Research Update from the 2007 HDSA convention: Part Two

HD Lighthouse Contributing Editor's Comment:

-- Marsha Miller, Ph.D.
Posted to the HDL: 21 Jun 2007

Dr. Robert Pacifici, Chief Scientific Officer of CHDI, spoke. The mission of CHDI is to "rapidly discover and develop drugs which prevent or slow Huntington's Disease." He updated the attendees on the progress on the strategic plan he presented in 2005. He summarized it this way: "We have a plan, we have the people, we have a portfolio, we have positives, and we have a pipeline."

Projects in the portfolio are an HDAC platform, htt induced cyto-toxicity, screening in primary striatal cultures, existing pharmacopoeia, cellular aggregation, toxic fragment production, stress and folding, transglutaminase, RNAi-based therapies, trophic factors, excitotoxicity, in vivo portfolio, adenosine A2a antagonist, KMO, mGluR, antioxidants, and model organism screening.

By positives he means compounds that are promising enough to study further. He showed a chart with 43 compounds in various stages of pre-clinical efficacy trials. These are not drug candidates yet but the goal for this year is to nominate a candidate for the animal toxicity studies. There are 4 or 5 potential treatments moving into that stage -- the research pipeline. These are compounds which affect histone deactylases, adenosine receptors, and bioenergetics and antioxidants, as well as RNAi technology.

To review, CHDI is a not for profit 'virtual' or outsourced biotech company with 501(c)3 status. It is motivated by time, not money. It is funded by a private foundation and all monies come from donors. The 2007 budget will probably reach $40 million. It is exclusively dedicated to Huntington's Disease. There are about 30 full time positions or their equivalents in NYC and LA, covering all necessary scientific competencies. There are no internal labs; the research is done by collaborative partners and contract research organizations.

CHDI sponsors critical up or out experiments so that resources can be quickly reallocated to more promising areas as needed. They don't start off with biases or 'favorite' compounds.

CHDI sponsors what is called translational research, doing the work necessary to develop potential treatments based on the knowledge gained by academic research which can be tested in people through the clinical trial process.

CHDI pursues four kinds of outreach strategies:

1. CHDI - driven programs. These programs contract with other organizations on a fee for service basis. CHDI owns the intellectual property.
   
2. Leverage integrated biotechs - CHDI will give the resources to certain venture capital driven biotechs to include HD in their research and development.
   
3. Enable HD translational efforts - The 'ah ha' moment may come out of left field so it's important to make sure that there are biological and chemical repositories for academic researchers to participate in HD research.
   
4. Lower the barrier for entry into HD drug development. Pharmaceutical companies have libraries of compounds sitting on the shelf. These are well categorized compounds and one or more of them just might turn out to be a treatment for HD. CHDI will test the compounds for the companies and the companies will retain their rights.

Dr. Pacifici then discussed caspase 6 inhibitors as an example of what happens when there's a good target identified. The Lighthouse covered this groundbreaking basic academic research last year: http://www.hdlighthouse.org/research/drugs-supps/updates/1266caspase6.php

First of all, they needed to think and work through potential pitfalls. Is it really caspase 6 or is it another enzyme that recognizes the same site? Second, they need to find a potent and selective inhibitor that works on caspase 6 and not the other caspases. Third, they need to find out if caspase 6 has another 'good' function so that inhibiting it would cause unacceptable side effects.

Two other promising targets include type 2 transglutaminase (a calcium-dependent acyltransferase) and kynurenine 3-monooxygenase (an enzyme in the kynurenine pathway of tryptophan degradation).

Dr. Pacifici then reviewed some 'positives' from four biotech collaborators. ISIS is working on antisense oligonucleotides to target the huntingtin's protein. They have some exciting brain penetrance data from animal models. They have an antisense drug for ALS which is in preclinical testing and may go to clinical trials in as early as 18 months. The ALS research is farther along that the HD research but much will be learned from the ALS efforts. You can learn more about ISIS's RNA technologies here: http://www.isispharm.com/index.html

CHDI is collaborating with Methylgene on HDAC research. The Lighthouse covered this effort earlier this year: http://www.hdlighthouse.org/research/drugs-supps/updates/1329hdac_inhibitors.php . As a result of this effort, the researchers are now able to show if the target is engaged and they working on demonstrating clinical efficacy and preparing for clinical trials.

CHDI is also collaborating with Hermes on a way to penetrate the blood brain barrier using a trojan horse technology. Only small molecules can cross the blood brain barrier and this has been a huge limiting factor in developing drugs to treat neurological conditions. This is a very exciting effort and research are now in the process of testing promising molecules which have been on the back burner because of poor brain penetrance.

