In the phase 2b PARADIGM trial, 68 adults with amyotrophic lateral sclerosis (ALS) were randomized 2:1 to PrimeC or placebo for 6 months, followed by a 12-month open-label extension in which all participants received PrimeC. At month 6, the adjusted mean ALS Functional Rating Scale-Revised (ALSFRS-R) score favored PrimeC by 2.23 points, but the difference was not statistically significant. By month 18, participants originally assigned to PrimeC had a 7.92-point higher adjusted ALSFRS-R score than those initially assigned to placebo. Early treatment was associated with a lower risk of the composite of death, respiratory insufficiency, or ALS-related hospitalization. Overall adverse-event rates were similar during the double-blind phase, although treatment-related events occurred more often with PrimeC and were generally mild to moderate and transient.

The findings remain preliminary. The trial was not powered to establish clinical efficacy or survival benefit, secondary and exploratory outcomes were not adjusted for multiple comparisons, and the open-label extension limits interpretation of long-term between-group differences. Neurofilament light levels did not differ significantly between groups, while exploratory iron-regulatory and microRNA biomarkers showed changes that may support PrimeC’s proposed multitarget mechanism. The authors conclude that PrimeC was generally well tolerated and that the observed functional, time-to-event, and biomarker signals warrant confirmation in a larger, adequately powered phase 3 trial.

Reference: Cudkowicz M, Drory VE, Chio A, et al. Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial. JAMA Neurol. 2026 May 1;83(5):471-480. doi: 10.1001/jamaneurol.2026.0230.

Authors of a retrospective Cleveland Clinic study evaluated 114 patients who tested positive for voltage-gated potassium channel (VGKC)-complex antibodies to determine how antibody levels related to neurologic disease and autoimmunity. Only 11 patients had classic VGKC-complex-associated syndromes-limbic encephalitis or neuromyotonia—while 103 had a wide range of other neurologic or non-neurologic diagnoses. Higher antibody levels were much more strongly associated with classic disease: a cutoff of at least 0.25 nM provided 90.9% sensitivity and 78.6% specificity for limbic encephalitis or neuromyotonia, and 75% of patients with titers at or above this threshold had a definite or probable autoimmune basis. By contrast, most patients with lower titers had conditions considered unlikely to be autoimmune.

The findings underscore the importance of interpreting VGKC-complex antibody results within the patient’s overall clinical presentation rather than treating a positive result as diagnostic on its own. Low-level antibodies were found across nonspecific, neurodegenerative, and other conditions and may also occur in healthy individuals, making isolated low titers difficult to interpret. Malignancy was documented in 26.3% of the cohort. Antibody level did not predict cancer, most malignancies had already been diagnosed before antibody testing, and referral and selection bias may have contributed to the high observed rate. The authors therefore recommend particular caution with low-level results and emphasize clinical judgment, while noting that more specific antibody testing could improve diagnostic value.

Reference: Jammoul A, Shayya L, Mente K, et al. Clinical utility of seropositive voltage-gated potassium channel-complex antibody. Neurol Clin Pract. 2016 Oct;6(5):409-418. doi: 10.1212/CPJ.0000000000000268.

Authors of a systematic review and network meta-analysis of 60 studies evaluated enzyme replacement therapy (ERT) versus best supportive care in late-onset Pompe disease. Among patients who were ERT-naive, approximately 1 year of treatment was associated with significant improvements in 6-minute walk distance versus placebo—about 25 m with alglucosidase alfa and 54 m with avalglucosidase alfa. No statistically significant differences were found for forced vital capacity percentage predicted. Evidence for cipaglucosidase alfa with miglustat was limited by the small number of ERT-naive participants available for analysis. Although avalglucosidase alfa initially appeared superior to other ERTs for walking distance, that difference was no longer significant after sensitivity analysis accounted for skewed data.

Overall, the evidence did not demonstrate clear, consistent differences in clinical outcomes among the three ERT options. Longer-term observational studies suggest that early improvements may be maintained for 1 to 3 years before walking and respiratory function gradually decline over subsequent years, but small sample sizes, missing data, and limited comparative evidence make the durability of treatment effects uncertain. Two of the three randomized trials were also judged to have a high risk of bias. The authors conclude that ERT provides short-term functional benefit, while its long-term effect on disease progression and supportive-care needs remains unclear.

Reference: Corbett M, Umemneku-Chikere C, Nevitt S, et al. Enzyme replacement therapy compared with best supportive care for the treatment of Pompe Disease: a systematic review and network meta-analysis. Health Technol Assess. 2026 Feb 11:1-58. doi: 10.3310/GJRH0730.