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

A phase 2 randomized, double blind, placebo controlled study evaluating the efficacy and safety of AL002 in participants with Early Alzheimer's Disease.

Start Date22 Jan 2021

Sponsor / Collaborator

Alector, Inc.

[+1]

NCT03635047 / CompletedPhase 1

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

This is a multi-centre, randomized, double-blind, placebo-controlled, dose escalation first in human (FIH) study in healthy adults and in patients with mild to moderate Alzheimer's disease. The study is designed to systematically assess the safety (including immunogenicity) and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL002.

Start Date12 Nov 2018

Sponsor / Collaborator

Alector, Inc.

100 Clinical Results associated with AL-002

100 Translational Medicine associated with AL-002

100 Patents (Medical) associated with AL-002

Literatures (Medical) associated with AL-002

07 Sep 2020·Journal of Experimental MedicineQ1 · MEDICINE

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model

Q1 · MEDICINE

Article

Author: Tassi, Ilaria ; Rosenthal, Arnon ; Rhinn, Hervé ; Long, Hua ; Ward, Michael ; Ibrahim, Adiljan ; Wang, Shoutang ; Paul, Robert ; Mustafa, Meer ; Kong, Philip ; Yuede, Carla M. ; Schwabe, Tina ; Gilfillan, Susan ; Salazar, Santiago Viveros ; Siddiqui, Omer ; Colonna, Marco

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.

Alzheimer's Research & Therapy

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease

Article

Author: Rychkova, Anna ; Rosenthal, Arnon ; Budda, Balasubrahmanyam ; Schwabe, Tina ; Ward, Michael ; Nguyen, Tuan ; Long, Hua ; Mayorga, Arthur ; Simmons, Adam ; Yeh, Felix ; Kenkare-Mitra, Sara ; Burgess, Brady ; Tassi, Ilaria ; Rhinn, Herve ; Paul, Robert

BACKGROUNDVariants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.METHODSPreclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.RESULTSIn cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.CONCLUSIONSThese findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.TRIAL REGISTRATIONClinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.CLINICALTRIALSgov/study/NCT03635047 .

Frontiers in ImmunologyQ2 · MEDICINE

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Q2 · MEDICINE

ReviewOA

Author: Imbimbo, Bruno P ; Watling, Mark ; Chiesa, Patrizia A ; Akman-Anderson, Leyla ; Lucía, Alejandro ; Vergallo, Andrea ; Hampel, Harald ; Valenzuela, Pedro L ; Caruso, Giuseppe ; Toschi, Nicola ; Ávila, Jesús ; Lista, Simone ; Hernández, Félix ; Caraci, Filippo ; Garaci, Francesco ; Nisticò, Robert ; Emanuele, Enzo ; Cuello, A Claudio ; Verdooner, Steven R ; Corbo, Massimo ; Baldacci, Filippo

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants-TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1-potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

News (Medical) associated with AL-002

28 Oct 2024

·medcitynews.com

AbbVie Adds Another Alzheimer’s Prospect With $1.4B Aliada Therapeutics Acquisition - MedCity News

