On June 8, the FDA issued an accelerated approval to Biogen/Eisai's powdered protein antibody Aduhelm (generic name aducanumab) for the treatment of Alzheimer's disease (AD).
There has been considerable public debate on whether Aduhelm should be approved.
Many experts expressed their support for this. For example, Ronald Petersen, a neurologist at the Mayo Clinic Alzheimer's Disease Research Center, said he's "hopeful" for AD patients. The opposition from the other side is also strong. Some experts voiced their concern about the approval. They argued that there was almost no data to support that Aduhelm can improve the cognitive function of AD patients, illustrating that the clinical benefits of the drug are not ideal.
Despite of controversy in Aduhelm's approval by the FDA, the approval undoubtedly signals a major advance in the field of AD research, which has driven the development of AD treatment research, and presented a promising development prospect for similar drugs and therapies on the market.
In the meantime, it has grabbed a cluster of pharmaceutical companies to return to the potential blue ocean market of AD.
Before long after Aduhelm was approved, Biogen/Eisai ushered in another piece of welcoming news. On June 24, Biogen/Eisai declared that the humanized monoclonal antibody Lecanemab (BAN2401) for the treatment of AD has been granted the Breakthrough Therapy Designation (BTD) by the US FDA.
BTD is designed to accelerate the development and review of innovative drugs for the treatment of serious and life-threatening diseases, empowering developers to access closer guidance from the FDA and is hopeful to be eligible for priority review.
Lecanemab is acknowledged as an anti-amyloid β (Aβ) fibril antibody to be targeted to AD patients. This TBD is endorsed based on Phase II study results of early AD of BAN2401-G000-201, a code for the treatment of 856 patients with MCI and mild AD confirmed by the accumulation of amyloid in the brain. It is reported in the results that the level of amyloid was significantly reduced after treatment with the highest dose of Lecanemab.
In March of this year, patient registration of the drug has been performed for a Phase III clinical trial (Clarity) in patients with early AD, and the Phase III trial is running smoothly. The trial included 1,795 registered patients as of March 2021, and it is estimated that indicators of the main evaluation items will be acquired by the end of September 2022. Furthermore, the Phase III clinical trial (AHEAD 3-45) for the effect of Lecanemab in patients with preclinical (latency period) AD whose Aβ accumulation level in the asymptomatic brain has arrived at a critical value or a positive range is also in progress.
On June 25, Eli Lilly's donanemab ushered in the BTD. Donanemab is noted as an antibody drug under development that targets Aβ protein modified by N3pG (a modified type of β-amyloid protein). The FDA BTD is given based on its Phase II clinical trial TRAILBLAZER-ALZ. This trial aims to evaluate the effectiveness and safety of donanemab in patients with early symptomatic AD. The trial data have been made public at the AD/PD™ 2021 and simultaneously published in the New England Journal of Medicine. The results exhibited that the trial had met the primary clinical endpoint. The BLA is expected to be submitted in H2 of this year.
Bristol-Myers Squibb/Prothena Corporation--PRX005
Therapies other than targeting Aβ have also made headway. On June 25, Bristol-Myers Squibb (BMS) proclaimed that it had procured the exclusive US license for the antibody drug PRX005 developed by Prothena Corporation with 80 million US dollars.
Phase I clinical trials have kicked off. Based on this cooperation, Prothena will garner a total of 230 million US dollars, and be qualified to gain 2.2 billion US dollars, including US licensing fees of up to 160 million US dollars, global licensing fees of 165 million US dollars, and regulatory and commercialization milestone payments of up to 1.7 billion US dollars.
Tau is accepted as a microtubule-associated protein, which accumulates and is hyperphosphorylated in the brains of AD patients to form pathological neurofibrillary tangles. Tau tangles and amyloid β plaques stand for typical pathological features of AD. The presence of tau pathology is bound up with the neurodegeneration and cognitive impairment in AD and their progression pattern throughout the brain. Preclinical studies displayed that antibodies targeting the MTBR had advantages in blocking tau uptake and the neurotoxicity caused by it.
PRX005 refers to an anti-tau antibody that targets a key region within the MTBR and aims to be the best of its kind. PRX005 in animal models presented significant inhibition of cell-to-cell transmission and neuronal internalization both in vitro and in vivo, and substantially slowed the pathological progress in the tau transgenic mouse model.
On June 29, Simcere Pharmaceutical made an announcement that it has come to a regional strategic cooperation with Vivoryon Therapeutics, a biotechnology company focusing on the development of small molecule innovative drugs in Germany, on AD treatment drugs, with a transaction amount surpassing 565 million US dollars.
Simcere, in line with the agreement, will be authorized to develop and commercialize two AD drugs developed by Vivoryon in the Greater China region, i.e. the N3pE-targeted oral small molecule QPCT inhibitor in clinical phase IIb. Varoglutamstat (PQ912), and the monoclonal N3pE antibody PBD-C06 in the preclinical research phase.
Varoglutamstat is noted as an oral small molecule inhibitor of QPCT. The transferase can catalyze the production of a neurotoxic molecule N3pE amyloid, which is not only associated with the beta amyloid peptides that are widely observed in AD patients, but also has adverse effects to other pathological factors of AD, such as tau pathological manifestations, neuroinflammation and impaired synaptic function. Varoglutamstat comes into play in the early pathogenesis of the disease by preventing the formation of this toxic variant, thereby revealing its potential to prevent neuronal damage. Varoglutamstat is currently in Phase II clinical development.
PBD-C06 is identified as a humanized and deimmunized IgG1 antibody drug in the pre-clinical development stage, the structure of which is specially designed to bind and remove N3pE amyloid in the brain. The antibody bears low immunogenicity and low ARIA inducing efficacy after optimization, which can bring down the main serious side effects of antibody drugs in the treatment of AD.
AD is a fatal disease that leads to a progressive decline in memory and other cognitive functions. Dementia caused by AD is the most common type of its kind, representing 60%-80% of all dementia cases. At this moment, there are more than 50 million dementia patients in the world, and it will increase to nearly 152 million by 2050 based on an estimation. Nearly 10 million cases of dementia are newly diagnosed worldwide each year, indicating one new case every 3 seconds, which put considerably heavier care burden on the society and families.
It is revealed in a report from Zion Market Research that the global AD drug market is expected to hit 5.66 billion US dollars by the end of 2024. This also boosts Chinese and foreign biopharmaceutical companies to develop new drugs against AD. However, the complex pathogenesis of AD and its unknown cause have led to far more difficulties for drug development than imagined. The approval of Aduhelm surely injects confidence to pharmaceutical companies committed to conquering AD.
2. Alzheimer’s Association. Facts and Figures.
3. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed December 8, 2020.
4. Retrieved April 7, 2021, from https://www.who.int/zh/news-room/fact-sheets/detail/dementia
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