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FDA investigates: Aduhelm™ – Expensive Alzheimers drug with no effect?

The drug treatment of Alzheimers dementia is still in its infancy despite intensive research and continues to focus on the symptoms and not on their cause. When Biogen approved the medicinal product Aduhelm ™ as an Alzheimers drug, expectations were high. The amazing thing about the drug: it should not only stop the progression of the disease, but also fight its causes. That would make it the first of its kind.

In the States, drugs are approved only by the FDA, (Food and Drug Administration), if their effect has been proven by studies. Now, however, it turned out that not only the study analysis of Biogen is highly controversial, but also the approval by the FDA itself. The studies did not reveal any promising results. Nevertheless, the drug was provisionally approved. The FDA is now investigating several of its members, as there should have been consultation and close cooperation between them and Biogen.

Researchers and doctors worry about the new Alzheimers drug

In June 2021, the American regulatory authority FDA granted Biogen’s drug Aduhelm™ a preliminary marketing approval. Aduhelm™ is not only the first new drug against Alzheimers in almost 20 years, but it is also the first drug ever to combat one of the causes of this disease.

However, what should be a reason for joy worries researchers and doctors worldwide, because the decision of the FDA is by no means as clear as one might assume.

How is the drug supposed to work?

Aduhelm™ contains an antibody, (aducanumab), as active ingredient, which is injected intravenously every four weeks. This achieves passive immunization, which activates the body’s own defense system and is directed against the typical protein deposits of Alzheimers. In professional circles, however, there is still disagreement about the role of these protein deposits in the course of the disease.

The improvement of the health status could not be proven

Aduhelm™ was examined in two phase-3 clinical studies. The aim of the two studies was to show that the treatment with Aduhelm™ prevents or at least slows down the progression of Alzheimers dementia. The progression of the disease was assessed by means of a points system that measures the cognitive abilities of the study participants.

Before the completion of the studies, an interim analysis was carried out which showed that only one of the two studies could possibly achieve the objective. Due to these inconsistent and disappointing results, both studies were discontinued.

There are still no publications in which the study results have been comprehensively assessed by experts. Thus, independent researchers, who would like to assess the quality of the study results, are limited to the data selected by Biogen.

Study data were subsequently made appropriate for approval

The way in which Biogen received the approval from the FDA, despite the initially negative or contradicting results, is due to an unusual approach.

Usually, before the beginning of the studies, the framework conditions are defined as to how and which data will be collected. Furthermore, it is specified how the data should then be evaluated. This is to avoid analyzing the study data until the desired result is obtained at the conclusion.

However, in the Aduhelm™ case, Biogen decided to carry out a so-called post-hoc analysis in order to better understand the different results of the two studies. However, subsequent studies do not have the same informative value as those that were determined before the start of the studies. Therefore, they usually serve only to optimize the approach for future studies.

In the case of Aduhelm™, Biogen decided to take an unusual step: The results acquired subsequently were and will be used to apply for approval for Aduhelm™.

While they originally measured the progression of the disease in the patient, using the aforementioned point system, a different parameter was selected in the subsequent studies: the protein deposits. The extent to which a reduction in protein deposits can reduce the clinical symptoms that are relevant for those affected is highly controversial. Moreover, such a change in methodology does not correspond to the general consensus on the ethically correct conduct of clinical studies.

Conclusion: Since the original design of the study did not lead to the desired result, Biogen focused afterwards on reducing the protein deposits. The pure reduction of protein deposits does not necessarily lead to an improvement in the patients’ symptoms. The removal of these deposits is crucial. You can find out more about this in Part 5 “Research on waste disposal in the brain” in our video series with Alzheimers researcher Prof. Pahnke.

Members of the Advisory Committee protest against the approval

An advisory committee consisting of eleven experts involved in the approval process, voted unanimously against the approval of Aduhelm™. An evaluation of the study data by internal statisticians of the FDA has also shown that the effectiveness of the drug has not yet been proven.

Despite these critical voices, the FDA decided in the end to grant Aduhelm™ preliminary marketing approval. Behind the limitation “provisional” is the obligation to conduct a clinical phase-4 study within nine years that confirms the effectiveness, (or in this case even proves it?). Following the FDA’s decision, several members of the commission have tendered their resignations. Among them, the renowned medicine professor Dr. Aaron Kesselheim, who teaches at Harvard Medical School. Kesselheim explained to the New York Times:

Anführungszeichen

It could be the worst approval decision the FDA has ever made

– Kesselheim

There is simply no reliable evidence that the drug works. However, that is not all: Shortly after the approval, a report was published showing that there was an unusually close collaboration and strategic meetings between Biogen and the FDA, even at a time when Aduhelm™ was presumed dead. Acting FDA Commissioner, Janet Woodcock, requested afterwards an independent investigation into these allegations. However, also Woodcock herself is heavily criticized, as it is unclear how much she knew about the collaboration.

A drug worth US$56.000 with significant risks

While the original approval recommended Aduhelm™ for all Alzheimers patients, shortly later it was specified that the treatment should start at the early stages of the cognitive impairment. For many patients, the drug may anyway no longer be an option.

As described, however, the effectiveness is highly controversial also for those patients, who could receive treatment.

However, Aduhelm™ is immediately available in the US and it is possibly prescribed. This incurs high costs for patients and their insurance companies. Expensive diagnostic tests must be first carried out to find out whether a patient belongs to the target group. Thereafter, the treatment costs an average of US$ 56,000 per year. Since the treatment should start at an early stage and must be continued constantly to have an effect, it can be easily understood that a treatment with Aduhelm™ is associated with astronomical costs. This money may then be unavailable for other things.

Not only is it unclear whether and how the affected persons benefit from the treatment, they also run significant health risks if, for example, side effects such as cerebral edema appear. Thus, they get a “questionable” drug for a lot of money, the effectiveness of which is highly controversial among experts and has not really been proven in studies.

Approval of the questionable drug also in Europe?

It will be interesting to see whether the European Medicines Agency (EMA) can also be convinced by the poor availability of data. A decision on Aduhelm™ can be possibly expected this year.

Yet the hope remains that the research regarding the treatment of Alzheimers will not be negatively affected by the approval of Aduhelm™. All resources are still needed to find a highly effective treatment from which all patients can benefit.

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