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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).

Latin American HD Network: Thoughts after the Initial Meeting

This chapter, like many others, begun from the desire to help others, to not forget those less fortunate to have access to the same resources I and some of my Americana and European colleagues have. I was aware of the fact that the gene for Huntington's disease (Huntingtin) was identified through a heroic effort of a multinational team of scientists, who used DNA obtained from the blood samples of a large set of families from a region in Venezuela bordering Lake Maracaibo in the north west of the country. In this area, the prevalence of Huntington's disease was high; there were large families with 3 or 4 generations of affected individuals, which allowed for the type of genetic analysis necessary to identify genetic contributions to the disease. Through a process called 'positional cloning', patterns of inheritance of DNA regions, or 'markers', can be traced to isolate regions where the disease gene resides. These regions became progressively better 'mapped' and this lead to the final identification in 1993 of the gene harboring the mutation responsible for HD. The pictures below are from some of the Venezuelan patients, next to a wonderful person named Aleska de Zambrano, who is the voice of the Venezuelan HD patient and families association.

The importance of Latin America, and Venezuela in particular, has already been large in the field of HD. There are other regions in Colombia and Brazil, and probably others I don't know of as of yet, where HD is highly prevalent. Yet the representation of our efforts in Latin America, from a scientific and clinical perspective, is small. It is almost as if Latin American countries were largely kept 'outside' of many scientific and medical international enterprises. I felt we could do something to change this. I also thought that we needed our colleagues, doctors and scientists, as well as patients and their families, to be more actively involved with the efforts of CHDI. I was aware that recruiting patients for clinical and observational trials was proving challenging, and if we are to develop medicines, we will necessarily need additional patient participation, and also probably additional clinical sites to conduct these studies.

Through my friend Gerardo Jimenez, the then director of the Institute of Genomic Medicine in Mexico, I organized a visit to the National Institute of Neurology, where we met the team coordinated by Dra. Elena Alonso, the director of the medical genetics department. Even though this meeting was rather unsuccessful in initiating efforts to bring our efforts together with theirs, it represented an initial step in consolidating our interest in working with our Latin American colleagues. I invited Dr. Bernhard Landwehrmeyer, from Germany, who is the acting chairman of European HD Network (www.euro-hd.com), and a very accomplished scientist and neurologist. EHDN has established an impressive network through most of Europe of clinicians, patients, scientists and advocacy groups (this network is funded exclusively by CHDI). Bernhard was part of the initial team of scientists headed for Venezuela. His passion and dedication to help cure this disease are unparalleled. He immediately responded to my invitation to come to Mexico and shared his (unknown to me at the time) long standing desire to make a Latin American Network a reality.

Through the support of Robi Blumenstein (the President of CHDI), myself, Bernhard and Dr. Michael Orth from EHDN, organized the first meeting of clinicians and patient groups in Rio de Janeiro (Brazil) this past Feb. 05 and 06. The meeting brought together neurologists and patient representatives from Argentina, Brazil, Cuba, Chile, Venezuela and Spain. The meeting was chaired by Dr Francisco Cardoso of Belo Horizonte (Brazil), who managed to get together several prominent neurologists, to discuss both the incidence and management of HD care in their countries, as well as to discuss common interests in establishing the network. Representatives from Colombia and Peru were unable to come, but will undoubtedly participate in future events. We discussed our vision for why having a Latin American network is important for CHDI and EHDN; why we think that by working together we can maximize the changes of being successful and shortening the time to an effective treatment. A few hours before the meeting begun in Rio, we received notice of the positive preliminary outcome of the ACR-16 trial (carried out by the company Neurosearch in collaboration with EHDN). It was an auspicious beginning. The meeting proved a clear success in terms of excitement among our Latin American colleagues, both the doctors and the lay people. The meeting lead to a selection of an initial committee to consider formalizing such network, and beginning to craft a set of initial objectives, a mission and a constitution for how they want to operate. We agreed to meet next in Buenos Aires in June for the International Meeting of the Association for Movement Disorders.

I don't know what my longer term role will be, as this is outside of my 'day job'… I can only thank the people who have participated and are trying to make this network a reality. I feel that HD is a global disease and therefore our efforts should be global. That together we have a stronger chance at defeating this disease. During the meeting, I met many patients and relatives, who came from all over Brazil, some from far away. They came to talk to us, to ask questions about whether there was any hope of finding any treatments soon… I felt powerless, frustrated, almost emasculated… I could not give them much good news yet… I realized my struggles with work and life are petty compared to the anxiety of knowing that a certain and terrible death awaits them and their relatives, their spouses and children. No statements such as 'please be patient', 'it takes years to do a clinical study', 'we don't understand the disease enough' make justice to the fear of imminent death for those one loves. They sound like a set of excuses for not being able to help… and yet I know we do the best we know, the best we can, to find answers. I went to Rio because I wanted to extend a message of Hope to those in Latin America – this is not an American or European enterprise, it's a global fight to find a cure, which should be made available to all, rich or poor, in NY or Maracaibo. But I also went there because we need more people to work with us. I need every affected person to participate: by donating blood, by speaking out, by enrolling in observational studies, in clinical studies. We simply cannot do it without the patients and the people at risk.

When I was asked many questions about potential therapies, like stem cell transplantation studies, I failed to understand their desperation. I want to communicate to them that right now there are no therapies available, and that therefore they should not expose themselves to treatments unknown to be effective, and which can cause them a lot of harm. My only advice is that they need to educate themselves, through the patients' international or national associations, and through their doctors. The patients should not remain paralyzed, waiting for a pill. There are ways to get involved, and we need to raise that awareness. Go to the following websites: HSG, HDF, EHDN and CHDI. Reach out and ask questions to those who only have the best interest of the patients in mind. I almost cried feeling the sincere gratitude the families and patients expressed to us. Because we had come to them, to be able to converse and answer some of the many questions they have. I left with a strong feeling of urgency, but also of fulfillment, of gratitude for being able to live this moment, and of being able to help in whatever way possible. After all, this is why I became a scientist… so thank you to all who believe in our mission and who understand that there are good scientists working for your health and your life. Obrigado!