP at the date mentioned in the section 2.2 of the RFP.
In order to keep a fair bidding process, questions will only be answered in a document shared with all the bidders on the date indicated in section 2.2 of the RFP
To submit your questions, please use the form attached as Annex 2.
2.3.2 Confirmation of Intent
Please transmit your Intent to participate by using and signing the document attached in Annex 1.
Each bidder is required to provide GARDP with a written confirmation of intent or decline to participate by the date as indicated in the section 2.2.
Please, note that the "Intent to participate letter" is a standard document which GARDP cannot afford negotiating due to project priorities, time and resources dedication. This template is based on several years of experience working with suppliers and contains widely acceptable terms in RFPs.
Confirmations of intent should be sent by email to Christophine Marty-Moreau (contacts details below)
Questions types Contact person Title Contact information
15 Chemin Louis Dunant, 1202 Contractual & Christophine MARTY Senior Procurement Geneva, Switzerland Technical aspects MOREAU Manager Phone: +41 22 906 92 61 Email: [email protected]
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2.4 Format and content of the proposal
Responses to this RFP must be in English and should contain the following information:
A cover letter including: o Name and address of the service provider o Name, title, phone number and email address of the person authorized to commit contractually the service provider o Name, title, phone number and email address of the person to be contacted in regards of the content of the proposal, if different from above o Signature of this letter done by a duly authorized representative of the company o Acceptance of the consultation principles as detailed in section 2.1 o Acceptance of GARDP agreement template: Clinical Trial Agreement will be provided at a later stage of the process.
A technical proposal o Detailed proposal explaining how your company approach will enable GARDP team to meet project timelines and insure quality results.
Financial proposals o A Budget template to be completed for each study (1 for the Food Effect Study and one for the SAD) and attached as Annex 3.
Administrative information o Business Company information: directors and officers, creation date, corporate headquarters, locations, business turnover of the past 3 years (global and in the field of service provided), headcounts (global and in the field of service provided), general services provided, customer’s reference, pricing strategy for NGOs. o Any other relevant information enabling GARDP to assess the opportunity of contracting with your company.
2.5 Conflict of Interest
The Company shall disclose any actual or potential conflicts of interest in the Intent to Participate letter.
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3 GARDP STI PROGRAM OVERVIEW
GARDP R&D strategy for Sexually Transmitted Infections aims at delivering, within 7 years- time, at least one treatment that i) works against drug-sensitive and drug-resistant gonorrhea; ii) is suitable for integration into WHO-recommended STIs case management (including syndromic management); iii) works in both uro-genital and extra-genital (i.e. pharyngeal and anorectal) infections. In order to fulfill this aim GARDP has partnered with Entasis Therapeutics to accelerate the development and registration of Zoliflodacin for the treatment of uncomplicated gonorrhea. It constitutes the first and main priority of the overall STI program. The objective of the GARDP zoliflodacin project is to accelerate the development and registration of zoliflodacin, a first-in-class oral gyrase inhibitor that has shown high efficacy in adult patients with uncomplicated urogenital gonococcal (GC) infection.
4 SCOPE OF WORK
The present RFP is for a food-effect study to investigate the pharmacokinetics of a new immediate-release formulation of zoliflodacin. Up to 20 evaluable healthy subjects are planned per cohort. All subjects will receive 2 single doses of zoliflodacin separated by an expected washout period of 4 complete days on which there is no dose administration. This RFP is also for an optional single dose study to assess pharmacokinetics, safety and tolerability of Zoliflodacin in healthy subjects. In this optional study, up to 32 subjects will be randomized 6 active/2 placebo in 2 sub-cohorts (1 active/1 placebo then 5 active/1 placebo).
Both studies are covered by this RFP and the Service Provider is kindly requested to provide two separate cost evaluations.
GARDP will provide the IMPD, Investigator Brochure, Clinical Study Synopsis, and packaged IMP and placebo (part B of the study).
4.1 Phase I Clinical trial: Key data
Indication: Uncomplicated gonorrhea
Study design: Open-label, food-effect study and an optional single dose study in healthy male and female subjects.
Objective of the study: The objective of the present study is to determine the PK parameters of zoliflodacin in healthy volunteers after single doses (3 g) of the granules for oral suspension formulation administered by oral route in fasting and fed (high fat, high calorie meal) conditions. The relationship between zoliflodacin concentrations in plasma and change in QTcF will also be explored. Safety of the drug in healthy subjects after administration of single oral doses will also be assessed.
