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					                         Strategic Translation Awards in
                           Seeding Drug Discovery
                           Information for Applicants

(http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfer/docu
                      ments/web_document/wtx027225.doc)



Note: Seeding Drug Discovery is an initiative focused on the early
development of small molecule therapeutics. Applicants interested in other
areas of translation, such as those listed below, should apply for a Translation
Award at http://www.wellcome.ac.uk/Funding/Technology-
transfer/Awards/Translation-Awards/index.htm

Biological therapeutics
Diagnostics
Enabling technologies
Medical devices
Regenerative medicine
Vaccines



How to Contact Technology Transfer
Technology Transfer
The Wellcome Trust
The Gibbs Building
215 Euston Road
London NW1 2BE UK
Tel: +44 (0)20 7611 8202
Fax: +44 (0)20 7611 8857
Email: techtransfer@wellcome.ac.uk

http://www.wellcome.ac.uk/funding/technologytransfer/

The Wellcome Trust is a charity registered in England no 210183. Its Trustee is The Wellcome Trust       1
Limited, a company registered in England (no. 2711000), whose registered office is at 215 Euston Road,
London NW1 2BE, UK.
Aim

The initiative is designed to provide Strategic Translation Award
funding for applicants with innovative therapeutically relevant
biology or chemistry so that they may embark on drug-like
compound discovery and/or lead optimisation involving the
disciplines of disease biology, medicinal chemistry and
pharmacology. The goal is for funded projects to progress to a
stage whereby there is sufficient evidence to make the project
results, intellectual property and outcomes attractive to follow-on
developers/investors who may be from the commercial or not-for-
profit sectors. To achieve this it is expected that typical projects
will deliver patentable, drug-like lead candidates, with optimised
and favourable pharmacological, physicochemical, toxicological
and metabolic characteristics.




                                                                   2
                          Information for Applicants

                                    Contents

                                                       Page

Important notice                                        4

Key points at a glance                                  5

Application process at a glance                         6

Documents related to the initiative                     7

Mission and purpose                                     8

Thinking behind the initiative                          8

Eligibility, terms and conditions                       9

Types of project                                       10

Review process in general                              12

Outsourcing                                            14

Expert project advisors                                15

Project management and oversight                       15

Milestones                                             16

Intellectual property and translation                  17

Outcomes                                               17

Guidance notes for preliminary applications            18

Appendix 1: Definitions                                21

Appendix 2: Typical organogram                         22

Appendix 3: Example milestones                         23

Appendix 4: Sample screening cascade                   25




                                                              3
                           Important Notice

   This and related documents are designed to inform applicants about the
    Seeding Drug Discovery initiative and are meant for guidance only. They
    should not be relied upon as definitive.
   Applicants will be expected to disclose proprietary information in their
    full application, including chemical structures. They should be aware
    that their project applications (and any supplementary information
    provided) will be made available to staff of the Wellcome Trust and
    external advisors for the purposes of peer-review and due diligence.
   The Wellcome Trust operates a conflicts of interest policy and places
    obligations of confidentiality on its external advisors (some of whom are
    employed in the industrial or financial sectors). Whilst the Wellcome
    Trust attaches great importance to its policies and procedures
    concerning confidentially and conflicts of interest, it cannot provide any
    warranty to applicants in this regard.
   Because the day-to-day business of the Wellcome Trust involves the
    receipt and review of confidential grant applications, it is only under
    highly exceptional circumstances that it will enter into a confidentiality
    or non-disclosure agreement with applicants.
   Under some circumstances applicants may receive feedback from the
    Wellcome Trust on their project proposal. This feedback is meant to
    inform and guide applicants but is not meant to be definitive. Applicants
    should seek their own independent advice on feedback and its validity.
 Any invitation to apply for funding from the Wellcome Trust does not
    necessarily mean that such funds will be forthcoming.
   Not-for-profit organisations may download the terms under which
    funding               is            provided             in        the
    http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_t
    ransfer/documents/web_document/wtx027998.doc. It is normal with
    Strategic Translation Awards that the Trust actively leads on the
    translation of intellectual property arising under the award.
   SMEs may download the terms under which funding is provided at
    http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_t
    ransfer/documents/web_document/wtx027997.doc.
   Two signed copies of a funding agreement must be submitted by
    applicants at the time of submitting an invited full proposal for the
    application to be considered. For the avoidance of doubt, agreements do
    not need to be completed for making a preliminary application.
   Other organisations considering making a preliminary application
    should contact Technology Transfer in connection with the potential
    funding arrangements.




