[Event Summary] Aducanumab approval and its impacts on CNS drugs
Author: Daniel Luo Editor: Huiwen Han
On June 7th, the FDA announced the accelerated approval of Biogen's aducanumab, the first novel disease-modifying therapy for Alzheimer's disease (AD) since 2003. In this event on June 19th, we discussed the circuitous journey of aducanumab's approval and why CNS drugs are notoriously difficult to gain approval.
For more information, see event annoucement: Aducanumab approval：FDA's biggest mistake or CNS drugs' new era?
Contents of this meeting record
Summary of guest speaker presentations
Summary of guided free discussion
Summary of Q&A session
Guest speaker presentation
Background
The pathway that was utilized was for accelerated approval was based on the ability of the drug to reduce amyloid on amyloid imaging, and with the prediction that it would have clinical benefit.
However, the concept that amyloid reduction would be expected to have a cognitive benefit has been challenged since 2010 - Pfizer's bapineuzumab was able to deplete amyloid oligomers yet did not lead to reduction in cognitive decline - a fact that was known since Rinne and colleague's publication in Lancet Neurology in 2010.
Furthermore, previous trials conducted by Eli Lilly and others have also shown reduction of amyloid plaques in PET scans within 18 months, also did not lead to clinical benefits. Given these known results, it shouldn't have been surprising that reduction of amyloid on amyloid PET scans did not mean immediate clinical benefit, yet FDA made the accelerated approval based on these assumptions anyway.
"Six Main Issues with Aducanumab"
Dr. Sam Gandy
Discussed article written by Dr. Gandy
can be found at:
https://www.statnews.com/2021/06/15/6-ways-fda-approval-aduhelm-does-more-harm-than-good/
01 Pull of desperation
Patients could choose to resign from trials that might have assigned them to placebo, in favor of taking aducanumab. Patients who are currently on other trials will also choose to go on aducanumab instead of worrying about whether they have been put on placebo in these trials.
02 Elbowing aside existing treatments.
A large prospective study done in Sweden had shown that cholinesterase inhibitors such as galanthamine alone could reduce disease progression in AD patients. None of the treated patients progressed from moderate to severe stage. (see article: https://n.neurology.org/content/96/17/e2220)
03 Amyloid fibril reduction alone is no help
Amyloid fibril reduction alone is no help - oligomers are more toxic, but do not show up on PET scans, making it difficult to correlate adcuanumab's effects on these forms of beta amyloid.
04 An unpredictable trial.
The trials are unpredictable. Aducanumab was used in two major trials. In the second trial, subjects in the control arm did not show cognitive decline, making the trial uninterpretable. This had led to the advisor committee to suggest a tie-breaker trial, which Biogen is required to conduct.
05 Trials and labeling disconnect.
Disconnect between trial design and product labeling. The trial was designed with precision medicine, where patients were tested for APOE4 genotype. The results of the trial showed that APOE4+, mildly affected subjects benefitted the most from aducanumab. However, the labeling of the product does not reflect this. The labeling is for all Alzheimer's, ranging from pre symptomatic to persistent vegetative state with late stage dementia. Furthermore, high dose of aducanumab also could lead to brain bleeds; and while subjects in the trial who had 10 brain bleeds were removed from the trial, no guidance was given on the label regarding brain bleeds, making it hard for physicians to come up with best practices.
06 Cost and equity issues.
The cost of aducanumab alone is $56,000 a year, with infusion costs, this would roughly double to $100,000 that's currently not reimbursed. Furthermore, genotyping and PET scans are currently also not reimbursed, but are needed to identify patients who could benefit. These costs willcreate a greater problems with equal access and disparity in various socio-economic groups.
In summary, we should look at the science and avoid going down the wrong pathway; aducanumab was only tested to show benefits for APOE4+ patients with mild decline,and patients with amyloid beta-independent pathophysiology might not benefit from aducanumab. It is likely that many doctors will prescribe aducanumab to their patients (including Dr. Gandy himself), and the above should serve as a basis to inform best clinical practice and to help manage patient expectations.
"The Uniqueness of Aducanumab"
Dr. Sheng Feng
01
Adumanuamb was developed using a reverse translational medicine platform. In 2007, Neurimmune stroke an alliance with Biogen. Neurimmune was to conduct research to identify potential therapeutic antibodies using a "reverse translational medicine (RTM) platform, and Biogen will be responsible for the development and commercialization of all products.
02
A protocol modification was done to increase the dose of aducanumab from 6mg to 10mg after the trial has started, leading to efficacy in the subgroup that received the highest dose.
03
Aducanumab phase I trial was one of the largest ever, and reduction of beta amyloid (Figure 3, third panel) was extremely convincing. Hence after trials phase I, phase Ib, phase II were skipped to directly go to phase III.
04
Frequent communication with FDA. The level of FDA involvement had led some expert to criticize the FDA for not acting like a "judge" but more like a "participant" in the approval of this drug. Similar large trials, such as candidates for heart disease, for example, would not require such level of communication with the FDA. In fact, this level of communication is almost similar to novel therapies such as cell or gene therapy.
05
Biogen's use of real world data, such as Alzheimer's Disease Neuroimaging Initiative (ADNI) and many others, to help decision makers.
RWD enabled Biogen and other Alzheimer's disease researchers to ask questions such as:
Should Biogen design another trial incorporating ApoE?
Is ApoE still predictive in amyloid beta+ patients?
