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A01 What are we looking for in a Huntington disease (HD) drug?
  1. C Sampaio1,2
  1. 1CHDI Foundation, USA
  2. 2Faculdade de Medicina de Lisboa, University of Lisbon, Lisbon, Portugal


Therapeutic interventions (TI) can be drugs, devices, or complex interventions. Category independent, a TI must produce a clinical benefit that the patient perceives as RELEVANT for his or her well-being. This benefit must compensate the risks and the overall burden the intervention represents for the individual, the family and the society. We are looking for drugs in HD that can produce a sufficiently large effect (or can contribute to such an effect in combination with other TI) in one or more of the affected domains of HD (motor, behaviour, cognition, metabolism) with an acceptable safety profile. The beneficial effect can be either the deferral of the disease manifestation or the reduction of symptom intensity; or both. HD is a neurodegenerative disorder not simpler than Alzheimer's or Parkinson's disease, sharing progressive selective neuronal death, long-term compensatory mechanisms and numbers of accessory pathogenic processes, which might be useful as auxiliary therapeutic targets. The underlying pathogenic processes are evidently similar, demonstrated by the current efforts of the scientific community revising the concepts of the evolution in these diseases. Regarding the commonalities, it is considered that there is a preclinical period without detectable clinical or biomarker changes, a presymptomatic period where only biomarkers indicate changes, a premanifest period with robust biomarker and first clinical changes and finally the manifest period with manifestation of classical symptoms of the disease. Drugs that will be used in these different periods will have very different characteristics. It is contentious whether or not a drug should be considered in the early periods of slow progressing diseases like HD if its safety profile is riskier than for example, aspirin as prophylaxis for myocardial infarction. This situation will be different for juvenile HD. There is plenty of room for different trade-offs between the benefits and the risks, depending on the risk acceptance of individuals and the society, compliance issues and time horizons. HD is a monogenetic, fully penetrant disease which gives HD a head start advantage over the other neurodegenerative diseases in the search for targeted drugs. By knowing the gene and its ultimate product, it was possible to design the first specific interventions using iRNA technologies, which will enter clinical trials soon (early 2013). However, they are extremely interesting but highly experimental interventions. For issues as important as pharmacokinetics, techniques of application, brain diffusion, and dosage details still must be worked out. This will bring the discussion to the ideal characteristics of a drug being fully brain penetrant, and what technical challenges are acceptable if a TI offers a realistic promise of efficacy. In summary, in our search for drugs for HD, we expect to develop TI which are effective and have a manageable safety profile. In addition, we hope (1) to learn which is a drug's best target population and to establish appropriate subgroups; (2) to define the proper disease phase in which drugs can be used for optimal results; and (3) to find the ideal dosage, regime and drug combination (as in chemotherapy protocols).

  • Drug development
  • clinical trials
  • benefit-risk

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