CHDI Foundation, privately funded by a small group of anonymous donors started work on Huntington's disease (HD) about a decade ago. Many have wondered what criteria this organization would require to launch a new drug into clinical trial. The PDE10A inhibitor story answers that question and shows the careful and powerful process that CHDI utilizes before promoting a drug candidate to clinical trial. "Aligning the stars" has nothing to do with serendipity or luck. It is about a lot of hard work, with the CHDI role that of "collaborative enabler" with financial clout: to guide, support, and coordinate a multitude of scientists and drug developers.
Get your telescope ready: The stars are being moved into place...
Aligning PDE10A Inhibitor Stars
The PDE10A information discussed here was presented at the CHDI Foundation's 8th annual HD Therapeutics Conference less than a month ago, and represents only one of many drug related topics from this meeting. See HDBuzz for up-to-date summaries of the entire conference.
The 1st Star: PDE10A is a phosphodiesterase (PDE) enzyme molecule present almost exclusively in the neurons most damaged in HD. In normal situations, this enzyme modulates important energy molecules necessary for keeping neurons healthy. When the PDE10A action is blocked by a drug in HD models, several important aspects of cell function improve. Further, studies in several model systems of HD suggest that blocking the action of PDE may be neuroprotective. This first star represents years and years of research showing this might be an important drug target in HD.
The 2nd Star: While work was being done to test this drug in HD models, other researchers from the Institute for Neurodegenerative Disorders worked on complex imaging methods that showed that the PDE10A inhibitor drug acts in people as predicted from animal model study. This hasn't been done in any previous HD human trial. CHDI requires this because mouse models and HD people are so different. This research also found the best predicted dose, which is important since it would be a shame to lose an effective drug in a failed clinical trial because the dose wasn't adequate to give the response.
While this type of imaging research is important for optimizing chances of success in the PDE clinical trial, it goes important steps further that may speed future clinical trials. They will study cortico-striatal function during this trial -- which may become an important biomarker system for both premanifest and symptomatic HD trials. Though cortico-striatal function is a mouthful, it is a good one to remember because we'll be hearing a lot more about this system over the next few years.
The 3rd Star: Bringing this drug candidate to clinical trial is the collaborative effort of CHDI and Pfizer, Inc, a pharmaceutical giant with the many millions of dollars needed to pay for the clinical trials that will be needed for FDA approval. And if successful, Pfizer will be ready to quickly manufacture and market the new drug -- getting it to people as quickly as possible. Before CHDI, no large pharmaceutical company was interested in HD. This was a big star to move into alignment.
The 4th Star: This part of the story belongs to the participants in HD studies and trials. As with aligning the other stars -- getting things ready before they are needed -- an important part of this process is (or soon will be) in place. The former COHORT and Registry studies, now rolled into one international Enroll-HD (all funded by CHDI) will make identifying and recruiting those persons fitting criteria for this trial (and others) more efficient. And if recruitment is efficient, other pharmaceutical companies will be more interested in working on HD -- to help align stars for more new drugs.
Author's comment: And - the PDE10A story isn't the only one. The stars are aligning for another potential therapy enabled by CHDI: Isis and Roche Pharmaceuticals have partnered to bring a type of gene-lowering therapy (oligonucletide drugs) to clinical trial. This type of drug is only one of several gene-lowering therapies being worked on. Read up on this and other stories at HD Buzz.
Though it is never a good time to have Huntington's -- now may be the best time as the stars start aligning for new drug therapies.