                                                                            4
Key points at a glance

      Seeding Drug Discovery is a Strategic Translation Award initiative,
       administered by Technology Transfer at the Wellcome Trust.
      UK based not-for-profit organisations and companies may apply and may
       collaborate or partner with parties located overseas.
      Proposals should have a focus on a specific drug discovery challenge and
       should address an unmet medical need. Applications for capacity building or
       infrastructure support will not be considered.
      Project funding will be expected to build on novel insights from the study of
       disease biology or the activity of compounds, with the objective of developing
       advanced or optimised drug-like leads.
      There is no set amount for the size of these awards. This will be determined
       on the basis of the justified costs of yielding a chemical series and intellectual
       property that is attractive to follow-on developers/investors.
      As a guide, it is expected that most awards will be in the range £1M-£3M, run
       for 2-3 years and will provide support for 10-20 FTEs (including contract
       research services, as appropriate).
      Funding will be milestone based.
      Outsourcing should be used where appropriate and providers or collaborators
       may be based overseas.
      Applicants who are short-listed for submission of a full proposal will be
       expected to engage with independent drug discovery advisor(s) during the
       detailed planning of the project, and beyond if the project is funded.
      An identified project manager will be necessary to co-ordinate day-to-day
       tasks, and to monitor and compile progress reports.
      The Principal Investigator, or alternate, will be expected to organise a
       Research Steering Group to oversee the project.
      Intellectual property and translation strategy will be managed via an
       Intellectual Property Management Group that will meet on an „as-needed‟
       basis.
      As with all Strategic Translation Awards, it is normal for the Wellcome Trust to
       take the lead on implementing the translation strategy.
      Funded projects may be subject to periodic review by a Wellcome Trust
       convened Project Advisory Group.
      The initiative will make 2 calls for proposals per year, tentatively scheduled for
       November 2010 and May 2011.
      Funding decisions will be made within approximately 6 months from the close
       of proposals.

Note: The initiative is not intended for the development of platform technologies
expected to improve the discovery or medicinal chemistry process.           Such
applications may be submitted to the Translation Award scheme
(http://www.wellcome.ac.uk/Funding/Technology-transfer/Awards/Translation-
Awards/index.htm).




                                                                                       5
Application process at a glance

     There are two meetings per year at which the Seeding Drug Discovery
      Committee will make funding decisions on invited full applications.

     First, applicants must submit a preliminary proposal form available at
      http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfe
      r/documents/web_document/wtx027222.doc.

     Preliminary proposals must be submitted not later than 19 November 2010 for
      a funding decision on the programme in May 2011.

   The preliminary proposals will be assessed by the Technology Transfer
      Challenge Committee and applicants will be notified during December 2010
      whether or not they have been invited to submit a full proposal.

     The 25 February 2011 is the closing date for receipt of full applications which
      must be submitted with two signed copies of the funding agreement.

     Invited applicants will be required to present on their proposal to the funding
      committee on either 25 or 26 May 2011.

     Applicants will be notified of the committee‟s decisions during the course of
      early June 2011.




                                                                                   6
Documents related to the initiative
Preliminary application form
http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfer/docu
ments/web_document/wtx027222.doc

Full application forms for invited applicants will be sent directly to applicants.

Funding agreement for not-for-profit institutions
http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfer/docu
ments/web_document/wtx027998.doc.

Funding agreement for small companies
http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfer/docu
ments/web_document/wtx027997.doc.

Wellcome Trust general terms and conditions for not-for-profit organisations
www.wellcome.ac.uk/grantconditions

Wellcome Trust eligibility
http://www.wellcome.ac.uk/Funding/Technology-transfer/Awards/Seeding-Drug-
Discovery/index.htm

Wellcome Trust allowable/non-allowable costs for not-for-profit organisations

Full economic costs http://www.wellcome.ac.uk/About-us/Policy/Policy-and-
position-statements/WTX026852.htm

Allowed costs http://www.wellcome.ac.uk/Funding/Technology-transfer/What-we-
fund/WTD038051.htm

Disallowed costs http://www.wellcome.ac.uk/Funding/Technology-transfer/What-
we-fund/WTD038052.htm




                                                                                     7
Mission and Purpose
The Wellcome Trust is a UK based biomedical research charity with the mission:
To foster and promote research, with the aim of improving human and animal health.

Technology Transfer at the Wellcome Trust contributes to the mission through its
high-level purpose which is:
To maximise the impact of research innovations on human and animal health by
facilitating their development to a point at which they can be developed further by the
market.

Thinking behind the initiative
The objective of the scheme is to develop drug-like, small molecules that will be the
springboard for further research and development by the biotech and pharmaceutical
industry in areas of unmet medical need.

                     The Seeding Drug Discovery concept




                        interdisciplinary research by a “customised” team
                        focus on a specific drug discovery challenge
                        outsourcing to bring in missing skills/resources and
                          industry-experienced consultants

This initiative is needed because it has become increasingly difficult for research
groups outside industry to secure funding for translational research in small molecule
therapeutics. Whereas there is much interest from the pharmaceutical companies
and venture capital community in new and compelling opportunities, it is no longer
sufficient to have a putative drug target or novel chemistry in dissociation from one
another. What is required is a higher level of evidence that a target or biochemical
pathway is 'druggable', or that a proprietary chemistry has biological relevance that
can be measured in the context of disease. Typically, the requirement to attract
commercial interest in the current climate is to have intellectual property around a
novel disease mechanism and an optimised lead compound (or better).
With these considerations in mind, the Wellcome Trust wishes to facilitate
interdisciplinary research groups to engage in early drug discovery projects where


                                                                                     8
this builds on novel perspectives from the study of disease mechanisms or the
activity of compounds.

