Aβ monoclonal antibody is broken again, Alzheimer's disease new drug research and development is a long way, who can break the deadlock?

On November 14, Roche once again announced the failure of its new Alzheimer's disease (AD) drug. This time it was a subcutaneous injection of Abeta monoclonal antibody Gantenerumab.

Roche said in his claim that Gantenerumab did not meet its primary endpoint in the two phase III studies in Graduate I and II, which was to fail to significantly slow the progression of dementia and solve problems such as memory loss and reduced executive ability in early Alzheimer's disease patients. The drug clears lower than expected levels of β-amyloid (Aβ).

The field of Alzheimer's disease has always been a "black hole" for the development of new drugs, not only Gantenerumab, but also other drugs, and even marketed drugs have been controversial.

Roche defeated one after another, what is the next move?

Roche's R&D pipeline includes two Aβ antibody drugs for Alzheimer's disease, Gantenerumab and Crenezumab, the clinical development of the two drugs has lasted for many years, frequent failures, and the corresponding investment in R&D costs is even deeper.

Gantenerumab

Gantenerumab is a fully humanized IgG1 monoclonal antibody that is the first subcutaneous injection of investigational Aβ monoclonal antibody to enter phase I clinical studies, with high affinity for all types of aggregates and the highest affinity for Aβ fibers and plaques, which can promote the phagocytosis of aggregated Aβ by Fcγ receptor-mediated microglia.

Roche conducted two Graduate I and II studies in 2017, two global, double-blind, randomized, placebo-controlled phase III clinical trials evaluating the safety and efficacy of Gantenerumab in patients with mild cognitive impairment (MCI) caused by Alzheimer's disease and mild Alzheimer's dementia. A total of 1965 patients were randomized to either Gantenerumab or placebo in a 1:1 ratio to achieve a target dose of 510 mg. The primary endpoint was the change in the score of the Clinical Dementia Score Sum Scale (CDR-SB) from baseline at 116 weeks.

The results showed that the dementia severity score (CDR-SB) in the Gantenerumab group in the GRADUATEI and GRADUATEII studies was -0.31 (p=0.0954) and -0.19 (p=0.2998), respectively, but neither was statistically significant. Patients in the Gantenerumab group in the GRADUATEI and GRADUATEII studies experienced a reduction of 8% and 6% in clinical progression delay compared to placebo. In addition, Gantenerumab clears lower than expected levels of the Aβ protein.

In addition to the failures of the Graduate I and II studies, Gantenerumab has suffered two previous failures —

In 2010, Roche initiated a Phase II clinical trial to test the efficacy of Gantenerumab, a β-targeting amyloid peptide monoclonal malyte, and expanded this clinical trial to a Phase II/III clinical trial in 2012. However, in 2014, Roche terminated the ScarletRoAD clinical trial based on the results of the interim invalidity test. (Subsequent biomarker and efficacy signal analysis showed that high doses of ganteneurumab showed some efficacy in patients with the fastest disease progression, hence the Graduate I and II studies.)

Another phase II/III study, codenamed DIAN-TU-001, evaluated the efficacy of Ganteneurumab in patients with autosomal dominant Alzheimer's disease (ADAD), and in February 2020, Roche announced that the study did not meet the primary endpoint.

Crenezumab

Crenezumab is a specific monoclonal antibody drug targeting β-amyloid for patients with early-stage (prodromal or mild) Alzheimer's disease. Genentech was acquired from ACImmune in 2006. After Roche acquired Genentech, the drug fell into Roche's hands.

In June, Roche announced that Crenezumab's Phase II clinical trial in the Alzheimer's Disease Prevention Initiative (API) program did not meet the primary endpoint.

The APIADAD trial, originally proposed by researchers at the Banner Alzheimer's Institute (BAI), is a prospective, randomized, double-blind, placebo-controlled, parallel-group phase II efficacy-validation study in patients who have not yet developed cognitive impairment but exhibit the earliest biological signs of AD. A total of 252 participants were recruited and randomized to receive crenezumab or placebo for 5-8 years, with 94% of participants completing the study. The study was designed to assess the potential of crenezumab to slow or prevent Alzheimer's disease in cognitively impaired people who carry specific gene mutations that cause early-onset Alzheimer's disease.

The results showed that the trial did not show statistically significant clinical benefit for the two common primary endpoints of changes in cognitive ability or episodic memory function; No new security issues were identified during the study.

Similar to Gantenerumab, Crenezumab's research and development has repeatedly failed —

In 2014, a phase II study of Crenezumab failed to significantly delay cognitive and functional decline in patients with mild to moderate Alzheimer's disease compared with placebo, and did not meet the primary endpoint.

