Trial of Lixisenatide in Early Parkinson’s Disease
N Engl J Med. 2024-04-04; 390(13): 1176-1185
DOI: 10.1056/NEJMoa2312323
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Meissner WG(1), Remy P(1), Giordana C(1), Maltête D(1), Derkinderen P(1), Houéto
JL(1), Anheim M(1), Benatru I(1), Boraud T(1), Brefel-Courbon C(1), Carrière
N(1), Catala H(1), Colin O(1), Corvol JC(1), Damier P(1), Dellapina E(1), Devos
D(1), Drapier S(1), Fabbri M(1), Ferrier V(1), Foubert-Samier A(1),
Frismand-Kryloff S(1), Georget A(1), Germain C(1), Grimaldi S(1), Hardy C(1),
Hopes L(1), Krystkowiak P(1), Laurens B(1), Lefaucheur R(1), Mariani LL(1),
Marques A(1), Marse C(1), Ory-Magne F(1), Rigalleau V(1), Salhi H(1), Saubion
A(1), Stott SRW(1), Thalamas C(1), Thiriez C(1), Tir M(1), Wyse RK(1), Benard
A(1), Rascol O(1); LIXIPARK Study Group.
Collaborators: Anheim M, Ansquer S, Benard A, Benatru I, Boraud T, Boudjema N,
Brefel-Courbon C, Carrière N, Cazal Y, Chatelain A, Colin O, Corbillé AG, Corvol
JC, Damier P, Defebvre L, Dellapina E, Derkinderen P, Devos D, Drapier S, Fabbri
M, Ferrier V, Foubert-Samier A, Frismand S, Georget A, Germain C, Giordana C,
Grimaldi S, Hardy C, Hopes L, Houéto JL, Krystkowiak P, Boukbiza OL, Laurens B,
Le Dily S, Lefaucheur R, Longato N, Maltête D, Mariani LL, Marques A, Marse C,
Meissner WG, Moreau C, Ory-Magne F, Phillipps C, Rabois E, Rascol O, Remy P,
Rigalleau V, Rouaud T, Salhi H, Saubion A, Spampinato U, Thalamas C, Thiriez C,
Tir M, Tranchant C.
Author information:
(1)From the French Clinical Research Network (F-CRIN) for Parkinson’s Disease
and Movement Disorders (NS-Park-F-CRIN) (W.G.M., P.R., C. Giordana, D.M., P.
Derkinderen, J.-L.H., M.A., I.B., T.B., C.B.-C., N.C., O.C., J.-C.C., P. Damier,
E.D., D.D., S.D., M.F., V.F., A.F.-S., S.F.-K., S.G., C.H., L.H., P.K., B.L.,
R.L., L.-L.M., A.M., C.M., F.O.-M., H.S., C. Thiriez, M.T., O.R.), Centre
d’Investigation Clinique (CIC) 1436 and the Departments of Clinical Pharmacology
and Neurosciences, Centre Expert Parkinson, University Hospital of Toulouse,
INSERM, University of Toulouse 3 (C.B.-C., H.C., M.F., F.O.-M., C. Thalamas,
O.R.), and CIC 1436, INSERM (E.D., A.S.), Toulouse, Service de Neurologie des
Maladies Neurodégénératives, Centre Expert Parkinson, Institut des Maladies
Neurodégénératives (IMN) Clinique (W.G.M., T.B., A.F.-S., B.L.), and Service
d’Information Médicale, Unité de Soutien Méthodologique à la Recherche (USMR)
(A.G., C. Germain, A.B.), Centre Hospitalier Universitaire (CHU) Bordeaux, Unité
Mixte de Recherche (UMR) 5293, Université de Bordeaux, Centre National de la
Recherche Scientifique (CNRS), IMN, Unité Mixte de Recherche (UMR) 5293 (W.G.M.,
T.B., A.F.-S.), and the European Clinical Trials Platform and
Development-F-CRIN, CIC-Clinical Epidemiology Unit 1401, University of Bordeaux,
INSERM, Institut Bergonié, CHU Bordeaux (A.G., C. Germain, A.B.), Bordeaux, the
Department of Neurology, Centre Expert Parkinson, Equipe 01-Neuropsychologie
Interventionnelle L’Institut Mondor de Recherches Biomédicales, CHU Henri
Mondor, INSERM et Faculté de Santé, Université Paris-Est Créteil, Créteil (P.R.,
H.S.), the Department of Neurology, Centre Expert Parkinson, Centre Hospitalier
Universitaire de Nice, Université Côte d’Azur, Nice (C. Giordana, V.F., C.M.),
the Department of Neurology, Centre Expert Parkinson, Laboratory of Neuronal and
Neuroendocrine Differentiation and Communication, UMR 1239, Rouen University
Hospital, University of Rouen, INSERM, Mont-Saint-Aignan (D.M.), and the
Department of Neurology, Centre Expert Parkinson, Rouen University Hospital and
University of Rouen (C.H., R.L.), Rouen, the Department of Neurology, Centre
Expert Parkinson, CIC 1413, CHU Nantes, INSERM, Nantes (P. Derkinderen, P.
