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Amyloidosis
July 23, 2012
Alnylam Pharmaceuticals announced positive topline results from a phase I trial of ALN-TTR02 for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR). This randomized, single-blind, placebo-controlled, single-ascending dose study completed treatment in 17 healthy patients enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50mg/kg. Preliminary data showed a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable and specific knockdown of serum TTR levels. The drug achieved up to 94% reduction of serum TTR and a nearly 80% level of TTR suppression that was sustained at one month. This suppression was observed at doses as low as 0.15mg/kg, with a mean 81.9% knockdown at nadir. In subjects treated with 0.30mg/kg, an 86.8% mean knockdown was achieved at nadir, and a mean 66.7% reduction was observed 28 days post-dose. In the one patient treated with the 0.50mg/kg dose, knockdown of 93.8% was demonstrated at nadir, with 76.8% reduction maintained at day 28. ALN-TTR02 was generally safe and well tolerated, with no significant treatment-emergent adverse events. Based on the positive results, Alnylam is advancing ALN-TTR02 into a phase II dose-escalation trial.
May 21, 2012
Alnylam Pharmaceuticals reported results from a phase I trial of ALN-TTR01 for the treatment of transthyretin-mediated amyloidosis (ATTR). This randomized, placebo-controlled, single-dose escalation study enrolled 32 patients. Subjects were enrolled in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0mg/kg or placebo. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day seven to 10 in the 1.0mg/kg group (geometric mean relative to placebo, p&equiz;0.01). One patient exemplified the rapid onset of ALN-TTR01, who after one dose showed 63% TTR lowering at 48 hours, peak TTR knockdown of 81% at day 10, approximately 50% lowering at 30 days post-dose and full recovery at 60 days. ALN-TTR01 was found to be generally safe and well tolerated. Mild-to-moderate acute infusion reactions were observed in five of 24 (20.8%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. Alnylam will use the data to advance ALN-TTR02 to phase II in the second half of 2012.
November 28, 2011
Alnylam Pharmaceuticals issued preliminary results from a phase I trial of ALN-TTR01 for the treatment of TTR-mediated amyloidosis (ATTR). Data are from 31 subjects enrolled in this randomized, placebo-controlled, single-dose escalation study. The subjects were placed in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0 mg/kg. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean 41% reduction at the 1.0 mg/kg dose level relative to placebo (p≡0.02). All subjects in the 1.0 mg/kg group (n≡5) showed lowering of serum TTR protein which ranged from 25 to 81%. Nadir levels were achieved approximately seven days after dosing and serum TTR levels remained decreased through at least 24 days. One subject in the 1.0 mg/kg dose group showed 63% lowering at 48 hours, peak suppression of 81% at 7 days, and approximately 50% lowering of serum TTR protein at 28 days post dose. ALN-TTR01 was well tolerated and there were no serious adverse events.
April 18, 2011
Pfizer issued results from a phase II/III trial of tafamidis for the treatment of Transthyretin Familial Amyloid Polyneuropathy. This open-label, 12-month extension study (Fx-006) was conducted to evaluate long-term safety and efficacy in 86 subjects who completed an 18-month pivotal study. All subjects received tafamidis 20 mg orally once-daily for 12 months; the subjects randomized to placebo in the previous study crossed over to active drug. Data showed that earlier treatment with tafamidis resulted in better outcomes. Subjects treated with tafamidis for 30 months had less neurologic deterioration than those who began tafamidis 18 months later, showing a 55.9% preservation of function as measured by the Neuropathy Impairment Score-Lower Limb (NIS-LL), or a mean change from baseline of 3.0 for those treated for 30 months versus 6.8 for those initiating treatment 18 months later (p≡0.04). In addition, subjects treated with tafamidis over 30 months showed preservation in large nerve fiber function (66% preservation or 1.6 versus 4.7 for those treated 18 months later, p≡0.007) and small nerve fiber function (45.5% or 1.2 versus 2.2 for those treated 18 months later.
April 25, 2005
Neurochem issued negative results of a phase II/III trial of Fibrillex, for the treatment of Amyloid A (AA) amyloidosis. Study data did show a trend towards statistical improvement in the number of patients achieving stable or improved disease states vs. placebo (13.4% more subjects; p=0.06), but failed to meet the primary p-value endpoint of p<0.01. Secondary endpoints, including progression to end-stage renal failure/dialysis and slope of decline of creatinine clearance, suggested that the drug was active in the disease. This double-blind, placebo-controlled study enrolled 183 subjects with AA amyloidosis, who received Fibrillex (n= 89) or placebo (n=94) for 24 months. The company announced that they do plan to continue the development of Fibrillex, and that they would meet with the FDA in the near future to discuss the next steps in development.