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Objectives of the optional study: The primary objectives of the optional study is (1) to assess the safety and tolerability of zoliflodacin after single doses administered as oral suspension of zoliflodacin in healthy male and female subjects, compared to matching placebo and (2) to determine AUC∞, AUC∞/D, Cmax, Cmax/D for zoliflodacin in plasma after single doses, administered as oral suspension in healthy male subjects. The relationship between zoliflodacin concentrations in plasma and change in QTcF will be explored.
No. of participating countries: 1 country, USA
Participating clinical sites: 1 site
4.2 Short presentation of Zoliflodacin
Zoliflodacin (AZD0914, ETX0914) is a spiropyrimidinetrione that inhibits bacterial DNA biosynthesis through a novel mode of action that is distinct from that of the fluoroquinolones.
Zoliflodacin has demonstrated in vitro activity against all Neisseria gonorrhoeae isolates tested so far (≥1’400), including isolates resistant to Extended Spectrum Cephalosporins (ESC), azithromycin and fluoroquinolones (Foerster et al. 2015, Front. Microbiol. 6: 1377). So far, three clinical trials with zoliflodacin have been completed: a phase 1 Single-Ascending Dose (SAD) trial, a phase 1 Absorption, Distribution, Metabolism, Excretion (ADME) trial and a phase 2 study involving patients with uncomplicated uro-genital gonococcal infection
4.3 General Information on the Phase studies
4.3.1 Inclusion criteria
Male and female healthy volunteers between the ages of 18 and 55 years, inclusive. Body mass index (BMI) calculated as weight in kg/ (height in m2) from 18 to 30.1 kg/m2 at screening, Light smokers (less than 5 cigarettes per day) or subjects who are non-smokers. No smoking (or use of smoking substitute e.g. nicotine patch) is permitted from screening throughout the study, Normal arterial blood pressure (BP) and pulse rate or, if abnormal, considered not clinically significant by the Principal Investigator. These will be measured after resting for 10 min, Standard 12-lead electrocardiogram (ECG) parameters after 10 minutes resting in supine position in the following ranges; 120 ms Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 8 of 14 4.3.2 Exclusion criteria Who on direct questioning and physical examination have evidence of any clinically significant acute or chronic disease, including known or suspected HIV, HBV or HCV infection, Who previously received zoliflodacin, or who participated in another clinical trial within 3 months prior and during the study, or 5-times the half-life of the drug tested in the previous clinical trial, whichever is longer (time calculated relative to the last dose in the previous clinical trial), With any clinically significant abnormality following review of pre-study laboratory tests (i.e. ASAT, ALAT, ALP, Creatinine and Urea must be within normal ranges), vital signs, full physical examination and ECG, Who have a positive laboratory test for hepatitis B surface antigen (HbsAg), or anti- HIV 1/2 or anti- HCV antibodies, Who have a history of allergy, intolerance or photosensitivity to any drug, or excipient used to formulate zoliflodacin, Who have a history of serious allergy, asthma, allergic skin rash or sensitivity to any drug, Who have a rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency, Who are known or suspected alcohol abusers (more than 14 units of alcohol per week, one unit = 8 g or about 10 mL of pure alcohol), Who drink more than 8 cups daily of beverage containing caffeine, Who are known or suspected drug abusers or have a positive laboratory test for urine drug screening (opiates, cocaine, amphetamine, cannabis, benzodiazepines), Who have undergone surgery or have donated blood within 12 weeks prior to the start of the study, Who have any clinical condition or prior therapy which, in the opinion of the Investigator, made the subject unsuitable for the study, Who had surgery (e.g. stomach bypass) or medical condition that might affect absorption of study drug taken orally, Who had febrile illness within 1 week before the start of the study, Who has regular daily consumption of more than one liter of xanthine-containing beverages, Who used a prescription medicine during the 28 days before the first dose of trial medication or use of an over-the-counter medicine (including antacid drug, except for acetaminophen (paracetamol)), during the 7 days before the first dose of trial medication, Who use dietary supplements or herbal remedies (such as St John’s Wort) known to interfere with the CYP3A4 and/or P-gp metabolic pathways during the 28 days before the first dose of trial medication. Grapefruit should also be avoided. Study design and procedures/assessments Up to 20 evaluable subjects are planned per cohort in this study. All subjects will receive 2 single doses of zoliflodacin separated by an expected washout period of 4 complete days on Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 9 of 14 which there is no dose administration. The actual length of washout period may change pending emerging PK data. All subjects in the food-effect cohort(s) (N=20 evaluable subjects/cohort) will receive 2 single doses of zoliflodacin with and without food in a crossover fashion such that: • 10 subjects will be fasted in Period 1 and fed in Period 2, periods will be separated by a 4-day washout, • 10 subjects will be fed in Period 1 and fasted in Period 2, periods will be separated by a 4-day washout. Subjects who are in a period in which they are fed will be dosed 30 minutes after the start of a high calorie, high-fat meal. The volunteers are expected to consume the entire meal within the 30 minutes prior to dosing). Eligible healthy volunteers will come to the Clinical Study Unit in the late afternoon/evening of Day -1 (the day before the first dose of study medication). Twenty-four h 12-lead Holter recording will be obtained on Day0 and Day 1 (up to 25 h post dose) and Holter recordings will be archived. ECG analyses will be conducted at the end of the trial. On Day 0, the healthy subjects will receive in a randomized fashion (1:1), a single oral dose of zoliflodacin as suspension in water, under fasted conditions or immediately following a high calorie, high fat meal. Intensive PK sampling and clinical and laboratory safety monitoring will be conducted post- dose during Days 0-2 (please see schedule of events). Healthy volunteers are expected to remain at the research facility until the 48-hour post-dose PK sample is obtained and safety assessments (on Day 2) are performed. Subsequently, after a washout period (Days 3-5), healthy subjects will return to the Clinical Study Unit in the late afternoon/evening of Day 6 to be re-confined for receipt of their second zoliflodacin dose on Day 7 (in the alternate fed or fasting conditions to their first study conditions). Intensive PK sampling and clinical and laboratory safety monitoring will be conducted post- dose during Days 7-9 (please see schedule of events). Healthy volunteers are expected to remain at the research facility until the 48-hour post-dose PK sample is obtained and safety assessments (on Day 9) are performed. A safety follow-up visit will be conducted on Day 16-19 days of the last period, or at the time of early termination (if applicable) Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 10 of 14 o PK sampling Blood sampling: On Days 0-2 and Days 7-9: Serial blood samples for plasma zoliflodacin determination will be collected at 0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0, 12.0, 24.0, 48.0 hours post- dose. Optional study One single oral administration per subject. Duration of clinical phase by subject (apart from the screening period): 4 days (from Day -2 evening to Day 2 morning). Up to 4 cohorts of 8 subjects are planned with dose escalation every 1.5 to 2 weeks, for a total of 2 months of recruitment. Bioanalysis (in plasma and urine) will be performed in open conditions. Decision on dose escalation will be taken by a Safety Review Group in blinded conditions, based on safety interim report and zoliflodacin plasma exposure. o PK sampling Blood sampling: Day 0: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9 and 12 h post-dose Day 1: 24 h post-dose On Day 2: 48 h post-dose On Day 3: 72 h post-dose. Statistical considerations FDA (Guidance for Industry “Food-Effect Bioavailability and Fed Bioequivalence Studies”, 2002) recommended 12 subjects should complete the food-effects study, to achieve adequate power for a statistical assessment of food effects on bioavailability. Twenty subjects are to be investigated. Assuming that 15% of the subjects with have unevaluable PK data, a total of 23 subjects will be enrolled. For the optional study, up to 32 subjects will be randomized 6 active/2placebo in 2 sub-cohorts (1 active/1 placebo then 5 active/1 placebo). GARDP, investigators and subjects will be blinded to treatment allocation. Site pharmacist will be open to treatment allocation. 4.4 List of activities to be performed Review of draft synopsis – technical input Protocol writing Volunteer Information Sheet and Informed Consent Form development Regulatory and Institutional Review Board(s) (IRB) submissions Case Report Form (CRF) design (please include both paper and eCRF options if currently in use by Service Provider) Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 11 of 14 Storage and management of IMP, including accountability and return to sponsor or designee (please also include an option to destroy IMP onsite or through 3rd party) Pharmacy manual development Technical input on labelling as per local requirements (validation of labels proposed by Sponsor ahead of labelling procedure) Randomization Clinical trial conduct: subject recruitment, screening, dosing, and all clinical procedures detailed in section 4.1. and draft synopsis, including Holter