Therapeutics

BIIB076

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Overview

Name: BIIB076
Synonyms: NI-105, 6C5 huIgG1/l
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Biogen, Eisai Co., Ltd., Neurimmune

Background

BIIB076 is a human recombinant, monoclonal anti-tau IgG1 antibody generated by Neurimmune's reverse translational medicine platform. Biogen acquired it in 2010. 

Initially called 6C5, this antibody targets the mid-domain of tau. It was reported to block tau aggregation in vitro and also to block neuron-to-neuron propagation of tau (Nobuhara et al., 2017). At the 2017 AD/PD and AAIC conferences, Biogen reported that BIIB076 binds with subnanomolar affinity to human and cynomolgus monkey recombinant tau. It recognizes monomeric and fibrillar forms, as well as tau isolated from healthy human and Alzheimer's disease brains.

In young monkeys, a single 100 mg/kg dose of BIIB076 had a half-life in blood of eight to 11 days. It reached maximum CSF concentration in 24 to 48 hours, but its CSF concentration was 1,000 times lower than in plasma. Using ultrasensitive single-molecule array (Simoa) assays to measure tau concentration in blood and CSF, Biogen reported that after BIIB076 administration, plasma total tau rose; CSF total tau stayed unchanged but free tau unbound to BIIB076 dropped 75 percent after 24 hours, returning to baseline after three weeks. This was taken to indicate CNS target engagement (April 2017 conference news). 

A separate toxicity study evaluated three doses of up to 16 times the highest predicted efficacious dose, given intravenously or subcutaneously over the course of a month to 48 young cynomolgus monkeys, and compared to vehicle. Blood and CSF were sampled to measure BIIB076 and tau levels. This study reported no toxicology or pathology findings related to BIIB076, but did report dose-dependent increases in serum BIIB076 levels as well as exposure with subcutaneous delivery. CSF total and free tau were reported to be reduced at the highest doses used (Czerkowizc et al., 2017).

Findings

In February 2017, Biogen started a six-center Phase 1 trial in the U.S., aiming to enroll 56 healthy volunteers and people whose mild or probable AD was ascertained by CSF Aβ42, t-tau, and p-tau levels. This is an ascending-dose study giving a single intravenous infusion; healthy volunteers will be grouped into five successive dosing cohorts, AD patients into two. Primary outcomes were adverse events, clinical labs, vital signs, neurological exam, EKG, and MRI; secondary outcomes include eight pharmacokinetic parameters of exposure and clearance, as well as BIIB076 immunogenicity, all in blood.

In June 2019, the company modified the trial protocol, reducing participant number to 48, dropping the more advanced AD cohort, and adopting adverse events as the sole primary outcome. The trial was completed in March 2020, and results were presented at the 2021 CTAD conference. Twenty-four healthy controls received five doses, six people with AD received one, 12 controls and two AD patients got placebo. Safety issues appeared in the next-to-highest dose, so the investigators backed off for the fifth group, to a dose midway between the third and fourth. The same dose was tested in the AD patients. Most adverse events were mild to moderate, and more common at higher doses. They included headaches, dizziness, nausea, vomiting, and decreased blood pressure. BIIB076 engaged its target, reducing by half the amount of mid-region-bearing tau in the cerebrospinal fluid one week after infusion. The reduction persisted up to three weeks (Nov 2021 conference news).

In July 2022, Biogen announced it had ended development of BIIB076 for business reasons (Q2 earnings call transcript).

For all trials of BIIB076, see clinicaltrials.gov.

Last Updated: 28 Jul 2022

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Therapeutics

Cinpanemab

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Overview

Name: Cinpanemab
Synonyms: BIIB054, NI-202
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Discontinued)
Company: Biogen, Neurimmune

Background

Cinpanemab is a human-derived monoclonal antibody directed against α-synuclein. Genetic and pathology evidence implicate this protein in the molecular pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies such as dementia with Lewy bodies (DLB). In 2010, Biogen licensed cinpanemab from Neurimmune (see company press release). The antibody was generated with reverse translational medicine technology from naturally occurring, presumably protective antibodies found in healthy aged donors, as were aducanumab and other antibodies in the Biogen-Neurimmune partnership.

