Treatment Effect of Idebenone in Leber Hereditary Optic Neuropathy Using an Alternate Threshold of Clinically Relevant Visual Acuity Change
Prem Subramanian1, Patrick Yu-Wai-Man2, Valerio Carelli3, Xavier Llòria4, Thomas Klopstock5
1Sue Anschutz-Rodgers University of Colorado Eye Center, 2University of Cambridge, 3IRCCS Istituto di Scienze Neurologiche di Bologna, 4Chiesi Farmaceutici S.p.A, 5Friedrich Baur Institute
Objective:

To re-assess LEROS visual acuity (VA) outcomes using the stricter FDA-recommended threshold for clinically relevant VA change (±0.3 logMAR).

Background:

LEROS, a phase IV, open-label, natural-history (NH) controlled study (NCT02774005), improved VA outcomes with idebenone for patients with Leber hereditary optic neuropathy over 2 years, although response varied by disease phase and mitochondrial DNA (mtDNA) mutation.

Design/Methods:

Idebenone-treated and matched NH eyes were assessed for clinically relevant benefit (CRB), recovery (CRR), and worsening (CRW) at 12 months. Clinically relevant VA change was defined as ±0.3, rather than ±0.2 logMAR. Eyes were stratified by time since onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year), and by mtDNA mutation: m.11778G>A, m.3460G>A, m.14484T>C.

Results:

In the subacute/dynamic phase, a significantly higher CRB rate (36.6% [n=52/142] vs 20.7% [n=40/193], p=0.039, odds ratio [OR] 1.75), and significantly lower CRW rate (23.1% [n=27/117] vs 53.1% [n=69/130], p<0.001, OR 0.31) was observed for idebenone-treated versus matched NH eyes, respectively. CRR was observed in 26.1% (n=37/142) of idebenone-treated versus 17.6% (n=34/193) of matched NH eyes (p=0.538, OR 1.20).

In the chronic phase, a significantly higher CRB (46.2% [n=66/143] vs 36.6% [n=56/153], p=0.031, OR 1.71) and CRR rate (26.6% [n=38/143] vs 16.3% [n=25/153], p=0.016, OR 2.03), and a significantly lower CRW rate (3.1% [n=3/96] vs 12.4% [n=11/89], p=0.010, OR 0.20) was observed for idebenone-treated versus matched NH eyes, respectively. Overall, VA outcomes by disease phase were similar to previous analyses using ±0.2 logMAR.

VA outcomes assessed by mtDNA mutation showed similar trends to those in previous analyses using ±0.2 logMAR.  However, there were differences in the magnitude of CRR/CRW (treated vs NH) observed in some cases.

Conclusions:

Using the stricter FDA-recommended threshold for clinically relevant VA change to re-assess the LEROS data, idebenone treatment still improved outcomes in many cases. However, treatment effect varied by disease phase and mtDNA mutation.

10.1212/WNL.0000000000216742
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