Safety and tolerability of intravenous liposomal GM1 in patients with Parkinson disease: A single-center open-label clinical phase I trial (NEON trial).

Abstract

Background: Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non-motor impairment, often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood-brain barrier in animals. We assessed the safety and pharmacokinetics (PK) of TLN in patients with PD.

Methods and findings: We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with TLN. The maximum suitable dose of TLN was determined by dose escalation in three patients. All three patients tolerated the predetermined maximal dose of 720 mg. Subsequently, these and nine additional patients received weekly infusions at the maximum suitable dose of 720 mg TLN over two months (1 patient stopped prematurely). PK were determined for the additional nine patients as a secondary outcome measure. Cmax was reached 4 h after infusion start for all but one participant, who reached Cmax after 1 h, while the median plasma half-life was reached at 12.6 h. All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behavior, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used as further secondary outcomes as well as assessing the Levodopa-Equivalent Daily Dose (LEDD). Overall, 304 adverse events (mean: 25.33; 6-75 events per patient) occurred, 267 of which were mild (mean: 22.25; 3-72 events per patient). 23 were considered related to the study treatment (0-8 events per patient). Very mild-to-severe acute infusion reactions at the second, third, or fourth administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when TLN administration was resumed at a very low rate. Beyond the fourth administration, infusions could be given at increased rates up to 370 ml/h, and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after TLN following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease -11.09; 95% Confidence Interval [CI]; -18, -4.1; p = 0.006), the Parkinson's disease Questionnaire-39 (PDQ-39) summary index (mean decrease -2.91; 95% CI; -4.4, -1.4; p = 0.005), and the Non-Motor Symptoms Questionnaire (NMS-Quest) (mean decrease -4.27; 95% CI; -6.5, -2.1; p = 0.009). No statistically significant improvements were seen in the Montreal Cognitive Assessment (MoCA) (mean decrease -0.73; 95% CI; -2.1, 0.62; p = 0.255), Epworth Sleepiness Scale (mean increase 0.09; 95% CI; -2.6, 2.8; p > 0.999), Beck Depression Inventory (BDI) (mean decrease -1.27; 95% CI; -3.8, 1.3; p = 0.257), and the Starkstein Apathy Scale (mean increase 0.36; 95% CI; -1.6, 2.4; p = 0.822). Dopaminergic medications remained stable during the study (LEDD mean increase 8.18; 95% CI; -7.7, 24; p = 0.423). While clinical improvements indicate a benefit associated with TLN treatment, the trial design does not allow for definite conclusions regarding efficacy. A randomized, placebo-controlled trial will be required to corroborate our exploratory findings.

Conclusion: TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD.

Trial registration: The NEON trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04976127 and in the Swiss National Clinical Trials Portal (SNCTP000004631).