Calling All Innovators

DARPA looks to new therapeutics and equipment to
prevent and treat high altitude-related health issues.

DARPA is soliciting research proposals (through a broad agency announcement, or BAA) that demonstrate innovative approaches to accelerate natural acclimatization at high altitudes (4,000–6,000 meters) and alleviate the effects of high altitude illnesses and hypoxia. They are interested in research that investigates novel pharmacological, biological or technological approaches to adapt to high altitude while preventing and treating HAI.

This BAA is novel in clinical drug development in that it requires an end-to-end reconsideration of established timelines for the development and pre-clinical evaluation of candidate therapeutics and technologies. DARPA will consider solutions that include reformulated FDA-approved therapies, although new therapies and/or alternative non-pharmacological strategies that meet all the metrics below are preferred.

At the conclusion of this program, candidate therapeutics will need to have completed toxicology data and evidence of efficacy for altitude or non-altitude hypoxic indications. Specifically excluded from consideration is research that primarily results in incremental and evolutionary improvements to the existing therapeutics or current state of practice. Also excluded are strategies that involve transfusion of human- and animalderived hematopoietic factors (e.g., recombinant erythropoietin), approaches based on the introduction of exogenous nucleic material (e.g., adenoviral up-regulation of pyruvate dehydrogenase phosphatase isoenzyme 2, or PDP2) and strategies proposing modest increases in oxygen through concentrator technologies (e.g., N2 scrubbing, Xeolyte or equivalent) for temporizing the effects of hypobaric hypoxic-associated illnesses. Preference will be given to novel small molecule strategies and alternative technologies that induce physiologic conditions found in wellacclimatized humans.

Submitted proposals must meet the rapid altitude and hypoxia acclimatization’s (RAHA) programmatic milestones to identify adaptive, preventive and therapeutic strategies or technologies that can alleviate the impact of altitude-related illness on the warfighter. Strategies may include novel physiologic conditioning pathways, development of preventive and rapid treatment therapies for high altitude illnesses, and new technologies that dramatically advance the ability of the warfighter to operate in hypobaric and hypoxic environments.

The ultimate goal of the RAHA program is to develop both fast-acting/short duration (minutes/hours) therapeutic agent(s) or strategies and slower-acting/long duration (hours/continuous with altitude exposure) therapeutic agent(s) or strategies that either alone or in combination will reduce altitudeinduced illness incidence or severity without impeding natural acclimatization processes. The BAA includes three technical areas.

1. Alleviate pathogenesis of high altitude illness and hypoxia

HAI is a constellation of altituderelated syndromes that affect soldiers who ascend rapidly or who operate continuously above 5000 meters. Major HAI syndromes addressed in this BAA include acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). Chronic manifestations of HAI addressed in this BAA include high altitude-related cachexia and chronic mountain sickness. In each of these cases, HAI interferes with the ability of military personnel to work effectively with well-acclimatized personnel and local inhabitants. Approaches for this will need to alleviate HAI and hypoxia resulting from low oxygen conditions as demonstrated by physical performance in a standard low oxygen environment.

2. Field deployable strategies

Proposed strategies must be field deployable with minimal demands on supporting infrastructure, few requirements for training and fast acquisition of natural acclimatization to altitudes between 4,000 and 6,000 meters.

3. FDA Phase II clinical trial preparation

Proposed strategies for all approaches must include details of how the performer will generate the data necessary to initiate a future FDA Phase II clinical trial following the RAHA program.

PROGRAM PHASES

The RAHA Program is a two-phase program. DARPA Phase I will identify candidate processes/drugs for exploratory investigational new drug study or investigational device exemption. These novel products will be positioned for use in an FDA Phase I clinical trial by the end of DARPA programmatic Phase I.

The RAHA goal of DARPA Phase II is to prove efficacy in a large animal model; completion of a limited FDA Phase I clinical trial for pharmacokinetics, surrogate-efficacy markers and tolerance in healthy adults ages 18–24 (n=20 minimum); and completion of requirements for initiation of an FDA Phase II clinical trial.

It is expected that DARPA will give preference to efforts that will satisfy the metrics in less time or provide study designs allowing for greater statistical significance under abbreviated research timelines. Contingency planning in the search, testing and evaluation of candidate therapy or technology selection and the multidisciplined capabilities of proposer teams will be a priority consideration in the evaluation of proposals. Multiple awards are anticipated.

