Here are the clinical trial abstracts:
Thursday, September 10, 2009, 15:30 - 17:00
The effect of oral temsirolimus on brain atrophy
F. Barkhof, E. Fisher, I. van den Elskamp, M. Miller, B. Jasperse, R. Allen, R. Rudick, L. Kappos (Amsterdam, NL; Cleveland, US; Philadelphia, US; Basel, CH)
Introduction: In MS most active immunomodulatory agents have only modest effects on brain volume. CCI-779 (temsirolimus) is an immunosuppressive compound which suppresses cytokine-driven cell proliferation specifically blocking the interleukin 2-driven T-cell proliferation. In addition, as a neuroimmunophilin ligand (binding to FKBP-12) temsirolimus potentially exerts a neuroprotective effect; thereby targeting two key pathological mechanisms in MS. Previously, CCI-779 demonstrated its immunosuppressive efficacy in a phase II MS clinical trial, with a significant decrease in relapse rate and a reduction in the number of enhancing lesions on MRI in the 8mg group. Here we report the effect of CCI-779 on brain volume change on MRI.
Methods: In a phase II trial, 297 MS patients were randomized to receive either placebo or different doses (2, 4, 8 mg orally per day) of temsirolimus for 9 months. The MRI protocol included conventional T1-weighted and dual-echo T2-weighted 2D spin-echo images with 3mm slices. Brain volume changes were assessed on the former using a registration based method (SIENA) and on the latter using a segmentation based method (BPF). Brain volume changes were compared between treatment groups using ANCOVA with adjustment for baseline brain volume and log-transformed number of enhancing lesions.
Results: Technically successful analyses were possible in 262 patients for SIENA and 274 for BPF. At baseline, all groups were well-matched in terms of normalized brain volume and BPF (p > 0.4 for BPF, p>0.3 for SIENAX). In the placebo-group, a significant change in brain volume occurred: -0.37% (SE=0.13%) for SIENA and -0.32% (SE=0.08%) for BPF. Treatment with temsirolimus significantly reduced the rate of brain atrophy measured by both methods in the 8mg group, with complete stabilization or even minor increase in brain volume in the 8mg group: +0.14% (SE= 0.13%) for SIENA and +0.02% (SE=0.07%) for BPF (p=0.0063 and p= 0.0015 vs. placebo respectively). A dose-dependent effect on the rate of brain volume decline was observed using both methods - for BPF, comparison of the lower doses reached significance versus placebo (p=0.042 for 2mg and p=0.0097 for 4mg).
Conclusion: In addition to an anti-inflammatory effect of CCI-779 on MRI lesion development and relapses, this drug demonstrated a beneficial effect on brain volume change using two independent analysis methods. These results suggest a possible neuroprotective effect of temsirolimus.
Immunomodulation - 1
Thursday, September 10, 2009, 15:30 - 17:30
A phase II open-label multicentre safety and efficacy study of oral recombinant ovine interferon tau administered daily in patients with relapsing-remitting multiple sclerosis
G. Buckle, D. Bourdette, E. Waubant, N. Kachuck, B. Healy, R. Bakshi, C. Guttmann, D. Gilman, C. Liu, H. Weiner (Brookline, Portland, San Francisco, Los Angeles, Reno, Alameda, US)
Objective: To determine the safety and obtain preliminary evidence of efficacy of a novel oral interferon (Tauferon) 3.0 mg TID for nine months, in patients with RRMS.
Methods: This was a Phase II, open-label, multi-center study to evaluate the safety and preliminary efficacy of oral IFN tau (Tauferon) administered daily to patients with RRMS. All patients had at least one Gadolinium (Gd)-enhanced lesion on at least one of three run-in MRIs taken during the three months prior to treatment. Patients received 3.0 mg of oral IFN tau three times per day (TID) for nine months. Patients were followed for an additional three months off treatment and MRI was repeated. The primary analysis compared the mean number of new lesions observed at the scans for months 7-9 after treatment to the mean number of new lesions observed at the second and third pre-treatment scans using a Wilcoxon signed rank test. Secondary analyses compared the pre-treatment mean to the mean at months 1-3 and months 4-6 after treatment using a Wilcoxon signed rank test.
