Article Impact Level: HIGH Data Quality: STRONG Summary of: JAMA Network Open, 8(2), e2459058. https://doi.org/10.1001/jamanetworkopen.2024.59058 Dr. Sabrina Paganoni et al. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2024.5249 Writing Committee for the HEALEY ALS Platform Trial et al. JAMA. https://doi.org/10.1001/jama.2024.27643 Writing Committee for the HEALEY ALS Platform Trial et al. JAMA. https://doi.org/10.1001/jama.2024.26429 Writing Committee for the HEALEY ALS Platform Trial et al.
Points
- The HEALEY ALS Platform Trial assessed the efficacy of zilucoplan, verdiperstat, CNM-Au8, and pridopidine in decelerating the progression of amyotrophic lateral sclerosis (ALS).
- Zilucoplan, a complement C5 inhibitor, demonstrated no notable effect on disease progression (DRR: 1.08, 95% CI: 0.87–1.31). The trial was concluded prematurely because it did not demonstrate effectiveness, yet it posed no unforeseen risks.
- The myeloperoxidase inhibitor showed no significant effect on slowing ALS progression (DRR: 0.98, 95% CI: 0.77–1.24). Nausea, insomnia, and elevated thyrotropin levels were frequently observed, yet the medication was largely well tolerated.
- CNM-Au8 (gold nanocrystals) and pridopidine (a sigma-1 receptor agonist) demonstrated no notable advantage in decelerating ALS progression or enhancing functional outcomes (DRRs: 0.97 and 0.99, respectively). Adverse effects reported were diarrhea, nausea, fatigue, falls, and muscular weakness.
- None of the four interventions showed effectiveness in slowing ALS progression, underscoring the critical demand for more effective treatment alternatives in ALS research.
Summary
Four distinct studies within the HEALEY ALS Platform Trial evaluated the effectiveness of different treatments for amyotrophic lateral sclerosis (ALS). The initial investigation evaluated zilucoplan, a complement C5 inhibitor, revealing no significant impact on disease progression in ALS patients. In a study involving 162 participants, zilucoplan demonstrated no significant advantage, presenting a disease rate ratio (DRR) of 1.08 (95% credible interval [CI], 0.87–1.31), which suggests no reduction in disease progression over a 24-week period. The trial was terminated prematurely because it was deemed ineffective, and there were no unforeseen risks associated with the treatment.
The second study examined verdiperstat, a myeloperoxidase inhibitor, and similarly reported no notable effect on ALS progression. A total of 167 participants were involved in the randomized trial, revealing an estimated DRR of 0.98 (95% CI, 0.77–1.24), indicating a slight 2% decrease in disease progression. Verdiperstat demonstrated good tolerability, with frequent adverse events including nausea, insomnia, and increased thyrotropin levels; however, the findings showed no significant advantage in decelerating ALS progression.
The third study involved testing CNM-Au8, an oral suspension composed of gold nanocrystals. Among the 161 participants, 120 were administered CNM-Au8, while 41 were given a placebo. The DRR for CNM-Au8 was 0.97 (95% CI, 0.783–1.175), indicating no notable impact on ALS progression throughout the study duration. Common adverse events observed were diarrhea, nausea, fatigue, and muscular weakness, with no evident benefit noted in either the primary or secondary endpoints.
The fourth study assessed pridopidine, which acts as a sigma-1 receptor agonist. This trial involved 163 participants, revealing a DRR of 0.99 (95% CI, 0.80–1.21), indicating no significant difference in disease progression between the treatment and placebo groups. The predominant adverse events included falls and muscular weakness, with no observed benefits in ALS functional ratings or survival outcomes. In conclusion, none of these interventions demonstrated effectiveness in decelerating ALS progression, underscoring the persistent demand for viable treatment options.
Links to the articles:
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2830151
https://jamanetwork.com/journals/jamaneurology/fullarticle/2830248
https://jamanetwork.com/journals/jama/article-abstract/2830508
https://jamanetwork.com/journals/jama/article-abstract/2830509
References Paganoni, S., Fournier, C. N., Macklin, E. A., Chibnik, L. B., Quintana, M., Saville, B. R., Detry, M. A., Vestrucci, M., Marion, J., McGlothlin, A., Ajroud-Driss, S., Chase, M., Pothier, L., Harkey, B. A., Yu, H., Sherman, A. V., Shefner, J. M., Hall, M., Kittle, G., … Torti, M. (2025). Efficacy and safety of zilucoplan in amyotrophic lateral sclerosis: A randomized clinical trial. JAMA Network Open, 8(2), e2459058. https://doi.org/10.1001/jamanetworkopen.2024.59058 Writing Committee for the HEALEY ALS Platform Trial, Hayden, D. * D., Lai, P.-Y., Donahue, R. A., Chen, H.-W., Wang, J., Mathai, N., Lopes, G., McCaffrey, A., Scalia, J., Luppino, S., Lagier-Tourenne, C., Sadri-Vakili, G., Kolb, S., Heintzman, S., Sufit, R., Szymanski, A., Jenkins, L., Martin, A., … HEALEY ALS Platform Trial Study Group. (2025a). Verdiperstat in amyotrophic lateral sclerosis: Results from the randomized healey als platform trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2024.5249 Writing Committee for the HEALEY ALS Platform Trial, Hayden, D., Lai, P.-Y., Donahue, R. A., Chen, H.-W., Wang, J., Mathai, N., Lopes, G., McCaffrey, A., Scalia, J., Luppino, S., Lagier-Tourenne, C., Sadri-Vakili, G., Kolb, S., Heintzman, S., Sufit, R., Szymanski, A., Jenkins, L., Martin, A., … HEALEY ALS Platform Trial Study Group. (2025b). Cnm-au8 in amyotrophic lateral sclerosis: The healey als platform trial. JAMA. https://doi.org/10.1001/jama.2024.27643 Writing Committee for the HEALEY ALS Platform Trial, Hayden, D., Lai, P.-Y., Donahue, R. A., Chen, H.-W., Wang, J., Mathai, N., Lopes, G., McCaffrey, A., Scalia, J., Luppino, S., Lagier-Tourenne, C., Sadri-Vakili, G., Kolb, S., Heintzman, S., Sufit, R., Szymanski, A., Jenkins, L., Martin, A., … HEALEY ALS Platform Trial Study Group. (2025c). Pridopidine in amyotrophic lateral sclerosis: The healey als platform trial. JAMA. https://doi.org/10.1001/jama.2024.26429