The antibody, previously known as BIIB054, binds to α-synuclein residues 1-10, with 800-fold higher affinity for aggregated over monomeric α-synuclein. The antibody inhibits α-synuclein spreading in cell-based assays, and slows pathology and motor symptoms in mice (Weihofen et al., 2019).

Cinpanemab was one of several α-synuclein antibodies being investigated for PD. Others include ABBV-0805, MEDI1341, LU AF82422, and prasinezumab.

Findings

From July 2015 through 2017, Biogen evaluated single-ascending, intravenous doses of cinpanemab in 48 healthy volunteers and 18 people with early Parkinson's, at eight sites in the U.S. Outcomes included safety measures, the MOCA cognition screen, cinpanemab serum levels and pharmacokinetics, as well as presence of anti-cinpanemab antibodies.

In 2017 at AD/PD, Biogen reported some data on the healthy participants, aged 40 to 65. They had received infusions of 1, 5, 15, 45, 90, or 135 mg/kg, had MRI scans at baseline, day three, and week four, and had CSF samples drawn at baseline, eight hours, 24 hours, and week three. Participants had been followed for 16 weeks after dosing with clinical assessments and electrocardiograms. Doses up to 90 mg/kg were reported to have been well tolerated; in the 135 mg/kg cohort, one participant developed asymptomatic ischemia in the right parietal lobe. Side effects included headache, dizziness, pain, or skin rash related to the infusion. Cinpanemab’s half-life was 28 days, the CSF/serum ratio was 0.2 percent at all doses, and maximum concentration in blood was dose-proportional (see May 2017 conference news).

At the 2018 AAN conference, Biogen presented first results of the same trial's PD cohort. Thirteen men and five women, aged 47 to 75, had received a single infusion of either zero, 15, or 45 mg/kg of cinpanemab. Nine were not on PD medication, five were on levodopa, two on rasagiline, two on both. The pharmacokinetics of cinpanemab in patients were similar to those in healthy volunteers, with a 33-day serum half-life, a threefold higher plasma concentration in the high-dose versus low-dose group, and 0.4 and 0.3 percent reaching CSF in the high- and low-dose groups, respectively. None of the patients developed anti-cinpanemab antibodies.

According to Biogen, cinpanemab formed plasma complexes with α-synuclein in both cohorts. Both doses formed similar amounts of complex, suggesting saturation of blood synuclein with antibody. Cinpanemab is more selective for aggregated than soluble α-synuclein, but at high doses binds soluble protein, according to Biogen. No serious adverse events were reported, and trial results were subsequently published (May 2018 conference news; Brys et al., 2019).

In December 2017, Biogen started SPARK, a two-year Phase 2 study originally meant as a safety trial, in 357 people with a diagnosis of PD and evidence of dopaminergic neuron loss by dopamine transporter imaging (DaT-SPECT). Year one compared monthly infusions of three doses of cinpanemab—250 mg, 1,250 mg, or 3,500 mg—to placebo to evaluate safety, pharmacodynamic effects on nigrostriatal dopaminergic nerve terminals, pharmacokinetics and immunogenicity of cinpanemab. Doses were selected to attain 50 percent, 90 percent and greater than 90 percent target binding, respectively, in brain interstitial fluid, based on modeling of Phase 1 and other data (Kuchimanchi et al., 2020). In year two, placebo recipients switched to receive cinpanemab, as well. The trial ran at 75 sites in the U.S., Canada, and Europe. The one-year placebo-controlled treatment period ended in May 2020, with trial completion planned for summer 2021.