PROGRAM METRICS

Proposals must address a DARPA Phase I proof-of-concept stage encompassing all pre-clinical small-animal efficacy studies, GLP animal toxicology studies, and a DARPA Phase II development stage that includes large-animal efficacy studies and an FDA Phase I clinical trial. The FDA Phase I clinical trial will occur during DARPA Phase II of RAHA, concurrent with confirmation of efficacy in a large animal model.

RAHA PHASE I MILESTONES

The single milestone for Phase I is the “generation of data sufficient to support an exploratory IND study of one or more candidate processes, drug leads or investigational device exemption for novel technologies.”

An aggressive timeline for approval will require that the candidate therapy or technology can undergo an expedited review by the FDA. Premarket submissions that are accompanied by a letter indicating the impact on national security by the Department of Defense receive such a review, although approval can be delayed by many factors.

Example requirements for meeting the DARPA Phase I milestone are noted below. Proposers are encouraged to put forward their own approach that may reflect novel, unique and unpublished approaches to accelerated drug development, screening and testing for safety and efficacy. Novel, emerging strategies and technologies that have not been associated with prior approval of a drug or device by the FDA are encouraged.

The following are requirements for meeting the milestones with a therapeutic:

• The therapeutic product—must not already be submitted for application for the management of altitude-related illnesses or hypoxia.

• Treatment regimen—statement of clinical regimen(s) or technical protocol (for device) that is likely to be effective in preventing and treating altitude-related illnesses syndromes.

• Chemistry-Manufacturing-Control (CMC)—proposer must demonstrate access to CMC information sufficient to support an exploratory IND.

• Non-clinical toxicology—toxicology and toxicokinetics sufficient to support likely clinical regimens, if already available.

• Clinical toxicity—data suggesting that proposed regimens will be tolerated in young adults with systemic changes that result from acute exposure to altitude.

The following are requirements for meeting the milestones with a medical device:

• The technology—must not already be submitted for application for the management of altitude-related illnesses or hypoxia.

• Demonstrate a viable path forward to device testing within given program timelines.

ANIMAL MODELS (PHASE I ONLY)

Potential solutions must justify their large animal model and the method by which the candidate therapeutic, or technology, will be tested for efficacy in Phase I. Candidate therapies and technologies must meet all of the following criteria:

• Fast-acting: onset within one minute and last for at least two hours, with a demonstrable increase of at least 50 percent in exhaustive exercise performance (at 80 percent of acclimatized maximal performance workload) following 15 minutes of exposure to 4,000 meters simulated altitude (attained in an ascent within 12 minutes). This effect should be maintainable with re-dosing or retreatment.

• Long-lasting: onset within 24 hours at low altitude with effects lasting at least 14 days at 4,000 meters, as demonstrated by at least a 90 percent reduction in a 100 percent lethal exposure high altitude pulmonary edema model. The model can be minimally adjusted to achieve the desired parameters of lethal exposure (for example, by raising the altitude). A necropsy should demonstrate prevention of wet-dry lung weight increases of 10 percent above low altitude control values. • Include any physiological, biochemical or histopathological markers to be measured.

RAHA PHASE II MILESTONES

The final product at the end of Phase II will be two or more therapeutic agents or technologies (at least one fast-acting and one long-lasting) for which the clinical Phase I data suggests that the plasma levels effective in animals are obtainable and tolerated clinically, good laboratory practices toxicology has been completed, and a signed commitment with a pharmaceutical partner for further development has been established.

Recommended therapy product or technology actions in the large animal efficacy model are the following:

• Fast-acting: onset within one minute and last for at least two hours, with a demonstrable increase of at least 50 percent in exhaustive exercise performance (at 80 percent of acclimatized maximal performance workload) following 15 minutes of exposure to 4,000 meters simulated altitude (attained in an ascent within 12 minutes). This effect should be maintainable with re-dosing. Additional physiological, biochemical or histopathological markers to be measured should be included.

• Long-lasting: onset within 24 hours at low altitude with effects lasting at least 14 days at 4,000 meters, as demonstrated by at least a 90 percent reduction in a 100 percent lethal exposure high altitude pulmonary edema model. The model can be minimally adjusted to achieve the desired parameters of lethal exposure (for example, by raising the altitude). A necropsy should demonstrate prevention of wet-dry lung weight increases of 2 percent above low altitude control values.

• Additional physiological, biochemical or histopathological markers to be measured should be included. ♦