On November 14th Roche announced yet another failure of its new Alzheimer's (AD) drug. This time it was A subcutaneous injection of Aβ monoclonal antibody Gantenerumab.
Roche said in its statement that Gantenerumab did not meet its primary endpoint in either of the Phase III studies, GraduateI and II, which significantly slowed the progression of dementia and addressed memory loss and executive impairment in patients with early Alzheimer's disease. The drug cleared levels of beta-amyloid protein (Aβ) that were lower than expected.
The field of Alzheimer's disease has been a black hole in the development of new drugs. Gantenerumab is not the only one, but many other drugs have also failed, and even the ones already on the market have been controversial.
Roche has two Aβ antibodies in its pipeline, Gantenerumab and Crenezumab, for Alzheimer's disease. Both of these drugs have been in clinical development for many years, with frequent failures and bottomless research and development costs.
Gantenerumab
Gantenerumab is A fully humanized IgG1 monoclonal antibody. It was the first Aβ monoclonal antibody to enter phase I clinical studies and was injected subcutaneously. Gantenerumab has A high affinity for all types of aggregates, with the highest affinity for Aβ fibers and plaques, and promotes the phagocytosis of FC-γ receptor-mediated microglia to aggregates of Aβ.
Roche initiated GraduateI and II studies in 2017, two global, double-blind, randomized, placebo-controlled Phase III trials evaluating the safety and efficacy of Gantenerumab in patients with Alzheimer's disease and mild Alzheimer's dementia-induced mild cognitive impairment (MCI). A total of 1965 patients were randomized to receive Gantenerumab or placebo in a 1:1 ratio, reaching the target dose of 510mg. The primary endpoint was the change from baseline in the Summation Clinical Dementia Score Scale (CDR-SB) at 116 weeks.
The results showed that in the GRADUATEI and GRADUATEII studies, the reduction of dementia severity score (CDR-SB) from baseline in the Gantenerumab group was -0.31 (p=0.0954) and -0.19 (p=0.2998), respectively, but neither of them were statistically significant. Compared with placebo, patients in the GRADUATEI and GRADUATEII studies with Gantenerumab experienced an 8% and 6% reduction in delayed clinical progression, respectively. In addition, Gantenerumab cleared Aβ protein at lower levels than expected.
In addition to the failures of GraduateI and II, Gantenerumab had suffered two previous failures
In 2010, Roche initiated a phase II clinical trial to examine the efficacy of Gantenerumab, a monoclonal antibody targeting amyloid beta peptide, and expanded this trial to Phase II/III trials in 2012. However, in 2014, Roche terminated the ScarletRoAD clinical trial based on the results of an interim ineffectiveness test. (Subsequent biomarker and efficacy signal analysis showed that higher doses of ganteneurumab were effective in patients with the most advanced disease, leading to GraduateI and II studies.)
Another Phase II/III study, code-named DIAN-TU-001, evaluated Ganteneurumab in patients with autosomal dominant Alzheimer's disease (ADAD). In February 2020, Roche announced that the study did not meet its primary endpoint.
Crenezumab
Crenezumab, a monoclonal antibody specific to beta-amyloid protein, is indicated for patients with early (prodromal or mild) Alzheimer's disease. Genentech acquired it from ACImmune in 2006. Roche's acquisition of Genentech put the drug back in Roche's hands.
In June, Roche announced that Crenezumab did not meet its primary study endpoint in a Phase II trial under the Alzheimer's Disease Prevention Initiative (API) program.
The APIADAD trial, originally proposed by researchers at Banner Alzheimer's Disease Institute (BAI), was a prospective, randomized, double-blind, placebo-controlled, parallel-group Phase II validation study in patients who did not have cognitive impairment but showed the earliest biological signs of AD. A total of 252 participants were recruited and randomly assigned to receive crenezumab or placebo for five to eight years, with 94% of participants completing the study. The study was designed to evaluate the potential of crenezumab to slow or prevent Alzheimer's disease in cognitively unimpaired people who carry a specific gene mutation that causes early-onset Alzheimer's disease.
Results showed that the trial did not show a statistically significant clinical benefit for the co-primary endpoints of changes in cognitive ability or episodic memory function; No new safety issues were identified during the study.
Like Gantenerumab, Crenezumab has had its share of failures
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 to placebo, failing to meet the primary endpoint.