Eligibility, terms and conditions
Eligibility for these awards extends to UK-based not-for-profit organisations, such as
universities (with local Technology Transfer offices as co-applicants) and privately
held or publicly listed small/medium sized UK-based companies, Funding to not-for-
profit organisations will be provided as a grant under the terms of the Not-For-Profit
Funding Agreement and applicable Grant Conditions. Companies will be funded as
a Programme-Related Investment, using charitable funds under the terms of the
Company Funding Agreement. Overseas institutions and companies should check
their eligibility first with Technology Transfer and may be invited to apply.

Allowable costs will include the services of contract research organisations and the
reasonable costs of collaborators, either of which may be located overseas. The
costs of independent consultant advisors and new patent applications will also be
allowable, subject to a justified case.

For more information on eligibility, costs and terms, see „Documents related to the
initiative‟.

Companies seeking venture capital investment as opposed to project support should
send their plans to:-

Direct Investments
Wellcome Trust Investment Division
215 Euston Road
London NW1 2BE




                                                                                    9
Types of project
The initiative is intended to be complementary to industry and not-for-profit or Public-
Private Partnerships involved in drug development. Applicants must demonstrate
how their project is differentiable from others or how they possess a significant
competitive advantage. For example, the project might be based on a completely
new target or disease mechanism. In the case of targets with precedent in drug
discovery, the project might be based on an under recognised disease indication for
the target, or may be directed toward a novel binding domain, or mode of action not
otherwise being pursued by others.

Applicants will be expected to have compelling evidence that a small molecule ligand
can yield a therapeutic benefit in the disease indication under investigation. Since
the purpose of the initiative is small molecule R&D, applicants should normally have
a chemical starting point for a programme of medicinal chemistry. Alternatively,
applicants may propose a route that has a high probability of success of yielding a
chemical starting point for the project‟s medicinal chemistry. Such a route may
typically be a chemical library screen, but applicants must demonstrate why it will
have a good probability of success. For example, it might be a class of target such
as an ion channel or kinase, or phenotypic screen, for which it can be demonstrated
a track record of success exists in generating confirmed hits with appropriate
chemical libraries.

Applicants with less certainty about the likely success of a screen should contact
Technology Transfer at the Wellcome Trust.

Typical projects might include those that:

      seek to develop an optimised lead compound or pre-clinical drug candidate,
       building on new biological or chemical insights.
      will evaluate the potential of modifying existing compounds for a new
       indication.
      seek to rectify deficiencies in a promising compound (or family of compounds)
       using approaches that have not been applied to the problem previously
       (subject to a case being made that these approaches are worthwhile
       pursuing).

The Seeding Drug Discovery initiative will not normally consider proposals designed
to develop a platform technology that impacts on the discovery process, such as new
chemo-informatic approaches or methods of pharmaceutical profiling or testing.
These types of applications can be considered under the Translation Award scheme
(http://www.wellcome.ac.uk/Funding/Technology-transfer/Awards/Translation-
Awards/index.htm).




                                                                                     10
Following consideration of the preliminary application, applicants may be invited to
submit a full project proposal for which the main type is a:

   Discovery Project: These will be the main project type, where the goal of the
    project is to enter drug discovery and develop a drug-like advanced or optimised
    lead for which a data and IP package can be developed that has a good
    probability of being adopted by a follow-on developer/investor.

Occasionally applicants may be invited to submit an:

   Interim Project: These will be invited less frequently and will address specific
    concerns identified by the Funding Committee in an otherwise convincing
    Discovery Project. A condition of an Interim Project award will be that the
    Wellcome Trust has the right of first refusal to fund any follow-up work.

Invited full applicants will be advised at the time of invitation if they have been
awarded a:

   Feasibility Award: These are designed to allow applicants to draw down
    professional and consultancy fees up to a pre-agreed amount to access expert
    advice for the planning of their full application. Such fees might be used to hire
    the services of a drug discovery advisor or patent attorney.




                                                                                   11
Review process in general

To be read in conjunction with the Important Notice and Application process at a
glance (which includes important dates) sections above.

