To say that the FDA’s approval of Biogen and Eisai, Co., Ltd.’s Alzheimer’s disease treatment Aduhelm (aducanumab-avwa) on June 7, 2021, garnered an immense amount of attention would seem to be an understatement. That said, the drug has somehow gathered even more notice over the past few months due to multiple developments, with CMS most recently issuing a proposed National Coverage Determination (NCD) on Aduhelm and other monoclonal antibodies that target beta amyloid plaque that will allow Medicare coverage for the therapies but only under certain circumstances. While commercial payers often follow CMS’s lead, it remains to be seen whether that decision — plus a dramatic price cut on Aduhelm — will prompt payers that have declined to cover the therapy to change course.
There is a 30-day public comment period on the proposed NCD, which was published Jan. 11. A final decision is expected on April 11.
When the FDA approved Aduhelm, it did so via the accelerated approval pathway — and against the recommendation of an advisory committee. Accelerated approval allows a drug to come onto the market based on a surrogate endpoint — in this case, the reduction of amyloid beta plaque. The decision was immediately derided by various entities that questioned the drug’s effectiveness, as well as its price: $56,000 per year for an average patient.
Various major medical centers and multiple health plans have declined to offer or cover Aduhelm. During its third-quarter earnings call on Oct. 20, Biogen revealed that the drug had brought in $300,000 in revenue from July to September. On Dec. 17, the European Medicines Agency recommended the refusal of the drug’s marketing authorization. A few days later, Biogen and Eisai disclosed that Japan’s First Committee on New Drugs of The Pharmaceutical Affairs and Food Sanitation Council was delaying a decision on the agent and requesting additional data.
The FDA gave the companies up to nine years to complete a new randomized, controlled trial to confirm the drug’s clinical benefit. However, on Dec. 16, Biogen and Eisai said they were accelerating that timeline, with patient screening for the trial expected to start in May 2022, “with a primary clinical endpoint at 18 months after treatment initiation. Based on enrollment rates from the previous Phase 3 trials with ADUHELM, the primary completion date is expected to be approximately four years after the study begins. The trial will also include a long-term extension to collect longer-term treatment data for up to 48 months.”
Then on Dec. 20, Biogen said that it was reducing the wholesale acquisition cost of Aduhelm by half as of Jan. 1, dropping the annual cost for an average-weight patient to $28,200.
“When any manufacturer has invested a boatload of cash into developing a product, any sales, even if at break even, are good for cash flow — which any business needs to keep the lights on — and sweetening financial ratios for their stock,” observes long-time industry expert Bill Sullivan. “They also benefit from proof of concept, assuming there is ‘some’ measurable efficacy, increasing prescriber adoption. (Look at how many oncology products have nearly zero improved efficacy and are still reimbursable!)”
The drug’s initial average $56,000 price tag had been part of the reason behind Medicare’s highest increase ever of its Part B premium for 2022, unveiled Nov. 12. The standard monthly Medicare Part B premium in 2022 is $170.10, an increase of $21.60 from 2021. And the annual deductible is $233, an increase of $30. One of the reasons CMS gave for the increases was “additional contingency reserves due to the uncertainty regarding the potential use of” Aduhelm by Medicare beneficiaries. CMS acknowledged that although the NCD’s outcome was not known and that “our projection in no way implies what the coverage determination will be,” the agency must plan for “potential coverage for this high-cost Alzheimer’s drug which could, if covered, result in significantly higher expenditures for the Medicare program.”
“Medicare could see a significant financial impact with Aduhelm, given that it is estimated that 85% of patients eligible for Aduhelm are covered by Medicare,” says Dea Belazi, Pharm.D., M.P.H., president and CEO of AscellaHealth. “In fact, an analysis released by the Kaiser Family Foundation estimated that if 500,000 Medicare recipients received Aduhelm at its initial price, Aduhelm would cost the program nearly $29 billion a year, significantly more than any other medication. With the recent price reduction, this would lower the cost to nearly $15 billion, still a significant cost driver for the Medicare program.”
