The Road Ahead for Donanemab: Will the Therapy be the Next Imminent Breakthrough in the Alzheimer’s Disease Treatment Landscape?

Alzheimer’s disease (AD) is becoming a rapidly growing public health concern due to the rise in the world’s aging population. Based on the data obtained from the 2019 Global Burden of Disease (GBD) database, the incidence and prevalence of Alzheimer’s disease and other dementias increased by 147.95 and 160.84%, respectively, from 1990 to 2019. Monitoring the disease burden and providing potential therapeutic solutions is the way forward to curbing the burden.

The existing conventional Alzheimer’s disease medications have certain drawbacks. The majority of the Alzheimer’s disease treatment regimen is symptomatic, and as the illness progresses, its efficacy may eventually decline. As a result, there is an unmet demand for therapies that can alter Alzheimer’s disease progression and its trajectory. With the increase in the knowledge of biology for Alzheimer’s disease, research focus has turned from symptom relief medications to disease-modifying drugs that attempt to lessen the development of anti-amyloid β (Aβ) plaques and neurofibrillary tangles in the brain factors causing Alzheimer’s disease.

In June 2021, the FDA authorized Biogen’s Aduhelm (aducanumab) as the first disease-modifying medication for Alzheimer’s disease treatment. A high-affinity immunoglobulin gamma 1 monoclonal antibody to Aβ, Aducanumab is administered intravenously once a month. By lowering soluble and insoluble Aβ oligomers and fibrils, which are linked to the pathophysiology of Alzheimer’s disease, Aducanumab reduces levels of Aβ.

To help in reducing the burden of Alzheimer’s disease, another disease-modifying drug Eli Lily’s Donanemab, is in the Preregistration stage of development and is currently being investigated in a Phase III trial for early Alzheimer’s disease treatment. It helps in modifying the disease by reducing or preventing amyloid plaques in the brain that may slow cognitive decline. Donanemab is different from other Alzheimer’s disease treatments as it targets amyloid plaque, which is a key characteristic of the disease. This is a unique approach as compared to other Alzheimer’s disease treatments, which are mostly symptomatic. By targeting the underlying cause of the disease, Donanemab has the potential to slow the progression of Alzheimer’s disease.

Distinctive Highlights of Donanemab

Targets the underlying cause of disease

Donanemab is designed to slow the progression of Alzheimer’s disease by removing amyloid plaque from the brain, unlike other Alzheimer’s disease treatments that only address symptoms. Monoclonal IgG1 humanized antibody Donanemab, also known as N3pG, was created from mouse mE8-IgG2a. This biologic medication detects Aβ, which aggregates in amyloid plaques in the form of pyroglutamate. Although most Aβ antibodies are in therapeutic development, they have little affinity for amyloid plaques that have already been formed. 

The rationale behind Donanemab is that, rather than only preventing the deposition of new plaques or the growth of existing plaques, targeting deposited plaque itself is necessary to eliminate the amyloid burden from the brain. Some earlier plaque-binding antibodies were discontinued because they led to brain microhemorrhages. According to research, the mE8 antibody cleared plaques in mice without inducing microhemorrhages.

Safety and Efficacy Rate

The results of Donanemab have been strong compared to other competitors in the Alzheimer’s disease treatment market. For instance, In TRAILBLAZER-ALZ Phase II clinical trial, Donanemab was shown to slow cognitive decline by 32% compared to placebo. It was the first late-stage study in Alzheimer’s disease to meet its primary endpoint at the primary analysis and the first study to screen and enroll patients based on their tau pathology. Not only had it slowed the cognitive and functional decline, but it also showed very substantial clearance of amyloid plaques and slowing of the spread of tau pathology. 

The constellation of clinical and biomarker results indicated the potential for long-term disease modification. These results have led to Breakthrough Therapy designation and Priority Review Designation from the U.S. Food and Drug Administration (FDA).

Strong Comparative Results

Donanemab decreased brain amyloid plaque levels in an Alzheimer’s disease clinical trial comparing the two treatments by 65.2% at six months compared to baseline, whereas Aduhelm achieved that by 17%. The Donanemab data came from Lilly’s ongoing Phase III research, known as TRAILBLAZER-ALZ 4, and were presented in late November at the Clinical Trials on Alzheimer’s disease conference.

There will be 12-month and 18-month secondary analyses for TRAILBLAZER-ALZ 4, which is still in progress. The investigation is one of five that comprise the clinical program to assess the effectiveness and safety of Donanemab. These results suggest a strong uphold of the drug compared to its competitors and significant advantages over others.

Designation

Donanemab has received a Breakthrough Therapy designation and Priority review designation, which expedites the development and review of drugs that significantly improve existing Alzheimer’s disease therapies.

