Good News in the Anti-AβAntibodies Field, Two Drugs were Successively Granted Breakthrough Drug Qualification by the FDA

Two AD drugs have been granted BTD by the FDA recently, namely Eisai/Biogen's Lecanemab (BAN2401) and Eli Lilly's Donanemab. Lecanemab is known to be an anti-amyloid β(Aβ) fibril antibody under development for the treatment of AD, Donanemab is recognized a humanized antibody of IgG1 subtype that targets a specific form of Aβ protein (i.e., pyroglutamate at the 3rd position of Aβ, hereinafter referred to as N3pG-Aβ). The form of N3pG-Aβ is highly associated with occurrence of aggregation, which is a target of AD treatment under the spotlight. 

Lecanemab (BAN2401) is accepted to be a humanized antibody of the mouse monoclonal antibody mAb158 developed by BioArctic based on its proprietary antibody technology, targeting β amyloid (Aβ) fibrils. In 2007, Eisai came to terms with BioArcticto to obtain the rights of global research, development, production and sales to the drug. In 2014, Eisai and Biogen achieved consent for joint development and commercialization of the drug. 

The BTD for Lecanemab Was Bestowed Based on the Results of Study 201, which is a Phase 2b clinical trial. Study 201 is established as a randomized, double-blind proof-of-concept clinical trial involving 856 patients with MCI due to AD or mild AD. This study is performed to evaluate the effect of Lecanemab in patients with early AD on mitigating brain amyloid (aβ) and clinical decline. The pre-set analysis plan has suggested that in the highest dose group, the clinical decline of multiple clinical and biomarker endpoints have been consistently brought down. 

At present, two Lecanemab-related Phase 3 clinical trials named Clarity AD and AHEAD3-45 are in progress. Clarity AD is designed to be an 18-month placebo-controlled, double-blind, parallel group, open-period extension trial. It has completed the enrollment of 1,795 symptomatic early AD patients, to look at the safety and efficacy of Lecanemab in subjects with early AD (EAD). AHEAD 3-45, consisting of two trials A3 and A45, aims to assess the efficacy and safety of Lecanemab in (asymptomatic) patients with AD in the preclinical stage but with amyloid in the brain. 

Donanemab's BTD by the FDA is based on the results of its Phase II clinical trial, TRAILBLAZER-ALZ. The study recruited 257 patients with AD, of which 131 received Donanemab treatment and 126 accepted placebo for control. In January this year, Eli Lilly announced that the Phase II clinical TRAILBLAZER-ALZ has come up to the primary clinical endpoint. 

The results show that: Following 76 weeks of treatment, patients who received Donanemab experienced a reduction in Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) by 32% compared with the placebo group, reaching the primary endpoint. Meanwhile, PET imaging suggested that Donanemab can quickly remove amyloid deposits in the patient's brain: Following 6 months of treatment, 40% of patients tested negative in PET; Following 18 months of treatment, 68% of patients met a level of negative PET result. 

Currently, a Donanemab-related randomized double-blind, placebo-controlled Phase 3 clinical trial is undergoing to further test its safety, tolerability and efficacy. 

There is a new AD drug approved at home and abroad: GV-971 VS Aduhelm 

Alzheimer's disease (AD), a degenerative brain disease characterized by progressive neurological degeneration, can typically lead to impaired thinking, memory and independence, and is deemed as the third leading cause of death in the elderly worldwide, next only to cardiovascular and cerebrovascular diseases and cancer. It is reported in World Alzheimer Report 2018 that there are at least 50 million dementia patients in the world, and it will increase to nearly 150 million by 2050 based on an estimation, of which AD patients represent approximately 60%-70%. 

Currently, the exact cause of AD remains unknown, which may be associated with factors such as aging, genetics, environment, oxidative stress, inflammation. Abnormal deposition of amyloid β (Aβ) and irregular phosphorylation of tau protein are main molecular mechanisms of AD for the time being. Drugs traditionally approved for the treatment of AD consist of N-methyl-D-aspartate receptor (NMDA) receptor antagonist memantine, acetylcholinesterase inhibitor (AChEI) tacrine, donepezil, and galanthamine, rivastigmine and huperzine A, as well as the compound Donepezil/Memantine, which can only treat symptoms and fail to slow the progression of AD disease. 

Two new AD drugs have been certified in recent years at home and abroad, namely Green Valley's Sodium Oligomannate Capsules (trade name: GV-971) and Biogen/Eisai's Aducanumab (trade name: Aduhelm). 

Sodium Oligomannate, a low-molecular-weight acid oligosaccharide compound prepared from marine brown algae extract as a raw material, is recognized as an innovative drug independently researched and developed by China with independent intellectual property rights. It reshapes the balance of intestinal flora and inhibits the abnormal increase of specific metabolism of intestinal flora, reduces peripheral and central inflammation, and lowersβ-amyloid protein deposition and Tau protein hyperphosphorylation, thereby mitigating cognitive dysfunction. In November 2019, this drug was conditionally approved for the treatment of mild to moderate AD in China to improve the cognitive function of patients. 

Aducanumab (Aduhelm) is a monoclonal antibody targeting β-amyloid acquired by Biogen from Neurimmune. In 2017, Biogen and Eisai partnered to develop and commercialize the drug worldwide. In June 2021, Aducanumab was conditionally approved with an acceleration by the FDA for the treatment of AD. 

