DoD Amyotrophic Lateral Sclerosis Therapeutic Development Award

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The FY20 ALSRP Therapeutic Development Award supports research ranging from validation of therapeutic leads through U.S. Food and Drug Administration (FDA) Investigational New Drug (IND)-enabling studies. The proposed studies are expected to be empirical in nature and product-driven. Preliminary data are required, including efficacy in at least one ALS-relevant model system with a lead molecule/class of compounds . The availability of validated biomarkers or biomarker development/characterization, in parallel to the main therapeutic effort and for use in eventual clinical trials, is a critical component of the FY20 ALSRP Therapeutic Development Award. Applicants with limited ALS experience are strongly encouraged to include collaborators with substantial expertise in the relevant ALS model systems, endpoints, and pathophysiology. Examples of activities that will be supported by this award include: • Confirmation of candidate therapeutics obtained from screening or by other means, including optimization of potency and pharmacological properties and testing of derivatives and sister compounds • Validation of early pilot studies, including the use of multiple ALS model systems and/or replicating preliminary data with more time points or additional doses • Studies on formulation and stability leading to Good Manufacturing Practice production methods • IND-enabling studies, to include compound characterization, absorption, distribution, metabolism, and excretion (ADME) studies, and dose/response and toxicology studies in relevant model systems Clinical trials are not allowed, however, validation of treatment approaches in appropriately powered and controlled studies using biological correlates of disease activity and progression in pre-existing, de-identified human specimens from well-characterized patient cohorts is encouraged. Examples of acceptable sources for pre-existing biosamples or datasets include controlled clinical trials, observational studies, publicly available biorepositories, and registries (e.g., Centers for Disease Control and Prevention [CDC] National ALS Registry and/or Biorepository; https://www.cdc.gov/als/). A list of suitable resources can be found on the ALSRP web page (https://cdmrp.army.mil/alsrp/resources/ALSRPresources. Other resources may be used, provided a letter of support that adequately describes the relevant repository parameters and mechanisms for broad access to data and samples is included in the application. Active duty military and/or Veteran patient populations or resources should be considered. All specimens must exist at the time of application submission; collection of new specimens will not be supported . Applications supported by this award must begin with lead compounds in hand and must include preliminary data relevant to the phase of development, such as: • Proof of identity and purity • Selectivity for the intended target over closely related targets • Availability of primary and secondary in vitro bioactivity assays for optimization or structure-activity relationship studies • Availability of proof-of-concept efficacy data in at least one preclinical model system of ALS, including whole animal and cellular model systems Biomarker development and/or characterization (if not already validated), in parallel to the main therapeutic effort, is a critical component of the FY20 ALSRP Therapeutic Development Award. Efforts may include development/characterization of target engagement biomarkers, pharmacodynamic biomarkers to measure the biological effect of an investigational therapeutic, and/or predictive/cohort-selective biomarkers that indicate whether a specific therapy will be effective in an individual patient or patient subgroup. Development of markers for the purposes of diagnosis, prognosis, or measurement of disease progression without consideration of the therapeutic development process will not be supported. Applicants must clearly describe the marker and its potential to improve the efficacy of the therapeutic development process. For further description, see Section II.D.2.b.ii, Full Application Submission Components. Before preparing the Therapeutically Relevant Biomarker Statement, applicants are encouraged to review the draft guidance issued by the FDA, "Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment," as well as the patient-focused document developed by the ALS community, "Drug Development for Amyotrophic Lateral Sclerosis Guidance for Industry," which provides direction beyond the FDA guidance and includes the community consensus on key therapeutic development topics.

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