Alzheimer’s disease medicines commercialized in the past two years validated amyloid beta as a drug target, but these antibody therapies still have a hard time penetrating the membrane that covers blood vessels supplying the brain. AbbVie aims to best those drugs through its acquisition of Aliada Therapeutics, a clinical-stage biotech whose technology enables large molecules such as antibodies to cross this protective barrier. AbbVie announced Monday it is paying $1.4 billion in cash to acquire Aliada, a biotech that just entered the clinic earlier this year. Boston-based Aliada gets drugs across the blood-brain barrier (BBB) by leveraging receptors that transport substances into the brain. Lead Aliada program ALIA-1758 is an antibody engineered with binders for transferrin, which transports iron into the brain, and CD98, which transports certain amino acids. The drug comes from a platform technology called Modular Delivery, or MODEL. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health “We’re essentially taking advantage of normal physiological brain transport processes, and if you like, we’re hijacking those by attaching therapeutic cargos to our delivery modules to allow brain delivery,” Aliada Chief Scientific Officer John Dunlop explained in an interview during the BIO Conference in June. Aliada licensed MODEL from Johnson & Johnson subsidiary Janssen, which had used the technology to develop ALIA-1758. Aliada co-founder Danielle Feldman, who is senior director of corporate development for the company, was with RA Capital Management when her search for new technologies led her to Johnson & Johnson Innovation—JJDC, Dunlop said. Those discussions led both parties to conclude that the best way for the MODEL technology to realize its value was as a standalone company undistracted by the goings-on of a big pharmaceutical company. Aliada was formed at the end of 2021, with seed financing from RA Capital and J&J. OrbiMed and Sanofi Ventures later joined an extension of the financing. Dunlop declined to disclose how much was invested, but securities filings show the company raised $1 million in 2021, followed by nearly $32 million in late 2022. Dunlop did say Aliada had enough capital to support the lead program through Phase 1b proof-of-concept testing in Alzheimer’s. Clinical trial records show a Phase 1 trial began in May with a targeted enrollment of 52 healthy adults. According to Dunlop, ALIA-1758’s affinity for its target receptors means that more drug can get into the brain per dose, which should translate to needing a lower dosage level to achieve the desired therapeutic effect. A lower dose could reduce the adverse effects associated with amyloid-reducing drugs. Eisai’s Leqembi, which won full FDA approval last year, and Eli Lilly’s Kisunla, approved in July, carry warnings on their labels for risks of bleeding and swelling complications. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB AbbVie has been spreading its bets in Alzheimer’s drug R&D. The company earlier this year reportedly discontinued development of ABBV-916 as a monotherapy, but is still leaving the door open for applications of the antibody as part of combination treatments. An Alzheimer’s partnership with Alector began in 2017. Two years ago, AbbVie terminated one program that had reached Phase 1 testing, opting to focus the alliance’s efforts on a second Alector program, AL002. This drug is an antibody designed to modulate the TREM2 receptor as a way of enhancing the activity of microglia, immune cells found in the central nervous system (CNS). Alector is responsible for Phase 1 and 2 testing, after which AbbVie has the option to license the drug. AbbVie’s pipeline currently shows AL002 is still in Phase 2 testing. In 2022, AbbVie paid $130 million up front to acquire Syndesi Therapeutics, developer of small molecule drugs that modulate synaptic transmission. Syndesi’s most advanced program, renamed ABBV-552, targets synaptic vesicle protein 2A (SV2A). AbbVie’s pipeline currently shows this program is in Phase 2 testing. AbbVie said it expect to close the Aliada acquisition by the end of this year. In the company’s announcement of the deal, Roopal Thakkar, executive vice president, research and development and chief scientific officer, AbbVie, said neuroscience is one of the company’s key growth areas. “This acquisition immediately positions us to advance ALIA-1758, a potentially best-in-class disease-modifying therapy for Alzheimer’s disease,” he said. “In addition, Aliada’s novel BBB-crossing technology strengthens our R&D capabilities to accelerate the development of next-generation therapies for neurological disorders and other diseases where enhanced delivery of therapeutics into the CNS is beneficial.”

Phase 1AcquisitionDrug ApprovalPhase 2

28 Oct 2024

·www.biospace.com

AbbVie Doubles Down on Alzheimer’s With $1.4B Aliada Buy

iStock/ Evgeny Gromov The acquisition of Aliada Therapeutics gives AbbVie access to a Phase I anti-amyloid antibody as well as the biotech’s novel platform engineered for efficient blood-brain barrier transport. With several early- to mid-stage assets already in its pipeline , AbbVie took an even deeper dive into the Alzheimer’s space Monday with the acquisition of Aliada Therapeutics. At the heart of the deal—which will see AbbVie pay $1.4 billion in cash to acquire the Boston-based biotech—is ALIA-1758, an anti-amyloid antibody currently in Phase I development for Alzheimer’s disease. This is the same drug class that recently burst onto the scene in the form of Biogen/Eisai’s Leqembi and Eli Lilly’s Kisunla , both approved in the last two years as the first disease-modifying therapies for Alzheimer’s. The acquisition also gives AbbVie access to Aliada’s Modular Delivery (MODEL) platform, which is “engineered for both efficient BBB (blood-brain barrier) transport and downstream therapeutic functionality,” according to the company’s website . In an investor note Monday, BMO Capital Markets analyst Evan David Seigerman said BMO views the deal “as positive for AbbVie shares, albeit risky given the indication and stage of development, expanding into a therapeutic area it knows well and continuing to bolster its pipeline for long term growth beyond recent commercial success with Skyrizi & Rinvoq.” Stifel analysts added in an investor note that the deal “seemingly offers a vote of confidence in amyloid, just as sentiment in the space is reaching an all-time low.” ALIA-1758 targets pyroglutamate amyloid beta, which is similar to the epitope targeted by Eli Lilly’s Kisunla , John Dunlop, chief scientific officer at Aliada, previously told BioSpace . The novel technology targets transferrin and CD98 receptors TfR and CD98, which are highly expressed in the brain’s endothelial cells, and uses the transferrin receptor to drive its cargo to cells and force degradation and elimination of the plaques, Dunlop explained. By transporting the cargo in this way, a higher concentration of the antibodies is delivered across the blood-brain barrier to drive therapeutic benefit. “Many promising CNS-targeted therapies fail to reach late-stage trials due to their inability to cross the blood-brain barrier,” Michael Ryan, chief medical officer at Aliada, said in a statement Monday, adding that the company is “excited about AbbVie’s commitment to bringing ALIA-1758 to patients with Alzheimer’s disease.” AbbVie already has a considerable presence in the Alzheimer’s R&D space, and Seigerman noted that Aliada’s assets are potentially complementary to a number of Alzheimer’s assets that AbbVie already has in development. The company’s pipeline includes ABBV-916, an anti-AβpE3 antibody; ABBV-552, an SV2A modulator being evaluated to target nerve terminals to enhance synaptic efficiency; and AL002, an antibody being developed in partnership with Alector Therapeutics. “Neuroscience is one of our key growth areas and we are committed to driving innovation in this field to address critical unmet needs for patients living with seriously debilitating neurological diseases such as Alzheimer’s disease,” Roopal Thakkar, EVP of research and development and chief scientific officer at AbbVie, said in a statement . Aliada’s platform “strengthens our R&D capabilities to accelerate the development of next-generation therapies for neurological disorders and other diseases where enhanced delivery of therapeutics into the CNS is beneficial.” The deal is expected to close in the fourth quarter of 2024, subject to regulatory approvals and other customary closing conditions.

