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AL 002

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Drug Profile

AL 002

Alternative Names: AL 002; AL 002a; AL-002c

Latest Information Update: 29 Aug 2023

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At a glance

  • Originator AbbVie; Alector
  • Class Antibodies; Antidementias; Immunotherapies; Monoclonal antibodies; Neuroprotectants
  • Mechanism of Action TREM2 protein-stimulants
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Phase II Alzheimer's disease
  • Preclinical Neurodegenerative disorders

Most Recent Events

  • 16 Jul 2023 Pharmacodynamics data from a preclinical study in Alzheimer’s disease presented at the Alzheimer's Association International Conference (AAIC-2023)
  • 16 Jan 2023 Alector initiates a phase II trial for Alzheimer's disease (Early-stage disease, In adults, In elderly) in Spain (EudraCT2022-002987-57)
  • 22 Apr 2022 Phase-II development is ongoing in the UK and Australia

Development Overview

Introduction

AL 002 is a TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) activating, humanised monoclonal IgG1 antibody being jointly developed by Alector and AbbVie, for the treatment of Alzheimer's disease and other neurodegenerative disorders. Reduced function of TREM2 is associated with Alzheimer’s disease (AD) risk. AL 002 binds to TREM2 and activates the TREM2 signaling pathway to increase the ability of microglia to clear pathology and protect neurons. Clinical development for Alzheimer's disease is ongoing in in the US, Australia, Canada, France, Germany, Italy, the Netherlands, New Zealand, Poland, Spain, and the UK. Preclinical development for neurodegenerative disorders is underway in the US.

AL 002 has emerged from a research programme of Alector in collaboration with AbbVie on antibody therapeutics [see Adisinsight drug profile 800050570].

Company Agreements

In February 2023, Alector and AbbVie amended the AbbVie agreement, which will result in Alector receiving a $US 17.8 million milestone payment for the dosing of the first patient in a long-term extension study. If AbbVie exercises its option for the TREM2 program, Alector will receive $US 250.0 million. Additionally, under the terms of the AbbVie Agreement, Alector will be eligible to earn up to an additional $US 225 million in milestone payments related to the regulatory approval for up to three indications. Following AbbVie’s option exercise for the TREM2 program, Alector may opt out of sharing in development costs and profits or and instead receive a tiered royalty on sales of products. Following AbbVie's exercise of an option for the TREM2 program, AbbVie would be responsible for certain development activities and global commercialization, taking advantage of its global clinical trial expertise and commercialization networks. In June 2022, AbbVie terminated the CD33 collaboration program after AbbVie and Alector collaboratively reviewed progress for AL 003 and concluded that further development of AL003 was not warranted. Alector will continue the development of the AL002 program (TREM2) under the AbbVie Agreement but will not be eligible for any future milestones related to the CD33 collaboration program from AbbVie. In October 2017, AbbVie entered into a global research and development agreement (AbbVie agreement) with Alector, to develop and commercialise immune therapies for the treatment of Alzheimer's disease and other neurodegenerative disorders. Under the terms of the agreement, AbbVie and Alector have agreed to research a portfolio of antibody targets and AbbVie has an option to global development and commercial rights to two targets which include a triggering receptor expressed on myeloid cells 2 (TREM2) and Siglce-3 receptor (CD33). Alector will conduct exploratory research, drug discovery and development for lead programs up to the conclusion of the proof of concept studies including the design and execution of phase I and phase II studies. Upon exercising the option, AbbVie will lead development and commercialisation activities. Alector and AbbVie will co-fund development and commercialisation and will share global profits and losses equally after marketing approval. Alector will receive a $US205 million upfront payment and a potential, future equity investment of up to $US20 million if AbbVie exercises its option for either program (or both programs), Alector is eligible for additional option exercise and milestone payments totaling up to $US986M. Additionally, under the terms of the AbbVie Agreement, Alector is eligible to earn up to an additional $242.8 million in milestone payments related to the initiation of certain clinical studies and regulatory approval for up to three indications. [1] [2] [3] [4] [5]

Key Development Milestones

In January 2023, Alector initiated a phase II trial to evaluate the safety, tolerability, and efficacy of AL 002 in participants with Alzheimer’s disease (EudraCT2022-002987-57; AL002-LTE). The double-blind study is designed to enrol approximately 190 patients in Spain and may expand to Argentina, Australia, Canada, the United States, France, Poland, the Netherlands, Germany, Italy, and the United Kingdom [6]