The application process will involve the following elements:

      Preliminary        application         forms       are        available        at
       http://www.wellcome.ac.uk/stellent/groups/corporatesite/@technology_transfe
       r/documents/web_document/wtx027222.doc. The focus of the preliminary
       application is to set out the biological rationale for the proposed small
       molecule intervention and whether this will be tractable to small molecule
       discovery. The future small molecule R&D plan is not the main focus of the
       review process at this stage.
      Preliminary applications will be triaged at a special meeting of the Technology
       Transfer Challenge Committee to produce a short-list of competitive
       Discovery (or exceptionally Interim) projects to be invited to submit a full
       proposal.
      Discovery Project applicants will be required to submit a full proposal which
       incorporates the detailed small molecule R&D programme.
      Interim Project applicants will submit a proposal that addresses the specific
       concern(s) of the Technology Transfer Challenge Committee.
      Invited applicants from not-for-profit organisations will be advised if they are
       eligible for a Feasibility Award (see above – Types of Project). At this time
       they will be informed as to whether the Wellcome Trust expects to take the
       lead in any translation of the project outcomes (in consultation with the
       interested parties represented on the Intellectual Property Management
       Group (see Intellectual Property and Translation)
      At the time of submission to the Wellcome Trust, each full application must be
       accompanied by two signed copies of the appropriate Funding Agreement
       (see Documents related to the initiative above). This will be counter-signed
       by the Wellcome Trust if an award is made. Note for Strategic Translation
       Awards such as under this Initiative, the Trust expects to actively take the
       lead on translation of the project outcomes (in consultation with the interested
       parties represented on the Intellectual Property Management Group, see the
       section Intellectual Property and Translation)
      Full applications will be subject to external review by experts, whose written
       opinions will be considered by the Funding Committee.
      Applicants will be required to present on their project to the Funding
       Committee.
      Applicants will be notified of the Funding Committee‟s decision as soon as
       practicable.
      There are two Funding Committee meetings per year and preliminary
       proposals may be submitted at anytime during the year. Deadlines for receipt
       at the Wellcome Trust of a preliminary proposal for consideration at the next
       meeting is outlined in the section Application process at a glance.




                                                                                     12
Preliminary applications will be considered by the Technology Transfer Challenge
Committee taking into account, amongst other things:

Healthcare objective(s)
Disease indication(s)
Extent of unmet need
Prevalence trends
Current therapies
Therapeutic rationale (e.g. curative, symptomatic control)
Novelty

Mechanism of action
Target validation criteria
   o Genetic, biological and/or clinical evidence.
   o Evidence that modulation of the target will generate a clinical benefit.

Biological tractability
   o Location of the target
   o Agonist, antagonist, etc
   o Probability of target-related adverse effects
   o Selectivity issues
   o Screening cascade, primary and secondary assays, throughput

Chemical feasibility, such as
  o Known leads for the target family
  o Credible chemical starting point
  o Probability of obtaining useful hits
  o Binding sites for drug-like molecules

Clinical tractability
    o Approximate size and duration of proof of principle study
    o Availability of patients

Logistics
   o Availability of in vivo and in vitro models for testing chemical compounds
   o Availability of sufficient quantities of key materials and equipment (purified
       drug target, labels, antibodies, etc) for assay development, screening cascade
       and crystallography
   o Feasibility of configuring a screening assay for chemical library screening

Intellectual Property
    o Background intellectual property
    o Arising intellectual property
    o Freedom to operate

Competitive advantage

Background, qualifications and experience of the Principal Investigator, researchers,
collaborators and advisors.


                                                                                  13
Invited full applications will be considered by the Funding Committee, taking into
account the following additional points:

   Aims and objectives
   Project plan and timelines (e.g. Gantt chart)
   Clearly defined funding-dependent milestones and go/no-go decision points
   Clearly outlined target product profile to be achieved at each milestone
   Hit, lead and candidate selection criteria

   Medicinal chemistry strategy
    o Quality of out-sourced/in-house resources
    o Screening cascade
    o Structure-based design
    o Pharmaceutical profiling
    o PK/ADMET

   Budget
   Approximate number of FTEs and balance of skills (e.g. biochemists, medicinal
    chemists, pharmacologists)
   Availability of (existing) key people and resources
   Management and integration of project functions (see Project Management)
   Composition of the Research Steering Group (see Project Management)
   Professional opinions pertinent to the proposal, such as a patent attorney report
    on the progress of background patent filings or prior art and freedom to operate
    searches.

Outsourcing
Awards will be made to the Principal Investigators‟ employing organisation. However,
where there is a requirement for a project to outsource certain elements of the work,
the host institution will be expected to sub-contract this to the appropriate contract
research organisation(s) or collaborator(s). Outsourcing can be used to overcome
the scarcity of drug discovery resources in many not-for-profit organisations, ensure
projects proceed as expeditiously as possible and avoid duplicating or hiring a
resource for which an appropriately priced and quality alternative is accessible
elsewhere.

The applicants, through their Technology Transfer Office (or equivalent), will be
responsible for the arrangements made with outsource suppliers.              Such
arrangements must be on a value for money, fee-for-service basis, and should not
involve intellectual property sharing or joint-ownership unless such arrangements
have been specifically agreed with the Wellcome Trust. Both background and
arising intellectual property must be free of encumberance for translation.

Sub-contractors and collaborators may be located overseas.




                                                                                   14
The applicants must evaluate and select their own sub-contractors and may call on
the advice of an independent project advisor, as appropriate (see below).

