Safety and tolerability of intravenous liposomal GM1 in patients with Parkinson disease: A single center open-label clinical phase I trial (NEON trial)
Authors: Halbherr Stefan , Lerch Stefanie , Bellwald Sebastian , Polakova Petra , Bannert Bettina , Roumet Marie , Charles Roch-Philippe , Walter Martin A. , Bernasconi Corrado , Peitsch Camille , Baumgartner Pascal C. , Kaufmann Céline , Mattle Heinrich P. , Kaelin-Lang Alain , Hartmann Andreas , Schuepbach Michael 
Published: September 2024

ABSTRACTBackground: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 of TLN in patients with PD.Methods and FindingsWe 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 Talineuren. The maximum suitable dose of Talineuren was determined by dose escalation in three patients. Subsequently, these and nine further patients received weekly infusions at the maximum suitable dose of Talineuren over two months (1 patient stopped prematurely). 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, behaviour, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used. Dose escalation identified a maximum suitable weekly dose of 720 mg. Overall, 304, mostly mild adverse events occurred. Twenty- three were considered related to the study treatment. Very mild to severe acute infusion reactions at the 2nd, 3rd, or 4th 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 Talineuren administration was resumed at a very low rate. Beyond the 4th 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 Talineuren 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±10.47 points; p=0.006) and the PDQ-39 summary index (mean decrease 2.91±2.25 points, p =0.002). Dopaminergic medications remained stable during the study.Conclusion:Talineuren is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the 2nd, 3rd, or 4th 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.