Primary outcome measures were listed as adverse events, clinical labs, vital signs, neurological exam, as well as EKG and MRI, with secondary measures being DaT-SPECT, cinpanemab serum concentration, and percent of participants generating anti-cinpanemab serum antibodies. However, in August 2020, Biogen changed this study into a clinical efficacy trial. The new primary outcome was change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score.

In March 2019, a Phase 1 trial in 24 people with Parkinson's started at nine sites in Japan.

In February 2021, Biogen announced that it had halted development of cinpanemab after the SPARK study missed its primary and secondary endpoints (industry news). SPARK, and the Phase 1 study in Japan, were both terminated in spring 2021. Results were later published (Lang et al., 2022). Biomarker screening indicated enrollment of the intended population, as DaT-SPECT revealed loss of dopamine terminals in 96 percent of screened participants (Hutchison et al., 2021). Likewise, 93 percent of enrollees had detectable α-synuclein seeds in baseline CSF samples. However, the study found high interindividual variability, and no significant change over the course of the study in these and other biomarkers, in the presence of clear clinical progression (Hutchison et al., 2024).

For all trials on this antibody, see clinicaltrials.gov.

Last Updated: 08 May 2024

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Research Models

TREM2-BAC X 5xFAD

Synonyms: BAC-TREM2 X 5xFAD

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Species: Mouse
Genes: TREM2, APP, PSEN1
Modification: TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Cognitive Impairment

No Data

  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

Observed at 7 months, the youngest age examined.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

Microgliosis observed; however, fewer plaque-associated microglia and altered microglial morphology (more ramified processes) compared with 5xFAD at 7 months, the only age examined.

Changes in LTP/LTD

No data.

Cognitive Impairment

5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired.

Last Updated: 04 May 2018

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Research Models

TREM2-BAC

Synonyms: BAC-TREM2

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Species: Mouse
Genes: TREM2
Modification: TREM2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques
  • Gliosis
  • Changes in LTP/LTD
  • Cognitive Impairment

No Data

  • Tangles
  • Neuronal Loss
  • Synaptic Loss

Plaques

Not observed at 7 months.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No microgliosis was observed at 7 months.

Changes in LTP/LTD

Normal LTP at 10 months.

Cognitive Impairment

Normal contextual fear conditioning at 10 months.

Last Updated: 04 May 2018

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Therapeutics

Posdinemab

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Overview

Name: Posdinemab
Synonyms: JNJ-63733657
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Mild AD
U.S. FDA Status: Mild AD (Phase 2)
Company: Janssen

Background

This humanized IgG1 monoclonal antibody recognizes the microtubule-binding region (MTBR) of tau, on the rationale that such antibodies will more potently interfere with cell-to-cell propagation of pathogenic, aggregated tau than do antibodies targeting the tau N-terminus. It has high affinity for tau phosphorylated at residue 217. JNJ-63733657 was reported to eliminate pathogenic tau "seeds" in a cell-based assay and inhibit spread of tau pathology in a mouse model (see Apr 2018 conference news). The antibody was used to develop a sensitive assay for p217Tau in cerebrospinal fluid from Alzheimer’s disease patients (Bijttebier et al., 2021).

Findings

From December 2017 to January 2020, Janssen Research and Development ran a Phase 1 trial at seven sites in Europe, evaluating JNJ-63733657's safety and tolerability in 72 participants. Part 1 of this trial administered a single, ascending dose by intravenous infusion to healthy volunteers; based on data from part 1, part 2, then infused multiple ascending doses to participants with prodromal or mild Alzheimer's disease. Outcomes include adverse events, JNJ-63733657 exposure in blood and CSF, pharmacokinetic parameters of antibody accumulation, distribution, and clearance, as well as presence of anti-JNJ-63733657 host antibodies. Results of the single-dose study were presented in July 2019 (see AAIC abstract). No safety issues were noted. Serum pharmacokinetics were linear with dose, and 0.2 percent ended up in CSF. In November 2020, the multiple dosing results were presented at CTAD. Pharmacokinetics were similar in healthy or AD volunteers receiving three monthly doses. The drug was deemed tolerable, most frequent complaints being back pain and headache. Single or multiple administration led to dose-dependent reductions in free p217 tau in CSF.