Drug ApprovalPhase 1Acquisition

16 Nov 2023

·www.biospace.com

Alzamend Neuro Regains Compliance with Nasdaq’s Minimum Bid Price Requirement

ATLANTA--(BUSINESS WIRE)--Alzamend Neuro, Inc. (Nasdaq: ALZN) (“Alzamend”), an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s disease (“Alzheimer’s”), bipolar disorder (“BD”), major depressive disorder (“MDD”) and post-traumatic stress disorder (“PTSD”), today announced that it has received a notification letter (the “Compliance Notice”) from the Listing Qualifications Staff of the Nasdaq Stock Market, LLC (“Nasdaq”) dated November 15, 2023, informing Alzamend that it has regained compliance with Nasdaq Listing Rule 5550(a)(2) (the “Minimum Bid Price Requirement”). In order to regain compliance with the Minimum Bid Price Requirement, Alzamend’s common stock was required to maintain a closing bid price of at least $1.00 per share for a minimum of ten consecutive trading days. The Minimum Bid Price Requirement was met on November 13, 2023. Accordingly, in the Compliance Notice, Nasdaq stated that the matter is now closed. The Compliance Notice is unrelated to the previously disclosed notice received by Alzamend from Nasdaq on September 26, 2023 regarding the minimum Market Value of Listed Securities (“MVLS”) for Alzamend’s common stock being below the $35 million minimum MVLS requirement for continued listing on The Nasdaq Capital Market under Nasdaq Listing Rule 5550(b)(2) (the “MVLS Rule”). As previously disclosed, Alzamend has 180 calendar days, or until March 25, 2024, to regain compliance with the MVLS Rule. About Alzamend Neuro Alzamend is an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s, BD, MDD and PTSD. Our mission is to rapidly develop and market safe and effective treatments. Our current pipeline consists of two novel therapeutic drug candidates, AL001 - a patented ionic cocrystal technology delivering lithium via a therapeutic combination of lithium, proline and salicylate, and AL002 - a patented method using a mutant-peptide sensitized cell as a cell-based therapeutic vaccine that seeks to restore the ability of a patient’s immunological system to combat Alzheimer’s. Both of our product candidates are licensed from the University of South Florida Research Foundation, Inc. pursuant to royalty-bearing exclusive worldwide licenses. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “believes,” “plans,” “anticipates,” “projects,” “estimates,” “expects,” “intends,” “strategy,” “future,” “opportunity,” “may,” “will,” “should,” “could,” “potential,” or similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties. Forward-looking statements speak only as of the date they are made, and Alzamend undertakes no obligation to update any of them publicly in light of new information or future events. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors. More information, including potential risk factors, that could affect Alzamend’s business and financial results are included in Alzamend’s filings with the U.S. Securities and Exchange Commission. All filings are available at and on Alzamend’s website at .

100 Deals associated with AL-002

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	DE	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	US	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	NL	AbbVie, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	DE	AbbVie, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	NL	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	CA	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	FR	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	ES	AbbVie, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	AR	Alector, Inc.	22 Jan 2021
Alzheimer Disease	Phase 2	US	AbbVie, Inc.	22 Jan 2021

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