Idebenone, a substance believed to act as an antioxidant and to aid in energy production in cellular structures called mitochondria, has failed to benefit people with Friedreich's ataxia (FA) in a phase 3 trial conducted at several European centers. The drug is similar to coenzyme Q10, a naturally occurring molecule.
The trial involved 232 people, most of whom were adults, and was conducted by Santhera Pharmaceuticals, a Swiss company that's developing idebenone for FA and other diseases under the brand names Catena and Sovrima.
Although idebenone (Catena/Sovrima) was safe and well tolerated at doses up to 2,250 milligrams per day, it failed to meet its primary measure of success (end point), which would have been a significant change in the International Cooperative Ataxia Rating Scale (ICARS).
"We are surprised and disappointed by the [trial] results," said Thomas Meier, chief scientific officer at Santhera, in a May 20, 2010, press release. (See Santhera's MICONOS Trial with Catena/Sovrima in Friedreich's Ataxia Misses Primary Endpoint.)
In a May 20 teleconference, Santhera executives emphasized that they will continue to pursue idebenone development for other diseases, including Duchenne muscular dystrophy (DMD) and the mitochondrial myopathy known as MELAS, and that they have not yet made a final decision about pursuing development of idebenone for FA.
About the new findings
The 232-person, primarily adult trial of idebenone in FA lasted one year. Known as MICONOS (Mitochondrial Protection with Idebenone in Cardiac Or Neurological Outcome Study), it evaluated the safety and efficacy of three doses of Catena/Sovrima and compared these to a placebo.
There was no statistically significant difference in the average ICARS score change from the start to the end of the trial in the idebenone-treated versus the placebo groups. The ICARS measures functions such as posture, stance, limb coordination, speaking ability and eye movement.
The trial also evaluated several secondary end points, including the proportion of patients improving on the ICARS score and the change in another score, the Friedreich's Ataxia Rating Scale (FARS), and some measures of cardiac function and anatomy.
Although some of the cardiac analyses are still under way, Santhera said that so far no significant differences between the treated and the placebo groups have been found for any of the secondary end points.
The company is, however, conducting a combined analysis of 344 patients from three of its idebenone studies in FA, and that combined analysis has shown a "trend" toward improvement for people on the drug, said Santhera CEO Klaus Schollmeier in a May 20 teleconference, archived on the company's website. (See Miconos Study Results.)
In fact, he said, when the mid- and high-dose groups were combined and compared to the combined placebo groups, the difference was statistically significant in favor of the treated trial participants.
About previous trials of idebenone in FA
A year ago, Santhera's phase 3 trial of idebenone in 70 children with FA ages 8 to 17 likewise did not show benefit. That trial, known as IONIA (Idebenone Effects On Neurological ICARS Assessments) was conducted in the United States and lasted six months. (See Idebenone Not Effective in 70 Children with FA and Santhera's US Phase III IONIA Trial in Friedreich's Ataxia Misses Primary Endpoint.)
An earlier, phase 2 study, known as NICOSIA (National Institutes of Health Collaboration With Santhera in Ataxia), lasted six months, included 48 patients, and showed a statistical trend toward dose-related improvements in neurological function. Those results were announced in 2006. (See NIH Completes Collaborative Phase II Study with Santhera's Compound SNT-MC17/Idebenone in Friedreich's Ataxia.)
Meaning for people with FA
Santhera has not made a final decision on a path forward for idebenone in FA.
"It is too early to conclude whether or not it is beneficial for individual Friedreich's ataxia patients," Santhera CEO Schollmeier said of idebenone in Santhera's May 20 teleconference.
An open-label extension study of the U.S. idebenone trial will be available soon, Schollmeier said, and an open-label extension of the MICONOS trial is still under way. There is no placebo group in open-label studies.
Santhera's idebenone product has received conditional approval for FA in Canada under the brand name Catena, and Schollmeier emphasized that, for now, this conditional approval remains in effect.
He said Catena's safety profile is excellent and that the company remains convinced "that some patients benefit from Catena/Sovrima" even though it has "not been able to demonstrate this conclusively” in the MICONOS trial. He noted that the MICONOS trial may have been too short and too small to show an effect in a highly variable disease like FA.
Meaning for people with DMD, MELAS
During the May 20 teleconference, Santhera CEO Schollmeier said the FA trial findings will not affect the company's development of idebenone for other indications, such as Leber's optic neuropathy, MELAS or DMD. He said Santhera will "soon report" on the results of a trial of the drug in MELAS and that it expects to see data towards the end of the 2010 in DMD.
Meanwhile, he said, "We will wait for these data before deciding on a way forward for Catena/Sovrima in any of the indications, including Friedreich's ataxia."