In January 2019, Roche announced the termination of two Phase III clinical studies of CREAD1 and CREAD2 for Crenezumab in early-stage AD, Because first-line results from an interim analysis by the Independent Data Monitoring Board suggested that Crenezumab may not meet the primary endpoint of improving patients' CDR-SB scores on the Comprehensive Clinical Dementia Rating Scale.
Despite a succession of setbacks in Alzheimer's disease, Roche has continued to suffer. After a new round of defeats, what is Roche's next move? The path to the dark side or the end may depend on finding new benefits in a detailed analysis of the data from two new drugs under development.
At present, there are two new Alzheimer's drugs on the market at home and abroad, namely Bojian's Aduhelm (on the market in the United States) and Green Valley Pharmaceutical's Manamide sodium capsule (on the market in China). And the two drugs have been a storm.
Aduhelm
Aduhelm is A human monoclonal antibody that targets amyloid beta (Aβ), selectively binds to amyloid deposits in the brain of patients with AD, and then removes the deposits from the brain by activating the immune system.
On June 7, 2021, the FDA announced accelerated approval of Bojian's monoclonal antibody Aduhelm for the treatment of Alzheimer 's-derived mild cognitive impairment (MCI) and mild Alzheimer's disease. However, the drug has been controversial. After the approval, Aduhelm has suffered a series of negative effects, such as setbacks in the launch of important markets, restricted use, poor sales performance and disbanding of the sales team
Aduhelm was nearly unanimously rejected by an FDA advisory committee because of incomplete clinical trials and conflicting results from two Phase III trials.
After Aduhelm received accelerated FDA approval in June, three experts on the FDA's advisory committee resigned in protest.
Due to the lack of effective and persuasive results of Aduhelm test, many American doctors publicly said that they would not recommend the use of Aduhelm in clinical practice.
On July 8, 2021, FDA announced to narrow the range and use method of Aduhelm, making it consistent with the disease stage and population studied in clinical trials, and only used to treat patients with mild symptoms of AD.
After the commercial launch of Aduhelm, patients receiving Aduhelm therapy need intravenous administration (about 1 hour) in the hospital and coordination of monitoring. Each infusion is given every 4 weeks, and the cost of each infusion is about $4312. The cost of high-dose infusion is about $56,000 / year, which is quite expensive. The third quarter of 2021, Aduhelm's first full quarter after approval, was a dismal $300,000 in sales.
In early November 2021, an elderly patient died after receiving Bojian's Alzheimer's drug Aduhelm.
In November 2021, Bojian received a "negative trend vote" on the application of Aduhelm from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, which rejected the marketing of Aduhelm in Europe.
Earlier in December 2021, due to the poor performance of Aduhelm and the failure of its commercial listing, Bojian planned to lay off up to 1,000 employees, among which Bojian's chief research and development officer, AlfredSandrock, was forced to resign.
On December 20, 2021, Bojian decided to significantly reduce the price of Aduhelm by half, from $56,000 to $28,000.
In March this year, Eisai revised its Alzheimer's disease alliance cooperation agreement with Bojian. According to the new agreement, Eisai will receive a layered royalty based on net sales from Bojian from January 1, 2023, while Zaventai and Bojian will share the sales profits and losses of Aduhelm. From the content of the change, Aduhelm became Eisai's "abandoned son".
In April 2022, the U.S. Centers for Medicare and Medicaid Services (CMS) officially decided to strictly limit the coverage of Bojian's controversial Alzheimer's drug Aduhelm to only patients participating in clinical trials.
In April 2022, Bojian decided to withdraw the marketing authorization application (MAA) for Aduhelm submitted in Europe.
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Mannose sodium capsule
Manut sodium capsule (GV-971, trade name: Phase 9 1) is a low molecular acid oligosaccharide prepared from Marine brown algae extract. Studies on its mechanism of action have shown that GV-971 can improve 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 Tau protein hyperphosphorylation.
On November 2, 2019, GV-971 was conditionally approved by the National Food and Drug Administration for marketing in mild to moderate Alzheimer's disease to improve cognitive function in patients. After domestic approval, Green Valley pharmaceutical began to GV-971 began layout. The GV-971 International Multi-center Phase 3 Clinical Trial Application (IND) was approved by the U.S. FDA in April 2020 and was initiated in October 2020.
In May this year, GV-971 suspended its international layout. Green Valley Pharma explained that due to the impact of increased shedding rate and funding, the Phase IX ® international multi-center Phase III clinical trial currently under development will be terminated in advance.
