Defining SOD1 ALS natural history to guide therapeutic clinical trial design

Abstract

Importance: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.

Objective: To establish an updated natural history of ALSSOD1.

Design, setting and participants: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.

Main outcomes and measures: Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.

Results: Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02).

Conclusions and relevance: SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

Conflict of interest statement

TB, WS, JL, TS, LHW, ER, NA, KBB, JDG, NJM, JBC, LFM, SHA, JPW, SG, LZ, ALM, JJ-B, PA, ERF, GL, AP report no disclosures. TDB receives licensing fees from Athena Diagnostics, Inc. TM served on a medical advisory board for Biogen Idec. BC receives research support from Impeto Medical Inc and performs medical consultations for Advance Medical and consults for a PCORI grant. MEC is a consultant for Denali Inc, Cytokinetics Inc, AstraZeneca, Biogen Idec, and Voyager Therapeutics. TMM receives research support from Biogen Idec, Ionis Pharmaceuticals and research reagents from Regulus Therapeutics. Washington University, with TMM as a co-inventor, has submitted the US non-provisional patent application ‘Metabolism of SOD1 in CSF’ (Docket #011873-PCT1/1). C2N Diagnostics has licensed IP associated with this patent. TMM served on a medical advisory board for Biogen Idec, and for Ionis Pharmaceuticals.

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Figures

Figure 1

Mean age at onset and disease duration for ALSSOD1 . (A) The mean age at onset and (B) mean disease duration were reported for each mutation population with a minimum n=2. There was no statistical significance between all SOD1 patients (n=162), SOD1non-A4V patients (n=105), SOD1A4V patients (n=57; p=0.7217, Kruskal-Wallis). (A) Average age at onset varied among mutations, with the SOD1G37R and SOD1D133A mutations associated, respectively, with the youngest and oldest mean ages at onset among mutations with more than one patient. (B) Average disease duration varied with different mutations, with SOD1A4T and SOD1G41D mutations associated, respectively, with the shortest and longest disease durations. SOD1A4V disease duration (n=51) is significantly shorter than SOD1non-A4V disease duration (n=83; p<0.0001, Kruskall-Wallis). Error bars represent SD. ALS, amyotrophic lateral sclerosis.

Figure 2

Decreased survival probability from time of disease onset for SOD1A4V compared with SOD1non-A4V familial ALS. (A) Plot for survival probability of all SOD1 mutation patients. One hundred and twelve participants were analysed. The median survival for all SOD1 patients is 2.7 years. The survival probabilities for SOD1 patients and the corresponding 95% CIs were 0.82 (0.73 to 0.88), 0.51 (0.41 to 0.60) and 0.43 (0.33 to 0.53) at years 1, 3 and 5, respectively, after disease onset. (B) Plot for survival probability for SOD1A4V versus SOD1non-A4V mutation patients. Analysis consisted of 33 SOD1A4V and 79 SOD1non-A4V. The presence of SOD1A4V mutations was associated with shorter survival (p<0.0001, log-rank). The survival probability for SOD1A4V patients and the corresponding 95% CIs were 0.60 (0.41 to 0.75), 0.04 (0.00 to 0.15) and 0.00 (NA, NA) at years 1, 3 and 5, respectively, after disease onset. No SOD1A4V patients survived to year 4. The survival probability of SOD1non-A4V patients was 0.91 (0.82 to 0.96), 0.70 (0.59 to 0.79) and 0.60 (0.48 to 0.71) at 1, 3 and 5 years after disease onset. ALS, amyotrophic lateral sclerosis; NA, not available.

Figure 3

SOD1A4V patients with ALS exhibit greater decline in ALS-FRS and FVC rates compared with SOD1non-A4V patients. (A) Least squares mean of ALS-FRS over multiple assessment periods. SOD1A4V patients decline from mean ALS-FRS 37.6 (35.1 to 40.6; 95% CI) at assessment point 1, 29.9 (26.2 to 34.3) at assessment point 2, to 22.3 (16.1 to 31.0) at assessment point 3. SOD1non-A4V patients decline from mean ALS-FRS 35.9 (34.1 to 37.8) at assessment point 1, 35.9 (34.1 to 37.8) at assessment point 2, to 29.9 (27.4 to 32.2) at assessment point 3. The SOD1A4V FRS decline is significantly increased compared to SOD1non-A4V (p=0.0168). (B) Least squares mean of FVC over multiple assessment periods. SOD1A4V patients decline from mean ALS-FRS 86.2 (78.6 to 94.5; 95% CI) at assessment point 1, 58.8 (49.6 to 69.8) at assessment point 2, to 50.8 (34.8 to 74.0) at assessment point 3. SOD1non-A4V patients decline from mean FVC 74.7 (69.5 to 80.4) at assessment point 1, 63.4 (57.5 to 69.8) at assessment point 2, to 55.6 (48.4 to 64.0) at assessment point 3. The SOD1A4V FVC decline is significantly increased compared with SOD1non-A4V (p=0.0168). Error bars represent SEM. ALS, amyotrophic lateral sclerosis; FRS, Functional Rating Scale; FVC, forced vital capacity.