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Aducanumab approval highlights value of brain disease biomarkers – STAT

People living with Alzheimer’s dementia — the forgetfulness, the confusion, and the ultimate erasure of identity — and their families pushed hard for the Food and Drug Administration to approve aducanumab, Biogen’s drug for it. Clinicians and scientists working on Alzheimer’s were split in their opinions on its clinical benefit. The FDA’s own expert panel advised against it.

In the statement accompanying its ruling, the FDA laid out its decision to approve aducanumab based on the reduction of amyloid protein — a hallmark of Alzheimer’s disease — seen in PET scans of the brain, the biomarker used to assess effectiveness. This change was seen across both Biogen Phase 3 trials, though the high dosage resulted in less cognitive decline over time in only one of them.

Additional clinical information will be required for full approval: The FDA is requiring Biogen to conduct a post-approval trial to verify the anticipated clinical benefit. The field will wait those results with great anticipation to see what happens next.

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Biomarkers — objective measures of disease like imaging and blood tests — have long been recognized as the critically necessary and often absent linchpin for drug studies of degenerative brain disorders. The problem is that these disorders can take a long time to develop and progress slowly, so without biomarkers it may take years to see clinical results. Biomarkers provide a window into the onset of disease, its progression, and the response to therapy. They make possible rapid and efficient assessment of drug effect, which is no minor issue in the astronomically expensive realm of clinical research.

In Biogen’s trials, biomarker data demonstrated that amyloid accumulation in the brains of Alzheimer’s patients was dramatically reduced as the dosage and duration of aducanumab treatment increased. Several other Alzheimer’s drugs have shown similar decreases in brain amyloid, suggesting that these may also be candidates some day for drug approval.

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Another piece of biomarker data, in some ways the most convincing to me, was a small substudy in the Biogen trials that showed an important change in tau, another Alzheimer’s-related protein, in the group receiving aducanumab.

Larger studies already are using PET imaging to assess tau as a fundamental outcome measure. A recent study of Eli Lilly’s experimental anti-amyloid drug, donanemab, was the first to enroll participants based on the accumulation of tau across key brain regions. In a recent presentation at an international meeting, Lilly investigators reported that baseline tau levels may influence disease progression.

Aducanumab’s clinical development and the FDA’s decision about it have already changed how research is done to treat Alzheimer’s and will continue to change it. It also provides a clear path for the development of therapies for a host of other degenerative brain diseases, including the one I study, Parkinson’s disease. The scientific and regulatory conversation leading up to this approval will have implications well beyond this single drug.

Aducanumab’s approval rests substantially on 15 years of study and validation of Alzheimer’s imaging biomarkers by an academic, industry, and National Institutes of Health collaboration called the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than 1,000 volunteers across a spectrum of cognitive ability — normal function, mild impairment, and Alzheimer’s dementia — have contributed data and samples toward better diagnostics and disease tracking. ADNI is now using imaging and newly developed blood biomarkers to go one step further: identify people at risk for Alzheimer’s before symptoms arise in order to test drugs that might prevent the disease altogether.

For patients, families, and those worried about their risk of developing a brain disease, it’s essential to recognize that projects like ADNI are entirely dependent on the participation of everyday people in these observational studies. We can pull together the world’s most elite teams of scientists, raise hundreds of millions in funding, and establish a global scientific infrastructure, but without study participants it’s all for naught.

For those in Parkinson’s research, the aducanumab story should redouble our commitment to develop and test biomarkers for Parkinson’s that will provide a clear understanding of the biology of this disease. This is the only way to efficiently test whether drugs slow the disease process and ultimately slow Parkinson’s-related disability. Researchers need to work with pharmaceutical teams to give them these tools to ensure that their studies will meet every standard that’s required, so when encouraging data emerge, they can move forward effectively.

I’m leading a study, the Parkinson’s Progression Markers Initiative, designed to identify imaging, genetic, biochemical, and digital biomarkers in people at all stages of the disease, including those who don’t have it but are known to be at increased risk for it. (Known risk factors include, but aren’t limited to, genetics, family history, and diagnosis with depression or REM sleep behavior disorder.) This project, funded by the Michael J. Fox Foundation, is a collaboration of academic, industry, and nonprofit teams that builds on the ADNI. Underway for 10 years, the Parkinson’s initiative is methodically compiling — and sharing with researchers in real time — a large, reliable, well-characterized, and highly standardized dataset to generate and validate biomarkers.

Like the Alzheimer’s initiative, the Parkinson’s Progression Markers Initiative relies on thousands of volunteers raising their hands to help expand the frontiers of disease biology understanding — knowledge the biopharma industry can ingest and use in drug trials to improve the odds of unambiguous outcomes. PPMI recently expanded to grow its research population to include people newly diagnosed with Parkinson’s as well as those who may be at risk for it. In addition to conducting comprehensive clinical assessments of some groups of participant, the initiative also include a robust online longitudinal study that invites anyone interested to enroll and contribute data online. My colleagues and I especially seek men over age 60 and people with close relatives with Parkinson’s disease to participate.

I believe that the best way to put the approval of aducanumab into perspective is to see it as just the beginning of a pipeline of therapies that target the underlying biology of brain disease. This drug won’t cure Alzheimer’s, but it may prove helpful to alleviate suffering for many. Either way, it is giving us a road map to a therapeutic future of much more rational, targeted, and effective treatments for devastating brain disorders.

Ken Marek is a neurologist, distinguished scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn., a scientific adviser for the Michael J. Fox Foundation for Parkinson’s Research, and principal investigator of the Parkinson’s Progression Markers Initiative. He consults for several pharmaceutical and biotech companies but has not received any payments from Biogen, though the company has provided some funding for the Parkinson’s Progression Markers Initiative.

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