The controversy surrounding GV-971 mostly comes from the academic community, mainly aimed at clinical trial data, unclear mechanism and other issues
On November 28, 2019, Rao reported Geng Meiyu's falsification under his real name, saying that the research was "impossible without falsification". This is mainly based on a paper by Geng Meiyu's team at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, which was featured on the cover of CellResearch on September 6, 2019, introducing the principle of GV-971.
On July 6, 2020, Professor Rao again posted a brief commentary on CellResearch, questioning the "citation problems" of Geng's team's paper and the "utility problems" of GV-971. Rao also expressed potential concern about the credibility of the study, saying he had never come across a drug with so many targets that could treat or alleviate a disease.
On January 21, 2021, the Ministry of Science and Technology issued a Notice on the Investigation and Treatment of Suspected Fraud in the Paper, in which the investigation conclusion of Geng Meiyu's research paper was: no fraud was found, but there was some misuse of pictures.
In December 2021, the judgment of the first instance of the defamation infringement case of Geng Meiyu versus Rao Yi was handed down, rejecting Geng Meiyu's lawsuit request that Rao apologize and restore his reputation on the relevant platform. The court heard that legitimate academic controversy and criticism should be allowed in the context of medical development.
On May 16, 2022, on the public account of "Raouyi Science", an article titled "Green Valley announces to stop the foreign 971 test without the" dark night "? Stopping domestic sales is the first step to change course "was again questioned. In a speech entitled "Hiding from What? One section states, "Green Valley has made a lot of money because of the 971. Isn't that enough money for this clinical study? I am afraid to continue because I am afraid I will be exposed."
At present, Alzheimer's disease patients account for about 60% to 80% of all dementia patients, has become a serious social problem. According to statistics, the number of people with Alzheimer's disease has exceeded 50 million worldwide, and it is expected that the number will exceed 152 million in 2050, among which 13.8 million people will be over 65 years old.
In addition to Roche and Bojian, multinational drug companies such as Pfizer, Johnson & Johnson, Eli Lilly, Merck and Astrazeneca have also been attracted by the big pie in the Alzheimer's disease market, but almost all have been wiped out.
In 2012 Pfizer and Johnson & Johnson announced they were halting development of Bapineuzumab, an Alzheimer's drug;
In 2016, Eli Lilly's high-profile AD drug solanezumab failed to meet expectations in a Phase 3 trial;
In 2017, Merck announced it was discontinuing development of verubecestat, a BACE inhibitor that reduces plasma levels of beta-amyloid.
In 2018, Lilly and Astrazeneca announced the discontinuation of Phase III clinical trials of Lanabecesta (BACE inhibitor), an oral inhibitor for Alzheimer's disease.
In 2018, Pfizer announced its withdrawal from AD research and development.
Although there have been many examples of the failure in the research of AD drugs, but in the face of the huge blue ocean market, there are still drug companies in one after another.
Bojian and Eisai lecanemab
While Bojian and Eisai's first AD drug, Aduhelm, fell into trouble, their second drug, lecanemab, seems likely to be a blockbuster. Bojian and Weisai's expectation of Aduhelm is also gradually shifting to lecanemab. Living up to expectations, lecanemab reached its primary endpoint in September in a Phase 3 validated clinical trial for the treatment of patients with mild AD and AD-related mild cognitive impairment. At the same time, the trial met all key secondary endpoints.
Hengrui Medicine SHR-1707
A domestic company, Hengrui Pharmaceutical, is also developing a monoclonal antibody injection, SHR-1707, targeting Aβ protein, to be used in the treatment of Alzheimer's disease. On March 10, 2021, the clinical trial application of SHR-1707 received the implied approval of NMPA for the treatment of Alzheimer's disease. SHR-1707 is the first clinically declared Aβ antibody in China. In addition, a Phase I, randomized, double-blind, placebo-controlled study of SHR-1707 has been conducted in the United States to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous administration of SHR-1707 in healthy adults and elderly subjects.
Novartis Amilomotide
A phase IIb double-blind placebo-controlled trial of Amilomotide, an Aβ vaccine developed by Novartis, showed A strong serological response in the Amilomotide group, with 55.1% in the 150μg dose group and 81.1% in the 450mg dose group. Get positive results.
Finding new drugs is not easy, and the track for the "black hole" of Alzheimer's disease is even tougher. Giving up is very simple, but, choose this path, what if it succeeds?
