UPDATED: Panel of neuroscience experts lays out the complications with using Biogen's new Alzheimer's drug
Treatment of early Alzheimer’s patients with Biogen’s new drug Aduhelm should closely resemble how the drug was studied in its pivotal clinical trials, according to new recommendations from a panel of neuroscience experts led by UNLV’s Jeffrey Cummings.
“Those considering aducanumab therapy should understand that the expected benefit is slowing of cognitive and functional decline; improvement of the current clinical state is not anticipated,” they wrote Tuesday in The Journal of Prevention of Alzheimer’s Disease, noting that some of their recommendations are more specific or more restrictive than the information provided in the FDA’s prescribing information.
Cummings has received more than $45,000 in payments from Biogen since 2014, according to Open Payments data. Second author Paul Aisen of the Alzheimer’s Treatment Research Institute at the University of Southern California, who’s also editor in chief of the Journal of Prevention of Alzheimer’s Disease, also received more than $38,000 in payments from Biogen in 2014. Third author Alireza Atri of the Banner Sun Health Research Institute took more than $32,000 in payments from Biogen since 2014.
An academic in neuroscience who asked to remain anonymous told Endpoints News that these recommendations are essentially an extension of Biogen’s marketing arm.
One of the biggest issues with aducanumab is that it substantially increases the rate of amyloid-related imaging abnormalities, also known as ARIA, compared to rates observed in natural history studies or trial placebo groups.
And while ARIA only led to about 6% of patients on aducanumab stopping their involvement short in the trials, compared to 0.6% of patients on placebo, ARIA (ARIA-E and ARIA-H) occurred in about 35% of patients on the high dose of aducanumab compared to about 3% of those in the placebo group, the panelists note.
“If patients with ARIA (ARIA-E or ARIA-H) have symptoms, treatment should be suspended, and a clinical assessment and neurological examination performed. MRI should be repeated in 1 month; if the ARIA-E has resolved or the ARIA-H is stabilized, treatment can be resumed. If ARIA-E has not resolved and ARIA-H is worsening, treatment is withheld, and monthly MRIs obtained until treatment can be re-initiated or a decision is made to terminate treatment … Aducanumab should not be re-initiated in patients with severe symptomatic ARIA (e.g., seizure, stroke-like syndromes),” they wrote.
But ARIA-E was most commonly observed in participants who were APOE-4 gene carriers (43%) and least often in those without the APOE-4 gene (20.3%).
While the FDA-approved prescribing information for using aducanumab do not require APOE genotyping, the expert panel “recommends that patients and care partners be engaged in a patient-centered discussion of the risk that an APOE-4 genotype confers for the risk of ARIA. This discussion will determine if genotype information would influence their decision to be treated with aducanumab and if they wish to pursue APOE genotyping,” particularly as genetic testing to determine the APOE genotype of the participants was required in the pivotal trials.
Aducanumab’s label, tightened by the agency a month after the accelerated approval, notes on ARIA: “Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration. If a patient experiences symptoms which could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated.”
The panel added: “Dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommends MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA.”
The panelists also noted that their guidelines were written despite the current lack of peer-reviewed publications about aducanumab’s Phase III pivotal studies, which the company recently said it expected to do. Changes in the guidelines may be required once all the data is available in the public domain, they noted.
As far as what to do if a patient misses one of his monthly doses of aducanumab, the panel notes that this conundrum has not been studied.
“The Expert Panel recommends that if a patient misses a dose, the next infusion should be administered as soon as possible at the dose administered in the previous infusion. If a patient misses three or more doses and requires continued treatment, titration should be re-initiated beginning at a dose level one step below that previously administered (e.g., if the patient was at 6 mg/kg previously, they would resume at a dose level of 3 mg/kg) with the dose increased every other month as described for treatment initiation,” they wrote.
They also noted certain patients who were excluded from Biogen’s clinical trials and might need further consideration:
“Patients with evidence of microhemorrhage on MRI or with clotting abnormalities or who were on anticoagulants were excluded from the pivotal trials. It is not known if these exclusions affected the rate of microhemorrhage associated with aducanumab therapy. The risk of severe ARIA in a person receiving anticoagulants or with a clotting disorder is sufficient to exclude them from treatment with aducanumab. Platelet anti-aggregation agents are allowable as concomitant therapy. Lumbar puncture for confirmation of amyloid status should not be performed on patients being treated with anticoagulants; the occurrence of perispinal hemorrhage and spinal cord compression are low but can occur and the risk should be avoided.”
As far as when to even start amyloid imaging, or when such imaging is appropriate, the neuroscientists point to three conditions: “a) there is a cognitive complaint and cognitive impairment has been objectively confirmed impairment; b) AD is a possible diagnosis, but the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and c) knowledge of the presence or absence of amyloid-beta pathology is expected to increase diagnostic certainty and alter management.”
The panel recommends that programs offering aducanumab and using amyloid PET to confirm the diagnosis of AD should ensure its employees are properly trained in amyloid PET interpretation, as all patients included in the pivotal trials had positive amyloid PET.
The panel also says that patients with neurological disorders, such as Parkinson’s disease, evidence of stroke or rapidly progressive dementia, should not be treated with aducanumab.
“Aducanumab has not been tested in patients with moderate or severe AD and progression into the more advanced phases of AD will prompt reassessment of treatment continuation,” they note. “The Expert Panel recommends that clinicians carefully review the evidence of benefit and the potential risk in patients who progress to moderate dementia after appropriate use of aducanumab in early AD.”
Overall, the panel explains how aducanumab requires “substantial infrastructure” to appropriately administer the drug, as well as expert clinicians skilled in recognition of early AD; amyloid PET or lumbar puncture capability; experts in amyloid PET interpretation or CSF analysis; infusion center availability; and access to MRI and experts in recognition and management of ARIA.
In an accompanying commentary, Serge Gauthier of the Department of Neurology and Neurosurgery at McGill University in Montreal, called for another placebo-controlled trial.
“Future recommendations could address the need of confirmatory data on clinical efficacy, taking advantage of the FDA requirement for another placebo-controlled study: it is an opportunity to establish if anti-amyloid therapy can be stopped once the amyloid load has been rectified, through a repeat PET amyloid scan after 12 or 18 months, followed by randomization to continuation of aducanumab, to placebo, to an anti-tau drug or a combination of the two drug class. This randomized delayed start factorial design may go a long way in influencing future therapy of AD,” he wrote.
Editor’s note: Article updated with the expert panel’s financial conflicts with Biogen.