Therapeutic focus - Friedreich's ataxia a goal with few shots

For patients with Friedreich’s ataxia, a candidate to be the first pharmacological treatment for their rare inherited disorder has failed to meet its primary endpoints in two phase III trials and looks to be unlikely to ever make it to market (Catena once again Santhera's downfall, May 20, 2010). Unfortunately for them, the pipeline does not leave much hope for an immediate solution, as only three other candidates have entered the clinic.

The approach of using coenzyme Q10 (CoQ10) to improve mitochondrial function has proven itself to be a popular one, but as Catena, the Santhera drug that just read out with failed phase III numbers, is an oral formulation of CoQ10, research in that space could tail off. However, Penwest is testing alpha-tocopherolquinone in a phase II trial.

A second approach, carbamylated erythropoietin, is in a phase II trial. Both phase II trials are expected to finish next month, so the second half of the year may prove interesting for specialists in Friedreich’s treatment (see table). 

Debilitation, early death

Friedreich’s ataxia is a degenerative neuromuscular disorder that results from a mutation that inhibits production of a protein called frataxin, necessary for proper mitochondrial function. It affects about 1 in 50,000 in the US.

The condition typically affects the spine and peripheral nerves, causing muscle weakness, impaired gait, loss of balance, slurred speech and other neuromuscular symptoms. Heart disorders such as atrial fibrillation, along with type 1 diabetes, can also affect patients.

Symptoms usually appear between the ages of 5 and 15, and the median age of death is 35. No treatment exists, although physicians and patients can manage the condition for example with surgical implants of a rod to prevent spine curvature and mobility devices.

Diverse approaches

As it is a condition that affects the mitochondria, hence CoQ10 is considered a candidate for treatment as it assists in the transport of electrons in the mitochondria. However, Santhera’s synthetic analogue Catena has failed to prove that theory. In the pipeline, however, is New York-based Penwest’s alpha-tocopherolquinone, which is scheduled to complete a 42-patient phase IIa trial in June.

A different approach is being taken by Danish company Lundbeck, which is trying out an erythropoietin for clinical effects. Its carbamylated erythropoietin, LU AA24493, targets production of frataxin. It, too, completes a phase II trial in June, leaving hope that one or both of these candidates will move forward to larger phase III trials in the next year.

Farther back in the pipeline is stem cell technology being tested in phase I by Chinese company Beike Biotechnology, being tested in multiple autoimmune and neuromuscular indications. Pre-clinical programmes include a histone deacetylase inhibitor (HDAC) from Repligen and a beta amyloid aggregation inhibitor with Intellect Neurosciences. Those pre-clinical programmes are being tested in multiple neurodegenerative indications, so it’s not at all clear that they will have a clean shot on goal with Friedreich’s ataxia.

There is still some hope therefore that a new treatment for Friedreich’s ataxia could emerge in the near future. However, given the particularly high R&D attrition rate at phase II, especially in such a hard-to-treat disease, it is unlikely that both phase II candidates will be viable past the end of this year. More shots on goal are needed for patients with this progressive, debilitating and fatal condition.