Expert project advisors
A condition of award will be that the Principal Investigator retains the services of an
independent project advisor (or advisors) with credible and relevant drug discovery
experience. The purpose of the advisor is to augment the project team with
expertise in the disciplines of drug discovery. In particular, their role will be to
provide critical advice on progress towards the objectives of the project and on the
services delivered by a contract supplier(s). For example, if the project relies on
external chemistry, then there should be an independent medicinal chemist advising
the Principal Investigator on the plans and results generated by the service provider.

It is the responsibility of the applicants and their Technology Transfer Offices to
evaluate, select and contract with their expert advisor. The consultancy costs of
advisors can be budgeted for in the application and it is expected that these advisors
will be members of the Research Steering Group (see Project management and
oversight) and shall meet frequently with the project team on an as-needed basis.

Company applicants may be exempt from the requirement for expert advisory input if
they demonstrate appropriate expertise is available to the company through other
mechanisms.

Project management and oversight
The applicants are required to involve a Research Steering Group and a Project
Manager to assist in the management of the project. In addition the Wellcome Trust
may review progress through a Project Advisory Group.

The purpose of the Research Steering Group is to provide a focus for the team and
bring together internal and external project functions.

   The Group should meet routinely to review progress (e.g. bi-monthly). Additional
    ad hoc meetings might be arranged on a needs-basis.
   The Principal Investigator will normally be the Chair and will be responsible for
    administering the Group and providing facilities, particularly ensuring the advance
    circulation of papers and production of minutes.
   The composition of the Group should be agreed with Technology Transfer at the
    Wellcome Trust. Typically, the core membership will include:
     The Chair.
     Any additional applicants.
     At least one independent, industry-experienced advisor.
     Key personnel from outsource supplier(s).
     The Project Manager (see below).
     A representative from Technology Transfer at the Wellcome Trust (optional).
     A nominee advisor to represent Technology Transfer at the Wellcome Trust
        (optional).



                                                                                    15
      A representative from the technology transfer office of the host institution
       (optional).


Typical business of the Research Steering Group will include:
 Monitoring of progress against plan.
 Co-ordination of different activities.
 Assessment of what has been learned e.g. SAR, assay robustness, biological
   testing etc.
 Challenging of assumptions.
 Confirmation of whether milestones have been reached.
 Identification of weaknesses or delays and the planning of remedial action.

The Principal Investigator must also agree with Technology Transfer a key member
of their research team who will take responsibility for managing and co-ordinating
day-to-day activities and integration of outsource suppliers with the in-house team.
This individual will be known as the Project Manager and will work closely with the
Principal Investigator.

A typical organogram for project steering, management and integration is given in
Appendix 2.

Company applicants may be exempt from the requirement for a Research Steering
Group if they can demonstrate the project will be subject to similar oversight within
the company.

The Wellcome Trust Project Advisory Group
This will comprise a small team of experts, convened by the Wellcome Trust and
accompanied by one or more observers from Technology Transfer, that will
periodically visit each project and report to the Trust on progress, performance and
key issues. Typically, this will occur annually. The results of these reviews will be
made available to the Research Steering Group at the Wellcome Trust‟s discretion.
The purpose of the Project Advisory Group will be to provide independent advice to
help maximise the probability a project will achieve its objectives. The Group will
also make recommendations to the Wellcome Trust regarding the attainment of
funding-dependent milestones and the continuing feasibility of the project (see
below).

Milestones

The size of the awards is such that for successful projects there will be sufficient
funding to allow them to make significant advances and avoid “drip-feeding”. On this
basis, the Wellcome Trust needs to manage its financial exposure. Applicants are
therefore required to propose a small number (typically around 3) project-specific
and funding-dependent milestones at key go/no-go points in the project. Examples of
such milestones are provided in Appendix 3.




                                                                                  16
In the event a milestone is not achieved, the Wellcome Trust will normally agree a
reasonable period for the implementation of corrective steps against an action plan
designed to address the issues that have arisen. Should the future viability of the
project be in question and the Project Advisory Group recommend termination, the
Wellcome Trust may need to invoke its right to conclude funding of the project as set
out in the Funding Agreement.

Intellectual property and translation

Intellectual property that arises under the award will be owned by the applicants‟
employing organisation(s). Background intellectual property owned or under the
control of the employer must be freely available to enable both the project to be
performed and translation of the arising intellectual property to be realised.

Intellectual property in the form of new patent filings will clearly be a critical outcome
to attract follow-on funding. Applicants will be required to form an Intellectual
Property Management Group that will meet at least once a year and more frequently
on an as-needed basis. The Chair will need to be agreed with the Wellcome Trust
and other members will normally include:

      A representative from amongst the applicants.
      A representative from the host organisation‟s technology transfer office.
      Up to two representatives from Technology Transfer at the Wellcome Trust.
      A nominee advisor appointed by the host institution.
      A nominee advisor appointed by the Wellcome Trust.
      The Project Manager (as observer).

