Abstract

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme.To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics.Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community’s chances of successfully bringing new rare disease drugs to registration and ultimately to market.

Highlights

  • Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials

  • Despite hundreds of publications on potential therapies for these diseases based on work in cell and animal models [14], only a handful were moving forward into clinical trials, and there was no systematic way for such potential therapies to be evaluated for their development potential

  • While patient organisations and other funders were being asked to fund therapeutic development programmes, not all of them have established objective advisory system to appraise the clinical potential for candidates, independent from their existing internal scientific advisory boards who were responsible for making funding decisions

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Summary

Discussion

Utilisation and outputs of TACT 2010–2014 To date TACT has held 10 review meetings, 6 in Europe and 4 in the US and reviewed 29 program applications from both academic investigators and industry in several diseases: Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Becker Muscular Dystrophy, Congenital Muscular Dystrophy, Inclusion Body Myositis and X-Linked Myotubular Myopathy. Of the 29 programs reviewed, (Table 1) 19 (66%) were from industry and 10 (34%) were from academia; 15 (52%) were for novel compounds and (48%) were for repurposed drugs; (58%) were small molecules and 11 (42%) were biologics; (48%) were preclinical stage applications and (52%) were clinical stage applications. Preclinical: The need to use gold standard operating procedures for animal model experiments, for example, utilising SOPs available via TREAT-NMD for models of three neuromuscular diseases: (www.treat-nmd.eu/sopdmd) (www.treat-nmd.eu/ sopsma) and (www.treat-nmd.eu/sopcmd). In a number of cases TACT encouraged the applicants to ensure their results were reproducible through independent validation [16]

Formulation
Repurposing
Findings
Clinical Trial design
Manufacturing
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