cinpanemab (BIIB054) / Biogen, Neurimmune - LARVOL DELTA

Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples. (PubMed, J Pharmacol Exp Ther) - "Observed dose- and time-dependent binding was consistent with cinpanemab's affinity for α-syn and provided confidence the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the central nervous system."

Journal • P1 data • CNS Disorders • Movement Disorders • Parkinson's Disease

An update on immune-based alpha-synuclein trials in Parkinson's disease. (PubMed, J Neurol) - "Specifically, UB-312, AFFITOPE PD01A, PD03A and ACI-7104.056 are designed to provoke an immune response against α-syn (active immunisation), while Prasinezumab and Cinpanemab, MEDI1341 and Lu AF82422 focus on directly targeting α-syn aggregates (passive immunisation). Despite some promising results, challenges such as variable efficacy and trial discontinuations persist. Future research must address these challenges to advance disease-modifying therapies for PD around this therapeutic target."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Limitations and potential strategies of immune checkpoint blockade in age-related neurodegenerative disorders. (PubMed, J Physiol Sci) - "Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aβ monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aβ) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aβ and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aβ (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate..."

Checkpoint block • Checkpoint inhibition • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders. (PubMed, Int J Mol Sci) - "This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively."

Journal • Review • Alzheimer's Disease • CNS Disorders

Quantification of Cinpanemab (BIIB054) Binding to α- Synuclein in Cerebrospinal Fluid of Phase 1 Single Ascending Dose Samples. (PubMed, J Pharmacol Exp Ther) - "Observed dose- and time-dependent binding were consistent with cinpanemab's affinity for α-syn and provided confidence that the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the CNS."

Journal • P1 data • CNS Disorders • Movement Disorders • Parkinson's Disease

Transcytosis-Driven Treatment of Neurodegenerative Disorders by mRNA-Expressed Antibody-Transferrin Conjugates. (PubMed, Biomedicines) - "This approach will expedite safer discoveries that can be made available at a much lower cost than the recombinant process with in vitro conjugation. Most importantly, the recommendations made in this paper may save the antibodies against the NDs that seem to be failing despite their regulatory approvals."

Journal • Review • CNS Disorders

Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial. (PubMed, Neurology) - P2 | "Biomarker results indicated enrollment of the intended population with early PD, but there was no significant correlation with disease progression or clear evidence of a cinpanemab treatment effect on biomarker measures. Suitable biomarkers for evaluating disease severity and progression in early PD trials are still needed."

Biomarker • Clinical • Journal • P2 data • CNS Disorders • Movement Disorders • Parkinson's Disease • NEFL

The Construction and Validation of a Novel Ferroptosis-Related Gene Signature in Parkinson's Disease. (PubMed, Int J Mol Sci) - "Therapeutic drugs that target SNCA include ABBV-0805, Prasinezumab, Cinpanemab, and Gardenin A. The results of this study suggest that cellular DEF-MDRGs might play an important role in PD. AR, ISCU, SNCA, and PDK4 have the potential to be specific biomarkers for the early diagnosis of PD."

Gene Signature • Journal • CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Solid Tumor • Targeted Protein Degradation • MIR128 • MIR199A • MIR199B • MIR203A • MIR204 • MIR214 • PDK4 • SNCA

Single-neuron neurodegeneration as a degenerative model for Parkinson's disease. (PubMed, Neural Regen Res) - "Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson's disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • KEAP1

Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model. (PubMed, Sci Rep) - "Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

MODELING PHARMACODYNAMIC EFFECTS OF PUBLISHED CLINICALLY TESTED ANTI-TAU AND ANTISYNUCLEIN ANTIBODIES TO IMPROVE CLINICAL TRIAL DESIGN (ADPD 2023) - "We si mulated clinical trials of gosuranemab, tilavonemab, semorinemab, cinpanemab and prasinezumab using published clinical profiles. The current model suggests that the antibodies' effect on accessible biomarkers in CSF is quite different from changes in other brain compa rtments, notably in the synaptic cleft and neuronal uptake which are proxies for disease progression."

Clinical • PK/PD data • Immunology

Monoclonal Antibodies in Neurodegenerative Disease May Work, But They Don't Help: A Perspective from Physicians. (PubMed, J Parkinsons Dis) - No abstract available

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Prasinezumab and Cinpanemab - The Perspective of a Person with Parkinson's. (PubMed, J Parkinsons Dis) - No abstract available

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Trial of Cinpanemab in Early Parkinson's Disease. (PubMed, N Engl J Med) - P2 | "In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.)."

Journal • CNS Disorders • Infectious Disease • Movement Disorders • Pain • Parkinson's Disease

TREATMENT OF PARKINSON’S DISEASE: WHAT ABOUT THE NEXT FUTURE (ADPD 2022) - "The PASADENA study tested prasinezumab and despite the primary end-point was not met positive signals were seen...The PARK study with BIIB054 did not met primary and secondary en-points. The ORCHESTRA study with UCB0059, an oral Asyn antibody is also recruiting...Two molecules are in clinical trials for GBA mutation, ambroxol and venglustat and one for patients with LRKK2 mutation, DNL151...Moreover to achive a more contnuos delivery of drug two subcutaneous preparation of levodopa are in clinical trials and olso an otal micropump able to deliver levodopa continuously. A new dopamine agonist, tavapadon and two drugs for dyskinesia are in clinical trial too."