In November 2020, Alector in collaboration with AbbVie, initiated the phase II INVOKE-2 trial to evaluate the efficacy and safety of AL 002 administered intravenously in patients with early Alzheimer's disease (NCT04592874; AL002-2; EudraCT 2019-001476-11 ). The primary endpoint of the trial is to determine disease progression as measured by the CDR-SB through study completion, up to 48 through 96 weeks. As at April 2022, Alector reported discontinued dosing of APOE e4/e4 homozygotes in the INVOKE 2 trial, and proposed an additional voluntary amendment to the trial protocol to exclude APOE e4/e4 homozygotes from the trial. Under the guidance of an Independent Data Monitoring Committee (IDMC), necessary additional modifications will be made to the study protocol [7] . This randomised, double-blind, placebo-controlled trial will recruit approximately 265 patients in the US, Australia, Canada, France, Germany, Italy, the Netherlands, New Zealand, Poland, Spain, and the UK [8] . In January 2023, the first patient was enrolled and dosed in a long-term extension (LTE) of INVOKE 2 phase II clinical trial. In February 2023, Alector announced the intention to add up to an additional 64 participants in the ongoing INVOKE 2 trial to replace discontinuations, including APOE e4/e4 participants [5] .

As of June 2020, Alector completed the phase I INVOKE trial that evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of single and multiple doses of AL 002 healthy volunteers and patients with mild-to-moderate Alzheimer's disease (NCT03635047; AL002-1). The randomised trial was initiated in November 2018 and completed enrolment of 69 participants in Australia, the UK and the US. Prior to June 2020, 56 healthy volunteers were sequentially enrolled into 10 cohorts. In July 2021, data from the trial were presented at the Alzheimer's Association International Conference 2021 (AAIC-2021). In April 2022, data were presented at the 74th Annual Meeting of the American Academy of Neurology 2022 (AAN-2021) [9] [10] [3] [11] [12] .

In July 2023, preclinical data were presented at the Alzheimer's Association International Conference (AAIC-2023) [13] .

In June 2020, pharmacodynamics data from preclinical studies were released by Alector [3] .

In July 2019, Alector presented preclinical data of AL 002 at the Alzheimer's Association International Conference 2019 (AAIC-2019) [14] [15] [16] .

Financing information

In July 2018, Alector secured $US133 million in Series E financing round. The company has previously raised $US282 million. The company expect to utilize the proceeding from the financing to advance Alector’s clinical programs and expand the company’s discovery platform [17] .

Patent Information

As at April 2022, Alector owns seven patent families directed to the TREM2 programme, which includes two issued US patents, covering the compositions and uses of TREM2 programme candidates. The first patent family is expected to expire in 2035, the second patent family is expected to expire in 2036, the third patent family is expected to expire in 2038, the fourth patent family is expected to expire in 2040, the fifth and sixth patent families are expected to expire in 2041, and the seventh patent family, assuming that the applications are timely filed and the requirements are satisfied for the US provisional patent application, is expected to expire in 2042 [7] [18] [19] .

Drug Properties & Chemical Synopsis

  • Route of administration IV
  • Formulation unspecified
  • Class Antibodies, Antidementias, Immunotherapies, Monoclonal antibodies, Neuroprotectants
  • Target TREM2 protein
  • Mechanism of Action TREM2 protein-stimulants
  • WHO ATC code

    N06D-X (Other anti-dementia drugs)

    N07X (Other Nervous System Drugs)

  • EPhMRA code

    N7D (Anti-Alzheimer Products)

    N7X (All other CNS drugs)

Trial Landscape

Indication Phase 0 Phase I Phase II Phase III Phase IV
Alzheimer's disease - 1 2 - -

Development Status

Summary Table

Download Data (CSV)
Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Alzheimer's disease - Early-stage disease, In adults, In the elderly Phase II USA IV / unspecified AbbVie, Alector 30 Nov 2020
Alzheimer's disease - Early-stage disease, In adults, In the elderly Phase II Australia, Canada, France, Germany, Italy, Netherlands, New Zealand, Poland, Spain, United Kingdom IV / unspecified Alector 30 Nov 2020
Neurodegenerative disorders - - Preclinical USA IV / unspecified AbbVie, Alector 25 Jul 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Alector Originator USA
AbbVie Originator USA
Alector Owner USA
AbbVie Owner USA

Scientific Summary

Adverse Events

Intravenously administered AL 002 was safe and generally well tolerated in cynomolgus monkey toxicology studies, up to 250 mg/kg weekly dose for 4 weeks. No adverse findings were observed. The no observed adverse effect level (NOAEL) was 250 mg/kg [15] .