XenoPort also has an interesting technology, pumps which fool the brain into thinking that it is letting in something it wants.

A very promising collaboration is the effort to identify promising existing compounds using the technologies of CombinatoRx. They are screening an existing pharmacopeia of 2000 drugs, looking for effectiveness at various dosage levels. They are also looking for synergy; two compounds might not work separately but used in combination could turn out to be a treatment. There are three parallel programs in operation now and the first candidates for mouse testing and now being selected. Dr. Pacifici commented that "There is no faster path from discovery to the clinic."

Two compounds that the Lighthouse has been following for years have shown real promise in early clinical trials. Could creatine and CoQ10 be made more effective through the drug development process. The answer is likely to be yes. Phosophocreatine may be more effective than creatine but could not cross the blood brain barrier. Now the technology is available to do that.

Of particular interest in the drug development with CoQ10. Last year Dr. Pacifici announced the goal of developing CoQ10 analogs which would be more effective at lower dosages. Two analogs have indeed been developed through the collaboration with Edison Pharmaceuticals and data was presented which shows that both help energy challenged cells. They should be ready for clinical trials in approximately twelve months.

The CoQ10 effort is a good example of what the HD patient community needs. Here is a compound showing promise in a Phase III clinical trial (Care-HD). Although the results weren't statistically significant because there were enough study participants, a definite but modest trend in slowing progression was shown. There are indications from preclinical research and research into other diseases that higher doses may be more effective and a new Phase III clinical trial has been planned. Still, 2400 units is an awful lot of CoQ10. This compound seems like one that would benefit from drug development and that is what has been done.

To read more about the effort to develop CoQ10 analogs, see this earlier Lighthouse article: http://www.hdlighthouse.org/TreatmentNow/coq10/updates/1282coq10.php

To read more about CHDI's collaborations, go here: http://www.chdi-inc.org/news.php

Dr. Pacific ended his talk by pointing out that lots of promising compounds are making their way into animal trials. All of have gone through pretesting for brain penetrance and toxicity and other factors associated with likelihood of success. Multiiple measures of effectiveness are being used including survival, cognition, and motor function. So far the testing has been done in the R6/2 mice but promising results will be revisited with other mouse models.

News from Pharmaceutical companies

Later workshops included researchers from various pharmaceutical companies.

Perhaps the most exciting news was that ACR16 will be going into clinical trials this year! This is a dopamine stabilizer which has had exciting Phase II results. The Lighthouse covered this compound last year: http://www.hdlighthouse.org/research/drugs-supps/updates/1254acr16.php .

Since then, NeuroSearch has bought the rights. You can read about their plans for ACR16 here: http://www.neurosearch.dk/Default.aspx?ID=752 .

Joakim Tedroff, Ph.D. updated attendees. The planned clinical trials are intended to last six months. The goal will be to improve motor function rather than neuroprotection which means that the clinical trial can be shorter and if the results are good, the drug can be brought to market much sooner. This compound may subsequently be shown to be an actual treatment of the disease; it is just that the company's strategy will focus on symptomatic treatment and getting the drug to market quickly if it is found to be effective.

Belinda Tsao-Nivaggioli, Ph.D., updated convention attendees on progress with Avicena's formulation of creatine, reviewing results already presented on the Lighthouse as well as some unpublished results. They hope to start Phase III clinical trials early in 2008. Target enrollment is 650, but there will be an interim analysis after 150, 300, and 450 patients complete the trial in case the data warrants early FDA approval.

In addition, a trial with presymptomatic patients will start enrolling in July 2007.

Dinah Sah, Ph.D., from Alnylam also presented a research update on their progress with synthetic short interfering RNA. There are three stages required to turn siRNAs into drugs. First, there needs to be target specificity. This has been achieved. Second, there needs to be chemical stability. This too has been achieved. Finally, there needs to be an appropriate delivery system. They are still working on this goal.

Len Blackwell, Ph.D., presented for Amphora. They have a high throughput screening process to "identify small molecule chemical compounds to be used by researchers to elucidate the role of specific targets in Huntington's Disease." The compounds are evaluated for both potency and specificity.

They have their own library plus CHDI has acquired other compounds. Two exciting types of promising compounds have been identified, ones which affect histone deacetylases and ones which affect apoptosis.

I am feeling very encouraged about the progress with the research. The strategic plan is clearly a good one that is moving the research forward, there are many promising drugs in the pipeline, several moving through animal studies and several about to go into Phase III clinical trials.

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