Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease

A Randomized Clinical Trial

Joseph Jankovic, Ira Goodman, Beth Safirstein, Tonya K. Marmon, Dale B. Schenk, Martin Koller, Wagner Zago, Daniel K. Ness, Sue G. Griffith, Michael Grundman, Jay Soto, Susanne Ostrowitzki, Frank G. Boess, Meret Martin-Facklam, Joseph Quinn, Stuart H. Isaacson, Omid Omidvar, Aaron Ellenbogen, Gene G. Kinney

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Importance: Aggregated -synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of -synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of -synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum -synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P =.002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral -synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated -synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.

Original languageEnglish (US)
Pages (from-to)1206-1214
Number of pages9
JournalJAMA Neurology
Volume75
Issue number10
DOIs
StatePublished - Oct 1 2018

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Synucleins
Parkinson Disease
Randomized Controlled Trials
Monoclonal Antibodies
Safety
Placebos
Cerebrospinal Fluid
Intravenous Infusions
Half-Life
Serum
Antibodies, Monoclonal, Humanized
Neurons
Spinal Puncture
Vital Signs
Neurologic Examination
Constipation
Respiratory Tract Infections
Physical Examination
Area Under Curve
Headache

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease : A Randomized Clinical Trial. / Jankovic, Joseph; Goodman, Ira; Safirstein, Beth; Marmon, Tonya K.; Schenk, Dale B.; Koller, Martin; Zago, Wagner; Ness, Daniel K.; Griffith, Sue G.; Grundman, Michael; Soto, Jay; Ostrowitzki, Susanne; Boess, Frank G.; Martin-Facklam, Meret; Quinn, Joseph; Isaacson, Stuart H.; Omidvar, Omid; Ellenbogen, Aaron; Kinney, Gene G.

In: JAMA Neurology, Vol. 75, No. 10, 01.10.2018, p. 1206-1214.

Research output: Contribution to journalArticle

Jankovic, J, Goodman, I, Safirstein, B, Marmon, TK, Schenk, DB, Koller, M, Zago, W, Ness, DK, Griffith, SG, Grundman, M, Soto, J, Ostrowitzki, S, Boess, FG, Martin-Facklam, M, Quinn, J, Isaacson, SH, Omidvar, O, Ellenbogen, A & Kinney, GG 2018, 'Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease: A Randomized Clinical Trial', JAMA Neurology, vol. 75, no. 10, pp. 1206-1214. https://doi.org/10.1001/jamaneurol.2018.1487
Jankovic, Joseph ; Goodman, Ira ; Safirstein, Beth ; Marmon, Tonya K. ; Schenk, Dale B. ; Koller, Martin ; Zago, Wagner ; Ness, Daniel K. ; Griffith, Sue G. ; Grundman, Michael ; Soto, Jay ; Ostrowitzki, Susanne ; Boess, Frank G. ; Martin-Facklam, Meret ; Quinn, Joseph ; Isaacson, Stuart H. ; Omidvar, Omid ; Ellenbogen, Aaron ; Kinney, Gene G. / Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease : A Randomized Clinical Trial. In: JAMA Neurology. 2018 ; Vol. 75, No. 10. pp. 1206-1214.
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title = "Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease: A Randomized Clinical Trial",
abstract = "Importance: Aggregated -synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of -synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of -synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5{\%}; n = 78) and male (80{\%}; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5{\%} of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1{\%}; n = 5), infusion reaction (7.3{\%}; n = 4), diarrhea (5.5{\%}; n = 3), headache (5.5{\%}; n = 3), peripheral edema (5.5{\%}; n = 3), post-lumbar puncture syndrome (5.5{\%}; n = 3), and upper respiratory tract infection (5.5{\%}; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum -synuclein levels of up to 97{\%} were seen after a single infusion at the highest dose (F78,284 = 1.66; P =.002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3{\%} relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral -synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated -synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.",
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T1 - Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti--Synuclein Monoclonal Antibody, in Patients with Parkinson Disease

T2 - A Randomized Clinical Trial

AU - Jankovic, Joseph

AU - Goodman, Ira

AU - Safirstein, Beth

AU - Marmon, Tonya K.

AU - Schenk, Dale B.

AU - Koller, Martin

AU - Zago, Wagner

AU - Ness, Daniel K.

AU - Griffith, Sue G.

AU - Grundman, Michael

AU - Soto, Jay

AU - Ostrowitzki, Susanne

AU - Boess, Frank G.

AU - Martin-Facklam, Meret

AU - Quinn, Joseph

AU - Isaacson, Stuart H.

AU - Omidvar, Omid

AU - Ellenbogen, Aaron

AU - Kinney, Gene G.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Importance: Aggregated -synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of -synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of -synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum -synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P =.002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral -synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated -synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.

AB - Importance: Aggregated -synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of -synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of -synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum -synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P =.002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral -synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated -synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.

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