In the single ascending dose (SAD) portion of the phase I INVOKE study in healthy volunteers (n=64), AL 002 was safe and generally well tolerated with no drug-related serious adverse events or dose-limiting toxicities up to the highest dose [9] [3] [10] [12] .

Pharmacodynamics

Summary

In the single ascending dose (SAD) portion of the phase I INVOKE study in healthy volunteers (n=64), AL 002 decreased triggering receptor expressed on myeloid cells-2 (TREM2) or sTREM2 in cerebral spinal fluid (CSF), in a dose-dependent manner, demonstrating proof of target engagement in the brain. Treatment of healthy volunteers with AL 002 caused an increase in CSF levels of CSF1R, SPP1 and IL1RN in a dose-dependent manner [9] [10] [12] .

After multiple weekly dosing in cynomolgus monkeys, systemic exposure of intravenously administered AL 002 increased slightly less than dose proportionally with increasing doses. Some accumulation of AL 002 was observed. The ratio of serum and CSF levels of AL 002 appeared consistent across the three doses tested. A dose dependent effect on pharmacodynamic biomarkers in both serum and CSF was observed [15] .

In a preclinical study, results demonstrated that AL 002c treated CV-5XFAD and R47-5XFAD mice had a higher plasma Aβ42/40 ratio and lower plasma t-tau compared with their IgG1-treated genotype counterparts. No differences were observed between R47H and CV genotypes in plasma Aβ42/40 ratio or t-tau [13] . In preclinical study conducted in mouse models of Alzheimer’s disease (expressing either the common variant or the R47H variant of human TREM2), expansion of unique subpopulations of metabolically active and proliferating microglia was observed post treatment with a single injection of AL 002c (a variant of AL 002). Prolonged treatment with AL002c, reduced neuronal damage, tempered the microglial inflammatory response and reduced the formation of toxic filamentous plaques, which curtailed neurite dystrophy. Treatment with AL002c was beneficial after plaque formation, suggesting that anti-TREM2 antibodies may be helpful even if introduced at relatively late stages of disease. Improved cognitive and behavioral outcomes were exhibited by the treated mice versus the placebo control. Antibody-mediated engagement of TREM2 enhanced neuroprotective microglia. the peripheral injection of antibodies triggered TREM2 signaling microglial proliferation and activation in mouse brains. These data suggested that the antibodies efficiently cross the blood-brain barrier and that TREM2 signal induction was sufficient to shift the microglia phenotype. In 5xFAD mice, chronic treatment with a TREM2 agonist caused increased expression of synaptic and myelin genes. Administration of AL 002 activated microglia and increased clustering of microglia around amyloid plaques in 5xFAD mice models. Also a reduced amyloid deposition and improved cognition was reported with AL 002 in mice model [3] [16] [14] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2020 Trial Update Alector plans a phase II INVOKE trial for Alzheimer's disease in 2020 (NCT03635047) [3] 24 Dec 2020
30 Nov 2020 Trial Update Alector and Abbvie plan a phase II INVOKE-2 trial for Alzheimer's disease (Early-stage disease) (IV, Infusion) in November 2020 (NCT04592874) 30 Nov 2020
31 Dec 2018 Trial Update Alector plans a clinical trial for Alzheimer’s disease (Monotherapy, Combination therapy) in 2018 [20] 30 Jul 2018
01 Nov 2018 Trial Update Alector plans a phase I trial for Alzheimer disease (In volunteers) in Australia in November 2018 (IV, Infusion) (NCT03635047) (700298885) 02 Jan 2019