Damier), Service de Neurologie, Centre Expert Parkinson, CIC 1402, CHU Limoges,
CHU Poitiers INSERM, Limoges (J.-L.H., I.B., O.C.), the Department of Neurology,
Centre Expert Parkinson, Strasbourg University Hospital, and Strasbourg
Federation of Translational Medicine, Strasbourg University, Strasbourg (M.A.),
the Institute of Genetics and Cellular and Molecular Biology, INSERM Unité 964,
CNRS-UMR 7104, University of Strasbourg, Illkirch-Graffenstaden (M.A.), the
Department of Medical Pharmacology INSERM Unité 1172, Lille Neurosciences and
Cognition, Centre Hospitalier Régional Universitaire, University of Lille, Lille
(N.C., D.D.), the Department of Neurology, CIC Neurosciences, Sorbonne
Université, Paris Brain Institute, Assistance Publique-Hôpitaux de Paris,
INSERM, CNRS, Pitié-Salpêtrière Hospital, Paris (J.-C.C., L.-L.M.), the
Department of Neurology, Centre Expert Parkinson, CIC 1414, CHU Pontchaillou de
Rennes, INSERM, Rennes (S.D.), the Department of Neurology, Centre Expert
Parkinson, CHU de Nancy, Hôpital Central, Nancy (S.F.-K., L.H.), the Department
of Neurology, Centre Expert Parkinson, University Hospital La Timone, Marseille
(S.G.), the Department of Neurology, Centre Expert Parkinson, University
Hospital of Amiens, Amiens (P.K., M.T.), the Department of Neurology, CHU
Clermont-Ferrand, Université Clermont-Auvergne, CNRS, Image Guided Clinical
Neuroscience and Connectomics, Institut Pascal, Clermont-Ferrand (A.M.), the
Department of Nutrition-Diabetology, CHU de Bordeaux, Hôpital Haut-Lévêque,
Pessac (V.R.), and the Department of Neurology, Centre Expert Parkinson, CHU de
Caen, Caen (C. Thiriez) – all in France; the Department of Medicine, University
of Otago, Christchurch, and the New Zealand Brain Research Institute – both in
Christchurch, New Zealand (W.G.M.); Specialized Rehabilitation Hospital, Capital
Health, Abu Dhabi, United Arab Emirates (P.K.); and Cure Parkinson’s, London
(S.R.W.S., R.K.W.).
BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for
the treatment of diabetes, has shown neuroprotective properties in a mouse model
of Parkinson’s disease.
METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we
assessed the effect of lixisenatide on the progression of motor disability in
persons with Parkinson’s disease. Participants in whom Parkinson’s disease was
diagnosed less than 3 years earlier, who were receiving a stable dose of
medications to treat symptoms, and who did not have motor complications were
randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo
for 12 months, followed by a 2-month washout period. The primary end point was
the change from baseline in scores on the Movement Disorder Society-Unified
Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with
higher scores indicating greater motor disability), which was assessed in
patients in the on-medication state at 12 months. Secondary end points included
other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa
equivalent.
RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group.
MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At
12 months, scores on the MDS-UPDRS part III had changed by -0.04 points
(indicating improvement) in the lixisenatide group and 3.04 points (indicating
worsening disability) in the placebo group (difference, 3.08; 95% confidence
interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout
period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7
(95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with
placebo. Other results relative to the secondary end points did not differ
substantially between the groups. Nausea occurred in 46% of participants
receiving lixisenatide, and vomiting occurred in 13%.
CONCLUSIONS: In participants with early Parkinson’s disease, lixisenatide
therapy resulted in less progression of motor disability than placebo at 12
months in a phase 2 trial but was associated with gastrointestinal side effects.
Longer and larger trials are needed to determine the effects and safety of
lixisenatide in persons with Parkinson’s disease. (Funded by the French Ministry
of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).
Copyright © 2024 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2312323
PMID: 38598572 [Indexed for MEDLINE]