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CHDI 4th Annual Therapeutics Conference (Part 2)

By Dr. LaVonne Goodman

Truly remarkable in this year's conference was the impressive involvement of both big pharmaceutical and smaller biotechnology companies in work for Huntington's. It is good news for Huntington families that so much effort in so many places is being done to find treatments for HD. Companies presenting their HD drug development programs included some big names: Astra-Zeneca, Lillly, Merck, Novartis, Pfizer, and some smaller ones: ISIS, Evotec, and DeCode Chemisty.

Conference Highlights
Pfizer's Phosphodiesterase (PDE) inhibitor: In his talk entitled "How the discovery of Viagra opened the door to a potential new treatment for HD", Dr.s John Lowe related the story of how Viagra profits funded Pfizer's drug development program for Huntington's.

Among those presented at the conference, this drug is probably closest to human testing and is in planning stage for clinical trials. This drug is very selective which means that it works on the specific type of PDE that causes damage in HD -- while not interfering with the other 10 known types of PDE needed for cell health. This allows the Pfizer drug to be more potent (effective at lower doses) and cause fewer unwanted side effects.

This drug increases levels of CREB (an important energy chemical) and BDNF. Levels of these molecules -- that are needed for cell health -- are decreased in Huntington damaged cells. They also showed how this drug improves nerve communication between different parts of the brain most affected by Huntington's.

Dr. Bates and DeCode Chemistry HDAC 4 inhibitors: Scientist Gillian Bates presented work showing that HDAC 4 is critically involved with Huntington's. She did this by creating a mouse that had the mutant Huntington gene but lacked one copy of the HDAC 4 gene. She showed that Huntington damage was much less in the Huntington mouse with only one copy of the HDAC 4 enzyme.

Dr. Alex Kiselyov from DeCode Chemistry is developing drug HDAC 4 inhibitors and described techniques for designing selective drugs that fit into a unique area of HDAC 4 - while not interacting or interfering with the important functions of the many other HDAC molecules. These are very selective drug candidates -- those that are more potent and have fewer unwanted side effects. Several of these compounds have progressed to mouse testing at CHDI.

Though not presented at this conference, there is also HDAC work ongoing at other pharmaceutical companies including Repligen Corporation and Novartis

Evotec and KMO Inhibitors: This program focuses on an inflammatory pathway in Huntington's that results in increased levels of quinolinic acid and similar compounds. Quinolinic acid is the toxin that when injected into mice causes a Huntington like disease. This was the model most used before the development of genetic Huntington mice.

Dr. Leticia Toledo-Sherman from CHDI and Dr. Dirk Winkler from Evotec reported on their combined programs for designing and optimizing candidate KMO inhibitor drugs. The best of these compounds are about to enter CHDI's mouse testing phase of drug development.

Very Impressive: Dr. Alan Hollister from AstraZeneca: Dr. Hollister is a grey-haired veteran expert in drug development and clinical trials who gave one of the most important talks in this conference.. Hollister gave unbiased advice -- that only someone not working on HD could do -- on how to improve clinical trials in HD. He gave some sobering statistics and detailed some of the challenges in drug development for Huntington's:

• Cost: $1.2 - $1.6 Billion dollars - for each drug
• Slow disease: Up to 10 years to complete Phase 1 through Phase 3
clinical trials.
• High failure rates of clinical trials in all CNS diseases.

He calculated the time needed to show neuroprotective (not symptom related) efficacy for a Phase 3 trial in HD utilizing present UHDRS measures:

• 8 years for a drug that is 25% effective
• 4 years for a drug 50% effective
• 2.2 years for a drug 75% effective
• 1.8 years for a drug 100% effective

What was his advice for more successful neuroprotection clinical trials?

• Clear definition of disease stages and progression rates by stage
• Well-defined patient population for each trial
• Biomarkers of disease status or drug action
• Relevant Targets (Those that cause most damage)
• Potent Drugs (More than 50% effective)
• Willing population of study participants

In fact, he suggested that it would be unethical to perform long neuroprotective trials using experimental drugs until the development of better clinical trial tools.

Promising Biomarkers

HDRP: In a very exciting part of this conference Dr. David Eidelberg presented his work on FDG PET imaging studies. Using PET scans to measure metabolic patterns in different brain regions; he and his colleagues have identified a Huntington's disease related pattern (HDRP) that is very specific and sensitive to rate of progression in premanifest and early HD. This measure can also specifically identify conversion to onset of motor symptoms.

If further study validates this method, this could be an extremely important biomarker for use in clinical trials for premanifest and early symptomatic (as defined by motor onset) HD individuals. HDRP has potential for reducing the time needed for clinical trials to the 1.5-year range for this HD group. Your HDSA donations have funded this effort.

Novartis and Measuring Mutant Huntington and Aggregate Load: Scientists from Novartis have developed an assay that can directly measure levels of mutant Huntington protein in blood. They have also shown that the level of mutant protein inversely correlates with aggregate levels in brain (or blood levels of mutant protein go down as aggregates increase). Using blood samples from Huntington Studies (like COHORT) they are presently evaluating how sensitive this measure will be in predicting progression rates over time. If further work shows this to be a sensitive measure of progression - then this blood test -- has immense potential for use in clinical trials.

FDDNP-PET at UCLA: Though there was not a specific lecture on this topic, it is an important ongoing CHDI program in need of volunteer participants. FDDNP is a type of PET scan that measures aggregate levels and patterns in different brain regions. Patterns change and aggregate levels increase over time. Right now, investigators at UCLA need to enroll more individuals who are at risk (you do not need to know gene status), and individuals with motor symptoms to determine if this type of test will be a good biomarker. If interested please contact:

Curtis Thiede
Clinical Research Coordinator; SRAII
Department of Neurology
UCLA
310-206-3356

ISIS Update: As presented on a poster at CHDI: Studies have been completed on large dogs showing that ISIS oligonucleotides reach all areas of the in an animal with a large brain. This is a critically important positive step.

There is however a potential problem that may slow clinical trials: The precise modality for delivery has yet to be selected. As this drug will likely require central delivery (directly into the ventricles of the brain) various options including ports and pumps are under consideration. CHDI plans a meeting in July to help promote a resolution to this problem that won't interfere with timing of clinical trials.

ACR-16 Update: Neurosearch representatives report that enrollment is complete for the European Phase 3 clinical trials. And in what is potentially good news, the "buzz" was that investigators (not the drug company) report seeing probable benefit. Of course, final results - because investigators don't know which participants have received drug and which placebo -- from this trial will be needed before surety.

In very discouraging news Neurosearch also reported that enrollment is way behind in North America, having recruited only about 1/3 of needed participants. It is vitally important for every HDSA chapter to communicate the need, and for any potential participant to step up to this trial that is only 3 months long.

To take advantage of this drug trial -- available now -- see HDTrials.org or Clinical Trials.gov for site locations.