Development History

Event Date Update Type Comment
16 Jul 2023 Scientific Update Pharmacodynamics data from a preclinical study in Alzheimer’s disease presented at the Alzheimer's Association International Conference (AAIC-2023) [13] Updated 29 Aug 2023
16 Jan 2023 Trial Update Alector initiates a phase II trial for Alzheimer's disease (Early-stage disease, In adults, In elderly) in Spain (EudraCT2022-002987-57) Updated 24 Feb 2023
22 Apr 2022 Active Status Review Phase-II development is ongoing in the UK and Australia [7] Updated 22 Apr 2022
21 Apr 2022 Patent Information Alector has patent protection covering the compositions and uses of TREM2 programme products, including AL 002 in USA [7] Updated 22 Apr 2022
21 Apr 2022 Patent Information Alector has patents pending for the compositions and uses of TREM2 programme products, including AL 002 in USA [7] Updated 22 Apr 2022
02 Apr 2022 Scientific Update Updated adverse events and pharmacodynamics data from the phase I INVOKE trial in Alzheimer's disease presented at the 74th Annual Meeting of the American Academy of Neurology 2022 (AAN-2022) [9] Updated 04 Jun 2022
28 Dec 2021 Phase Change - No development reported No recent reports of development identified for phase-I development in Alzheimer's-disease in Australia, United Kingdom (IV) Updated 22 Apr 2022
08 Sep 2021 Scientific Update Adverse events and pharmacodynamics data from the INVOKE phase I trial presented at Alzheimer's Association International Conference 2021 (AAIC-2021) [10] Updated 14 Sep 2021
31 Dec 2020 Patent Information Alector has patent protection for TREM2 program in USA [18] Updated 18 Jun 2021
30 Nov 2020 Phase Change - II Phase-II clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in Spain, Poland, Italy, New Zealand, Germany, France, Canada (IV) (NCT04592874) (EudraCT 2019-001476-11) [7] Updated 22 Apr 2022
30 Nov 2020 Phase Change - II Phase-II clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in United Kingdom, Australia (IV) (NCT04592874) (EudraCT 2019-001476-11) [7] Updated 22 Apr 2022
30 Nov 2020 Phase Change - II Phase-II clinical trials in Alzheimer's disease (Early-stage disease, In the elderly, In adults) in Netherlands (IV) (EudraCT 2019-001476-11) Updated 08 Dec 2020
30 Nov 2020 Phase Change - II Phase-II clinical trials in Alzheimer's disease (In adults, In the elderly, Early-stage disease) in USA (IV) (NCT04592874) Updated 30 Nov 2020
25 Nov 2020 Trial Update Alector completes the phase I INVOKE trial in Alzheimer's disease in United Kingdom, USA, Australia (IV) (NCT03635047) Updated 24 Dec 2020
19 Oct 2020 Trial Update Alector and Abbvie plan a phase II INVOKE-2 trial for Alzheimer's disease (Early-stage disease) (IV, Infusion) in November 2020 (NCT04592874) Updated 30 Nov 2020
25 Jun 2020 Trial Update Alector plans a phase II INVOKE trial for Alzheimer's disease in 2020 (NCT03635047) [3] Updated 24 Dec 2020
25 Jun 2020 Trial Update Alector completes a phase I trial in Alzheimer's disease in USA and Australia (IV) before June 2020 [3] Updated 02 Jul 2020
25 Jun 2020 Scientific Update Pharmacodynamics data from preclinical studies in Alzheimer’s disease released by Alector [3] Updated 30 Jun 2020
14 Jul 2019 Scientific Update Pharmacodynamics data from preclinical trials in Alzheimer’s disease presented at the Alzheimer's Association International Conference 2019 (AAIC-2019) [14] Updated 31 Oct 2019
14 Jul 2019 Scientific Update Pharmacodynamics and safety data from preclinical trials in Alzheimer’s disease presented at the Alzheimer's Association International Conference 2019 (AAIC-2019) [15] Updated 24 Oct 2019
14 Jul 2019 Scientific Update Pharmacodynamics data from preclinical trials in Alzheimer’s disease presented at the Alzheimer's Association International Conference 2019 (AAIC-2019) [16] Updated 22 Oct 2019
28 Mar 2019 Patent Information Alector has patents pending for TREM2 program in USA [19] [18] Updated 04 Apr 2019
15 Nov 2018 Phase Change - I Phase-I clinical trials in Alzheimer's disease in Australia (IV) [11] Updated 02 Jan 2019
12 Nov 2018 Phase Change - I Phase-I clinical trials in Alzheimer's disease in United Kingdom (IV) (NCT03635047) Updated 24 Dec 2020
12 Nov 2018 Trial Update Alector initiates enrollment in the phase I INVOKE trial in Alzheimer's disease in USA (IV) (NCT03635047) Updated 24 Dec 2020
12 Nov 2018 Phase Change - I Phase-I clinical trials in Alzheimer's disease in USA (IV) after November 2018 (NCT03635047) Updated 30 Jun 2020
22 Aug 2018 Trial Update Alector plans a phase I trial for Alzheimer disease (In volunteers) in Australia in November 2018 (IV, Infusion) (NCT03635047) Updated 02 Jan 2019
30 Jul 2018 Trial Update Alector plans a clinical trial for Alzheimer’s disease (Monotherapy, Combination therapy) in 2018 [20] Updated 30 Jul 2018
25 Jul 2018 Phase Change - Preclinical Preclinical trials in Alzheimer's disease in USA (IV) [17] Updated 30 Jul 2018
25 Jul 2018 Phase Change - Preclinical Preclinical trials in Neurodegenerative disorders in USA (IV) [17] Updated 30 Jul 2018
24 Oct 2017 Licensing Status Alector and AbbVie agree to co-promote and co-develop antibody therapeutics worldwide for Alzheimer's disease and Neurodegenerative disorders [1] Updated 30 Jul 2018
24 Oct 2017 Phase Change Early research in Alzheimer's disease in USA (IV) [1] Updated 30 Jul 2018
24 Oct 2017 Phase Change Early research in Neurodegenerative disorders in USA (IV) [1] Updated 30 Jul 2018

References

  1. Alector and AbbVie Announce Collaboration to Advance a Novel Class of Immune Therapies for Patients with Alzheimer's Disease.

