Request for Proposals: Accelerating Drug Discovery for Frontotemporal Degeneration
Research investigating the pathogenic mechanisms underlying frontotemporal degeneration (FTD) is advancing, creating new targets for drug discovery. However, there remains a global gap in FTD drug discovery research. The Alzheimer's Drug Discovery Foundation (ADDF) and The Association for Frontotemporal Degeneration (AFTD) seek to accelerate and support innovative small molecule and biologic (antibodies, oligonucleotides, peptides, gene therapy) drug discovery programs for FTD through this request for proposals (RFP).
ADDF FUNDING PORTAL
Must be received by 5:00 pm ET on the deadline date.
Letter of Intent: July 12, 2019
Invited Full Proposal: August 9, 2019
One year with potential for follow-on funding.
$100,000-$150,000 based on stage and scope of research.
Funding is open to researchers and clinicians in the U.S. and worldwide working in:
- Academic medical centers and universities or nonprofits. Industry partnerships are strongly encouraged.
- Biotechnology companies that demonstrate a clear need for nonprofit funding. Funding is provided through mission-related investments (MRIs) that require return on investment based upon scientific and/or business milestones. Existing companies and new spinouts are both eligible.
The RFP supports:
- Lead optimization of novel disease-modifying compounds, including medicinal chemistry refinement and in vitro ADME.
- In vivo testing of novel lead compounds, biologics, or repurposed drug candidates in relevant animal models for pharmacokinetics, dose-range finding, target engagement, in vivo efficacy, and/or preliminary rodent tolerability studies.
Current target areas of interest include, but are not limited to:
- Genetic Causes of Disease (TDP43, progranulin, C9orf72)
- Mitochondria & Metabolic Function
- Vascular Function
- Synaptic Activity & Neurotransmitters
Other novel targets or pathways that are supported by compelling evidence that demonstrate a rational biological connection to the disease process are encouraged.
NOTE: This RFP does not support target identification, target validation, assay development, high-throughput and high-content screening.
Stage of discovery
This RFP supports lead optimization, in vivo pharmacokinetics, preclinical target engagement, preclinical efficacy, and/or preliminary rodent tolerability studies.
This RFP does NOT support target identification, target validation, assay development, high-throughput and high-content screening. IND-enabling work is supported through the PACT RFP.
The strongest applications will test a compound that has met many or all of the following criteria:
- Chemical structures of hits and leads have been assessed for structural liabilities
- Novel composition of matter patents have been filed or plans to generate novel composition of matter intellectual property (IP) have been developed
The strongest applications will test a repurposed or repositioned drug that has met many or all of the following criteria:
- The known side effects of the drug and how well they would be tolerated by the intended FTD population have been evaluated
- A supplier that will provide sufficient quantities of the drug or compound to complete the study aims has been identified
- Plans to develop novel IP around the repurposing/repositioning strategy have been addressed
Preclinical Efficacy Studies
Applications that include preclinical efficacy studies should:
- Provide data demonstrating blood-brain barrier penetration (if the intended target is in the CNS).
- Justify dosing administration and regimen with in vivo PK/PD data. (If this data is not yet available, a PK/PD study aim should be included in your proposal).
- Include measures of target engagement in the proposed animal study design.
All proposals will be evaluated for:
- Rational biological connection of the target to the disease pathophysiology
- Strength of the preliminary data
- Feasibility, research design and methodology, including justification for proposed the animal model for efficacy studies
- Investigative team, organizational capabilities, and project budget
The following criteria will be used to assess the proposed drug target(s):
- Is there human genetic evidence linking the target to FTD disorders? Targets without a defined genetic link will also be considered.
- Is the target expressed in disease-relevant regions of the brain (or where applicable, in the periphery) in humans and/or animal models?
- Are there changes in target mRNA/protein expression or activity in human disease specimens from FTD disorders, and do they correlate with disease severity and cognitive or behavioral functions?
- Does genetic and/or pharmacological manipulation of the target in disease-relevant in vitro (e.g., primary cultured neurons/glia or cells derived from patient iPSCs) or in vivo models alter disease phenotypes?
- Are there direct measures of target engagement that can be used experimentally and eventually in humans?
- How is the target more compelling than other related targets that have been tested for FTD disorders?
If the molecular target is unknown, the strength of the evidence for the mode of action and its link to disease pathophysiology will be evaluated. The applicant should summarize the existing evidence in the proposal.
There are numerous available models of dementia, including transgenic models with a host of different transgenes expressed alone or in combination. Each of these models reflect different aspects of disease, which vary from the number and types of phenotypes observed to their onset and severity; however, none of these models recapitulate all aspects of human disease. Instead, the appropriate model can provide valuable information on how the therapeutic engages with its target and its ability to modify phenotypes related to its mode of action.
Reviewers will evaluate the rationale for the proposed animal model using the following criteria:
- How well characterized is the animal model? Has it been characterized in the applicant's or collaborator's lab, or is there historical control data available from the contract research organization (CRO) that will run the study?
- Does the model mimic FTD-relevant pathology and FTD cognitive/behavioral symptoms (e.g., apathy, disinhibition, social disinterest, perseverative behavior, overeating/carbohydrate craving) or motor deficits (instability, gait changes, maintain balance, strength, reflexes, coordination, unilateral motor changes, decline in overall mobility)?
- Does the model exhibit the appropriate phenotype(s) to measure target engagement (e.g. a drug intended to reduce pro-inflammatory cytokines in the brain should be tested in a model shown to exhibit elevated pro-inflammatory cytokine levels)?
- Does the model exhibit other phenotypes relevant to the mode of action that can be measured as secondary outcomes (e.g. abnormal protein accumulation, synaptic changes, neuronal loss, cognitive defects, etc.)?
Review the Application Instructions* for steps on applying.
The ADDF considers its application process an iterative one and would be happy to talk to you about your program.
*Please note that you will be following the same application instructions as the Core RFPs.
ADDF FUNDING PORTAL
For program-related inquiries, please contact:
Meriel Owen, PhD, Scientific Program Officer, ADDF
Nadine Tatton, PhD, Scientific Director, AFTD
For application submission inquiries, please contact:
Grants and Mission-Related Investments Team