Breakthrough or Political Pressure: GV-971 and aducanumab for treatment of Alzheimer's Disease

Recently, we saw the breakthroughs in drug development for Alzheimer disease. The Chinese regulatory authority (NMPA) approved GV-971 (Oligomannate) for the treatment of mild and moderate Alzheimer’s disease. GV-971 is the first drug approved anywhere in the world for Alzheimer’s disease since 2003. While other Alzheimer’s drugs are developed based on the beta-amyloid theory, GV-971 targets a different mechanism. Based on the pre-clinical studies, GV-971 remodeled the gut microbiome in a way that reduced the accumulation of neuroinflammatory cells – a pathway that a lot of people are not convinced with. The GV-971 approval triggered a lot of discussions.

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GV-971 approval is also a hot topic in the Chinese social network (WeChat) discussions. There are supports and doubts, even some reports of the key paper with inappropriate handling of the data.

• 欢呼与质疑，抗老年痴呆药（GV971）的批准将成为中国创新药发展史上的标志性大事件
• 30亿研发的国产阿尔兹海默症新药，关键性论文涉嫌造假

GV-971的讨论已经遍布全网，错峰评论几句：1）不能因为Biogen做了36个月的AD trial就来要求971也做36个月，靶子不是由Biogen来画的。研究一下历史就知道，FDA批Aricept和Namenda，一个用的是24周数据、一个用的是28周数据；2）安慰剂效果到了临床实验末期骤然恶化也不是什么特别稀奇的，again，详见Aricept和Namenda的曲线也是到了后期陡降；3）对于生物标记物或者临床终点的选择，我同意浙江大学王立铭教授的看法，beta-amyloid或者tau的存在和AD的pathogenesis虽有相关性，但因果性从未确立。所以，要求测定脑脊液生物标记物，虽然说不过分，但未必relevant。况且，听说中国病人家属极度反对收集病人脑脊液（有创检查），此举恐降低病人依从性；4）AD机理本来本来就是一锅粥，971，maybe this is sth we don’t know that we don’t know, 所以要有一点开放心态；5）此药极安全，如果医保保，吃了，只有upside！没啥downside！这和癌症治疗不一样，癌症有很多好药，病人用了有争议的治疗，就可能产生机会成本。而AD，不用971，没有失去任何治疗机会；6）在中国大环境下，支持批准，支持医保覆盖。不覆盖这个，也是覆盖什么鼠神经营养因子这种具有中国特色的神药！还不如覆盖这个有点科学根据的呢；7）当然，以上一切讨论都是建立于对于给绿谷和耿教授的credibility 充足的benefit of doubt的前提下。至于绿谷作为一个药企，耿教授作为一名学者，他们的track record是不是支持NMPA对于数据的信赖，这是另外的讨论了。不过既然能批准，就还是信赖了嘛，哈哈哈

Two weeks ago, we saw the news about Biogen (and Eisai) was planning to submit the new drug approval for Aducanumab for treatment of early Alzheimer’s disease.

“Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer’s disease (AD). The Phase 3 EMERGE Study met its primary endpoint showing a significant reduction in clinical decline, and Biogen believes that results from a subset of patients in the Phase 3 ENGAGE Study who received sufficient exposure to high dose aducanumab support the findings from EMERGE. Patients who received aducanumab experienced significant benefits on measures of cognition and function such as memory, orientation, and language. Patients also experienced benefits on activities of daily living including conducting personal finances, performing household chores such as cleaning, shopping, and doing laundry, and independently traveling out of the home. If approved, aducanumab would become the first therapy to reduce the clinical decline of Alzheimer’s disease and would also be the first therapy to demonstrate that removing amyloid beta resulted in better clinical outcomes.
The decision to file is based on a new analysis, conducted by Biogen in consultation with the FDA, of a larger dataset from the Phase 3 clinical studies that were discontinued in March 2019 following a futility analysis….”

Early this year, the same phase 3 EMERGE and ENGAGE studies were terminated earlier for futility based on the suggestion by data monitoring committee “BIOGEN AND EISAI TO DISCONTINUE PHASE 3 ENGAGE AND EMERGE TRIALS OF ADUCANUMAB IN ALZHEIMER’S DISEASE”. The futility analyses indicated that primary efficacy endpoints would unlikely be met if the studies continued to their completion.  

• In shocking reversal, Biogen to submit experimental Alzheimer’s drug for approval
• Biogen resurrects aducanumab, arguing expanded data set supports FDA filing in Alzheimer's 
• Biogen’s good news on aducanumab could ‘open the floodgates’ for Alzheimer’s drugs
• Aducanumab: the beginning of the end of Alzheimer’s disease? 

 Both of the GV-971 approval and Biogen’s planned submission of aducanumab for approval benefit from the overall environment in the field of drug development for Alzheimer’s diseases. With so many failed trials and not a single new drug approval in the last 17 years, the pressures are on the regulatory authorities. We see that the US FDA has been willing to work with the sponsors to find a way to bring a new drug to millions of AD patients. This can be exemplified by the release of the guidance “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry”

Traditionally, an Alzheimer drug approval will require positive results from two phase 3 studies and each phase 3 study can demonstrate the co-primary efficacy endpoints: the AD Assessment Scale-cognitive (ADAS-cog) and one of these followings: activities of daily living global severity, or global change ratings. GV-971’s approval was based on a single pivotal clinical trial.

GV-971’s approval in China has the politics factor there. It is approved at a time when China needs to demonstrate it can develop the new, home-grown drug for deadly diseases and at a time when no other Alzheimer drugs have been successful in the last 17 years.

China Alzheimer's Approval Raises Hope But Also Questions
"While the approval in China of a novel algae-derived drug for Alzheimer's appears to be a breakthrough, it has also left some wondering about long-term efficacy and the reasons for the apparent rush to grant the clearance ahead of a major pending filing for the disease in the US."

If Biogen’s aducanumab can get FDA’s nods, politics will play a role. FDA verdict on Biogen’s Alzheimer’s drug likely to be a ‘political decision,’ analyst says

This is not the first time that politics play a role in the drug approval. Some of the examples are listed below:

• The Social Impact Of AIDS In The United States
• The first drug approved by FDA for treating Duchenne Muscular Dystrophy (DMD) - who win, who loses?
• Flibanserin: A controversial drug for female hypoactive sexual desire disorder
• How Big Pharma Used Feminism To Get The “Female Viagra” Approved