HD Lighthouse Contributing Editor's Comment:
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Posted to the HDL: 12 Mar 2006

Marsha Miller, Ph.D.

Thursday afternoon was devoted to the Spinal Muscular Atrophy Foundation Satellite Symposium. Like HD, SMA is an orphan disease with challenges in drug development.

Katherine Klinger, Ph.D. of Genzyme spoke on “Development Considerations for Orphan Diseases.” She noted that when screening drugs as potential treatments for any diesase, moving from a hit to a lead to a candidate for trials takes about 3-4 years with clinical trials addint another 4-6 years. Most compounds considered as treatments fail. The most common causes for failure are lack of efficacy (46%), animal toxicity (17%), and adverse effects in people (16%).

Oprhan disease drug development is harder because molecular pathophysiology is often poorly understood. How do you decide on a target when the disease pathways aren’t known. Animal models are helpful but of necessarily limited utility. Mice aren’t people. Applying her points to HD, since we don’t know wha the normal function of the Huntington’s Disease protein is, we can’t show that normal function has been restored. She also noted that the natural history of orphan diseases are often ‘old,’ carried out before symptomatic treatments improved. In general the challenges can be summed up in the following questions?

• Who are you going to treat?
• When are you going to treat?
• What are you going to measure?
• How long is it going to take you to demonstrate an effect?

She also spoke about the need for surrogate markers of the disease and surrogate endpoints. I think that these are greatly needed in Huntington’s Disease because the disease has such a slow progression, prolonging clinical trials.

Dr. Klinger noted that when surrogate markers and endpoints are used in clinical trials the researchers may be required to do a Phase IV trial which is essentially a follow up with the research subjects to verify that the disease has indeed been treated.

Although we had heard speakers in the morning focus on the role that pharmaceutical companies can and do play in drug development for orphan diseases, the take away message from this session is that those suffering from orphan diseases cannot afford to wait. We need foundations which will develop a strategic plan for drug discovery and fund efforts to fill in the gaps in research. Two of the presentations were particularly interesting to those in the HD community – Curtis Keith, Ph.D., of CombinatoRx and Dr. Robert Pacifici of CHDI.

CombinatoRx, Incorporated is a biopharmaceutical company focused on developing new medicines built from synergistic combinations of approved drugs. They have been able to discover drugs that separately have no effect on a disease but which combined act as a treatment. They have a contract from CHDI to work on drug discovery for HD. Read more about this interesting company here http://www.combinatorx.com/

Dr. Robert Pacifici of CHDI spoke on “Foundation Research Using the Virtual Model: A New Paradigm for Translational Drug Discovery.” CHDI (Cure Huntington’s Disease Initiative) “is pursuing a biotech approach to rapidly discover and develop drugs that prevent or slow HD. Through collaborations with industrial and academic partners, CHDI, Inc. participates in all aspects of drug discovery and development from high throughput screening to preclinical development.” Dr. Pacifici noted that the term ‘virtual’ sounds as if it’s somehow not ‘real’ but actually this refers to their practice of outsourcing to collaborative partners” while concentrating on their strategic plan. CHDI is time motivated, conscious of the need for treatment, and it works in parallel with multiple potential treatment areas being explored. If one fails, there won’t be a need to start over.

Other organizations such as High Q, the Hereditary Disease Foundation, and the Huntington’s Disease Society of America, are funding basic exploratory research in Huntington’s Disease. This includes areas such as targets, validation, assays, reagents, cellular models, animal models, biomarkers, and investigator networks. At the other end of the continuum are clinical trials to demonstrate safety and efficacy. The role of CHDI is in the middle, to direct the applied translational research to go from the lab to the clinic. This involves screening and finding lead candidates, validating ligands, drug discovery tools, and understanding mechanisms of actions.

Bookmark the link to the new CHDI site and follow the progress of this dedicated organization: http://www.chdi-inc.org/

Lee Rubin, Ph.D. spoke on “High Throughput Screening in Motor Neurons: A New Approach to Identifying Effective Therapeutics for Spinal Muscular Atrophy.” Of interest in his talk was that fibroblast screens identified two powerful compounds to treat this disease but they don’t work in motor neurons developed from embryonic stem cells. Thus, two different cell models give very different results. It will be interesting to find out whether the compounds treat the SMA mice.

Tracked on the Lighthouse:
ASENT

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