Posted by Jeff Berk, BOLT International
Okay, maybe not quite yet breakfast food for Alzheimer’s disease when added to Aricept (donepezil). But here’s my prediction: CONCERT will publish 1Q2012 and then we should officially be ready to butter dimebon (latrepirdine; Pfizer / Medivation) once and for all.
As for today’s news, results from the Phase 3 HORIZON trial: Dimebon (latrepirdine) in patients with Huntington disease, did not achieve statistical significance for either of the co-primary endpoints, the Mini-Mental State Examination (MMSE), which measures cognition (p=0.39), or the Clinician’s Interview-Based Impression of Change, plus caregiver input (CIBIC-plus), which measures global function (p=0.84). “We are disappointed with the results of the HORIZON trial given the high unmet need in this patient population. At this point, we will discontinue development of dimebon in Huntington disease, including the ongoing open-label extension study,” said David Hung, M.D., president and chief executive officer of Medivation. “We will continue our ongoing 12-month Phase 3 CONCERT trial of dimebon and its open-label extension in patients with mild-to-moderate Alzheimer’s disease. We expect to report top-line data from CONCERT in the first half of 2012.”
- We believe that when CONCERT (donepezil +/- dimebolin) publishes it will be a negative study. As far as an approvable therapeutic for Alzheimer’s disease we think Dimebon is toast. The basis for this is the changing view of BOLT’s Alzheimer’s Disease Thought Leader panel from 2009 to 2010. In 2009, there was some level of interest in dimebon for AD, as the Russian data had just been published. But by 2010, as our panelists who were involved with the drug once it hit Western clinical sites, had an opportunity to look more closely, their enthusiasm waned. That’s not a good predictive marker! (and that was a pretty poorly constructed sentence. With writing skills like this I should probably stop blogging and get a day job with the Associated Press). Anyway… here are some of the comments from BOLT’s Alzheimer’s Disease Thought Leader panel:
“I have to say I would have put Dimebon on that list. Dimebon might be a good adjunct to donepezil and memantine yet, but I think Dimebon’s day has come and gone. From all the signals I am seeing I don’t know that it has a long-term survival. I am going to take Dimebon off my list”.
“We had Dimebon. I would have mentioned Dimebon but I am not mentioning Dimebon now because it seems to have not done well in the most recent study. Now it seems like they have just continued some of their studies. That has dropped way down now on the list”.
“Dimebon is an interesting story. It was a molecule looking for a mechanism of action, not the other way around and even the company back away from the acetyl cholinesterase inhibition and the NMD antagonists and said we have exciting mechanism of action but we are not sure what it is. They really are moving toward their mitochondrial activity, which would be really terrific if it occurred. I asked them point blank why aren’t you going after mitochondrial myopathies because Dimebon could be a good treatment for mitochondrial myopathies and it is simply business. They said, look, there is a very low market in mitochondrial myopathies and there is a huge market in Alzheimer’s. It still might work in Huntington’s but I am, again, a little cautious about Huntington’s. If the CONCERT study is negative then the drug is dead. Period. And that will publish when? I think they could announce CONCERT data by the summer. The study is done in terms of enrollment. CONCERT was a donepezil adjunct. A lot of people worry on the basis that the CONCERT and CONNECTION is that their treatment periods are short, only six months. I think we are banking on the Russian data to show them a signal. But I think the issue with CONNECTION was that the placebo group did not decline. That is why it was negative. It is more inconclusive than it is negative. That is not going to get Pfizer an indication. I agree”.
- Dimebon is viewed as an important addition for patients whose disease has progressed beyond the point of reversibility, who need stabilization or a boost to their functional status. There is more uncertainty that the drug has a clinical effect related to its ability to stabilize mitochondria or affect NMDA.
“The Dimebon I found intriguing. That kind of falls into the same thing as analogous sirtuin-1. I don’t know how it is acting. That really intrigues me and easily could be important. So that seems useful. Why does it matter how it is working if it is working? It doesn’t. It just matters whether you believe it. Phase II trials sometimes even in the phase II sometimes look good and then fail, right. Right. Sure. So people would be just intellectually a little more confident if they knew how it was working but I totally agree with you. I don’t think it matters. Antidepressants, they didn’t know how they acted or antipsychotics for the longest time they didn’t know how they acted but they still were used. So I agree with you it doesn’t matter. And it is very intriguing and the mechanism appeals to me. I had even published something that is a mitochondrial protectant that also looks good so I like that approach. It is just a little bit different. So Dimebon is one that almost made it onto the list. I was debating, but without a mechanism, I just thought that might fail. But I certainly would really believe that it could be very useful”.
“So the landscape is always changing and in a very exciting kind of way. I will say to you right now that the drug that is at the top of the list of the fancy formulary despite the fact that I don’t think it is going to be as robust in the US data as in the Russian data I think the drug that is likely to emerge at the top of the list is Dimebon, strictly as a symptomatic drug. You can parse out all the mitochondrial data and NMDA data you like but at the end of the day I think it will be similar to a cholinesterase inhibitor in terms of its scope and magnitude of effect and will be part of the landscape sooner than later”.
“I think we can do better than what we are doing now. I am not sure whether that is going to be a 5HT drug or some unknown symptomatic mechanism, a Dimebon-like drug. I think we are going to do better than we are doing now. I think Dimebon is likely to succeed. I would probably put that in this category. I hope it is disease-modifying as well but I am certain it is symptomatic and looks better than what we have got. So I just put that on the list because I think we can do better for symptomatic treatments as well”.
“I don’t have anything against Dimebon. It is very attractive but without knowing its mechanism of action or without seeing more in the way of long-term clinical outcomes, it is hard for me to think that this is more than another symptomatic therapy. If it turns to that it is complimentary then that would be attractive. I think without some reason to think that it was really a disease-modifying therapy it would be hard to get too enthusiastic about just adding yet another symptomatic therapy to cholinesterase inhibitors and to Namenda. So that is why it didn’t make my list. Now I understand the evidence refutes the possibilities that this is a cholinesterase inhibitors or an NMDA antagonist. So I am comfortable it is not just another version of the existing therapies. But I don’t think there are any great evidences to what the actual mechanism of action is”.
“Then I would still like to have a symptomatic treatment. Is there anything that I would pick better than a cholinesterase inhibitor? I’m not sure if Dimebon really works? So the next one would be from the group of cholinesterase inhibitor or Dimebon or Memantine kinds of symptomatic treatment because I would not want to be limited to a formulary that didn’t have that safety net for the people that came to you late”.