The main business of the Group will be to decide on the merits of patenting any
inventions (which must be done in a timely manner) and to consult with and make
recommendations to the exploiting/translating party. Normally for strategic awards
made to a not-for–profit organisation, the Wellcome Trust will take the lead on the
exploitation of the patent and translation strategies.

The Intellectual Property Management Group above is not expected to apply to
company applicants where they can demonstrate that equivalent systems operate
within the company.

Outcomes

The primary outcome for the Wellcome Trust will be the discovery of drug-like small
molecules that form the basis of a subsequent drug development programme.
Publications are also expected that might include results and findings on the
following:
     Production of novel or modified bioassays.
     Configured high throughput and cell-based screens.
     Data on potential inhibitors from in silico screens.
     Validation of a putative drug target or pathway at the molecular level.
     Target validation at a higher organisational level (cellular or whole animal).
     Data on target specificity.


                                                                                       17
      Identification of chemicals with the properties of a selective inhibitor.
      Production of novel collections of compounds.
      Demonstration that a target is, or is not, druggable.
      Identification of a new activity for an existing compound.

Guidance notes for preliminary applications
These guidance notes should be used in conjunction with the preliminary application
form. Applicants should address the following questions as far as is possible in the
space provided.

Question 2. Title of Project.

Where possible, the title should include both the target name and disease indication.

Question 3. Primary objective of the proposal.

The specific project objectives should be outlined. Specifically if achieved, what will
the project deliver that will be attractive to a follow-on developer/investor.

Question 4. Briefly outline the project costs. The purpose is to provide an
indication as to the amount of funding required. The costs of independent advisors,
outsource suppliers and patenting can be included (at competitive rates). A detailed
budget with justification is not required at this stage, but is required in any invited full
application.

Question 5. Please define the disease indication, medical need and the
potential impact on healthcare of the proposal and the competitive advantage
of the proposed approach.

Each question should be specifically addressed where possible, and one or more of
the category boxes should be checked;

      (a) What is the intended primary disease indication? Each application
       must state only a single disease. Applications stating multiple indications will
       not be considered. Any disease indication will be considered under the
       initiative.  This includes conditions that class as so-called „neglected
       diseases‟, those that are commonly categorised as „orphan‟, „niche‟ or
       „speciality medicine‟, and the major therapeutic areas. However, in all
       instances the case must be made as to why the Wellcome Trust should
       support R&D in this area (i.e. that there is an unmet medical need and that the
       work is non-duplicative of R&D efforts taking place in industry)
      What is the prevalence of the indication and global distribution and burden of
       disease? Referenced information is preferable. Market analysis data is not
       required at this stage

      (b) What is the proposed medical need and potential impact on
       healthcare of the prospective treatment relative to other marketed drugs for
       the indication?



                                                                                         18
      Has the target or existing compound been investigated by other parties for
       alternative indications?

       (c) What is the competitive advantage of the proposed approach? Is the
       approach likely to yield greater efficacy or offer an improved safety profile
       over competing approaches / existing drugs. It is unlikely that any new
       treatment will capture an entire market share and therefore tangible reasons
       how the proposed approach compares with existing therapies should be
       described.

Question 6. Provide brief details on the technical background to the following
questions;

      (a) Description of the target. Is the target known? Summarise relevant peer-
       reviewed or experimental data describing the target structure,
       pharmacological family or class, basic signalling pathways and mechanism of
       activation. If target is unknown summarise the phenotypic model(s) and
       screening data.
      What is the likely action of the proposed small molecule (e.g. agonist /
       antagonist / inhibitor, etc)?
      How has the clinical tractability of the target been demonstrated
       experimentally? Is the target amenable to intervention by small molecules?

      (b) Validation of the therapeutic approach. What is the proposed nature of
       clinical benefit mediated by the target? Is the target directly involved in
       disease initiation or progression, or does the target mediate an indirect
       response that is beneficial or detrimental in terms of disease outcome?
      What are the genetic, in vitro, in vivo or clinical proof-of-concept/target
       validation studies? Are these proprietary or published data? Are models
       proprietary or industry accepted / standards

       (c) Proposed route of administration. Where is the target site of action and
       what is the proposed route of drug administration (e.g. intra- or extra-cellular,
       peripheral or central nervous system, systemic or topical, oral, intravenous,
       etc).

       (d) What are the known or potential side effects? Are there other functions
       of the target, or closely related targets of the same family/class known in man
       (or animals), that might provide a secondary indication or pose the risk of
       adverse side effects?

      (e) Biological screening assays and stage of optimisation. Biological
       screening assays to determine in vitro affinity, efficacy/potency and selectivity
       for the target against closely related members are required. Ideally these must
       be of a sufficient standard and reproducibility to allow the identification of
       compound specifically for the target of interest with no ambiguity. Where
       possible, applicants are asked to address the following questions:
      Do screening assays exist?




