Last week, the ALS Study Group, which is similar to the Huntington Study Group published distressing results from a large phase III clinical trial testing minocycline in amyotrophic lateral sclerosis. Results had been released to the ALS community in May, 2007, warning them to stop this drug. Of interest for the HD community, ALS scientists first privately and then publicly expressed concern about testing this drug in other neurodegenerative diseases. In this article Dr. Goodman reviews the study, discusses possible reasons for concern, and recommends against its use in Huntington's outside of clinical trials.
Why the Concern? ALS scientists are concerned about minocycline in Huntington's and other neurodegenerative diseases because several overlapping nerve injury mechanisms occur in all of these diseases. Specifically, no one knows why minocycline was shown to be harmful in ALS people, but these scientists are highly concerned that the drug's detrimental effects in ALS may have occurred in nerve cell mechanisms that are shared by people from other neurodegenerative diseases.
The Study: Four hundred and twelve ALS patients participated in this randomized and placebo controlled trial [Gordon PH 2007]. Half of the group received minocycline at dosages that varied between 200 and 400 mg/day, the other half received placebo. Participants were monitored for disease progression every month for 9 months, which is ¼ of the average life expectancy for ALS.
The Results: In an unexpected result, patients in the group who took minocycline did significantly worse. Minocycline treated patients showed a 25% faster decline in functional capacity than those who got placebo. The authors then showed two other important things: first that equally detrimental effects occurred at both 200 mg and 400 mg dose levels, and second that ALS worsening in the minocycline group was not due to drug side effects.
Prior to this phase III trial, two safety trials had been performed [Gordon PH 2004]. The first used 200 mg dosing, and the second trial used 400 mg. Though direct comparisons of these two trials can not be made, the trend was for no change in the lower dose group and worsening in the larger dose group. Though it's a moot point now, (and doesn't bear on implications regarding its use in HD) it could be questioned why the phase III ALS trial went forward without further safety testing.
Comments: While it isn't unusual for scientists to disagree, it is extraordinary for ALS scientific leaders to "stick their necks out" and go public with their concerns about minocycline for other neurodegenerative diseases. Why do they raise these concerns? Because they believe there is reasonable possibility for similar reactions in these other diseases. On the other side, Huntington Study Group leaders reviewed the study, and have assessed the potential risk as insufficient to delay minocycline trials in HD. Their decision is based on results in a 4 month safety trial in 60 HD patients (18 recieved 100 mg, 19 recieved 200 mg, 23 placebo) [Huntington Study Group 2004].
There are HD scientists who suggest that 4 months might be too short of a time to assess safety for minocycline in HD [Reynolds N 2007]. This author reported high rates of disfiguring pigmentation in 23 (out of 34) HD patients who took 200 mg per day for at least 1 year of treatment. In fact, a severe case from the ALS study (with impressive pictures I can't post) has been published [Mozaffar T 2006].
Which group, the ALS Study Group or the Huntington Study Group is right? The fact is that either group could be right, because nobody knows (yet) why minocycline was harmful in ALS.
HDDW Recommendations: It is my opinion that results from this clinical trial in ALS suggest a potential harm in HD when used long term. If you are taking this drug outside of a clinical trial, I recommend that you stop it until more is known about safety.
Why do I make this recommendation? Remember that minocycline seemed to help the ALS mouse, but this clinical trial definitively showed it hurt ALS people. Apparently this drug has very different effects on ALS mice and ALS people. Admittedly HD mice are probably better models than the ALS mouse, but remember even here there have been contradictory results of benefit in mouse models[Mievis S 2007].
Until more is known about what caused harm to people, I believe that results from this high quality ALS human trial trumps any results found in mice, some HD models included.
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R; Western ALS Study Group. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007 Dec;6(12):1045-53. Epub 2007 Nov 5. PubMed abstract
Gordon PH, Moore DH, Gelinas DF, Qualls C, Meister ME, Werner J, Mendoza M, Mass J, Kushner G, Miller RG. Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology. 2004 May 25;62(10):1845-7. PubMed abstract
Huntington Study Group. Minocycline safety and tolerability in Huntington disease. Neurology. 2004 Aug 10;63(3):547-9. PubMed abstract
Reynolds N. Revisiting safety of minocycline as neuroprotection in Huntington's disease. Mov Disord. 2007 Jan 15;22(2):292. PubMed abstract
Mozaffar T, Gordon PH. Minocycline-induced skin and dental pigmentations. Neurology. 2006 Dec 26;67(12):2185. PubMed abstract
Mievis S, Levivier M, Communi D, Vassart G, Brotchi J, Ledent C, Blum D. Lack of minocycline efficiency in genetic models of Huntington's disease. Neuromolecular Med. 2007;9(1):47-54. PubMed abstract