[Edaily Reporter NA EUN-KYUNG ] #G2GBIO, Inc. has obtained new data on repeated administration of a high 280 mg dose of GB-5001, a once-monthly long-acting donepezil injection. Following the results of the 140 mg repeated-dose domestic Phase 1 clinical trial released last month, the company confirmed stable blood concentrations and tolerability with the 280 mg dose when administered at four-week intervals. As the low- and high-dose candidates for GB-5001—corresponding to 5 mg and 10 mg of Aricept, respectively—have now been solidified, this is expected to serve as the basis for the design of subsequent regulatory clinical trials.

Four Doses of 280 mg… Evidence for High-Dose Candidate Secured

According to the pharmaceutical and biotech industry on the 8th, G2GBIO, Inc. recently obtained results from a pilot study conducted in Indonesia involving healthy adult males who received four doses of 280 mg of GB-5001 at four-week intervals. However, this study was not a formal regulatory clinical trial but rather an exploratory study to determine the dosage and administration schedule for future pivotal trials.

The company explained that even with repeated 280 mg doses, steady-state blood concentrations were maintained by the third or fourth dose, and good tolerability was confirmed without any serious safety issues. Previously, on August 27, G2GBIO, Inc. announced the results of a Phase 1 clinical trial in which 140 mg of GB-5001 was administered four times at four-week intervals to healthy Korean volunteers. In that trial as well, steady-state was reached by the third or fourth dose, and there were no serious adverse events or study withdrawals due to adverse events.

In the single-dose clinical trial in Canada, the repeated-dose clinical trial in Korea, and the pilot study in Indonesia, general pharmacokinetic trends—including dose-dependent drug exposure and sustained release—were observed. With monthly repeated dosing, blood concentrations remained within a stable range starting around the third dose. These results demonstrate the potential for maintaining stable concentrations without excessive accumulation of the drug in the body. Generally, reducing significant daily fluctuations in blood concentrations can help maintain stable drug efficacy and minimize side effects that may occur when blood concentrations rise sharply.

A representative from G2GBIO, Inc. stated, “It is not easy for dementia patients to take medication regularly every day, and it is well known that adherence to patch formulations is low due to skin side effects and other factors,” adding, “The once-monthly injection regimen could serve as an alternative that reduces the burden of medication management for both patients and caregivers.”

G2GBIO, Inc. explained that the average blood concentrations of GB-5001 at 140 mg and 280 mg were similar to the therapeutic concentration ranges of oral Aricept at 5 mg and 10 mg, respectively. These results were obtained by measuring donepezil blood concentrations following repeated direct administration to healthy adult Namsungs. However, the similarity in blood concentrations does not necessarily mean that the cognitive improvement effects will be equivalent in patients with Alzheimer’s disease. In particular, since the 280 mg dose was based on a pilot study rather than an official clinical trial, it must be reconfirmed in subsequent regulatory clinical trials.

Demand for Donepezil Persists Even in the Lecembi Era

Donepezil is a medication that inhibits the breakdown of the neurotransmitter acetylcholine in the brain, thereby alleviating symptoms of memory loss and cognitive decline. Aricept, developed by Japan’s Eisai and the U.S.’s Pfizer, was first approved in the U.S. in 1996 and is currently widely prescribed for Alzheimer’s disease ranging from mild to severe. Although it cannot eliminate the cause of the disease or halt its progression, its advantage lies in the fact that data on its efficacy and safety have been accumulated over approximately 30 years of use.

Although treatments such as “Leqembi” and “Kisunra” have emerged that slow the progression of Alzheimer’s disease by removing amyloid-beta, they are not immediate replacements for donepezil. While Lecembi and Kisunra are primarily intended for patients with mild cognitive impairment or early-stage Alzheimer’s disease in whom amyloid pathology has been confirmed, donepezil can also be used for patients with moderate to severe disease. In the Lecembi clinical trials, the safe concomitant use of existing symptomatic treatments, such as donepezil, was permitted. This means that disease-modifying therapies, which slow the progression of the disease, can be used in combination with donepezil, which manages symptoms.