Results: Twenty-five (25) subjects, 5 male and 20 female, at least 18 years of age, with a clinical diagnosis of RRMS according to McDonald (2001) criteria were enrolled and 22 completed the study protocol. The primary analysis showed no significant treatment effect at months 7-9 (p=0.15), but secondary analyses showed a significant decrease in the number of new lesions at months 1-3 (p=0.0001) and at months 4-6 (p=0.0006). Post treatment scans showed no evidence of a rebound effect. Five patients experienced an MS exacerbation on treatment. Laboratory values were typically within the normal range throughout the study. Adverse events were generally mild and did not result in discontinuation of the study drug.
Conclusion: Although Tauferon 3mg TID was not effective at reducing the number of new enhancing lesions at the original time point of interest, the treatment appeared effective during the first six months of treatment. Based on the clinical and laboratory data, daily doses of Tauferon 3mg TID for up to 9 months was safe and well tolerated. Given the safety and potential for efficacy of the treatment, future investigation of this treatment is warranted.
Late breaking news
Saturday, September 12, 2009, 09:30 - 09:45
Atorvastatin therapy in patients with clinically isolated syndrome and high-risk for conversion to multiple sclerosis: the STAyCIS study
E. Waubant, D. Pelletier, M. Mass, J. Cohen, M. Kita, A. Cross, A. Bar-Or, T. Vollmer, M. Racke, O. Stüve, S. Schwid, A.D. Goodman, N. Kachuck, J. Preiningerova, B. Weinstock-Guttman, P. Calabresi, A. Miller, M. Mokhtarani, L. Ding, E. Rosenberg, . ITN020AI Study Management Team, D. Iklé, C. Spencer, S.S. Zamvil (San Francisco, Portland, Cleveland, Seattle, St. Louis, US; Montreal, CA; Phoenix, Dallas, Rochester, Los Angeles, New Haven, Buffalo, Baltimore, New York, Bethesda, Chapel Hill, US)
Background: Oral atorvastatin reverses EAE and promotes immune modulation. Open-label studies suggest statins may be beneficial in RRMS.
Objective: A phase II, double-blind, placebo-controlled, multicenter trial tested efficacy and safety of atorvastatin (80 mg/day) in CIS patients.
Methods/design: Based on the CHAMPS study and the London, UK, CIS cohort, we assumed that 69% of placebo-treated subjects with CIS and at least two silent T2 areas on an initial brain MRI scan would develop 3 or more new T2 lesions, or 1 clinical exacerbation by 12 months. The protocol called for a sample size of 152 subjects, enabling us to detect a 39% therapeutic effect (power 0.80, 2-tailed, 0.05). Participants were randomized to atorvastatin or placebo (3:2) within 90 days of CIS onset. Visits occurred at baseline, months 1, 2 and 3, and then every 3 months (physical, EDSS, MSFC, brain MRI scans). Study drug was discontinued at month 12, with subsequent follow-up through month 18. Patients meeting the primary endpoint (PEP) continued study drug, but were offered additional weekly IM IFN beta-1a (Avonex).
Results: Due to slow recruitment, enrollment was stopped after 81 patients were randomized (76.5% female, 92.6% white, mean age 33.8 ± 9 years, mean duration of CIS at randomization 66 ± 25 days). Initial events included optic neuritis (40.7%), spinal cord syndrome (34.6%), brainstem/cerebellar (17.3%), and others (6.2%). Mean number of T2 and gadolinium-enhancing (Gd+) lesions at baseline were 20.8 ± 17 and 0.5 ± 2.1, respectively. Overall, atorvastatin was well tolerated. 49% of atorvastatin recipients (n=24/49) met PEP compared to 56.3% placebo recipients (n=18/32) (p=0.65). Median time to meet PEP was 386 and 285 days in the atorvastatin and placebo groups, respectively (HR=0.87, p=0.66, Cox proportional hazard ratio adjusted for type of symptoms at onset, and number of T2 lesions at baseline). The median cumulative numbers of new T2 lesions up to month 12 or to starting Avonex were 0 (range 0-17) and 2 (range 0-10) in atorvastatin and placebo groups, respectively. The proportion of patients who did not develop new T2 lesions up to month 12 or to starting Avonex was 55.3% and 27.6% in atorvastatin and placebo groups, respectively (p=0.032).
Conclusion: The study was underpowered to detect the planned effect size due to discontinuation of enrollment and did not meet its PEP. Nevertheless, atorvastatin decreased new brain MRI T2 lesion activity in patients with CIS.