“There is a ‘hold harmless’ provision to ensure that a Medicare increase does not exceed the COLA [i.e., cost-of-living adjustment] increase,” observes Scott Maibor, senior Medicare expert at AffordableHealthInsurance.com. “However, tying an increase to the anticipated cost of a drug is unusual and sets a dangerous precedent as new costly drugs are developed. How will this impact the costs of supplement plans that cover the 20% (Part B coinsurance) of these costly treatments?”
Becerra: Reassess Part B Premium
On Jan. 10, just one day before the release of the proposed NCD, HHS Secretary Xavier Becerra instructed CMS “to reassess the recommendation for the 2022 Medicare Part B premium, given the dramatic price change of the Alzheimer’s drug, Aduhelm. With the 50% price drop of Aduhelm on January 1, there is a compelling basis for CMS to reexamine the previous recommendation.”
According to STAT, “it is highly unusual for Medicare to make changes to premiums after a plan year has begun, multiple Medicare policy experts said. Normally, if Medicare has extra premium funds, officials factor that into the next year’s premium calculations.”
On July 12, CMS said it would open an NCD analysis on Aduhelm and other similar drugs for Alzheimer’s. NCDs determine whether coverage of items or services meets Medicare’s standard that they are “reasonable and necessary for the diagnosis or treatment of illness or injury.”
During a Jan. 7 webinar, Evercore ISI analyst Eric Musonza explained that CMS had four broad options:
(1) Medicare coverage,
(2) Coverage with evidence development (CED),
(3) Noncoverage, or
(4) Deference to the Medicare Administrative Contractors (MACs).
However, many layers within those options exist, noted Evercore ISI analyst Umer Raffat. CED, for example, could be limited to only certain trials or could include an observational registry.
Under an NCD with CED, data would be generated, so that decision would be reconsidered down the road, he pointed out during the webinar. This approach also could result in head-to-head clinical trials of monoclonal antibodies that target beta amyloid plaque.
Coverage with CED is the option that CMS proposed on Jan. 11. Specifically, the drugs will be covered for participants in randomized controlled trials that CMS approves and that are supported by the National Institutes of Health (NIH). In addition, the trials can be conducted in a hospital-based outpatient setting only. Participants must have “clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and evidence of amyloid pathology consistent with AD.”
That coverage approach could change, though. Musonza noted that with the NCD for chimeric antigen receptor T-cell (CAR-T) therapies, CMS made a preliminary decision for a CED only in clinical studies but eventually “backed off” this approach in a delayed final decision and “covered the therapies entirely.” That final decision was made two years after the first CAR-T agent — Novartis Pharmaceuticals Corp.’s Kymriah (tisagenlecleucel) — was approved. CMS could very well delay the Aduhelm April final decision to the fall, when more data will be available, he said.
However, Belazi points out that the proposed NCD “was developed and drafted based upon the available efficacy and safety data from the clinical trials and expert opinions. Unless new efficacy and safety information becomes available or is submitted for review, the proposed NCD will likely remain substantially the same.” Biogen has stated that it will make a formal response to the NCD during the comment period. “It will be interesting to review if Biogen provides any additional substantial objective clinical and safety information to support the use of Aduhelm outside of the proposed parameters,” he says. “Due to the lack of consensus on the product efficacy and questionable safety profile, it is unlikely that new information will be provided to substantially modify the NCD.”
NCD Addresses PET Scan NCD Concerns
Raffat also pointed out that “there is a separate NCD [220.6.20] which is also critical to Aduhelm” around head imaging. PET imaging is used to evaluate amyloid beta plaque levels in the brain. However, “amyloid PET diagnostics are not covered by CMS,” he noted. An NCD “limits beta amyloid PET to certain clinical trials that are approved by CMS.” In September 2020, Roche Group member Genentech, Inc. — which is investigating anti-amyloid beta antibody gantenerumab — submitted a request for CMS to reconsider its “significant coverage restrictions on amyloid PET imaging that limit beneficiary access to this important diagnostic tool, which can help to identify appropriate patients for anti-beta amyloid therapy.”