In particular, because Lecembi and Kisunra carry a risk of amyloid-related imaging abnormalities (ARIA)—manifesting as cerebral edema or microbleeds—magnetic resonance imaging (MRI) scans are required before and after administration. The FDA has included a boxed warning regarding ARIA in the approval labels for both products. In contrast, while donepezil has side effects such as nausea, vomiting, diarrhea, and bradycardia, risk management protocols have been established through extensive prescribing experience.

For this reason, the global donepezil market is also expected to grow for the time being. Global market research firm Research and Markets projected that the global donepezil market will grow from $1.04 billion (approximately 1.4 trillion won) in 2025 to $1.09 billion (approximately 1.47 trillion won) in 2026, $1.3 billion (approximately 1.8 trillion won) in 2030, at a compound annual growth rate (CAGR) of 4.5%. The market is expected to be driven by an increase in patients due to an aging population, as well as demand from patients who cannot use disease-modifying therapies and those requiring combination therapy.

G2G and Inventage Lab Inc. Compete in the Monthly Injection Market

Although donepezil must be taken daily, the actual target population consists of patients with impaired memory and cognitive function. Caregivers must verify whether patients have taken their medication, and some patients have difficulty swallowing pills, creating a significant need for long-acting formulations. While a twice-weekly donepezil patch has been launched, concerns remain regarding skin irritation and the burden of managing application and replacement.

There are currently no once-monthly donepezil injections commercially available domestically or internationally. The leading candidate compounds that have publicly entered the clinical trial phase are G2GBIO, Inc.’s GB-5001 and IVL3003 from Inventage Lab Inc.(389470)·CHONGKUNDANG(185750). Both candidates encapsulate donepezil in biodegradable microparticles to enable gradual release over the course of a month.

IVL3003 underwent Phase 1 and 2 clinical trials in Australia involving 62 healthy volunteers, with a group receiving repeated oral doses of Aricept serving as the control group. Last April, Inventage Lab Inc. announced at the American Academy of Neurology that blood concentrations of IVL3003 were maintained for more than four weeks after administration, and its acetylcholinesterase (AChE) inhibitory effect persisted for 28 days. It is currently being developed as a subcutaneous (SC) injection, and CHONGKUNDANG has acquired the technology. Inventage Lab Inc. is also separately developing IVL2008, a 3-month sustained-release donepezil injection, which is currently in the preclinical stage.

GB-5001 was evaluated via intramuscular (IM) injection in Canadian clinical trials and via both intramuscular and subcutaneous (SC) injections in domestic clinical trials. G2GBIO, Inc. has finalized the IM formulation for commercialization. The company emphasizes that the drug reached steady state following repeated dosing at four-week intervals after a single dose, and that it has secured candidate dosages of 140 mg and 280 mg, which correspond to Aricept 5 mg and 10 mg, respectively. However, since the two candidates differ in clinical design, dosage, comparator groups, and endpoints, it is difficult to determine which is superior based solely on the published results.

G2GBIO, Inc. has not yet submitted a plan for a follow-up regulatory clinical trial to the Ministry of Food and Drug Safety (MFDS). The company has also not disclosed whether it will proceed with a Phase 2 clinical trial based on these results or immediately design a pivotal trial for regulatory approval. The key issue is the extent to which the MFDS will recognize the similarity in plasma drug exposure between GB-5001 and oral Aricept as bridging evidence for clinical efficacy. If this can partially substitute for efficacy data from patients, there is potential to reduce the scale and duration of the clinical trial; however, if non-inferiority in cognitive function improvement is required separately, the development timeline and costs could increase.

G2GBIO, Inc. official stated, “We obtained stable steady-state pharmacokinetic results in both the domestic 140 mg repeated-dose clinical trial and the 280 mg pilot study in Indonesia,” adding, “Since the average blood concentration of GB-5001 was maintained at a level similar to the therapeutic concentration range of 5 mg and 10 mg Aricept, we will prepare for the next clinical trial based on the results obtained so far.”