                                                                                     19
      Define primary and secondary screening assays to determine affinity,
       efficacy/potency. Selectivity for the target over closely related targets should
       also be addressed ideally. A typical example is outlined for guidance in
       Appendix 4.
      Describe the level of development, throughput, reproducibility, signal to noise
       and validation of each assay. Are assays proprietary, available from peer-
       review publications or will they require a license?
      Will assay miniaturisation, re-design or reformatting be required to meet the
       required screening throughput?
      Can sufficient quantities of key materials and reagents be obtained for the
       assays and will these be cost effective?
      Will screening assays need to be run in specialist laboratories (e.g. specific
       categories of biological containment)? Have these been identified?

      (f) Potential chemistry start points. Describe any known ligands to the
       target or closely related targets.
      Are „drug-like‟ chemical start points available, either from novel research, or
       known from the peer-reviewed or patent literature? If start points are
       available, what are the properties of the compounds?
      Has any chemical screening been undertaken and identified possible hits?
       Describe the size and diversity of studies. Have „hits‟ been examined
       independently by an experienced medicinal chemist?
      Have structure-activity relationships of a chemical series been identified?
      Has computer-aided drug design been utilised to produce pharmacophore /
       scaffold structures for in silico screening?
      Are high-resolution crystallography studies of the target proposed or
       available?
      If no target specific chemistry is available, please describe the approach(es)
       that will be taken to identify a small molecule „hit‟ and why this approach is
       likely to be successful.

      (g) Provide up to 5 of the most relevant references to the background of
       this proposal. These may or may not be authored by the principal applicant.

Question 7. Summarise the project work plan, highlighting aspects to be
outsourced. Project funding is provided on a tranched basis, subject to
satisfactory achievement of milestones

      Consider in outline the workplan to achieve the objectives, key tasks,
       timescales including relevant milestone associated with clear go/no-go
       decision points.
      Identify research activities that will be outsourced. Specific outsourcing
       providers do not have to have been identified or contacted at this stage.

Question 8. Please give details of any patents covering the technology, identify
areas of potential new intellectual property and describe any freedom to
operate issues.




                                                                                    20
   Has directly relevant background IP that supports the application been filed?
    Describe the strategy and current stage of prosecution
   Do background patents on the target, chosen assays, indication and/or
    chemistry exist from other parties which may influence the freedom to
    operate? Provide a description and date of any patent search. Will a licence to
    this IP be required?
   How will a proprietary position be achieved?
   What is the potential for new IP?




                                                                                21
                                   Appendix 1

                                    Definitions
Back-up series: Structurally distinct from lead series, and amenable to medicinal
chemistry optimisation. Pharmacological characteristics may be less favourable that
those of the lead series.

Chemical tractability: The required starting materials and a route of synthesis can be
readily identified. Compound series or synthetic routes do not exhibit characteristics
that would be considered „unfavourable‟ from a medicinal chemistry standpoint.

Hit: Novel chemical entity (NCE) identified from a primary assay screen from a
chemical library or chemical series. Structure confirmed, compound re-synthesised
and characteristics re-confirmed.

Hit-to-lead: NCE displaying drug-like physiochemical properties that are amenable to
medicinal chemical optimisation. Meets stated pharmacological criteria as
determined by in vitro assays.

Lead series: NCE series displaying favourable physiochemical and pharmacological
characteristics. Clear and favourable route to chemical optimisation of series
available.

Pre-clinical candidate: Preferred medicinal chemistry optimised lead molecule
fulfilling agreed pharmacological, toxicological and physiochemical criteria.
Compound and series are protected by composition of matter patent filing(s). All
supportive data are complied in finalised Research Reports, signed by Principal
Investigator.




                                                                                   22
                                                Appendix 2

                   Typical organogram for Programme Management

                                      Research Steering Group                                        IPMG
                                      - Both Programme managers                      - Programme managers and Patent
                                      (Alternate Chair / Minute taker)               agents to ensure IP is protected
                                      - Meeting alternate between venues             -Informed of exploitation strategy
                                      - Both project leaders
                                      - WT observer
                                      - Med. Chem. consultant / poss.
                                      Biological consultant agreed by WT
 Outsourced Chemistry                 - Initiative co-applicant                                      Biology
      Programme Manager                                                            Programme Manager
      - 10yrs Med. Chem. experience                                         - SDDI principal applicant and project driver
                                             Encrypted data transfer
      - Responsible for data QC                                             - Collates and distributes all information
                                             Contact as necessary
      - Signs off monthly report                                            - Biologist with experience of running multi-
                                                                            disciplinary projects
                                                                            - Responsible for data QC


          Project leader                                                                Project leader
   - Day-to-day management of programme
                                                                           -Day to day management of programme
   - Represents an experimental FTE
                                             Contact as necessary          - Represents an experimental FTE
   - Highly organised
                                                                           - Highly organised, with „screening experience‟
   - Responsible for experimental QC
                                                                           - Responsible for experimental QC
   - Drafts monthly report
                                                                           - Drafts monthly report
   - Presents at steering group meeting
                                                                           - Chairs internal monthly meeting
                                                                           - Presents at research steering group meetings



FTE               FTE                 FTE                              FTE                      FTE                  FTE
                                                                            - Competent experimental scientists, trained in
                                                                            screening assays
*FTE = Full Time Equivalent
                                                                            - Produce reproducible and credible data




                                                                                                                              23
                                    Appendix 3

                              Example milestones


The applicants will be expected to propose in their application a small number
(typically 2 or 3) project-specific and funding-dependent milestones.