Aduhelm approved through ups and downs, and domestic and foreign companies making layouts in anti-Aβ antibody fields 

It is argued by β-amyloid (Aβ) theory that the disease-causing gene of AD is the APP gene that encodes Aβ precursor protein (APP). In case of mutation of the APP gene, it will cause a high volume of β-amyloid to accumulate and break the balance ofβ-amyloid production and degradation. Where the concentration of beta amyloid in the brain becomes considerably high, the protein will polymerize into small fibers and plaques which kill neurons, resulting in cognitive impairment of patients. 

On the basis of Aβ theory, targeting Aβ, resisting Aβ production and promoting Aβ clearance have become the research direction for the treatment of AD. BACE1 (i.e. β-secretase, also known as β-amyloid precursor protein lyase) inhibitors and anti-Aβ antibody homeopathy have further turned into the main direction of study. Nevertheless, the R&D of anti-Aβ antibodies was an extremely bumpy way, as many drugs have met serious failures. For example, Pfizer/Johnson & Johnson discontinued further research on Bapineuzumab in 2012, Roche declared the failure of Gantenerumab's Phase 3 clinical trial in 2014, and interrupted Gantenerumab in the treatment of early AD in two Phase III studies in 2019, and Eli Lilly's Solanezumab failed to achieve the desired effect in the EXPEDITION3 study in 2016. 

Even Aducanumab, which has recently been approved, also meets piles of challenges. In March 2019, Biogen proclaimed the termination of two of its trials on account of the poor results of the Aducanumab clinical trial. Afterwards, Biogen's analysis over the data set containing more patients has revealed that Aducanumab at a dose of 10 mg/kg is able to significantly improve the cognitive ability of patients in the clinical trial of EMERGE. Simultaneously, the clinical trials of ENGAGE also suggest the cognitive ability of some patients continuing to receive Aducanumab at a dose of 10 mg/kg also get better. This result helped Biogen and Eisai to determine to restart the application process for Aducanumab and intend to submit the BLA to the FDA in early 2020. However, the COVID-19 postponed the BLA submission until early July 2020. In August 2020, Biogen/Eisai declared that the FDA accepted the BLA of Aducanumab and granted priority review to it. 

Since November 2020, Aducanumab began to suffer from criticisms by the FDA committee. Originally, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee cast 1 affirmative vote, 8 negative votes, and 2 votes for uncertainty on the question "Does Dosage Study 302 (EMERGE) and Independent Observation Study 301 (ENGAGE) provide strong evidence  that Aducanumab is effective in the treatment of AD"; Such Committee cast 0 affirmative vote, 7 negative votes, and 4 votes for uncertainty on the question "Does Study 103 (PRIME) support the effectiveness of the drug". Later in April 2021, three members of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee, i.e. Caleb Alexander, Scott Emerson, and Aaron Kesselheim voiced their opposition to the drug in an article in JAMA. Still worse, following FDA approved Aducanumab disregarding the strong opposition of the expert panel, several members of the Advisory Committee resigned. 

Whereas AD patients have few treatment options, evidence suggests that Aducanumab reduces amyloid plaques in the brain, and there are applicable accelerated approval clauses, FDA finally prevailed over all dissenting views to accelerate the approval of Aducanumab's release. Yet, FDA required Biogen to run a new randomized and controlled clinical trials to validate the clinical benefits of Aducanumab. Where the trial fails to verify the clinical benefit, FDA may withdraw approval of the drug. Further, the information in the prescription of Aducanumab also mentioned warnings including amyloid-related imaging abnormalities (ARIA) and the risk of allergic reactions. 

Despite the bumpy process, the approval of Aducanumab will somehow build up confidence for companies deploying anti-Aβ antibodies. Nowadays, a bunch of domestic and foreign hospital medical supply companies are engaged in R&D of anti-Aβ antibodies, such as Eli Lilly and Hengrui Medicine. Therein, Hengrui Medicine’s SHR-1707 is recorded as a monoclonal antibody targeting Aβ protein. A phase I, randomized, double-blind, placebo-controlled study of SHR-1707 has been registered on the clinicalTrials.gov to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous injection of SHR-1707 administered in healthy adults and elderly subjects. In March this year, the drug was cleared for clinical use in China. 

Not to mention anti-Aβ antibodies, Novartis has reported an Aβ vaccine called Amilomotide developed. Amilomotide is found to induce N-terminal Aβ specific antibodies, thus mitigating amyloid deposition. Its Phase IIb double-blind, placebo-controlled trial has arrived at positive results: Subjects in the Amilomotide group experienced a strong serological response, as 55.1% of the subjects in the 150 μg dose group produced Aβ immunoglobulin, and 81.1% of the subjects in the 450 mg dose group created Aβ immunoglobulin. So far, the clinical study of Amilomotide and another AD drug CNP520 for the joint treatment of AD has progressed to Phase 3, and results are anticipated to be obtained in 2024. 

The reason that the R&D of anti-Aβ antibody is so bumpy is that the pathogenesis of AD and the pathogenesis of Aβ is not thoroughly figured out. Masses of basic research stand for the key to breaking the AD disease. We take stock in that this puzzle will eventually be tackled in the future and effective AD treatment drugs will be found based on the unremitting efforts of scientists and companies. 

References: 

1. Official websites of Eisai, Hengrui Medicine, etc. 

2. CDE's official website. 

3. With regard to the approval of Aducanumab, the FDA's response to PHARMCUBE goes..., PHARMCUBE, June 14, 2021 

4. With effective removal of amyloid, Eli Lilly’s Phase 2 clinical trial of Donanemab in the treatment of AD went well, Yidu Medicine, January 14, 2021 

5. From Bapineuzumab to Donanemab, why is the development of anti-Aβ antibodies in a fix? Pharmacodia, May 17, 2021