Triple Therapy with Darbepoetin Alfa, Idebenone, and Riboflavin in Friedreich’s Ataxia: an Open-Label Trial

Abstract

Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 μg darbepoetin alfa every 2 or 3 weeks, 10-20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.

Emerging Therapies in Friedreich’s Ataxia

“…LVMI decreased between 8.3 and 21.8 g/m 2 and LVEF decreased between 3.6 and 7.5%. Triple therapy yielded cardiac stability in participants during the 4 years of treatment [57]. …”

Milestones in Friedreich ataxia: more than a century and still learning

“…Considering that the effect of idebenone alone might be unremarkable, a small open study including nine patients with FRDA investigated the effect of triple therapy of idebenone 10-20 mg/kg/ day, riboflavin 10-15 mg/kg/day, and 150 μg darbepoetin alfa every 2-3 weeks for 32±19.4 months. Although there was no improvement in ataxia during the first months, a small decrease in disease progression during the following 2 years of treatment was observed [72].…”

“…Although some data demonstrated reduced iron accumulation in DN evaluated by apparent transverse relaxation rate on MRI study, no neurological improvement was observed [75]. In addition, Arpa et al studied a combined therapy with deferiprone, idebenone, and riboflavin and showed an uncertain benefit in cardiac hypertrophy and no neurological improvement [72] [56].…”

Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis

“…It is a potent antioxidant 50 and can donate electrons to complex III of the electron transport chain. This drug has also found utility in studies on mitochondrial diseases including Friedreich’s Ataxia 51 and is approved in Europe for Leber’s Hereditary Optic Neuropathy 52 . It is therefore possible that idebenone, while exhibiting only weak activity on Mtb whole cells, could have potential for repurposing against additional diseases as well.…”