rapamycin / sirolimus / temsirolimus

A board to discuss future MS therapies in early stage (Phase I or II) trials.

rapamycin / sirolimus / temsirolimus

Postby dignan » Fri Apr 02, 2010 12:34 pm

Two interesting studies were reported in the last two months on the effects of rapamycin (aka sirolimus and maybe other brand names) on memory and life span.

Rapamycin rescues learning, memory in Alzheimer's mouse model
February 24, 2010 - Rapamycin, a drug that keeps the immune system from attacking transplanted organs, may have another exciting use: fighting Alzheimer's disease.

for the rest: http://www.physorg.com/news186253105.html


A drug that extends life span prevents Alzheimer's deficits
April 1, 2010 - If research results continue to be repeated and are turned into clinical trials, a drug already approved for some uses could be marshaled -- sooner than we expect -- to prevent Alzheimer's disease in humans and improve health to the end of life.

A few weeks after a report that rapamycin, a drug that extends lifespan in mice and that is currently used in transplant patients, curbed the effects of Alzheimer's disease in mice, a second group is announcing similar results in an entirely different mouse model of early Alzheimer's.

for the rest: http://www.physorg.com/news189363163.html



OK, so that's sirolimus. Temsirolimus (CCI-779) is a derivative of sirolimus and goes after the same target (see: http://en.wikipedia.org/wiki/Temsirolimus). Temsirolimus went through a large phase 2 trial for the treatment of MS. On completion of the trial, Wyeth decided not to proceed but I never found any explanation for that decision. Last year, at the ECTRIMS conference, some promising results from that trial were reported:


Neuroprotection
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.


I don't know if these researchers are going to continue studying CCI-779 for MS, but I hope so.
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Postby dignan » Mon Apr 05, 2010 5:35 pm

A bit more about all the rapamycin hubub:

http://pipeline.corante.com/archives/20 ... eimers.php
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