The proposed NCD states that “for any CMS approved trials, or trials supported by the NIH, that include a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20), and one beta amyloid PET scan will be covered per patient, if the patient did not previously receive a beta amyloid PET scan.”
Ultimately, said CMS, it made the NCD with CED decision “because we strongly support rigorous clinical trials that will answer whether this treatment will benefit Medicare beneficiaries with AD. None of the trials completed as of the publication of this NCA [i.e., National Coverage Analysis] has convincingly demonstrated that use of antiamyloid mAbs [i.e., monoclonal antibodies] result in a meaningful improvement in health outcomes for AD patients. More trials are needed and the results of these trials will assist in providing answers to CMS, as well as to clinicians, patients, and caregivers, regarding the clinical benefits and harms of this treatment.”
In a statement released shortly after the proposed NCD was published, Biogen maintained that the decision “denies nearly all Medicare beneficiaries from accessing” Aduhelm. “It is imperative to change this draft decision to be aligned with reimbursement for other therapies for progressive diseases, where patients have immediate and equal access to medicines approved by the FDA,” said the company, which argued that the proposed randomized controlled trial likely would take more than a year to start enrolling patients.
In addition to asserting that the proposal would duplicate “robust efficacy and safety data collection efforts” that Biogen already has in place, the company also stated that the NCD with CED “could severely limit patient access for underserved patients. Any access would be wholly inequitable. While the draft CED requires a randomized controlled trial to be reflective of the national population, we believe that, in the real-world, such a CED would restrict coverage to Medicare beneficiaries who live close to, or can travel to, participating medical centers, which are typically limited to academic centers or major healthcare systems — exacerbating health inequity in dementia care. Medicare beneficiaries without access to these sites, even if they meet clinical trial criteria, would not have access to the treatment.”
Ira Studin, principal at Stellar Managed Care Consulting, LLC, agrees that the proposed NCD will result in “extremely limited coverage” of pipeline anti-myeloid monoclonal antibodies. However, “it should significantly shorten the timeline for adequately testing the amyloid hypothesis and producing a scientific consensus on the clinical significance of the benefit this class of drug confers.”
“The proposed NCD for Aduhelm and future anti-amyloid products will significantly limit the use of these products,” asserts Belazi. “The limitation of coverage of Aduhelm to having patients actively enrolled in a clinical trial will be a significant limitation for physician prescribing and patient impact. The requirements for enrollment in a clinical trial are much more significant and rigorous than typical commercial use and will limit the available patient population. We would not expect to see any significant uptick in utilization of Aduhelm, even with the recent price reduction due to this proposed NCD.”
While the NCD applies only to Medicare coverage, commercial payers often follow CMS’s lead when it comes to drug coverage and utilization management. Many large health systems and payers “were waiting to see what CMS was going to propose and what the final determination will entail,” says Renee Rayburg, R.Ph., vice president of specialty clinical consulting at Pharmaceutical Strategies Group (PSG), an EPIC company. “The proposed NCD does not appear to give commercial payers any additional evidence to support changing course and covering this drug at this time. I do not expect payers that decided not to cover Aduhelm to change anything right now as a result of this draft NCD.”
Commercial payers will use the proposed NCD “as one of their data points for creating reimbursement policies for Aduhelm,” Belazi states. “While the NCD will not be the sole determinant, the outlined criteria and requirements will likely be used in the development of commercial payer strategies. It is likely that commercial payers will model their reimbursement policies on the NCD and available clinical and safety data after the final NCD is published.”
“In theory,” says Studin, the NCD “effectively removes Aduhelm from having any near-term budget impact” on commercial payers. But “in practice, [it will have] no budget impact because commercial payers had virtually no utilization to speak of.”
