semorinemab (RG6100) / AC Immune - LARVOL DELTA

Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer's disease: a systematic review and network meta-analysis of randomized controlled trials. (PubMed, Front Aging Neurosci) - "Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols. https://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388."

Journal • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Dementia • Infectious Disease • Nephrology

Developing Topics. (PubMed, Alzheimers Dement) - "The cumulative mean changes for CDR-SB were -0.08; for ADAS-Cog it was -0.53, with both 95%CI including zero. The score range for CDR-SB is 0 to 18; the range for ADAS-Cog is 0 to 70/90. These mean differences across the many trials conducted cannot be considered to be either clinically or statistically significant."

Journal • Review

Biomarkers. (PubMed, Alzheimers Dement) - "Six CSF proteins highly correlated with tau PET were identified. Validation of these results by replicating the analysis on a secondary dataset with PET and CSF protein measurements may establish further confidence in these findings."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • MAPT • YWHAZ

Developing Topics. (PubMed, Alzheimers Dement) - P2 | "We replicated prior speech biomarker findings in an independent, more severe AD population, suggesting that the speech characteristics within this score are robust and aligned with clinical progression across disease stages. Additional validation work is ongoing, including the development of comparative biomarkers leveraging the combined dataset."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders

Drug Development. (PubMed, Alzheimers Dement) - P2 | "Data from the two semorinemab trials suggest that there may be regional differences in the impact of study partner type on retention. Further studies are needed to assess the generalizability of these findings, with an emphasis on cohorts with more representative samples of non-spousal dyads."

Journal • Alzheimer's Disease • CNS Disorders

Drug Development. (PubMed, Alzheimers Dement) - P2 | "The anchor- and distribution-based approaches suggest that clinically meaningful change on the ADCS-ADL may be greater than the 2 points that has previously been postulated (Dysken et al., 2014). Higher change thresholds may be required to reflect meaningful changes perceptible to caregivers."

Journal • Alzheimer's Disease • CNS Disorders

Synthetic receptors for programmable tau-responsive cellular therapies (Neuroscience 2024) - "Receptors with recognition domains derived from clinical anti-tau mAbs (semorinemab, gosuranemab, bepranemab) were built and expressed in mouse mesenchymal stromal cells (mMSCs) (Fig 1A; synNotch constructs displayed). We envision tau receptors being used in a cell-based therapy, outfitting microglia and astrocytes with novel therapeutic behaviors. In neurons, tau receptors may serve as useful tools for reporting the extent of local tau pathology in real-time."

Alzheimer's Disease • CNS Disorders • Dementia • BDNF

AC Immune reports full-year 2019 financial results and provides 2020 R&D outlook (GlobeNewswire) - "Initiation of a second Phase 2 trial of semorinemab in patients with moderate AD, by our collaboration partner Genentech, a member of the Roche Group. This antibody is also being studied in a separate Phase 2 trial in prodromal to mild AD; Presented initial interim data from an on-going Phase 1b trial of the ACI-24 anti-Abeta vaccine to treat Down syndrome (DS)-related AD...2020 Clinical Readouts: Semorinemab, anti-Tau antibody: Phase 2 trial primary completion (estimated last patient, last visit) in prodromal/mild in Q2; ACI-24 anti-Abeta vaccine in DS: Phase 1b full study reporting in H2; ACI-24 in AD: Phase 2, 12-month interim analysis in H2."

New P2 trial • P1 data • P2 data • Trial primary completion date • Trial status • Alzheimer's Disease • CNS Disorders

Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology. (PubMed, Alzheimers Dement) - P1, P2 | "AD pathophysiology biomarkers were measured to assess the mechanism of action. Semorinemab increased CSF YKL-40 in participants with AD but not in healthy controls. Semorinemab possibly stabilized plasma GFAP in the Lauriet trial. Semorinemab treatment may activate microglia and moderate reactive gliosis."

Biomarker • Journal • PK/PD data • Alzheimer's Disease • Amyloidosis • CNS Disorders • Inflammation • CHI3L1 • GFAP • p-tau181

CSF complement proteins are elevated in prodromal to moderate Alzheimer's disease patients and are not altered by the anti-tau antibody semorinemab. (PubMed, Alzheimers Dement) - "Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort. Baseline CSF complement protein levels were correlated with neuro-axonal degeneration and glial activation biomarkers in AD patients. The investigational anti-tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation

Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies. (PubMed, J Prev Alzheimers Dis) - "Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer's disease."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Plasma T-Tau

Robustness and generalizability of a speech-based digital biomarker derived from recordings of the Clinical Dementia Rating (CDR) interview (AAIC 2024) - P2 | " We analyzed CDR interview recordings at screening, baseline, week 25, and week 49 from 81 English-speaking mild-to-moderate AD patients enrolled in the placebo arm of the Lauriet Phase 2 trial of semorinemab (NCT03828747)... We replicated prior speech biomarker findings in an independent, more severe AD population, suggesting that the speech characteristics within this score are robust and aligned with clinical progression across disease stages. Additional validation work is ongoing, including the development of comparative biomarkers leveraging the combined dataset."