In January 2019, Roche announced the termination of two phase III CREAD1 and CREAD2 clinical studies of Crenezumab for the treatment of early-stage AD because the independent data monitoring committee's interim analysis first-line results showed that Crenezumab may not be able to meet the primary endpoint of improving the CDR-SB score in patients.

Despite successive blows in the field of Alzheimer's disease, Roche has become more and more courageous. After a new round of defeat, what is Roche's next move? Whether to go black or stop there may also depend on whether new benefits can be found in the detailed research data analysis of the two new drugs under development.

The two new drugs on the market are in turmoil, and it is difficult to find a way out

At present, two new Alzheimer's disease drugs have been launched at home and abroad, namely Biogen's Aduhelm (US market) and Green Valley Pharmaceutical's mannite sodium capsule (domestic market). And these two drugs are also in turmoil.

Aduhelm

Aduhelm is a human monoclonal antibody that targets β amyloid (Aβ), selectively binds to amyloid deposition in the brain of AD patients, and then clears the deposited protein from the brain by activating the immune system.

On June 7, 2021, the FDA announced accelerated approval of Biogen's monoclonal antibody Aduhelm for the treatment of mild cognitive impairment (MCI) and mild Alzheimer's disease by Alzheimer's disease. However, the drug has been controversial, and after approval, Aduhelm has successively suffered a series of negative effects such as setbacks in important market listings, restrictions on use, dismal sales performance, and the dissolution of the sales team.

Aduhelm was almost unanimously rejected by the FDA advisory committee due to incompleteness of the clinical trial and contradictory results from two phase III trials.

After Aduhelm received accelerated FDA approval in June, three FDA advisory committee experts resigned in protest.

Due to the lack of effective convincing results of the Aduhelm trial, many doctors in the United States have publicly stated that they will not recommend the use of Aduhelm in clinical practice.

On July 8, 2021, the FDA announced that it would narrow the scope of Aduhelm and its use to align with the disease stage and population studied in clinical trials to treat AD patients with mild symptoms.

After the commercial marketing of Aduhelm, patients receiving Aduhelm treatment need to be administered intravenously in the hospital (about 1 hour) and monitored with infusion every 4 weeks, each infusion is about 4312 US dollars, and the cost of high-dose infusion is about 56,000 US dollars / year, which is quite expensive. Aduhelm's first full quarter, the third quarter of 2021, had sales of just $300,000, which was quite dismal.

In early November 2021, an elderly patient died after receiving Biogen's Alzheimer's disease drug Aduhelm;

In November 2021, Biogen received a "negative trend vote" from the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) on Aduhelm's application, and the CHMP rejected Aduhelm's listing in Europe.

Earlier in December 2021, Biogen planned to lay off up to 1,000 employees due to Aduhelm's dismal performance and failed commercial launch, including Biogen's chief research and development officer, Alfred Sandrock, who was forced to leave.

On December 20, 2021, Biogen decided to significantly reduce the price of Aduhelm, from $56,000 to $28,000.

In March, Eisai revised its Alzheimer's Alliance cooperation agreement with Biogen, stating that starting January 1, 2023, Eisai will receive tiered royalties based on net sales from Biogen, after Eisai shared Aduhelm's sales profits and shared losses with Biogen. Judging from the content of the changes, Aduhelm has become an "outcast" of Eisai.

In April 2022, the U.S. Centers for Medicare and Medicaid Services (CMS) officially decided to strictly limit coverage to Aduhelm, a controversial Alzheimer's disease drug owned by Biogen, to patients participating in clinical trials only.

In April 2022, Biogen decided to withdraw Aduhelm's Marketing Authorization Application (MAA) submitted in Europe.

Mannite sodium capsules

Ganlute sodium capsules (GV-971, trade name: Phase 9 I) are low-molecular acid oligosaccharide compounds prepared from marine brown algae extract. Its mechanism of action studies have shown that GV-971 improves cognitive dysfunction by remodeling the balance of intestinal flora, inhibiting the abnormal increase of specific metabolites of intestinal flora, reducing peripheral and central inflammation, reducing β amyloid deposition and overphosphorylation of Tau protein.

On November 2, 2019, GV-971 was conditionally approved by the State Food and Drug Administration for mild to moderate Alzheimer's disease to improve cognitive function in patients. After the domestic approval, Green Valley Pharmaceutical began to layout GV-971. The GV-971 International Multicenter Phase 3 Clinical Trial Application (IND) was approved by the US FDA in April 2020 and initiated in October 2020.

In May this year, GV-971 suspended its international layout. The explanation given by Green Valley Pharmaceutical is: due to the increase in shedding rate, funds and other factors, the phase 3 clinical trial of phase 9 and one ® international multi-center currently under research will be terminated early.

