Report on The ALS Association's drug discovery workshop

A key aspect of a successful development program is the availability of validated biomarkers that can be used in a clinical trial. Several speakers from the pharmaceutical industry noted that having a validated biomarker is a critical step in reducing the fi nancial risk of a drug development program, since the biomarker allows the company to assess the likelihood of success of an agent much earlier in the development process. The ideal objective biomarker would supplement functional endpoints such as muscle strength or the ALS Functional Rating Scale. While both of these measures decline with disease progression, they may fl uctuate, leading to the need for larger patient numbers and longer trials. Two groups, taking two different approaches, presented their latest results at the meeting. Robert Bowser is looking for an ALS protein signature in the cerebrospinal fl uid. He uses liquid chromatography and mass spectrometry to separate and identify CSF proteins, controlling for patient age, gender, site of onset, and other variables. By comparing patients to controls, he has found that the ratio of the levels of phosphorylated neurofi lament heavy chain to complement C3 (pNFH/C3) identifi es ALS patients with a sensitivity of 96% and a specifi city of 90% (1). At the present time, the ratio is diagnostic, not prognostic, since longitudinal sampling has not been performed. He also reported preliminary evidence that the protease inhibitor cystatin C may help distinguish slow from fast progressors. Rita Sattler, John Gerdes and Richard Bridges have collaborated on the development of a PET ligand that tags the EAAT2 glutamate transporter, which they are developing as a potential therapeutic biomarker for treatments that increase the level of the transporter. Severe loss of EAAT2 on astrocytes In early March 2012, over 120 researchers, drug developers, government offi cials, and clinicians came together in Washington D.C. for three days of discussions focused on advancing drug discovery for ALS. The workshop, hosted by The ALS Association, examined the barriers and opportunities for translating basic science discoveries into therapeutics, with special emphasis on biomarkers, alternative targets, and clinical trial development. Many researchers generously presented new and unpublished results, in keeping with the goal of the workshop of fostering discussion at the leading edge of ALS therapy development. The report below includes discussion of some work that had not yet undergone peer review at the time of presentation, and should be considered in that context. In the keynote address, Chris Austin, Scientifi c Director for the National Center for Translational Therapeutics (NCTT) at the National Institutes of Health, placed the challenge for ALS within the context of rare or orphan diseases as a whole, of which over 6000 are known. Despite the identifi cation of genes for two-thirds of these, treatments exist for fewer than 250 of them. The reasons are multiple, but a major one is the gulf between the work of basic researchers, who identify mechanisms and targets, and pharmaceutical companies, who alone have the resources to conduct largescale clinical trials. That gap, often called the ‘ valley of death ’ , is diffi cult to bridge, as the cost for bringing potential drugs forward rises steeply and the likelihood of success falls even more steeply in this zone. The NCTT has been designed to improve the odds of bridging that gap, by providing expertise in translational drug development, including chemical genomics, quantitative high-throughput screening, and preclinical development. More information is available at http://nctt.nih. gov. REPORT