Biomarker • Clinical • Interview • Alzheimer's Disease • CNS Disorders • Dementia

Impact of Study Partner Type on Participant Retention Across Global Regions in the Tauriel and Lauriet Trials for Alzheimer’s Disease (AAIC 2024) - P2 | "Data from the two semorinemab trials suggest that there may be regional differences in the impact of study partner type on retention. Further studies are needed to assess the generalizability of these findings, with an emphasis on cohorts with more representative samples of non-spousal dyads."

Clinical • Alzheimer's Disease • CNS Disorders

Deriving meaningful within-patient change thresholds for the ADCS-ADL in trials of early and mild-to-moderate Alzheimer’s disease - a caregiver-rated, anchor-based analysis of the Tauriel and Lauriet trials (AAIC 2024) - P2 | "Methods : Our anchor-based analyses (and supportive distribution-based analyses) used data from two phase 2 semorinemab trials, Tauriel (NCT03289143; early AD) and Lauriet (NCT03828747; mild-to-moderate AD)... The anchor- and distribution-based approaches suggest that clinically meaningful change on the ADCS-ADL may be greater than the 2 points that has previously been postulated (Dysken et al., 2014). Higher change thresholds may be required to reflect meaningful changes perceptible to caregivers."

Clinical • Alzheimer's Disease • CNS Disorders

Identification of CSF proteins in Alzheimer’s Disease highly correlated with [18F]GTP1 (AAIC 2024) - "Method : AD CSF samples were from participants enrolled in Tauriel or Lauriet, two semorinemab PhII trials...Conclusion : Six CSF proteins highly correlated with tau PET were identified. Validation of these results by replicating the analysis on a secondary dataset with PET and CSF protein measurements may establish further confidence in these findings."

Alzheimer's Disease • CNS Disorders • MAPT • YWHAZ

A Review of Recent Advances in the Management of Alzheimer's Disease. (PubMed, Cureus) - "The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab...Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers...The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Diabetes • Inflammation • Insomnia • Metabolic Disorders • Sleep Disorder

[PREPRINT] Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology (medRxiv) - P2 | N=457 | Tauriel (NCT03289143) | P2 | N=272 | Lauriet (NCT03828747) | Sponsor: Genentech, Inc. | "Significant increases in plasma phosphorylated Tau 181 (pTau181) and CSF Chitinase-3-like protein 1 (YKL-40) followed administration of semorinemab in both studies. In the Lauriet study, plasma glial fibrillary protein (GFAP) levels rose progressively over the study period in the placebo group, but remained stable over time with the administration of semorinemab. In contrast, this was not observed in the Tauriel study. Semorinemab had no consistent impact on other biomarkers of AD pathophysiology that were evaluated."

P2 data • PK/PD data • Preprint • Alzheimer's Disease • CNS Disorders

[PREPRINT] CSF proteomic analysis of semorinemab Ph2 trials in prodromal-to-mild (Tauriel) and mild-to-moderate (Lauriet) Alzheimer`s disease identifies distinct trial cell-type specific proteomic signatures (medRxiv) - P2 | N=457 | Tauriel (NCT03289143) | P2 | N=272 | Lauriet (NCT03828747) | Sponsor: Genentech, Inc. | "Treatment-induced proteomic signatures were defined for each study as a set of proteins significantly elevated in the treatment arm in the respective study. Integration of the corresponding gene signatures with two independent brain single-nucleus RNA-seq datasets from AD and healthy aged controls revealed that Lauriet signature genes were enriched in microglial cells, while Tauriel signature genes were more broadly expressed across major brain cell types. Furthermore, the Lauriet trial gene signature was significantly upregulated in microglia from AD patients as compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state."

P2 data • Preprint • Alzheimer's Disease • CNS Disorders

[PREPRINT] CSF complement proteins are elevated in prodromal to moderate AD patients and are not altered by the anti-tau antibody semorinemab (medRxiv) - P2 | N=457 | Tauriel (NCT03289143) | P2 | N=272 | Lauriet (NCT03828747) | Sponsor: Genentech, Inc. | "All measured CSF complement proteins were increased in AD vs CN subjects, with cleaved C4 (C4a) displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins....Elevated levels of CSF intact/cleaved C4 and C3 are indicative of classical complement pathway activation in AD. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity."