monitoring Biometrics (database design, data entry, data management, data cleaning, and statistical analysis) Project Management of activities conducted by the Service Provider, including required plans for the activities where applicable (e.g. DMP, Monitoring Plan, SAP etc.) Clinical Trial Monitoring PK Analysis: Service Provider will prepare the plasma and urine samples and ship them to a third-party contracted by GARDP for the bioanalysis. Data to be transferred back to the Service Provider for data analysis. Storage of PK back-up samples and plasma/urine left-over (frozen) up to the end of the study (up to a maximum of 3 months after the end of the study) – Capacity to destroy the samples after written approval of the Sponsor Pharmacovigilance: Managed by GARDP – forms to be provided by GARDP Trial Master File (TMF) and Investigator Site Documentation 4.5 Expected reporting Study Status Reports (weekly): start-up progress, recruitment, data cleaning and AE log Meetings: weekly telephone meetings with the Sponsor, kick-off meeting Clinical Study Report writing (2 drafts, one final) TMF transfer (database and other documents transferred to Sponsor on CD-Rom or equivalent electronic support at the end of the study). 5 CRITERIA FOR SELECTING SERVICE PROVIDERS The decision to award any contract as a result of this RFP process will be based on Service Providers’ responses and any subsequent negotiations or discussions. The decision-making process will consider the ability of each service provider to fulfil GARDP’s requirements as outlined within this RFP and the cost of the offer. Proposals will be assessed against the main following criteria but not limited to: 5.1 Technical criteria Facilities and license to perform both studies in United States of America in compliance with US CFR part 11 Records of Audits/Inspections of the facilities/processes Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 12 of 14 5.2 Capacity to deliver Reasonable timelines including at least but not only the ones related to recruitment, and regulatory and IRB(s) submissions. Where applicable, please specify projected timelines in the proposal, including ‘best case’ and ‘worst case’. Capacity to respect study timelines (screening of volunteers, shipping of samples, availability of PK and safety reports, etc…) Access to subject population Project management capabilities and experience Experience with similar work Experience with GARDP/DNDi Profile of staff involved (CVs) 5.3 Financial criteria Realistic costing of the proposal with NGO rates when possible. 6 PROPOSAL REQUIREMENTS, DELIVERABLES & TIMELINES 6.1 Proposal requirements Following the issuance of the RFP, all interested bidders are invited to submit a proposal that describes: General information of the company as described in section 2.1 Technical and financial proposal as described in section 2.4. Budget with full details of your offer including fixed costs and Pass-Through Costs. Whole project timelines including Regulatory and Ethics submission and approval (taking into account holiday period as applicable) Project team involved List of tasks and responsibilities. In addition, please provide us with complementary information on: Standard QA package recommended by the Service Provider (e.g. audits, QC procedures etc.) Proposals for monitoring scope and schedule Options to front-load activities in order to gain time (e.g. pre-screening) Service Provider facilities for re-labelling (following shelf life extension) if required Phase I unit’s pharmacy capabilities (potential IMP preparation, dispensation, full accountability) Database, including details of transfer to Sponsor and corresponding costs TMF Documentation maintenance in DNDi’s eTMF (Veeva) and QC. Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 13 of 14 6.2 Deliverables Comments on draft synopsis Protocol ICF Pharmacy Manual eCRF/CRF, database specifications and edit-checks, CDisc format Regulatory and IRB(s) approvals Monitoring reports Interim lock following the food effect part Data management report Complete package of TMF documentation, for all activities managed by the Service Provider Final Clinical Study Report Database 6.3 Timelines Beginning of services planned in June 2018 First Subject First Visit planned in September 2018 Duration of recruitment: 1 month for the food-effects study and 2 months for the optional study. Last Subject Last Visit (Part A) in October 2018. Final Study Report in Q1 2019, or earlier Proposed timelines for the whole project are required for internal planning (include both ‘best case’ and ‘worst case’ options). 7 ANNEXES Annex 1: Intent to Participate letter Annex 2: Q & A Form Annex 3: Budget template Annex 4: Synopsis to be provided after signature of LoI. Annex 5: Clinical Trial Agreement template, to be provided at a later stage Zoliflodacin Food Effects and Optional Single Dose-Escalation in Healthy Male and Female Subjects RFP Page 14 of 14