Correspondence
Rasagiline in Parkinson's Disease
N Engl J Med 2010; 362:657-659February 18, 2010
- Article
To the Editor:
In their study of the use of rasagiline in patients with Parkinson's disease, Olanow et al. (Sept. 24 issue)1 report mixed results for 1-mg and 2-mg doses of the drug. My colleagues and I have shown that rasagiline has neuroprotective activity in cell culture and in vivo2-4 and neurorestorative activity in a murine model of Parkinson's disease with the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), resulting in restoration of tyrosine hydroxylase, dopamine, and dopamine neuron-cell numbers in the substantia nigra pars compacta.5,6 Transcriptome and limited proteome analyses have shown the activation of a tyrosine kinase receptor that regulates the neurotrophins glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the substantia nigra pars compacta.
In our neurorestoration studies,5 we examined several doses of rasagiline and established that no neurorestoration occurred if the dose was 0.25 mg or more per kilogram of body weight (which inhibits monoamine oxidase B in the brain). However, when the long-term dose was lower (0.01 or 0.005 mg per kilogram), neurorestorative activity was observed without inhibition of monoamine oxidase B. Thus, it is possible that the 2-mg dose used by Olanow et al. may be high enough to mask its disease-modifying activity, which may be neurotrophin-dependent. There are many examples in pharmacology in which an increased dose of a drug does not necessarily have a similar or greater effect.
Moussa B.H. Youdim, Ph.D.
Technion-Rappaport Family Faculty of Medicine, Haifa, Israel
youdim@tx.technion. ac. il Dr. Youdim reports being a coinventor of rasagiline and receiving royalties from Teva Pharmaceutical Industries. He also reports receiving research and consulting fees from Teva and being the scientific founder of Varinel.
No other potential conflict of interest relevant to this letter was reported.
6 References1
Olanow CW ,Rascol O ,Hauser R , et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009;361:1268-1278
Full Text | Web of Science | Medline2
Youdim MB ,Maruyama W ,Naoi M . Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. Drugs Today (Barc) 2005;41:369-391
CrossRef | Web of Science | Medline3
Youdim MB ,Wadia A ,Tatton W ,Weinstock M . The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 2001;939:450-458
CrossRef | Web of Science | Medline4
Bar-Am O ,Weinreb O ,Amit T ,Youdim MB . Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J 2005;19:1899-1907
Web of Science | Medline5
Sagi Y ,Mandel S ,Amit T ,Youdim MB . Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol Dis 2007;25:35-44
CrossRef | Web of Science | Medline6
Weinreb O ,Amit T ,Bar-Am O ,Youdim MB . Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci 2007;1122:155-168
CrossRef | Web of Science | Medline
To the Editor:
The findings of Olanow et al. regarding rasagiline are laudable but inconclusive and do not warrant a major change in clinical practice. The authors thoughtfully acknowledge several caveats to their suggestion of favorable disease modification with the 1-mg daily dose of rasagiline. An important additional caveat is uncertainty over whether the first of their three requisite efficacy criteria was fulfilled. This hierarchical end point of “superiority of early-start treatment versus placebo . . . between weeks 12 and 36” relies on their stated assumptions of “linearity in the rate of change in UPDRS [Unified Parkinson's Disease Rating Scale] points” during this period and that “the full effect of rasagiline on symptoms had been established” at week 12 (as depicted in Figure 1 of the article). However, changes in the UPDRS score for patients receiving rasagiline (as shown in Figure 3A of the article) suggest nonlinearity between weeks 12 and 36 and that symptomatic effects were not fully established until 24 weeks. Thus, clinical deterioration from disease progression between weeks 12 and 36 may be substantially underestimated for patients receiving rasagiline. Without validation of these explicit assumptions, the first critical end point cannot be considered to have been met, and efficacy should not be claimed.
Michael A. Schwarzschild, M.D., Ph.D.