    Media Release

  2. Alector Snags $133M to Activate Immune Cells Against Neurodegeneration. Internet-Doc 2018;.

    Available from: URL: https://www.xconomy.com/san-francisco/2018/07/25/alector-snags-133m-to-activate-immune-cells-against-neurodegeneration/2/

  3. Alector Announces Publication of Preclinical and Phase 1 Data Validating Potential of AL002, a TREM2 Activating Antibody for the Treatment of Alzheimers Disease, in The Journal of Experimental Medicine.

    Media Release

  4. Alector, Inc Form Q Sec Filing. Internet-Doc 2022;.

    Available from: URL: https://investors.alector.com/static-files/813eba5c-745b-4100-be5f-97873a288915

  5. Alector 10-K 18-Apr-2023. Internet-Doc 2023;.

    Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1653087/000095017023005111/alec-20221231.htm

  6. A MULTICENTER, LONG-TERM EXTENSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF AL002 IN PARTICIPANTS WITH ALZHEIMER'S DISEASE

    ctiprofile

  7. Alector_SEC Form 10-K_Apr 2022. Internet-Doc 2022;.

    Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1653087/000095017022001979/alec-20211231.htm

  8. A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of AL002 in Participants With Early Alzheimer's Disease

    ctiprofile

  9. Ward M, Paul R, Long H, Rhinn H, Rychkova A, Tu G, et al. A Phase 1 Study of AL002 in Healthy Volunteers. AAN-2022 2022; abstr. P5.004.

    Available from: URL: https://index.mirasmart.com/aan2022/PDFfiles/AAN2022-003133.html

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    Available from: URL: https://alz.confex.com/alz/2021/meetingapp.cgi/Paper/54669

  11. Alector Initiates Phase 1 Trial of AL002 for the Treatment of Patients with Alzheimer's Disease.

    Media Release

  12. A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Single and Multiple Doses of AL002 in Healthy Participants and in Participants With Mild to Moderate Alzheimer's Disease

    ctiprofile

  13. Burgess B, Ibrahim A, Stansley B, Schwabe T, Wang S, Colonna M, et al. AL002c-mediated reduction in amyloid beta pathology is reflected by changes in plasma Alzheimer?s disease biomarkers in 5XFAD mice. AAIC-2023 2023; abstr. P3-197.

    Available from: URL: https://alz.confex.com/alz/2023/meetingapp.cgi/Paper/72737

  14. Schwabe T, Tassi I, Rhinn H, Ibrahim A, Kong P, Salazar S, et al. Development of TREM2 Agonistic Antibodies to Treat Alzheimer?s Disease. AAIC-2019 2019; abstr. 32469.

    Available from: URL: https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AAIC19&id=32469

  15. Long H, Tu G, Schwabe T, Rhinn H, King R, Rosenthal A. Preclinical Development of TREM2 Agonist Antibody (AL002) in Cynomolgus Monkeys. AAIC-2019 2019; abstr. 32845.

    Available from: URL: https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AAIC19&id=32845

  16. Price BR, Sudduth TL, Weekman EM, Woolums A, Hawthorne D, Rosenthal A, et al. Therapeutic Targeting of TREM2 By an Activating Antibody Ameliorates Amyloid-Beta Deposition and Improves Cognition in the 5xFAD Model of Alzheimer?s Disease. AAIC-2019 2019; abstr. 31373.

    Available from: URL: https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AAIC19&id=31373

  17. Alector Announces $133 Million in Series E Financing to Advance Broad Portfolio of Immuno-Neurology and Immuno-Oncology Programs.

    Media Release

  18. Alector SEC filing, Form 10-K. Internet-Doc 2021;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/1653087/000156459021008860/alec-10k_20201231.htm

  20. Alector Closes $133 Million to Expand Alzheimer?s Programs. Internet-Doc 2018;.

    Available from: URL: https://www.biospace.com/article/alector-closes-133-million-to-expand-alzheimer-s-programs/
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