How could patient genetic sequencing inform treatment decisions and predict drug response? Why was ApoE not seen as important in Pfizers trials previously?
"Fact checking common misconceptions"
Dr. Sheng Feng
FDA requires confirmative trials to support continued approval.
Over the past weeks, conversations had focused on the claim that the FDA's approval is a big surprise - the FDA had failed to do what it was built to do. This claim is in fact not true due to the fact that the bar is often lower when approving the 1st drugin a disease where there is an urgent and tremendous unmet medical need. It had asked the sponsors for confirmative trials to support continued approval. Furthermore, COVID vaccines which received emergency use approvals.
Failure to provide confirmative trials can result in the drug being removed from the market.
Makena, a drug for preterm birth, had used accelerated approval in 2011, but after the sponsor AMAG failed to show efficacy in confirmative trials lasting 10 years, FDA took the drug off the market in 2020.
For the FDA, there are still many challenges to the accelerated approval + confirmation trial pathway, and many key decisions that could lead to serious implications. If "good, but not great," results from the confirmative trial is presented in the future, what should happen to the drug's approval?
Dr. Xianbo Zhou
The field has been going to the right direction, diversifying research on various targets in AD, including digital biomarkers (in collaboration with Bill Gates/ADDF Foundation).
It is the hope that resources spent on AD drug research will continue to be diversified, and that the approval of this drug will galvanize more research funding, not only in beta amyloid but also in other biomarkers.
Dr. Lina Wang
Aside from beta amyloid-targeting drugs, there are other drug candidates with other targets in AD, such as tau. Tau-burden correlates better to disease pathology and could predict disease severity better than amyloid beta, and naturally is a good biomarker for AD.
However, tau is an intracellular target and is therefore harder to target than beta amyloid, which is extracellular.
Neuro inflammation is another important aspect to consider on an individual patient level.
“A balanced view”
Dr. Chao Liu
Phase I study showed clear dose response on CDR-SB. In the two Phase 3 studies, although in study 301, the primary endpoint was not reached and secondary points therefore could not be tested. But formost of the dose level, the clinical endpoints (CDR-SB, MMSEandADAS-Cog) showed a correct trend, although those endpoints are weakly associated.
From a statistical perspective, if aducanumab is the same as placebo, then the probability of seeing the current data pattern is extremely low. In the advisory committee meeting, Biogen has indicated that the chanceof seeing this is less than 0.1%. In terms of whether or not the drug numerically improved the clinical endpoints (not just reducing a beta amyloid) there was some signal, and the signal was NOT weak.
Guided free discussion
01 The immediate impact onpatients (medical, social, and financial aspects).
The impact is on the public's understanding of AD particularly on ApoE4, beta amyloid imagining, etc. Everyday people might not be prepared for this level of nuanced scientific information.
However, this will hopefully bring more attention and investment dollars to this field.
More attentions should be paid to the heterogeneity of AD pathology. Hopefully more attention will be paid to other targets in AD and pathophysiologies that don't involve beta amyloid.
Future trials for new AD drugs candidates might have trouble recruiting.
02 Practice change of AD healthcare providers such as neurologists.
Since amyloid imaging is not covered by Medicare right now, it's hard to predict changes in practice, but it doesn't mean that they shouldn't be offered to the patients if they can afford it.
03 Impact on Medicare and financial burden on AD patients.
Dr. Gandy: It will depend on the resources available to the patients.
04 Impact on other experimental AD drugs.
It might be possible that Aducanumab will affect the availability of patients for other studies.
05 Basic research and VC funding on AD in the future.
Dr. Gandy: It is interesting that the most severely affected patients were not tested on.
06 The image of FDA in and outside of the US.
Dr. Gandy: The labeling from FDA is disappointing. Brain hemorrhage is a common SAE, and the trials had excluded patients on anti-coagulants due to increased risk of hemorrhage, but the labeling did not reflect this.
Chao: In terms of long-term image of FDA, it might not be so much of a concern, but for aduhelm filing in other regions, I think there would probably be communications between FDA and other agencies.
Audience questions
01 What about approval outside of US?
Dr. Sheng: When the FDA considers a drug application for approval, it does not consider the price of the drug. But China's FDA, for example, would consider it and if Biogen does not negotiate with the Chinese government, aducanumab could be hard to be approved in China.
02 How easy is it to take this IV infusion?
Dr. Gandy: You can do an IV infusion and you can do a subacute injection similar to insulin. There are 2 trials going on for this.
03 Does the approval mean all the failed small molecule beta amyloid programs could be revisited again?
Dr. Gandy: Yes, they might.
04 What are the chances of CMS not covering the drug?
Dr. Gandy: It is hard to tell at this point, but we should try to do best practicesand do APOE genotyping.
Summary
Dr. Gandy: Aducanumab will double the cost of care for AD patients. Each patient will cost on average $1M over 10 years, and with aducanumab, each patient will cost $2M. Alzheimer's is a heterogenous disease, and therefore other programs should also be continued. Changing the label and using best practices to inform reimbursement should be the way to go.
Dr.Feng: This drug is not the perfect drug but going with the mantra "don't let good be the enemy of perfect", we should make sure that the confirmative trials are run in a rigorous way. It is also necessary to fix the label (the trial is designed for ApoE4-screened, but the label is available to all AD patients).
That's all for this meeting. Thanks again to all participants for the wonderful presentations and discussions.
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