Eli Lilly and Biogen/Eisai continue to have a hold on the Alzheimer’s disease market after the approvals of their therapies Kisunla (donanemab) and Leqembi (lecanemab) in 2024 and 2023, respectively.

Both therapies target amyloid, highlighting the ongoing unmet need for alternative treatment approaches in Alzheimer’s disease. Given the safety concerns associated with amyloid-related imaging abnormalities (ARIA), experts agree it is encouraging to see a broader range of therapeutic options for patients emerging in the pipeline.

According to GlobalData analysis, the Alzheimer’s disease market is expected to grow at a high compound annual growth rate (CAGR) of 21.8% from $2.4bn in 2023 to $17bn by 2033 across the eight major markets (8MM: the US, France, Germany, Italy, Spain, the UK, Japan, and China).

Disease-modifying therapies (DMTs), like amyloid-targeting drugs, are expected to dominate the global Alzheimer’s disease market, contributing 69.2% of the market by 2033, with drugs targeting amyloid beta (Aβ) making up the majority of this. GlobalData forecasts that Leqembi and Kisunla could generate global sales of approximately $2.9bn and $2.3bn, respectively, by 2033.

GlobalData is the parent company of Clinical Trials Arena.

Eli Lilly’s second amyloid-targeting drug

Eli Lilly is looking to build on the success of Kisunla with a second amyloid targeting drug, remternetug.

A monoclonal antibody (mAb), remternetug acts by targeting N3pG beta-amyloid, known as amyloid precursor protein (APP). By binding to and clearing deposited amyloid plaques, remternetug aims to interrupt the pathological cascade associated with Alzheimer’s disease.

In a Phase II trial, the drug produced “rapid and robust” amyloid plaque clearance; however, there were 10 cases of ARIA in 41 patients, with only 24 of those having received the study drug. Just one case was classified as symptomatic and resolved after discontinuation of the study drug and dosing of oral steroids.

The Phase III TRAILRUNNER-ALZ 1 trial (NCT05463731) will initially enrol 600 patients in the double-blind treatment period to receive remternetug or placebo administered via subcutaneous injection or intravenous infusion. An additional 974 patients with early Alzheimer's disease will be enrolled to an addendum safety cohort of the trial. The patients will be administered open-label remternetug via subcutaneous injection or intravenous infusion. The study is due to complete in March 2026.

Erela Dana, Director of Neurology and Immunology at GlobalData, believes the subcutaneous administration of the drug will help against its primary rival, Biogen and Eisai’s Leqembi, which recently gained approval for a subcutaneous version of the therapy.

 “This drug benefits from Lilly's established expertise in Alzheimer's disease and strong commercial capabilities, while its subcutaneous formulation could address key access barriers associated with IV infusions that plagued anti-amyloid therapies until the recent approval of the subcutaneous maintenance dosing approval for Lilly’s main competitor, Biogen and Eisai’s Leqembi,” says Dana.

Dr Joy Snider, Professor in the Department of Neurology at Washington University School of Medicine, one of the sites for the Phase III study, agrees that the subcutaneous formulation is one of the main benefits of the drug over its predecessor.

Snider says: “I think of it as the son of Kisunla; it's a very similar compound. The key is that this is going to have a subcutaneous formulation, which will be a big step forward for these drugs. Since Leqembi now has a subcutaneous formulation for maintenance and they are working on getting it indicated subcutaneously for initiation, Lilly’s drug needs to be at least as efficacious as Kisunla and Leqembi, if not more so.”

GlobalData forecasts it as one of the most promising pipeline products with patient-based forecasts estimating potential peak sales of $901.2m in 2033.

Dana adds: “This assessment is tempered by limited available clinical data and the inherent risks of the anti-amyloid approach, namely ARIAs. The drug's success will largely depend on demonstrating superior safety or efficacy compared to existing anti-amyloid therapies in an increasingly competitive landscape.”

Annovis Bio hopes for triple targeting therapy

Annovis Bio is investigating its once daily buntanetap tartrate in a Phase III Alzheimer’s disease trial (NCT06709014).

Buntanetap offers a unique triple-pathway approach by inhibiting amyloid-beta, tau, and alpha-synuclein synthesis, potentially addressing multiple neurodegenerative mechanisms simultaneously.