P2 data • Preprint • Alzheimer's Disease • CNS Disorders

Fall-Related Risks with Pharmacological Interventions in Mild-to-Moderate Alzheimer’s Disease: A Bayesian Network Meta-Analysis (ISPOR 2024) - " A systematic literature search was conducted in Embase, PubMed, and clinicaltrial.gov (until December-2023) to identify randomized controlled trials (RCTs) on approved and in-development interventions among mild-to-moderate AD patients (i.e., donepezil, galantamine, memantine, solanezumab, and semorinemab). The findings suggested that though none of the interventions significantly reduced the risk of falls, these can be further evaluated as a way forward for reducing such risk potentially by targeting motor-cognitive interface. The results should be interpreted cautiously as the risks and benefits alter with disease progression and change in symptoms. Further long-term studies directly comparing the effect of these interventions on risk of falls and confirmation of their sustainability is warranted."

Retrospective data • Alzheimer's Disease • CNS Disorders • Musculoskeletal Diseases • Orthopedics

Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models. (PubMed, Front Neuroimaging) - P1, P2 | "The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates...LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test-retest variability. NCT02640092 and NCT03289143."

Journal • Tau PET • Alzheimer's Disease • CNS Disorders

CSF PROTEOMIC ANALYSIS OF SEMORINEMAB PH2 TRIALS IN PRODROMAL-TO-MILD (TAURIEL) AND MODERATE (LAURIET) ALZHEIMER'S DISEASE (ADPD 2024) - P2 | "Analysis of the Lauriet and Tauriel CSF signature indicate that the Lauriet proteomic drug response are likely of microglia origin, including some contribution from proteins that are further elevated in Alzheimer's-associated microglia."

Omic analysis • Alzheimer's Disease • CNS Disorders • CHI3L1 • GPNMB

AC Immune To Regain Global Rights To Crenezumab And Semorinemab (AC Immune Press Release) - "AC Immune SA...today announced that the Company will regain all global rights to the anti-amyloid beta antibody crenezumab and the anti-Tau antibody semorinemab following termination of the collaboration agreements with Genentech, a member of the Roche Group, and Roche. Both antibodies have been evaluated in clinical studies for Alzheimer’s disease (AD). AC Immune will also regain rights to existing GMP drug-product for clinical testing as well as associated data generated under each of the agreements. AC Immune will carefully review and evaluate available data sets, including the final open label extension results from the Lauriet trial when they become available and are received in full by AC Immune, before decisions are made on potential further development and other opportunities."

Licensing / partnership • Alzheimer's Disease • CNS Disorders

AC Immune Reports Second Quarter 2023 Financial Results And Provides A Corporate Update (AC Immune Press Release) - "ACI-24.060 anti-Abeta active immunotherapy: Additional interim safety and immunogenicity data from AD cohorts of ABATE study expected in H2 2023; Interim safety and immunogenicity data from DS cohort of ABATE study expected in H2 2023; Initial Abeta-PET data on amyloid plaque reduction in AD expected in H1 2024; ACI-7104.056 anti-a-syn active immunotherapy: Completion of recruitment of first cohort in the Phase 2 VacSYn study in Parkinson's disease expected in H2 2023; ACI-35.030 anti-pTau active immunotherapy: Initiation of next trial in AD expected in H2 2023 (to be followed by a milestone payment); Semorinemab anti-Tau antibody: Results from the open-label extension of the Phase 2 Lauriet trial in mild-to-moderate AD expected in H2 2023..."

Enrollment status • New trial • P1/2 data • P2 data • Alzheimer's Disease • CNS Disorders • Parkinson's Disease • Tauopathies And Synucleinopathies

Pharmacodynamic Effects of Semorinemab on Biomarkers of Tau, Synaptic Function, and Gliosis in a Phase 2 Trial of Mild-to-Moderate Alzheimer's Disease (Lauriet) (CTAD 2023) - P2 | "In participants with mild-to-moderate AD, administration of semorinemab was associated with changes to plasma and CSF species of tau linked to AD pathology. These data provide evidence that semorinemab engages tau in the CNS and periphery in a manner consistent with data previously reported in prodromal-to-mild AD patients (Tauriel, NCT03289143), and that modulation of extracellular tau levels may impact synaptic biology and moderate reactive astrogliosis."

Biomarker • P2 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Infectious Disease • Novel Coronavirus Disease • CHI3L1 • CSF T-tau • GFAP • Plasma T-Tau • p-tau181