Produced by丨Huxiu Technology Group
Author | Subei Foliangmi
Title image | Visual China
No one can be tripped by the same stone twice, unless he is Roche.
On November 14 local time, pharmaceutical giant Roche announced that its Phase III clinical trial for the investigational Alzheimer's disease (AD, dementia) drug gantenerumab had failed. The official statement cited — lack of statistically significant therapeutic effect.That is, it failed to significantly slow the progression of dementia, addressing issues such as memory loss and decreased executive function in patients with early-stage Alzheimer's disease.。
Foreign reviewers used the word "disappointment" to describe the news. Equally "disappointed" was Roche's stock price. In the early morning local time, Roche, listed on the Zurich Stock Exchange, fell by 5.7%, while its partner, German MorphoSys, plummeted by 25%. On the contrary, this gave its competitors Biogen and Eisai a head start, with Biogen's U.S. shares rising more than 3% pre-market.
Alzheimer's disease, a "swamp" in the jungle of biological science, has seen countless companies enter with an exploratory spirit, only to become hopelessly mired. From Eli Lilly and Pfizer to today's Roche, all have hoped to conquer it, yet without exception, they have stumbled on the battlefield.
But Roche is an exception again. This failure is the result of a second attempt. Has Roche finally reached the point of giving up on gantenerumab?
Winners Also Lose
Alzheimer's disease is considered by the medical community to be the biggest threat to public health, affecting more than 20 million people. Studies show that by 2050, approximately 135 million people will have Alzheimer's disease.
Since Alois Alzheimer reported the first case of Alzheimer's disease in 1906, medical professionals have been striving to explore its etiology. Among the numerous hypotheses regarding the pathogenesis of Alzheimer's disease, the amyloid-beta (Aβ) hypothesis has consistently held a dominant position.
This theory originated from brain examinations of patients with the disease, revealing extracellular β-amyloid plaques (β-amyloid plaques, Aβ plaques) deposition and intracellular neurofibrillary tangles are the main pathological features of Alzheimer's disease. Aβ plaques are formed from amyloid precursor protein (amyloid precursor protein，APP) Cleavage-formed β-amyloid protein (β-amyloid protein，Aβ) polymerization formation, while neurofibrillary tangles are formed by the polymerization of hyperphosphorylated tau protein.
β-Amyloid
In pathological conditions, APP is cleaved by β-secretase and γ-secretase to form Aβ. Depending on the cleavage site, Aβ of different lengths can be formed, among which Aβ1-40 (Accounting for approximately 90%) and Aβ1-42 (Approximately 10%) is dominant, and it is currently believed that Aβ1-42 is more toxic.The Aβ hypothesis suggests that the toxic effects of extracellular Aβ plaques lead to hyperphosphorylation of tau protein, neurofibrillary tangles, synaptic damage, and ultimately the onset of AD.。
This theory has dominated the specific direction of drug development. Earlier this year, Biogen and Eisai announced that their jointly developed anti-amyloid antibody lecanemab showed significant results in a major clinical trial, greatly alleviating the condition, although many questions about it still remain.
In 2021, Biogen's another anti-amyloid drug aducanumab (Adalimumab) was approved for marketing by the U.S. FDA. Although its efficacy can at best be described as "acceptable," a large number of patients have expressed that they do not believe in the drug's effects. At the policy level, the U.S. Medicare system has so far refused to cover the costs.
After Aducanumab was approved by the FDA, several experts from the FDA advisory committee resigned in succession to protest. Meanwhile, several American doctors openly stated that they do not recommend using the drug. Its commercialization path has also been continuously hindered.In the second quarter of this year, Adunamab generated only $100,000 in sales, with quite dismal performance.。
Eli Lilly and Pfizer in the past, and now Roche, have also conducted drug research and development under the guidance of this theory. Unfortunately, the three giants were not as "successful" as Biogen.
Secondary Failure
As early as 2014, Roche launched the first Phase III trial of gantenerumab, but it was prematurely halted by the end of that year after an interim analysis showed "lack of efficacy."
But with the progress and launch of Biogen's drug, Roche chose to "recast old wine in a new bottle" by reviving the previously "stillborn" research. They decided to attempt using higher doses of the antibody in two additional trials, which surprised many researchers. The two trials recruited nearly 2,000 patients across 30 countries who suffered from mild cognitive impairment or mild dementia due to Alzheimer's disease.
In these trials, compared with placebo, subcutaneous injection of gantenerumab (Targeting different parts of amyloid protein) can only slow down cognitive decline by 6% or 8%. As mentioned above, Roche also acknowledged that this result "is not statistically significant." The company added that the massive levels of beta-amyloid protein removed by the treatment were "lower than expected."
This outcome has led to increased skepticism about the pathological feature of the beta-amyloid hypothesis, with the golden theory now on the verge of collapse.
Based on past research on gantenerumab, many scientists and biotech analysts believe it has little chance of success in these two trials. Even proponents of the amyloid hypothesis are not holding high expectations. "Gantenerumab is the weakest candidate in the 'antibody' series, so I am not surprised by this outcome," said Bart De Strooper, director of the UK Dementia Research Institute, in an interview.
In fact, the scientific community's skepticism towards this hypothesis is nothing new. Scientific research has shown that if the Aβ Cascade Hypothesis were correct, the severity of dementia should be positively correlated with the amount of Aβ plaques. However, this is not the case— the density of Aβ plaques does not increase as the disease progresses but instead remains stable. Approximately 20% to 40% of cognitively normal individuals exhibit AD-related pathological changes but do not develop dementia.
There is even a type of atypical AD patient who exhibits clinical symptoms of dementia and has a large number of neurofibrillary tangles in the hippocampus similar to AD patients, but with little or no Aβ plaque formation. In early AD patients, the deposition sites of Aβ plaques in the brain do not correlate with the locations of synaptic damage and neuronal loss; the early sites of neuronal loss are in the entorhinal cortex and hippocampus, while Aβ plaques first accumulate in the cerebral cortex and amygdala.
The above all indicate that Aβ plaques are not associated with dementia. Therefore, can the dementia symptoms of AD patients with Aβ plaques improve after reducing these plaques?
Aβ42（AN1792) A 6-year follow-up of the phase II clinical trial found that, although AN1792 immunotherapy cleared Aβ plaques in AD patients, it could not prevent the progression of neurodegeneration. The severity of dementia and even long-term survival rates did not improve, prompting researchers to reconsider the role of Aβ plaques in the pathogenesis of AD.
This is like spending a lot of time and effort solving a math problem, only to be told after getting the result that the theorem you relied on was wrong. A heavy blow leaves you with no words to express your frustration. Now, the baton of silence has been passed to Roche. Faced with a devastating second failure, perhaps it's time to give up.