“It's always exciting when there's a different mechanism and it's an oral drug, so that's great,” says Snider. “It's a drug that's been around a while, and in prior iterations it did not meet efficacy endpoint, so that is where my enthusiasm for that is lower.”

In a Phase II/III trial, there was seemingly mixed data with the study endpoint not being met, sending the company’s stock tumbling. The Pennsylvania-based biotech did try to convince investors, however, stating that in the trial, the therapy led to a significantly higher rate of improvement on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) compared to placebo.

The Phase III trial is investigating the drug in an estimated 760 patients with early Alzheimer’s disease. Patients will receive the drug daily with a six-month and 18-month evaluation. The primary trial completion is in December 2027.

While Dana notes that “Buntanetap features an innovative dual trial design allowing evaluation of both symptomatic and disease-modifying effects, which could accelerate regulatory approval pathways. Its oral administration and absence of ARIA side effects associated with monoclonal antibodies position it as a potentially more accessible treatment option”, she adds that due to Annovis Bio's status as a smaller biotech, it could struggle with commercialisation. To compete effectively with established players like Eisai/Biogen and Lilly in the market, it will require a major partnership. Patient-based forecasts estimate global sales of $407m in 2033, as per GlobalData.

AriBio's oral PDE5 inhibitor shows biomarker promise

AriBio’s AR-1001 is being investigated in the Phase III POLARIS-AD trial (NCT05531526) in patients with early Alzheimer’s disease.

In a Phase II trial (NCT03625622), the 30mg once daily oral phosphodiesterase 5 (PDE5) inhibitor showed a statistically significant improvement in plasma pTau-181 levels compared to placebo after 26 weeks of treatment and in both the 10mg and 30mg cohorts after 52 weeks. Patients who were originally on placebo but assigned to treatment cohorts after 26 weeks also reached statistically significant improvements at the 52-week timepoint. In the Phase II study, there were no cases of ARIA reported.

Senior vice president of AriBio, Jae-young Ha, says that based on the Phase II data, the dosing level of 30mg has been chosen for the Phase III trial.

“In addition to compelling efficacy by significantly lowering plasma, pTtau-181, treated patients with higher levels of baseline pTau-181 showed consistent trends of improvement in both cognitive performance and daily living abilities compared to placebo, with the strongest effects at higher doses,” Ha says. “These results provide robust clinical proof of concept and underscore the drug's potential as a disease-modifying therapy in Alzheimer’s disease.”

Snider adds: “They met some of their endpoints in Phase II, but not all of them. This drug is a different mechanism of action, and people have been interested in these PDE5 drugs for a while. We don’t have any Phase III data yet, so we've got to see what that shows because things have been exciting in Phase II but not in Phase III.”

The Phase III trial has a primary endpoint of change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) and will evaluate patients for 52 weeks, with a 52-week optional extension phase.

Secondary endpoints include the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog 13), Geriatric Depression Scale (GDS), Mini-Mental Status Examination (MMSE), and changes in plasma and cerebrospinal fluid (CSF) biomarkers. Topline results are expected to be presented close to the end of Q2 2026.

GlobalData's patient-based forecasts predicts a global sales of $674m for AR-1001 in 2033.

“This drug scored highly in GlobalData's competitive assessment for its novel mechanism of action and oral dosing convenience, potentially offering significant disease-modifying potential as demonstrated in preclinical studies,” notes Dana. “The drug's differentiated mechanism and favourable administration profile position it as an attractive alternative to the current generation of complex anti-amyloid therapies.”

Ha explains that the oral administration is an important part of the therapy. “Alzheimer's disease is a chronic condition that requires long-term treatment for such chronic diseases; oral administration is essential,” he says. “By contrast, disease-modifying biologics must be administered via injection. There will also be a price advantage over monoclonal antibody infusions when you consider oral administration once a day versus a one-hour infusion at the hospital every two to four weeks.”

Dana adds that AriBio is actively pursuing major licensing partnerships, which could address the commercial limitations of being a smaller biotech company.

Correction: The sales forecasts for remternetug and buntanetap have been updated to reflect the correct year and forecast methodology, respectively.