From September 2018 to July 2019, Janssen ran a single-ascending dose safety and pharmacokinetics study in 24 healthy volunteers in Japan.

In January 2021, a Phase 2 study began for 420 people with early AD symptoms and a positive tau PET scan. Enrollees must have a Clinical Dementia Rating of 0.5 and report subjective cognitive decline in the previous six months. They are to receive low- or high-dose antibody or matching placebo every four weeks for up to 4.5 years. The primary outcome is cognition measured on the ADAS-Cog 13; secondary outcomes include other standard measures of cognition and function, plus tauopathy burden as per PET and CSF tau, safety, and pharmacokinetics. Later in 2021, the primary endpoint was changed to the integrated Alzheimer Disease Rating Scale, a composite of cognition and function. In December 2022, the company reported that using plasma ptau217 to screen participants before PET scanning helped the trial to more efficiently achieve the goal of enrolling equal numbers with high or low tangle burden (Dec 2022 conference news). The trial is fully enrolled with 523 participants at 141 sites in North America, Europe, Australia, and Japan, and will run until 2026. In an optional long-term extension, participants randomized to high or low dose will continue the same treatment; those on placebo will be randomized to high or low dose.

In 2022, Janssen conducted a Phase 1, single-dose study in Beijing to ascertain pharmacokinetics and safety in 10 healthy Chinese adults.

For all registered trials on this antibody, see clinicaltrials.gov

Last Updated: 28 Jun 2024

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Therapeutics

Bepranemab

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Overview

Name: Bepranemab
Synonyms: UCB0107 , UCB 0107 , Antibody D
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy, Alzheimer's Disease
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 1), Alzheimer's Disease (Phase 2)
Company: Hoffmann-La Roche, UCB S.A.

Background

This humanized, monoclonal IgG4 antibody binds to the central region of tau, recognizing amino acids 235–250 near tau's microtubule-binding domain. The rationale of this approach is that mid-region antibodies will more potently interfere with the cell-to-cell propagation of pathogenic, aggregated tau than do N-terminally targeted anti-tau antibodies. UCB0107 was reported to inhibit seeding in a cellular assay and inhibit spread of tau pathology in a mouse model (Apr 2018 conference news). UCB0107 also binds tau monomers.

This antibody's activity against pathologic tau seeds has been characterized in a cell-based seeding aggregation assay, in tau transgenic mice injected with Alzheimer's disease brain extract, and in mice injected with K18 P301L tau fibrils known to propagate pathology to regions distal of the injection. Peer-reviewed data are published in open-access articles (Courade et al., 2018; Albert et al., 2019). 

Findings

In February 2018, Brussels-based UCB Biopharma started a first, single-ascending-dose study to evaluate safety and tolerability of UCB0107 intravenous infusion. The trial enrolled 52 healthy men, and planned to use up to seven dose groups depending on safety review of the previous, lower dose. Besides adverse events, the 20-week trial measured UCB0107 exposure in blood and CSF, pharmacokinetic parameters of antibody distribution and clearance, as well as presence of anti-UCB0107 host antibodies. The trial ended in December 2018. According to results presented at a 2019 movement disorders conference, all participants in the seven dose groups completed the study. No drug-related adverse events or changes in safety results were reported. Serum and CSF concentrations increased with dose, and the CSF/serum ratio held constant across doses. There was no evidence of anti-drug antibodies (see press release and late-breaking abstract 3).

In March 2019, the company completed a Phase 1 trial in 24 healthy Japanese men who received a single, unspecified dose of UCB0107 dosage or placebo. Endpoints were adverse events and pharmacokinetics.

