Domestic Oral Dementia Drug Coming? Aribio "3rd Phase IND Approval in Korea Following US"

Oral Dementia Treatment 'AR1001'
Multi-Mechanism Targeting Based on PDE5 Inhibition

Significant Effects in Phase 2 Clinical Trial
Phase 3 Focused on Efficacy in Mild Cases and High-Dose Groups

With the successive emergence of antibody dementia treatments overseas, expectations for conquering dementia are growing. Amid fierce development competition in Korea, Aribio, which is developing the oral dementia treatment 'AR1001', has raised expectations as the 'first domestic dementia treatment drug' by receiving approval for the global Phase 3 clinical trial 'Polaris-AD' Investigational New Drug (IND) application, following the United States and now domestically as well.

On the 29th, Aribio received IND approval for the domestic Phase 3 clinical trial of AR1001 from the Korean Ministry of Food and Drug Safety. The trial is planned to involve a total of 1,250 participants, including 150 in Korea, 600 in the United States, 400 in Europe, and 100 in China. The United States already approved the IND from the Food and Drug Administration (FDA) last year, and patient dosing is underway. IND applications are also being prepared for Europe and China.

AR1001 aims to be an oral dementia treatment with multiple mechanisms of action. It is explained to have efficacy in inhibiting dementia progression and improving patients' memory and cognitive function through strong phosphodiesterase (PDE) 5 inhibitory action. The mechanisms are broadly threefold. First, it suppresses the intracellular production of amyloid-beta (Aβ) protein, one of the key factors in Alzheimer's dementia. While antibody treatments, which currently dominate dementia therapy, work by removing extracellular Aβ accumulated in the brain, AR1001, being a synthetic chemical drug, has a smaller molecular structure allowing it to penetrate cells and remove Aβ through autophagy, thereby inhibiting its accumulation.

Additionally, it activates the cAMP response element-binding protein (CREB) signaling pathway within brain nerve cells to inhibit neuronal death caused by toxic cells and promote the generation of new cells. There is also an extracellular mechanism: it activates the Wnt signaling pathway involved in cell proliferation or differentiation, enhancing synaptic plasticity by ensuring neurotransmitters function properly.

Phase 2 results stirred controversy... Company states "Phase 2 was exploratory... identified patient groups and dosage"

As the number of dementia patients continues to rise, the dementia treatment market is also expected to grow rapidly. According to the World Health Organization (WHO), the global number of dementia patients is projected to surge from 55 million in 2019 to 78 million in 2030 and 139 million by 2050. According to pharmaceutical research firm Kotelis, the Alzheimer's dementia treatment market is expected to grow at an average annual rate of 29%, from $1.6 billion (approximately 2.12 trillion KRW) in 2020 to $5.7 billion in 2030 and $20 billion (approximately 26.5 trillion KRW) by 2050.

Biogen and Eisai's Alzheimer's dementia treatment 'Leqembi (generic name: lecanemab)' [Image source=AP Yonhap News]

Global big pharma companies are also striving to capture the market with drugs such as Biogen and Eisai's 'Aduhelm' and 'Leqembi', and Eli Lilly's 'Donanemab'. Biogen and Eisai overcame the failure of Aduhelm last month, securing accelerated approval from the FDA in January and full approval for Leqembi. In Japan, the Ministry of Health, Labour and Welfare's expert review process has been passed, and final approval is expected soon. In Korea, since the approval application was submitted last June, domestic launch is also anticipated shortly.

AR1001, which is currently the most advanced pipeline in clinical development domestically, is attracting attention to catch up. The company stated that in the previous Phase 2 trial, the 30 mg monotherapy group showed a 3.5-point improvement in the primary efficacy endpoint 'Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 13' at week 26 and a 5.8-point improvement at week 52, with an especially notable 8.7-point improvement in the mild patient group, raising expectations for good results in Phase 3 as well.

However, criticism has arisen regarding Phase 2, noting that although some efficacy was observed in the experimental group, a statistically significant difference compared to the control group was not confirmed. In response, Ha Jae-young, Vice President of Aribio, emphasized that "Phase 2 was an exploratory stage to find the appropriate dosage and patient group for the drug." He explained, "Phase 2 involved dosing patients with mild to moderate dementia at 10 mg and 30 mg to identify the target group," adding, "Significant effects were observed in the mild and high-dose groups, with no meaningful differences in adverse reactions between groups." Since a clear target of mild patients and high dosage was identified, "we regarded the Phase 2 results as encouraging and decided to proceed with Phase 3 accordingly."

David Greely, Chief Medical Officer (CMO) of Aribio, presented on the biomarker analysis of AR1001 in Phase 2 clinical trials at the 2023 Alzheimer’s & Parkinson’s Disease Conference (2023 AD&PD) held in Sweden from March 28 to April 1.
[Photo by Aribio]

In fact, the upcoming Phase 3 trial is expected to administer AR1001 30 mg to patients aged 55 to 80 with mild cognitive impairment (MCI) or mild Alzheimer's dementia. The primary efficacy endpoint has also been changed. Instead of the Phase 2 primary endpoint, ADAS-Cog13, the 'Clinical Dementia Rating (CDR) - Sum of Boxes (SB)' has been set. CDR-SB is considered by the U.S. Food and Drug Administration (FDA) as the most appropriate primary endpoint in dementia drug guidelines, offering a more comprehensive cognitive function assessment than ADAS-Cog. Since other major dementia drugs also use CDR-SB as their primary endpoint, this trial is seen as a serious competition.

This content was produced with the assistance of AI translation services.