Some examples are:

   A system for producing sufficient quantities of target protein required for the
    project.
   Generation of compounds that satisfy hit-to-lead criteria, for example
             o Affinity and efficacy / potency against target determined in vitro or in
                 vivo
             o Selectivity affinity profile determined in vitro
             o Favourable physiochemical properties (e.g. aqueous solubility,
                 cLogP, pKa, mol wt, free of critical groups, etc)
             o No significant toxicity alerts (from basic groups or known
                 metabolites)
             o Absence of gross in vitro cell toxicity
             o Chemically attractive structure for medicinal chemistry optimisation
             o Patentable structures
             o Strategy to enhance chemical novelty

   Development of leads that meet the lead series criteria, for example
            o Nanomolar affinity and efficacy / potency against target determined
               in vitro and in vivo
            o Selectivity and specificity affinity profile determined in vitro and
               consistent with mechanism of action
            o Acceptable in vitro metabolism (multiple species microsome <50%
               disappearance of parent in 30 min; rat / human hepatocyte intrinsic
               clearance <14L/min/106 cells
            o Plasma protein binding accurately determined and acceptable
            o Acceptable in vitro tolerance of inhibition (<20% at 10M) and no
               measurable induction of rat / human native or recombinant
               metabolic / oxidative enzymes (mRNA or protein level) at 10M
            o No significant toxicity measured below 10M in 2 cell based assays.
               No significant toxicity alerts
            o Physiochemical properties acceptable (Lipinski pass, intrinsic
               solubility > 10g/ml, LogP < 3, Log D < 3, Mwt normally < 450)
            o in vivo pharmacodynamic effect determined against a biochemical
               or pharmacological marker of target action or a disease related
               activity. Supra-pharmacological effects identified at supramaximal
               concentrations to allow dose range to be determined
            o in vivo pharmacokinetics determined in 2-3 species (bioavailability
               (PO > 30%), clearance (<35ml/min/kg), half-life known and
               acceptable based on proposed route of administration (t1/2 > 30



                                                                                    24
               min), volume of distribution and metabolite identification in urine
               and faeces
             o Pharmacokinetic / pharmacodynamic relationship acceptable to
               route of administration
             o Proposed synthetic route feasible for scale-up
             o Composition of matter patent(s) filed

   Optimisation of leads to pre-clinical candidate criteria, for example,
              o in vitro HERG assay (QT prolongation) and 2-5 strain AMES tests ±
                 S9 fractions (mutagenicity) negative
              o Synthetic route determined and scaleability assured. Small-scale
                 batches (gram quantities) synthesised. Lead times, costs, purity,
                 solid state stability, moisture sorption acceptable
              o Formulation and pH salt screen completed
              o Cardiovascular safety pharmacology studies (rat and / or dog) clear
              o Mouse lymphoma test negative for teratogenicity
              o Rodent CNS behavioural test (Irwin test) clean
              o 2 week rat toxicology study clear




                                                                                25
                                                Appendix 4

                                Sample Screening Cascade

 Single concentration, duplicate point measurements at target in an in vitro primary assay
                                                          „Hit‟ produces > 50% response
                                                          at desired concentration
 Full concentration response curves, in duplicate, in primary assay to provide an accurate
                    measurement of affinity of „hit‟ compound for target
                                                          Affinity meets stated
                                                          product profile
     Full concentration response curves in an in vitro „secondary assay‟ to determine
                 measurement of target function (e.g. potency / efficacy)
                                                          Functional measurement (potency /
                                                          efficacy) meets stated product profile
Single concentration, duplicate point in vitro measurement of selectivity of „hit‟ compound
                         at closely related target primary assay
                                                          Fold selectivity meets stated product profile


 In vitro metabolism                            In vitro absorption                            In vitro toxicity
             <50% loss of parent in 30 min in             Acceptable absorption in                        No significant
             microsomes; hepatocyte intrinsic             established model                               toxicity at 10M
             clearance <14L/min/106 cells

Inhibition / induction of                 Plasma protein binding                              Physicochemical
  cytochrome P450s                                                                            characteristics
Acceptable inhibition and                                 < 99.5%                                  Solubility > 10ug/ml,
induction (< 20% at 10M)                                                                          Log P < 3, Log D < 3
                              Specificity screening at unrelated targets
                                                          No off-target affinity identified

                                         in vivo pharmacokinetics
                                                               Oral bioavailability >30%; clearance <35ml/min/kg, t
                                                               ½ acceptable, volume of distribution, metabolite ID
                                        in vivo pharmacodynamics




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