CHDI Therapeutics Conference in Palm Springs

From the 8-11 February we held the 5th annual conference on HD therapeutics. The conference brings together scientists from academia and industry (mostly CHDI funded investigators or collaborators), physicians, and patient relatives or support group representatives. The meeting focuses on discussing the most recent advances in drug development for HD, including exciting new clinical programs as well as academic research with fundamental implications for therapeutic development.

This year people left the meeting with a renewed sense of hope, since several programs in clinical stages for other indications were discussed in the context of a collaboration with CHDI for entering clinical development for HD. There are 2 in particular which I will comment on. The first is a CoQ10-analog (EPI-743) from the company Edison Pharmaceuticals; the second is an autophagy inducer, a Farnesyl-transferase inhibitor (FTI) coded LNK-754, from the company LINK Medicine. Since I want to discuss both of these approaches and my view on their relative potential, I will dedicate a single blog entry to each of them. I fear writing about them both now at length will make everyone fall asleep. The good news is that there are novel medical entities which have made their way into the clinic and which try to affect new mechanisms never tested in HD. This I believe is the beginning of a new period of hope for HD patients, since in the next few years we will see an explosion of new trials and potentially new medicines.

Before I conclude today I wanted to address the progress made in the clinical trials conducted by EHDN with Neurosearch on the Phase III evaluation of the molecule ACR-16. The results of the trial with this molecule (supposedly a 'dopamine stabilizer') have been positive in the motor domain, having an effect magnitude in both chorea (involuntary movements) and voluntary movements (including eye movements) in the UHDRS (the 'unified HD research scale') similar to that observed with Tetrabenazine. Dr Joakim Tedroff spoke about the mechanism of ACR-16 (Huntexil) and the results of the trial. In spite of the fact that this initial Phase III trial will likely not be sufficient for registration on its own, ACR-16 will very likely become a new drug for the treatment of the motor dysfunction in HD. A second Phase III trial in the USA will be conducted shortly, which hopefully will lead to a registration with the FDA and EMEA (the European equivalent of the FDA).

Please see the following link for more information:

http://www.neurosearch.com/Default.aspx?ID=16&M=News&PID=12&NewsID=15889

Currently the FDA requires at least evidence of positive effects on meaningful outcomes in two different trials. This view might be changing for orphan indications. A positive results from a smaller Phase II trial can sometimes be used for evidence of positive effects if the results from a single Phase III study are robust and there is a strong medical need for treating an orphan condition.

In spite of the fact that ACR-16 will not significantly enhance the cognitive or depression domains in HD, nor affect the progression of the disease (in my opinion based on this mechanism), there are reasons to celebrate. ACR-=16 was as effective as tetrabenazine in treating movement dysfunction (3 points in the UHDRS scale), but with far fewer side effects. ACR-16 was very well tolerated, suggesting that many more people might now be able to take a drug for controlling their motor dysfunction with few problems. The trial was also a large trial (over 400 patients completed the study) conducted in Europe under EHDN's monitoring. The trial was a clear success (and not only because the drug was effective): the coordination between the many centers, the high compliance rate, and the quality of the data processing and analysis, represents a clear advance in HD clinical work. I feel confident that, based on this work, we will be able to conduct large trials for other (more hopeful) drugs to slow the progression of HD.

The mechanism of ACR-16 is in my opinion very poorly understood - they term it a 'dopamine stabilizer' which means little (and is not a scientific term even if it sounds like one). I am speaking strictly as an individual scientist, and not as the head of biology at my company!

ACR-16 can bind and affect signaling by the dopamine receptors (D1 and D2), the main 'controllers' of movement initiation, termination, and coordination. They can bind these receptors and block their signaling at certain doses. However, the dopamine system is such that the levels of dopamine in the brain are self-regulated. It is thought that there are two modes for signaling of dopamine: 'tonic' and 'phasic'. Tonic means that there is always a low level 'tone' of dopamine which, due to its higher preference ('affinity') for D2 receptors (which can be considered the 'brakes' in movement control), keeps us in full control of movement. When these receptors are significantly lost, for instance in HD, involuntary movements can occur (the 'brake is gone'). Signaling through D1 in the basal ganglia (the area most affected in HD) controls movement initiation.

The 'phasic' dopamine signaling refers to the observation that large increases in dopamine release at the synapses are seen when animals are about to initiate movement or upon the expectation of a reward, for instance. When one encounters new situation or are faced with choices, there is a surge of dopamine in the brain. This leads to the 'phasic' dopamine increases (because it returns to baseline shortly thereafter). Apparently scientists have shown that ACR-16 (even though it can act to inhibit dopamine signaling, it leads to a maintenance of tonic dopamine levels in the brain (hence 'stabilizer'). This is supposedly having an effect on initiation of movement (which is affected in HD since it is thought that there is a stronger D1-drive, which is manifested in the uncontrolled movements and lack of coordination seen in HD patients). I am not convinced that this is how this drug works, although i cannot give a different explanation. It is possible that the drug can bind other receptors we don't know off. What it tells us is that probably the modulation of dopamine signaling can be important for HD in some domains, but that the normalization of its signaling is not sufficient to slow disease progression or lead to a great improvement in the quality of life of HD (specially as the disease advances).