In June 2021, Donanemab was granted Breakthrough Therapy designation by the FDA. Donanemab’s effectiveness and safety were examined in the company’s Phase II trial, TRAILBLAZER-ALZ, which involved patients with early-stage, symptomatic Alzheimer’s disease. These findings were concurrently published in the New England Journal of Medicine and presented at the 15th International Conference on Alzheimer’s & Parkinson’s Diseases, 2021.

While in August 2022, the company stated that FDA accepted the Donanemab application for review, with Priority Review designation, for Alzheimer’s disease treatment under the accelerated approval pathway.

Competitors of Donanemab

The amyloid beta-directed antibody Aduhelm, the first disease-modifying medication for Alzheimer’s disease treatment approved by the FDA in 2021, is the biggest competitor for Donanemab. However, in the recent updates and results from TRAILBLAZER-ALZ 4, a comparative trial of Donanemab and Aduhelm, Donanemab decreased brain amyloid plaque levels by 65.2% at six months compared to baseline, whereas Aduhelm achieved that by 17%.

Additionally, the data provide a side-by-side analysis of therapy-related adverse events, particularly amyloid-related imaging abnormalities (ARIA), a documented side effect of the amyloid treatment class. ARIA was the most frequent treatment-emergent adverse event in both groups, according to earlier trials that were published, and both therapies’ safety profiles were consistent with these findings. When compared to the Donanemab group, the incidence of ARIA in the Aduhelm cohort was 26.1%, with 4.3% of cases being symptomatic, while the Donanemab group was 25.4%, with 2.8% symptomatic.

While Lilly’s candidate appears to be doing well, Aduhelm is losing market share after a problematic introduction and stringent reimbursement policy. In April 2022, the U.S. Center for Medicare and Medicaid Services (CMS) implemented its guidance for Biogen’s controversial Alzheimer’s disease drug Aduhelm (aducanumab). The guidance significantly limited the drug’s availability. The recommendation restricts Aduhelm to reimbursement only being covered on Medicare for patients enrolled in approved clinical studies. As part of a cost-cutting strategy, Biogen discontinued most commercial efforts for Aduhelm and cut its sales team, leaving the business with minimal resources to manage current patient access programs.

With the significant and much-welcomed rise of the three monoclonal antibodies, Donanemab, Gantenerumab, and Lecanemab, the singular dominance of small molecules as the drug of choice for Alzheimer’s disease treatment may be at an end. Eisai’s release of its successful Phase III trial results for Lecanemab demonstrated a 27% slowing of neurocognitive decline in those suffering from the early stages of Alzheimer’s disease.

On January 6, 2023, the U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for Alzheimer’s disease treatment. Leqembi is the second of a new category of medications approved for Alzheimer’s disease treatment that targets the fundamental pathophysiology of the disease, which makes it the bigger competitor for Donanemab.

The third antibody, Gantenerumab, a fully human antibody that targets Aβ peptides and induces phagocytosis by activating microglia was in Phase III Alzheimer’s disease clinical trials. However, Gantenerumab failed to make a comeback after its Phase III Alzheimer’s disease clinical trial once failed in 2014, following which Roche revived the anti-amyloid beta antibody and inserted it into two additional late-stage investigations. In two Phase III clinical trials, the Alzheimer’s disease medication candidate could not slow the rate of cognitive and functional deterioration, dealing the field another setback. While this could be a major setback for Roche but for Eli Lilly, it will provide a great share and positive market for Donanemab.

Conclusion

Alzheimer’s disease is a devastating condition that affects millions of people worldwide, and there is a pressing need for new and effective Alzheimer’s disease treatments. Donanemab has the potential to rule the market in early Alzheimer’s disease treatment. With its intravenous route of administration, it allows for a higher concentration of the drug to reach the brain, potentially leading to more effective Alzheimer’s disease treatment.

Donanemab is a promising new Alzheimer’s disease treatment that has shown significant efficacy in clinical trials. The Alzheimer’s disease drug works by targeting a specific protein rather than simply attempting to address Alzheimer’s disease symptoms. This approach is thought to be more effective in the long term, as it addresses the underlying causes of the disease rather than just treating its symptoms. Additionally, Donanemab is well-tolerated by patients, with a low incidence of serious side effects.

Furthermore, the setback of Gantenerumab and the controversial initiation of Aduhelm cleared the path for Donanemab to have the potential to uphold in the Alzheimer’s disease treatment market. In addition, Leqembi’s certain similar mechanism of action and its recent approval before Donanemab makes it the major challenging competitor for the Alzheimer’s disease drug. The early launch of Leqembi in the Alzheimer’s disease treatment market will create a major barrier for Eli Lilly. However, the promising results, designations, and disease-modifying ability of Donanemab sets it apart from other existing Alzheimer’s disease therapies and will create several opportunities in the Alzheimer’s disease treatment market. Based on these factors, it can be stated that the drug has the potential to become “the Next Imminent Breakthrough in the Alzheimer’s disease treatment landscape.”

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