Hermona Soreq, PhD, discusses the complexities of aducanumab’s FDA approval, her initial reaction to the news, and whether it might be greenlit by other country’s regulators.
The highly anticipated decision from the FDA to approve aducanumab (Aduhelm; Biogen), the first disease-modifying therapy (DMT) for the treatment of Alzheimer disease (AD) since 2003, was met with as much controversy as the medical community expected. The therapy was approved under the accelerated approval pathway, which will require Biogen to conduct post-approval phase 4 studies to confirm the benefit of the drug.
On one side, clinicians treating AD have longed for a drug like aducanumab, which is the first therapy directed at an underlying pathophysiology of AD, in this case, the presence of amyloid-beta plaques in the brain. On the other side, many felt the data submitted in the final new drug application did not warrant an approval and that additional phase 3 studies were necessary to clear up the inconsistent results.
The impact of aducanumab and its effect on the patient community, the FDA decision process, and other agents within the pipeline cannot go understated. Hermona Soreq, PhD, professor of Molecular Neuroscience, Edmond and Lily Safra Center for Brain Sciences, sat down with NeurologyLive to discuss the approval from an international perspective. She provided insight on how other regulatory agencies may perceive the drug, who may be eligible for its use, and whether the controversy surrounding aducanumab is justified.
Hermona Soreq, PhD: I was surprised. I was present when the company announced the initial failure of their clinical trials and declared that they planned to re-analyze their findings and discover which subgroup of patients did respond positively to this treatment; and this is precisely what happened. It is a great step forward after 23 years of no development in this field, but it was surprising nevertheless.
It was mixed. It is well known that the great majority of tested therapeutics fail clinical trials, and that a previous attempt to immunize against amyloid-beta precipitates led to lethal brain edema and had to be terminated; but meanwhile, the Iceland study showed that inherited avoidance of amyloid precipitates thanks to a single replacement of 1 amino acid residue in this protein protects carriers of this mutation from Alzheimer’s disease. The Biogen approach was handled much more carefully than previous efforts and involved massive brain mapping tests in addition to the cognitive and blood tests. There was hope but also a careful watch for problems.
Do you believe aducanumab will be approved by other regulatory agencies around the world?
I’m not sure. I suspect that such authorities will wait to learn the next steps in the US before making the decisions to invest heavily in the equipment and methodologies required to approve this new costly treatment for a significant section of their communities. That being said, most of the Western world countries have approved treating macular degeneration by monthly intraocular injections of a biological agent with the aim to slow down the degenerative process for an annual cost of $6000, similar to the predicted one in the current case, once the brain mapping equipment will be established.
Who will be eligible to be treated with this agent? Are there difficulties in deciding which patients—early or advanced—should be treated?
This is the million-dollar question, of course. At present, the Biogen definition is ‘early,’ based on their combined brain and blood tests accompanied by psychological assessment. But this definition will have to be officially approved to enable the corresponding Health authorities involved to make compelling financial decisions. My own expectation is that this step by itself will be rather difficult, since much of the current tests (eg, the Mini-Mental State Examination) may have been developed for specific social communities and will need to be readapted for making such decisions.
There are [challenges in identifying these groups of patients]. I had an aunt who was a Professor of Chemistry and developed dementia. Her daughter, a professor of pharmacology herself, took her to a specialist, who asked my late aunt: “How old are you?” She answered, “I was born in 1916.” The interviewer asked again, “How old are you?” And the answer was, “young man, you seem to be rather intelligent, why don’t you calculate it yourself?” In other words, defining dementia in different individuals may be challenging. Advanced disease is easier to identify, but our current issue is how to define ‘early’ patients and make the decision that they merit this treatment.
The financial benefits for Biogen are huge, as is reflected already in the company’s value. Their prediction is of $10 to $15 billion in the US alone, and I keep receiving queries from Israeli family members of patients who inquire how can they get treated. Similar pressures are undoubtedly occurring elsewhere. In comparison, Teva flourished thanks to 1 innovative drug alone, which did not offer a cure but promised slower deterioration of patients.
I can see the reasons for that, yes; it is not a magic bullet offering cure, but rather a modest disease-slowing agent whose precise value needs further tests to be correctly estimated. Therefore, I find the FDA request of additional tests absolutely necessary.
That depends on the patients’ response to this new treatment and the accompanying adverse effects, of course. At present, several patients presented brain edema, but not a lethal one, unlike previous antiamyloid antibodies that were tried earlier but were removed from tests due to their lethal impact. Notably, anticholinesterase medications are the only currently available for treatment; and they do very little indeed. In France, the government stopped covering the expenses involved in their use due to the very small benefit they offer; in Israel, the dose was cut by half for women patients to limit the adverse effects; and that treatment as well is recommended for 1-2 years of use only, although it is administered to more advanced patients than the current one. Again, the currently requested additional clinical trial should be pivotal for defining who should be eligible for this treatment and based on what criteria should such treatment be stopped.
Transcript was edited for clarity.