MassGeneral Institute for Neurodegenerative Disease, Boston, MA
michaels@helix.mgh. harvard. edu No potential conflict of interest relevant to this letter was reported.
Author/Editor Response
Our delayed-start study was designed to determine whether an intervention could provide benefits that could not be accounted for by symptomatic effects and that would be consistent with disease modification. Two findings were critical for a positive result: one, that the UPDRS score had deteriorated less in the early-start group than in the delayed-start group between baseline and the final visit, even though all patients were receiving the same treatment; and two, that slopes of deterioration in UPDRS scores in period 2 did not converge, indicating that benefits were not due to a delayed symptomatic effect.1
In our study, slope analysis in period 1 was performed at the request of the Food and Drug Administration to determine whether the rate of deterioration in the placebo group was faster than that in the rasagiline group, as might be expected with a disease-modifying drug.2 This analysis was not critical, although it was positive for both doses. With respect to the comments by Schwarzschild, Figure 3A of our article shows raw mean scores for the second and third primary end points, not the calculated slope for the first primary end point, which was derived from a model of a different cohort of patients that included covariant effects and used all available data. Schwarzschild is correct that the model for the first primary end point assumed linearity in the rate of change in the UPDRS score. However, results were confirmed by an alternative categorical model.
We agree that our results cannot be considered definitive, since they differed for the 1-mg and 2-mg doses. Youdim notes that neuroprotection can follow a U-shaped curve, which could theoretically account for the failure of the 2-mg dose. However, these effects are usually observed with larger changes in concentration. We feel that the masking of a possible disease-modifying effect by a greater or more prolonged effect on symptoms with this dose in this population with very mild disease is a more likely explanation.
In the TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients (TEMPO) delayed-start study,3 in which the mean baseline UPDRS score was 25 (as compared with 20 in our study), the 2-mg dose was positive. Furthermore, patients in the highest quartile of baseline UPDRS scores (>25.5) in our study met all primary end points, despite the small sample size. A repeat delayed-start study testing the 2-mg dose in patients with higher baseline UPDRS scores could resolve this issue. For now, clinicians must use their judgment to determine whether the potential benefits and risks of the 1-mg dose of rasagiline warrant its use as a possible disease-modifying agent.
C. Warren Olanow, M.D.
Mount Sinai School of Medicine, New York, NY
warren.olanow@mssm. edu Olivier Rascol, M.D., Ph.D.
Centre Hospitalier Universitaire, Toulouse, FranceSince publication of their article, the authors report no further potential conflict of interest.
3 References1
D'Agostino RB Sr . The delayed-start study design. N Engl J Med 2009;361:1304-1306
Full Text | Web of Science | Medline2
Bhattaram VA ,Siddiqui O ,Kapcala LP ,Gobburu JVS . Endpoints and analyses to discern disease-modifying drug effects in early Parkinson's disease. AAPS J 2009;11:456-464
CrossRef | Web of Science | Medline3
Parkinson Study Group
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Jacques Joubert, Werner J. Geldenhuys, Cornelis J. Van der Schyf, Douglas W. Oliver, Hendrik Gert Kruger, Thavendran Govender, Sarel F. Malan. (2012) Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs. ChemMedChemn/a-n/a
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R. Takeuchi, A. R. Lambert, A. N.-S. Mak, K. Jacoby, R. J. Dickson, G. B. Gloor, A. M. Scharenberg, D. R. Edgell, B. L. Stoddard. (2011) Tapping natural reservoirs of homing endonucleases for targeted gene modification. Proceedings of the National Academy of Sciences 108:32, 13077-13082
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Peter Riederer, Gerd Laux. (2011) MAO-inhibitors in Parkinson's Disease. Experimental Neurobiology 20:1, 1
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Spyros N. Deftereos, Christos A. Andronis. (2010) Discordant effects of rasagiline doses in Parkinson disease. Nature Reviews Neurology 6:7,
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