IO biomarker • Alzheimer's Disease • CNS Disorders • Dementia • Infectious Disease • Lewy Body Disease • Movement Disorders • Parkinson's Disease • GBA

Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson's disease trial. (PubMed, BMC Neurol) - P2 | "A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects."

Biomarker • Journal • P2 data • P2 data • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] Cinpanemab in Early Parkinson’s Disease: Phase 2 SPARK Study Results (MDS Congress 2021) - P2 | "In this study, there was no evidence of a cinpanemab treatment effect in PD as indicated by MDS-UPDRS scores and DaT-SPECT data. The safety profile was acceptable."

P2 data • CNS Disorders • Parkinson's Disease

[VIRTUAL] Cinpanemab in Parkinson's Disease: Imaging and Fluid Biomarker Results from the Phase 2 SPARK Study (MDS Congress 2021) - P2 | "Biomarkers suggest the targeted patient population – those with abnormal striatal update and evidence of α-syn seeds – was enrolled in SPARK. No clear evidence of cinpanemab treatment effect was observed despite favorable numerical trends on some exploratory endpoints."

Biomarker • P2 data • CNS Disorders • Parkinson's Disease • MRI

[VIRTUAL] Evaluating Engagement of ABBV-0805, an Anti-Alpha-Synuclein Monoclonal Antibody to Physiological and Pathological Forms of Alpha-Synuclein for Phase 2 Dose Selection: A PBPK Modeling and Simulation Approach (MDS Congress 2021) - "This PBPK/PD modeling approach was used to identify monthly intravenous Phase 2 doses of ABBV-0805 to maintain ≥ 95% oligomeric α-synuclein binding in CSF at steady state in PD patients."

P2 data • CNS Disorders • Parkinson's Disease

[VIRTUAL] Measuring progression of Parkinson's disease cardinal signs in the Phase 2 SPARK study (MDS Congress 2021) - P2 | "Background: Cinpanemab, a monoclonal antibody, was being investigated as a therapeutic for Parkinson's disease in a Phase II, double blind, placebo-controlled clinical trial SPARK (NCT03318523)... A novel, digital composite score derived from the QMA sensor data provided an objective measure of increasing PD clinical severity over the course of the study. This approach has potential utility as an endpoint in future clinical trials for PD."

P2 data • CNS Disorders • Parkinson's Disease

SPARK: Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Participants With Parkinson's Disease (clinicaltrials.gov) - P2; N=357; Terminated; Sponsor: Biogen; Active, not recruiting ➔ Terminated; SPARK did not meet it's primary outcome measure for year 1 and failed to meet secondary outcome measures resulting in the development of BIIB054 (cinpanemab) for Parkinson's disease to be discontinued and SPARK study was closed.

Clinical • Trial termination • CNS Disorders • Movement Disorders • Parkinson's Disease

Immunotherapies for Parkinson's disease: Progression of Clinical Development. (PubMed, CNS Neurol Disord Drug Targets) - "This approach shows some positive outcomes on the efficacy in removing the aggregated species of alpha-synuclein, which is believed to be one of the causes of Parkinson's disease. In this review, an overview of how alpha-synuclein contributes to Parkinson's disease and the effects of a few new immunotherapeutic treatments, including BIIB054 (cinpanemab), MEDI1341, AFFITOPE and PRX002 (prasinezumab) that are currently under clinical development, will be discussed."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

A Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Japanese Participants With Parkinson's Disease (clinicaltrials.gov) - P1; N=24; Terminated; Sponsor: Biogen; Active, not recruiting ➔ Terminated; Affiliated study NCT03318523 did not meet its primary outcome measure of change from baseline measured by Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and did not demonstrate efficacy on secondary outcome measures

Clinical • Trial termination • CNS Disorders • Movement Disorders • Parkinson's Disease

SPARK: Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Participants With Parkinson's Disease (clinicaltrials.gov) - P2; N=357; Active, not recruiting; Sponsor: Biogen; Trial primary completion date: Jun 2020 ➔ Oct 2020

Clinical • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] ACTIVE AND PASSIVE IMMUNIZATION IN THE TREATMENT OF PARKINSON’S DISEASE (ADPD 2021) - "To obtain active immunization AFFITOPE PD01A/PD03A has been tested in patients and healthy controls...Passsive immunization has been tested using two human antibodies PRX002/RG7935, and BIIB054...BIIB054 is actually in phase IIb since 18 months, no significant side effects have been reported during the double blind phase and interim results on clinical end-points are expected. Two other studies are starting one with UCB compound and another study with PRX."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease