What do you think about the future of Alzheimer's disease treatment from Aduhelm to GV-971?

Amidst the overwhelming encouragement and controversy, the journey of mankind to fight Alzheimer's disease has finally taken a big step forward
.

On June 7th, US time, the FDA accelerated the approval of Bojian's biological monoclonal antibody drug Aduhelm for the treatment of early-stage Alzheimer's disease (AD)
.

This is the first new AD drug approved by the FDA since 2003, and it is also the first disease-modifying drug approved by the FDA for Alzheimer's disease for more than 100 years
.

What people are happy about is that they finally saw a new light in the medical field of a thousand sails
.

The focus of the controversy is that Aduhelm was almost unanimously rejected by the FDA advisory committee because of the incomplete clinical trials and the conflicting results of the two phase III trials
.

In addition, Aduhelm has been questioned because the underlying mechanism of action "Aβ" hypothesis itself has insufficient evidence for the treatment of Alzheimer's disease
.

Such surprises and doubts seem familiar.
Two years ago, when GV-971 was conditionally approved for listing in China, it also faced many controversies about its clinical trials and mechanism of action
.

       In this regard, an industry insider who has been engaged in Alzheimer’s disease research for a long time told Sina Pharmaceuticals: “Whether it is Aduhelm or GV-971, insufficient evidence reminds us not to be blindly optimistic, but it also reminds us not to rush to deny it.

All conclusions need to be proved by more sufficient evidence
.

       Behind the huge surprises and controversies of the two AD treatment drugs that have been approved domestically and internationally, we should calmly explore the significance of their practical needs for patients:

       ● Judging from the mechanism of GV-971 and Aduhelm, when will human beings find a new weapon to truly fight Alzheimer's disease?

       ● Using Aduhelm to make an exception and get Dongfeng approval, how far is the domestic GV-971 from further global listing?

       ● How far is Aduhelm, which is approved on the other side of the ocean, from benefiting Chinese patients?

       ● Of course, and most importantly, how much do they sell? How accessible is the patient's medication?

       .

       01 Fight against Alzheimer's disease, right cause treatment or become a real weapon?

       Under heavy pressure, the FDA and CDE withstood the pressure to approve the conditional listing of Aduhelm and GV-971.
Too much
.

       Data show that there are currently more than 50 million patients with Alzheimer's disease worldwide.
It is estimated that by 2030, there will be more than 74 million patients; in 2050, the total number of patients will reach 150 million
.

       And contrasting with the grim situation is the bleak reality
.

       For clinical research, Alzheimer's disease is an "absolute blind spot" in the field of human medicine, and it is the hardest hit area for new drug research and development-the clinical failure rate is as high as 99.
6%, and the difficulty is far better than landing on the moon
.

       It is reported that between 1998 and 2017, a total of 146 Alzheimer's disease drugs worldwide failed in clinical research and development centers
.

       ①Tacrine approved in 1993 (delisted);

       ② Donepezil approved in 1996;

       ③ Rivastigmine approved in 2000;

       ④Galantamine approved in 2001;

       ⑤Memantine hydrochloride approved in 2003;

       ⑥Memantine/donepezil compound preparation approved in 2014
.

       However, these drugs can only improve the symptoms of patients, and cannot reduce the pathological changes of AD, nor can they reverse or slow down the disease process
.

       The reason why two AD treatment drugs, Aduhelm and GV-971, have attracted much attention and are in a storm of controversy is that they target the basic pathology of Alzheimer’s disease and are drugs for the treatment (disease modification) of the cause.
The source of the research basis Yu hypothesis theory
.

       As the cause and mechanism of Alzheimer’s disease have not yet been clarified, drug development is currently based on various hypotheses, including brain β-amyloid (Aβ) deposition, neurofibrillary tangles, and neuroinflammation (brain-gut axis).
) and so on
.

       ◆ Bojian’s Aduhelm——Targeting Aβ

       "Abnormal deposition of β-amyloid protein" is the most extensive hypothesis explaining Alzheimer's disease, and Biogen's Aduhelm is based on this hypothesis
.

       At present, the biggest controversy about Bojian Aduhelm is that its road to market has been twisted and turned, and the results of two key clinical trials are contradictory and questioned; the other is the β-amyloid hypothesis itself, which is also full of controversy.

.

       It is reported that based on the phenomenon of β-amyloid protein deposition in the patient's brain, researchers have launched a large number of studies in an attempt to find specific drugs for the treatment of Alzheimer's disease
.

       According to clinical studies conducted by Aduhelm, it can selectively bind β-amyloid to clear the accumulation of β-amyloid in the brains of patients with Alzheimer's disease, but whether the removal of β-amyloid can lead to better clinical results As a result, further research remains to be done
.

       ◆ GV-971——Targeting the brain-gut axis

       GV-971 was jointly developed by Professor Geng Meiyu of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and Green Valley Pharmaceuticals.
In November 2019, it was approved by the CDE for conditional listing in China
.

       Traditional Alzheimer's disease drug research often focuses on the accumulation of β-amyloid in the brain and neurofibrillary tangles caused by the hyperphosphorylation of Tau protein
.

       GV-971 is a novel anti-cause therapy drug, and its target of action is the brain-gut axis
.

       To understand the mechanism of targeting the brain-gut axis, it is first necessary to understand the relationship between the intestinal flora and the central nervous system of the brain
.
Recent studies have shown that, as an important part of the body, the role of intestinal flora is not limited to the gastrointestinal tract, but also has a significant impact on brain function and behavior
.

       Research by Geng Meiyu’s team found that changes in the intestinal flora can cause the accumulation of phenylalanine and isoleucine in the peripheral blood, leading to neuroinflammation and eventually cognitive dysfunction
.

       GV-971, as a low-molecular-weight acid oligosaccharide compound prepared with marine brown algae extract as a raw material, can regulate the intestinal flora and reduce abnormal metabolites of the flora, thereby reducing neuroinflammation in the brain
.

       In addition, GV-971 can directly bind to Aβ and reduce the deposition of Aβ in the brain
.
According to the main efficacy indicators of the drug in the domestic phase III clinical study, GV-971 can continuously and steadily improve the cognitive function of patients during the 36-week observation period.
From the baseline to the 36th week, the GV-971 group is taking the fourth drug.
There was a significant difference compared with the placebo group after weeks.
By the 36th week of the end of the trial, the ADAS-cog12 score difference between the two groups reached the largest -2.
54 points.
The average model difference between the two groups during the entire trial period was- 2.
15 points (95% CI [−3.
07 to −1.
23])
.
The test results also confirmed that the safety of GV-971 was good, and the incidence of adverse events was not significantly different from that of placebo
.

       As a nearly new pathogenesis of AD, the proof of the causality rather than the correlation between each ring in the GV-971 brain-gut axis is critical and difficult
.
And it is precisely because the brain-gut axis is a new pathogenesis of AD, which has been questioned by many
.

       These disputes can only be verified by more time and more sufficient clinical evidence
.

       02 Two conditionally marketed drugs have the same heavy responsibilities and a long way to go

       Although both drugs have been controversial, there is no doubt that both have achieved results in their respective fields.
They have taken the lead and have attracted much attention.
Under the attention, they are also facing greater challenges and pressures
.

       ◆ Challenge of Aduhelm

       After the FDA rejected the consensus and released Bojian Aduhelm, Aduhelm did not "sit back and relax", and there are still many thorny issues hanging in front of us——

       ● Delisting risk: It is reported that after approval, Bojian needs to further confirm the expected clinical benefits of the drug, otherwise it may cause the drug to be withdrawn from the market
.

       ● Slow onset of action and insignificant effect: In ADUHELM's phase III clinical trial EMERGE, the ADAS-cog13 scores of the high-dose ADUHELM™ group and the low-dose group were not significantly different from placebo at 0-50 weeks.
It was not until 50 weeks later that the high-dose ADUHELM group gradually opened up a significant difference from the placebo group, reaching the maximum difference of -1.
4 points at 78 weeks, but this difference was not obvious compared with the effectiveness of similar drug trials
.
In another phase three clinical trial of ADUHELM, ENGAGE, the ADAS-cog13 scores of the three groups did not reach a significant difference from baseline to week 78
.

       Taking into account the weak evidence of ADUHELM's effectiveness in two clinical studies, the FDA announced in the announcement that the effectiveness of the drug in clinical trials was "mixed
.
"

       ● Side effects: According to Wall Street reports, according to detailed data released by Bojian, ~35% of patients receiving high-dose aducanumab treatment developed ARIA-related cerebral edema (ARIA-E), ~18% to 22.
7 % Of patients have ARIA-related microbleeds (ARIA-H)
.
These potential side effects have also caused many concerns and even criticism in the scientific research community
.

       ● Difficulty and high cost of administration: It is reported that patients receiving Aduhelm treatment need to be administered intravenously (about 1 hour) and monitored in the hospital.
The infusion is once every four weeks, and the cost of each infusion is about 4,312 US dollars.
The cost of high-dose infusion is about 56,000.
USD/year, for patients, this is undoubtedly a relatively high cost of treatment
.

       It can be seen that although Aduhelm has been approved by the FDA for listing, it is far from gaining a foothold.
Therefore, as to the question of when Chinese patients will be able to enter the Chinese market, some industry analysts say that Aduhelm should not be able to benefit Chinese patients.
There is a relatively long distance, the main reasons are:

       ● At present, Aduhelm still has many unsolved problems about itself, which need to be dealt with, and may not have time to enter the Chinese market temporarily;

       ● Aduhelm's entry into the Chinese market requires high-demand clinical trial equipment (such as pets and other complex analytical imaging diagnostics, there are currently no correspondingly marketed diagnostic products, etc.
), as well as strict medication management.
These specific operational problems may be temporary.
Difficult to solve, increasing the difficulty of entering the Chinese market;

       ● The current annual treatment cost of Aduhelm is about 56,000 US dollars, which is about 358,000 yuan.
If it enters the Chinese market at this price, it will be a very heavy burden for Chinese patients, and the availability of drugs is not high
.

       ◆ Challenge of GV-971

       After GV-971 is conditionally approved in China, it is also facing the regulatory pressure of continuing to conduct research on pharmacological mechanism and long-term safety and effectiveness after marketing, improve the analysis method of oligosaccharides, and submit relevant time data on time
.

       At the same time, many issues such as GV-971's signaling pathway and mechanism are still attracting attention
.
such as:

       ● Which bacteria in the intestine can be regulated?

       ● What is the control channel?

       ● What is the site of action?

       ● Has the clinical treatment of AD achieved satisfactory results after the market?

       ● Are there any new side effects found?

       .
.
.

       For these questions, GV-971 has been on the market in China for more than one and a half years, and many answers have gradually surfaced
.
A return visit to a survey conducted from the perspective of patients and doctors showed:

       ● 73% of AD clinicians believe that GV-971 can improve or maintain the cognitive symptoms of patients with Alzheimer's disease;

       ● 63% of doctors observed that GV-971 can improve neurobehavioral symptoms;

       ● 47% of doctors commented that AD patients taking GV-971 have an improvement in the ability of daily living;

       ● 35% of doctors believe that the language ability, mood, diet, sleep, etc.
of patients with GV-971 have improved significantly
.

       From this data point of view, GV-971 has been used in AD clinical treatment after being launched in China.
In addition, from the price point of view, the current domestic price of GV-971 is 895 yuan/box, "36 weeks The cost of the treatment period is about RMB 32,000
.
It is reported that the drug has a donation aid program in China and is actively applying for inclusion in medical insurance.
From this point of view, patients in China may be able to obtain the drug through more economical means
.

       In addition, from the perspective of drug efficacy, GV-971 has begun to go abroad and accept global testing:

       ● In April 2020, FDA approved GV-971 international multi-center phase III clinical trial IND;

       ● In November 2020, Green Valley Pharmaceutical started to recruit patients, and the first patient medication has been achieved so far;

       ● In 2024, GV-971 plans to complete the clinical phase of work, and it will be registered and listed globally in 2025;

       .
.
.

       What clinical effects will the GV-971 international multi-center phase III clinical trial show? This issue will undoubtedly attract more attention after Aduhelm goes public
.

       However, it is worth noting that, based on the huge social pressure and public opinion demands in the field of AD treatment, the FDA makes an exception for the release of Bojian Aduhelm, which not only provides new hope for AD patients around the world, but is also a development for the future of AD.
A cardiotonic for drug researchers
.

       In this regard, some insiders analyzed that “FDA’s attitude is bound to cause some market changes
.
AD drugmakers who have failed to market their drugs due to trial failures may seek other “alternative endpoints” to re-see the market
.
In the future, the FDA Whether it will consider letting go and using the'surrogate endpoint' as a basis for drug approval and marketing has become a matter of great concern
.
"

       Sina Pharmaceuticals will continue to pay attention to whether GV-971, which has been approved by the FDA in the international multi-center phase III clinical trial IND, can use Dongfeng to speed up its global market launch in the future
.

       03 Conclusion

       We are accustomed to using "nine deaths and a lifetime" to describe the difficulty of a thing, but in the global Alzheimer research field, the failure rate of 99.
6% has long exceeded the "nine deaths and a lifetime" probability
.
Over the years, the confidence of countless scientific researchers and pharmaceutical manufacturers has been hit and doomed
.
Some people describe the war between humans and Alzheimer’s disease as a complete “expedition”.
Fortunately, the approval of Aduhelm and GV-971 shows us that we are on this long and difficult road.
After all, someone walked down and brought hope
.

       Although the controversy is overwhelming, it will not break or stand.
While we are looking forward to more breakthroughs in the global medical community, we also call on everyone to prevent and intervene early in their daily lives.
Once diagnosed, we must adhere to standardized diagnosis and treatment, and jointly resist Alzheimer's disease
.

       Because many people regard Alzheimer’s disease as a phenomenon of aging, but in fact, Alzheimer’s disease is a fatal disease.
It is the fourth leading cause of death in the elderly (after heart disease and cancer).
And cardiovascular and cerebrovascular accidents), people need to pay more attention in their daily lives
.