Most of the controversies surrounding GV-971 come from academia, mainly targeting issues such as clinical trial data and unclear mechanisms.

On November 28, 2019, Rao Yi reported Geng Meiyu's fraud in his real name, saying that the study was "impossible without falsification." This is mainly based on the fact that on September 6, 2019, a paper by Geng Meiyu's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences appeared on the cover of CellResearch, introducing the principle of GV-971.

On July 6, 2020, Professor Rao Yi once again published a short review in CellResearch, questioning the "citation problem" of Geng Meiyu's team's paper and the "utility problem" of GV-971. Rao also expressed potential concerns about the study's credibility, saying he had never encountered a drug with so many targets to treat or alleviate a disease.

On January 21, 2021, the Ministry of Science and Technology issued the "Circular on the Investigation and Handling of Suspected Fraud of Papers", in which the investigation of Geng Meiyu's research paper concluded that no fraud was found, but there was misuse of pictures.

In December 2021, Geng Meiyu v. Rao Yi pronounced a judgment in the first instance of the case of reputation infringement, rejecting Geng Meiyu's lawsuit request that Rao Yi apologize and restore her reputation on the relevant platform. The court held that legitimate academic controversy and criticism should be allowed from the perspective of medical development.

On May 16, 2022, the article "Green Valley announced that there is no need for "moon dark wind and high night" to stop foreign 971 experiments on the public account of "Rao Discussion Science"? Stopping domestic sales is the first step to change course" questioned again. In a paper titled "Hiding What? The section states, "Green Valley has made a lot of money because of 971. Isn't that money enough to do this clinical study? Still because I was worried that I would show my stuffing, I didn't dare to continue. ”

Even if the chances are slim, the blue ocean of AD is still tempting

At present, Alzheimer's disease patients account for about 60%-80% of all dementia patients and have become a serious social problem. According to statistics, there are more than 50 million Alzheimer's disease patients in the world, and it is expected to exceed 152 million in 2050, of which 13.8 million patients over 65 years old.

In addition to Roche and Biogen, multinational pharmaceutical companies such as Pfizer, Johnson & Johnson, Eli Lilly, Merck Sharp & Dohme, and AstraZeneca have also been attracted by the big cake of the Alzheimer's disease market, but almost all of them have been wiped out.

In 2012, Pfizer and Johnson & Johnson announced that they would stop research and development of the Alzheimer's disease drug Bapineuzumab;

In 2016, Eli Lilly's widely anticipated AD new drug solanezumab did not meet expectations in phase 3 clinical trial data;

In 2017, Merck announced that it would stop developing the BACE inhibitor (reducing the level of β-amyloid in plasma) drug verubecestat;

In 2018, Eli Lilly and AstraZeneca announced the discontinuation of phase III clinical trials of oral inhibition of Lanabecesta, a BACE inhibitor, for Alzheimer's disease.

In 2018, Pfizer announced its withdrawal from AD research and development.

Although there have been many lessons from the fiasco of AD drugs under development, in the face of the huge blue ocean market, there are still pharmaceutical companies in the lead.

Biogen and Eisai lecanemab

While Biogen and Eisai's first AD drug, Aduhelm, fell into the abyss, its second drug, lecanemab, seemed promising to become a blockbuster. Biogen and Eisai's expectations for Aduhelm are also shifting toward lecanemab. Living up to expectations, in September this year, lecanemab met its primary endpoint in a Phase 3 validated clinical trial for the treatment of patients with mild AD and AD-induced mild cognitive impairment. At the same time, the trial met all key secondary endpoints.

Hengrui Pharmaceutical SHR-1707

Hengrui Pharmaceutical, a domestic company, is also developing a monoclonal antibody injection SHR-1707 targeting Aβ protein, which is intended to be used to treat Alzheimer's disease. On March 10, 2021, the clinical trial application of SHR-1707 received the implied permission of the NMPA for the treatment of Alzheimer's disease, and SHR-1707 is the first Aβ antibody declared for clinical trial in China. In addition, SHR-1707 has been conducted in a Phase I, randomized, double-blind, placebo-controlled study in the United States to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single intravenous administration of SHR-1707 in healthy adult and elderly subjects.

Novartis Amilomotide

Novartis developed an Aβ vaccine, Amilomotide, and a phase IIb double-blind placebo-controlled trial showed a strong serological response in the Amilomotide group, 55.1% of participants in the 150 μg dose group produced Aβ immunoglobulin, and 81.1% in the 450 mg dose group, with positive results.

The development of new drugs is not easy, and for the track of "research and development of black holes" Alzheimer's disease, it is even more difficult. Giving up is simple, but, choose this path, what if it succeeds?