Various immunotherapies attempt to treat Alzheimer’s

From antibodies to cell therapies: diverse new approaches emerge in Alzheimer’s drug development

NKGen enters Phase II trial…evaluates the potential of its NK cell therapy

Targets TREM2 and other antibodies… Immunotherapies emerge as a viable option after tau

A series of immunotherapy candidates are showing promise in the field of Alzheimer's disease treatment.

 

With the limitations of existing antibody therapies becoming apparent, multinational pharmaceutical companies are attempting approaches targeting new immune pathways.

 

In particular, pipelines targeting innate immune regulation, such as NK cell therapies and TREM2 antibodies, are gaining attention.

 

According to industry sources on the 12th, US biotech company NKGen recently administered its autologous NK cell therapy candidate ‘troculeucel (SNK01)’ for the first time to patients with mild Alzheimer's disease who did not respond to existing antibody therapies.

 

This is a case approved under the U.S.

 

Food and Drug Administration's (FDA) Compassionate Use program, applied to patients whose cognitive decline persisted despite treatment with the amyloid-targeted therapy lecanemab.

 

Troculeucel, NKGen’s cell therapy developed by using non-genetically modified ex vivo expanded autologous NK cells, is currently in a Phase IIa clinical trial in the U.S.

 

targeting moderate patients.

 

NKGen stated, “The therapy demonstrated efficacy in improving amyloid, tau, and alpha-synuclein levels in cerebrospinal fluid (CSF) by crossing the blood-brain barrier (BBB), as well as reducing neuroinflammatory markers such as GFAP.” In the previously conducted Phase I clinical trial, troculeucel demonstrated cognitive function stabilization and improvement in approximately 70% of patients, along with changes in biomarkers such as reduced pTau181 and GFAP levels in CSF.

 

Treatment responses were dose-dependent, and no significant adverse reactions were observed.

 

While existing antibody therapies have only slowed the progression of cognitive decline, NK cell therapy targets both inflammation control and protein aggregation resolution, opening up the possibility of a new mechanism of action for use.

 

In particular, its use in patients unresponsive to existing drugs suggests potential as part of a combination strategy or as a new treatment option.

 

NKGen

Major global pharmaceutical companies have also begun full-scale development of antibody and small-molecule therapies targeting TREM2.

 

Novartis recently began a multinational Phase II clinical trial of VHB937, a TREM2 antibody-based drug candidate, in multiple countries, including South Korea.

 

This study is designed as a randomized, placebo-controlled trial to evaluate the efficacy and safety of VHB937 in patients with early-stage Alzheimer's disease over 72 weeks.

 

VHB937 increases the expression of TREM2, a surface receptor on dendritic cells, and inhibits its shedding.

 

According to the company, this strategy aims to enhance intracellular signaling, thereby simultaneously targeting the phagocytic function of microglia and anti-inflammatory effects.

 

Sanofi recently acquired Vigil Neuroscience, a company developing a TREM2 small molecule agonist, and entered the field in earnest.

 

VG-3927, which Vigil is developing, binds only to cell membrane receptors and does not bind to soluble TREM2, enabling more precise regulation of microglia function, which is a key differentiator.

 

Sanofi plans to begin Phase II clinical trials of VG-3927 in the third quarter of this year.

 

Targeting TREM2 is a mechanism of action that leading companies such as AbbVie and Takeda have experienced a series of failures.

 

However, latecomers are shifting their focus to stabilization strategies and small molecule mechanisms after carefully analyzing the reasons for previous failures.

 

New mechanisms continue to be developed in Korea as well

In the field of Alzheimer's disease drug development, innovative approaches that go beyond the existing methods of removing amyloid beta and tau proteins and aim to regenerate and protect brain neurons are emerging.

 

SNR1611 (generic name: trametinib), developed by the Korean drug development company Genuv, is one representative example.

 

SNR1611 is a repurposed small-molecule compound derived from the already-approved anticancer drug trametinib.

 

It works by inhibiting MEK1/2 enzymes within the MAPK/ERK signaling pathway.

 

Through this mechanism, it suppresses the aberrant activation of MAPK signaling observed in neurodegenerative diseases such as Alzheimer’s disease, thereby promoting neural stem cell differentiation and the generation of new neurons.

 

Recent preclinical studies have shown that SNR1611 promotes the expression of specific genes involved in brain neuron differentiation, resulting in a more than 2.7-fold increase in brain neural regeneration and approximately a twofold improvement in memory.

 

These findings were published in “Experimental & Molecular Medicine,” a sister journal of the prestigious scientific journal Nature, thereby establishing scientific evidence.

 

When SNR1611 was administered to an animal model with Alzheimer's disease, neural regeneration increased by approximately 176% and 295% in the dentate gyrus and subventricular zone, respectively, which are critical regions for memory formation.

 

Additionally, neural regeneration effects were confirmed in the cerebral cortex, and memory improved by nearly twofold in the treatment group.

 

Notably, SNR1611 has drawn attention for its ability to induce neurogenesis—a process previously considered nearly impossible in the adult brain—through pharmacological intervention.

 

Genuv is also developing SNR1611 as a treatment for amyotrophic lateral sclerosis (ALS).

 

In ALS animal models, administering SNR1611 reduced abnormal protein aggregation through autophagy activation and confirmed motor neuron protection effects.

 

Currently, Phase 1/2a clinical trials for ALS are underway at five major hospitals in South Korea.

 

AriBio is developing AR1001, a new drug candidate for Alzheimer's disease.

 

In March, the company successfully transferred the technology to China's Q-BioTech.

 

AR1001 targets multiple causes of Alzheimer's disease, including PDE5 and toxic proteins.

 

This new drug candidate is an improved oral treatment based on mirodenafil (Mvix), a medication similar to Viagra for erectile dysfunction.

 

Recent findings suggesting that PDE5 inhibitors like Viagra and Cialis may prevent Alzheimer's disease provide further evidence supporting the mechanism of AR1001.

 

AR1001 is currently in Phase III clinical trials.

 

AriBio has initiated global Phase III clinical trials in the United States, where the first patient dosing began in December 2022, as well as in Korea, the United Kingdom, Germany, France, Spain, Italy, Denmark, the Netherlands, the Czech Republic, and China.