In December 2019, a Phase 1 study began to enroll 25 patients with progressive supranuclear palsy at 14 sites in Belgium, Germany, Spain, and the United Kingdom. Participants receive a predefined dose of UCB0107 or placebo for one year, with a four-month safety follow-up. The primary outcome is incidence of treatment-emergent adverse events. The study is expected to finish in November 2021. As of March 2021, no safety concerns had been reported (see Mar 2021 conference news); the study finished in November 2021. An open-label extension began in November 2020, to run for up to five years.

In July 2020, UCB announced a licensing agreement with Roche/Genentech to develop UCB0107 for Alzheimer’s disease. In the deal, UCB received $120 million and committed to conducting a proof-of-concept study in AD (press release).

The AD study began in June 2021. The Phase 2 trial plans to randomize 450 people with mild cognitive impairment or mild AD dementia to one of two doses of bepranemab or placebo for 80 weeks. Enrollment requires clinical diagnosis and evidence of amyloid accumulation by PET or CSF markers. The primary endpoint is change from baseline in the CDR-SB. Secondary outcomes include adverse events, ADAS-Cog14, Amsterdam Instrumental Activities of Daily Living, MMSE, tau-PET, and serum drug concentrations. A 48-week open-label extension is planned. The study will run until November 2025.

For trial details on this antibody, see clinicaltrials.gov.

Last Updated: 23 Jan 2022

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Research Models

TDP-43 (Q331K) Knock-In (Line 52)

Synonyms: TDP-43Q331K KI (Line 52)

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Species: Mouse
Genes: Tardbp
Mutations: Tardp Q331K
Modification: Tardbp: Knock-In
Disease Relevance: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Motor Impairment
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • NMJ Abnormalities

No Data

  • Muscle Atrophy
  • Gliosis

Cortical Neuron Loss

25% loss of parvalbumin-positive neurons at 5 months.

Lower Motor Neuron Loss

Not observed.

Cytoplasmic Inclusions

Not observed.

Gliosis

Unknown.

NMJ Abnormalities

Not observed.

Muscle Atrophy

Unknown.

Motor Impairment

Not observed.

Body Weight

Increased body weight.

Premature Death

Mutation may be deleterious to male embryos.

Last Updated: 20 Apr 2018

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Further Reading

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Research Models

TREM2, humanized (R47H) X 5XFAD

Synonyms: R47H+mTrem2−/−5XFAD

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Species: Mouse
Genes: Trem2, TREM2, APP, PSEN1
Modification: Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

Plaques observed in 8.5-month-old mice, the only age reported thus far.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

Microgliosis observed in 8.5-month-old mice, the only age reported thus far. Fewer plaque-associated microglia in mice expressing the R47H variant, compared with the common variant of human TREM2.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 06 Apr 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

TREM2, humanized (common variant) X 5XFAD

Synonyms: CV+mTrem2−/−5XFAD

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Species: Mouse
Genes: Trem2, TREM2, APP, PSEN1
Modification: Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

Plaques observed in 8.5-month-old mice, only age reported thus far.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

Microgliosis observed in 8.5-month-old mice, only age reported thus far.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 06 Apr 2018

COMMENTS / QUESTIONS

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Further Reading

No Available Further Reading

Research Models

APOE3 Knock-In (JAX)

Synonyms: APOE3 KI, APOE*3 KI

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Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-ApoEem2(APOE*)Adiuj/J

Summary

APOE3 knock-in mice express humanized APOE3 from the endogenous ApoE locus.

Homozygotes are viable and fertile.

Modification Details

APOE3 knock-in mice were generated by using CRISPR/Cas9 gene editing to introduce a point mutation (leading to an arginine-to-cysteine substitution at amino acid 130) into an existing humanized APOE isoform 4 knock-in allele (ApoEtm1.1(APOE*4)Adiuj).

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 29 Nov 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

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