Negative findings from trials with NLY01 or deferiprone for Parkinson's disease – Author's reply

We thank Thomas Müller and Jan Dominique Möhr for their thoughtful comments. The hypothesis that other GLP-1 receptor agonists (ie, liraglutide and lixisenatide) have shown a benefit in people with Parkinson's disease due to a combination of weight loss and dopaminergic treatment would seem to depend on the difference in bodyweight between the treatment and placebo groups. How much weight loss would be sufficient is unclear. Weight loss adverse events in our study were not common (two in the placebo group, five in the 2·5 mg NLY01 group, and five in the 5 mg NLY01 group), and the mean weight loss from baseline to week 36 was 1·5 kg (SD 3·1) for NLY01 5·0 mg, 1·2 kg (2·7) for NLY01 2·5 mg, and 0·4 kg (2·5) for placebo.1McGarry A Rosanbalm S Leinonen M et al.Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2024; 23: 37-45Summary Full Text Full Text PDF Google Scholar Although uncertain, an effect of weight loss does not seem likely to be robust in our study had standard therapies been used. How much weight was lost in the liraglutide study is not clear.2Wu T Bresee C Wertheimer J et al.Liraglutide once daily versus placebo in Parkinson's disease: a randomized, double-blind, placebo-controlled trial.Mov Disord. 2022; 37: S359-S360Google Scholar The phase 2 trial on lixisenatide3Meissner WG Remy P Giordana C et al.Trial of lixisenatide in early Parkinson's disease.N Engl J Med. 2024; 390: 1176-1185Crossref Scopus (2) Google Scholar reported six weight loss adverse events among 78 people who received treatment compared with none for placebo. Notably, although associated with benefit on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, mean weight did not change over time in the treatment group. These data are not consistent with our colleagues' hypothesis of weight loss driving benefit in treated participants. Müller and Möhr suggest nausea in the lixisenatide group within the phase 2 trial3Meissner WG Remy P Giordana C et al.Trial of lixisenatide in early Parkinson's disease.N Engl J Med. 2024; 390: 1176-1185Crossref Scopus (2) Google Scholar is suggestive of higher dopaminergic exposure; we note that nausea was also common in our study (49 [58%] of 85 with 5 mg NLY01, 33 [39%] of 85 with 2·5 mg NLY01, and 16 [19%] of 84 with placebo) when standard therapies were not used, and that nausea is an expected side-effect of GLP-1 receptor agonists. The lixisenatide group in the phase 2 trial3Meissner WG Remy P Giordana C et al.Trial of lixisenatide in early Parkinson's disease.N Engl J Med. 2024; 390: 1176-1185Crossref Scopus (2) Google Scholar had a numerically higher levodopa equivalent daily dose (LEDD) at month 12 than the placebo group, although the result was not statistically significant. One might expect a lower LEDD in the treatment group, not higher, had weight loss conferred a beneficial influence on levodopa exposure. We appreciate the previous work that Müller and Möhr reference showing modest inverse correlations between weight, levodopa area under the curve (R=–0·48, p=0·013), and levodopa plasma concentrations (R=–0·50, p=0·008), although these data are from a study with 26 participants.4Müller T Woitalla D Saft C Kuhn W Levodopa in plasma correlates with body weight of parkinsonian patients.Parkinsonism Relat Disord. 2000; 6: 171-173Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Evidence of efficacy for GLP-1 receptor agonists in Parkinson's disease is still unclear. The liraglutide study2Wu T Bresee C Wertheimer J et al.Liraglutide once daily versus placebo in Parkinson's disease: a randomized, double-blind, placebo-controlled trial.Mov Disord. 2022; 37: S359-S360Google Scholar was done in a single centre, 63 people were randomised, and no benefit was seen in MDS-UPDRS part III (ie, motor examination) measured in the practically defined off state (ie, the primary motor outcome). The abstract of the trial report mentions improvement in the secondary outcome MDS-UPDRS part II (p=0·001), but not whether this finding was formally significant in a statistical hierarchy.2Wu T Bresee C Wertheimer J et al.Liraglutide once daily versus placebo in Parkinson's disease: a randomized, double-blind, placebo-controlled trial.Mov Disord. 2022; 37: S359-S360Google Scholar Perhaps Müller and Möhr suspect putatively higher levodopa concentrations were sufficient to alter MDS-UPDRS part II and not part III in the practically defined off state, but whether these data overall constitute robust evidence of motor improvement is not clear. The hypothesis of weight loss driving higher levodopa exposure and clinical benefit is difficult to substantiate without levodopa concentrations or perhaps the measurement of off time, a patient-reported metric that might be more meaningful than examination changes in treated participants (either practically defined off or while on). Taken together, we think it premature to conclude that the apparent inefficacy of NLY01 in Parkinson's disease is because of the drug being tested in a levodopa-naive population. AM declares salary support from Neuraly for work in the study. Negative findings from trials with NLY01 or deferiprone for Parkinson's diseaseTwo clinical trials with the GLP-1 receptor agonist NLY011 and the iron chelator deferiprone2 have reported negative findings in people with Parkinson's disease. The aim of these studies was to improve the course of Parkinson's disease, but their findings are not surprising. Full-Text PDF Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trialNLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. Full-Text PDF