KNS-760704
KNS-760704 (dexpramipexole; also referred to by others as R-(+) pramipexole, RPPX) is an orally administered small molecule in clinical development by Knopp and Biogen Idec for the treatment of amyotrophic lateral sclerosis (ALS). The drug is the optical enantiomer of pramipexole, a selective, high affinity dopamine agonist for Parkinson’s disease and restless legs syndrome as Mirapex® (U.S.) and Sifrol® (Europe). Pramipexole is exclusively the S(-) enantiomer (i.e., not a mixture of both enantiomers) and KNS-760704 is exclusively the R(+) enantiomer. Both KNS-760704 and pramipexole demonstrate neuroprotective properties independent of dopamine receptor interaction, but KNS-760704 exhibits greatly reduced dopamine receptor affinity. This makes it possible to clinically evaluate the potential neuroprotective activity of KNS-760704 over a much broader dose range than pramipexole.
NOTE: KNS-760704 and pramipexole are very different drugs. Pramipexole should only be taken as indicated and prescribed by a physician.
DEVELOPMENT STATUS
Phase 1
Knopp has completed Phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of KNS-760704 in healthy volunteers. The first of these studies was a randomized, double-blind, placebo-controlled single ascending dose study, which demonstrated that single oral dosages of up to 300 mg of KNS-760704 were safe and well-tolerated in healthy adult volunteers and that KNS-760704 is rapidly absorbed, with plasma concentrations increasing in proportion to dose. Click here for a summary of the single-dose study results.
A second Phase 1 study examined the safety, tolerability, and pharmacokinetics of multiple doses of KNS-760704 in healthy volunteers. This study showed that KNS-760704 is safe and well tolerated in dosages of up to 150 mg twice a day for 4½ days, with concentrations increasing in proportion to dose. Click here for a summary of the multiple-dose study results.
Phase 2
Knopp has also completed a two-part Phase 2 study, a randomized, double-blind, placebo-controlled, two-part study of KNS-760704 in ALS patients. The principal aim of this study, designated CL201, was to evaluate the safety and tolerability of the drug in ALS patients. Secondary aims included determining the clinical effects of KNS-760704 on the ALS Functional Rating Scale-revised (ALSFRS-R), vital capacity (a measure of respiratory sufficiency), and survival.
The primary objective of the Phase 2 study was to assess the safety and tolerability of KNS-760704 in ALS subjects for up to nine months. Secondary objectives included measuring the clinical effects of KNS-760704 on functional decline and mortality. The two-part design of the study provided the opportunity to assess the effects of KNS-760704 in the same sample of ALS subjects in two randomized, double-blind treatment periods separated by a one-month placebo washout.
In Part 1 of the study, 102 subjects received daily doses of 50 mg, 150 mg, or 300 mg of KNS-760704 or placebo for 12 weeks. KNS-760704 showed a dose-dependent trend in slowing the rate of disease progression as measured by the difference in slopes of ALS Functional Rating Scale-Revised (ALSFRS-R) across treatment groups, with the greatest benefit observed in the 300 mg dose group.
In Part 2 of the study, 92 subjects were re-randomized to receive daily doses of 50 mg or 300 mg of KNS-760704 for 24 weeks. In addition to results again suggesting a dose-dependent trend in slowing the rate of disease progression as measured by the ALSFRS-R, there was also a trend toward a survival benefit in the 300 mg group compared with the 50 mg group. In an exploratory test combining mortality and functional outcomes, subjects in the 300 mg group had a significantly improved outcome compared with the 50 mg group.
The study showed that KNS-760704 is well-tolerated in ALS subjects for up to nine months, and further showed encouraging signs that KNS-760704 may slow functional decline and increase survival. The Phase 2 study supported further development and testing of KNS-760704 in larger Phase 3 studies. The CL201 results were presented by Dr. Merit Cudkowicz (MGH, Harvard Medical School) at the 20th International Symposium on ALS/MND in Berlin, Germany in December 2009, and again, by invitation, at the American Academy of Neurology meeting in Toronto in April, 2010. Results of this study will soon be submitted for publication in a major peer-reviewed journal.
An ongoing Phase 2 safety extension study, for which enrollment is now closed, is a longer-term, open-label trial for subjects who participated in CL201.
An FAQ for patients and caregivers is available by clicking here.
PREVIOUS CLINICAL EXPERIENCE
Approximately 100 ALS patients have received another formulation of dexpramipexole in open-label studies sponsored by James P. Bennett Jr., M.D., Ph.D., Professor of Neurology at the Medical College of Virginia (and formerly of the University of Virginia). To date, dexpramipexole has been safe and well-tolerated in studies conducted under Dr. Bennett's direction.
In the journal Amyotrophic Lateral Sclerosis, Dr. Bennett and his collaborators recently reported a dose-related reduction in the rate of functional decline among ALS patients receiving dexpramipexole. Although these open-label studies were not powered to demonstrate statistical significance, the investigators termed the clinical data encouraging and meriting the study of higher dosages of dexpramipexole. Click here for a link to the publication of these results.