So what are payers looking for to provide coverage of the drug?
Studin tells AIS Health, a division of MMIT, that it’s “highly unlikely” that the lower price will incentivize insurers to cover Aduhelm. “If clinical data do not justify use for a product at $56,000, they won’t justify use at $28,000. On the commercial side, health plans have the latitude to adopt ‘tighter than label’ coverage policy, so it’s entirely reasonable to expect precise inclusion/exclusion criteria and extremely specific trial factors to continue to limit coverage.” Until a final NCD is issued, “regional MACs also have the latitude to determine coverage based on trial data and appropriate use, and, here too, the drop in price is highly unlikely to change existing coverage policies.”
Belazi agrees. “The lower price will not incentivize payers to expand their current coverage policies for Aduhelm. Payers’ decisions on coverage are focused on the available safety, efficacy and comparative efficacy of new products to existing standards of care. Aduhelm has not provided any additional information in these areas and still has outstanding issues of the lack of demonstrated clinical benefit to patients, the ability to correlate amyloid plaque to patient symptoms and outcomes and regression or slowing of disease progression. Additional safety issues of brain swelling and bleeding need to be more fully evaluated to ensure that Aduhelm will not cause any additional patient issues and further potential patient deaths from Aduhelm. While a lower Aduhelm price is welcomed, the safety and clinical efficacy must be fully demonstrated prior to any further coverage modifications or enhancements.”
The lower price “may help” with getting insurers to cover the drug, “but my understanding is that payers want to see more clear evidence of benefit of the drug before they may become more comfortable with covering the drug,” says Rayburg.
Rayburg and Belazi both point out that Aduhelm’s lower price is still more than the $3,000 to $8,400 price per year recommended by the Institute for Clinical and Economic Review (ICER) in an August report.
Asked what it will take for insurers to cover Aduhelm, Studin replies, “hypothetically, peer-reviewed real-world data justifying Aduhelm use for specific types of mild AD patients. Realistically, though, it’s hard to imagine any new factor that could materially change Aduhelm’s current status. For Aduhelm, more likely than not, the noncoverage train has left the station.”
Other sources, however, are more cautiously optimistic that the drug could gain additional coverage, provided that Biogen and Eisai can offer evidence that Aduhelm works. “Results-/outcomes-based contracting could give life to this product,” asserts Sullivan. “It is hard enough to measure ‘results’ for rare (small population) therapies. Alzheimer’s is a big population therapy, so it makes it more challenging to measure outcomes to determine if the payer will get a refund from the manufacturer.”
When Aduhelm was approved, Biogen said it was working with payers to prepare them for the product’s launch. In particular, it cited Cigna Corp. and said the companies “intend to enter into a value-based contract to ensure that there is a streamlined path to access treatment for patients consistent with the population in which ADUHELM was studied.” Biogen did not respond to questions from AIS Health on whether the company has entered into value-based contracts with any other PBMs, health plans or employers and what metrics any such deals are tracking.
Insurers need “more confidence the drug will benefit patients for whom the drug is administered,” says Rayburg. “I think this is a real concern, as this disease does not lend itself to easy ways to measure evidence of benefit. There definitely is a need for effective treatments when it comes to such a devastating disease, but insurers need to feel their investment is resulting in benefit to the patients.”
More specifically, says Belazi, in addition to demonstrating Aduhelm’s safety and bringing its price in line with ICER’s recommendation, “Biogen needs to address and provide information that addresses the open questions on the product’s demonstrated efficacy data, including:
• “Clinical study information that supersedes their earlier clinical trials in which one trial showed no effect and the other showed non-clinically meaningful results;
• “Work with the FDA and Alzheimer’s experts to identify clinically meaningful endpoints for their clinical trials that support the drug’s effectiveness in this patient population and not use surrogate markers that are not universally accepted as clinical endpoints;
• “Utilize specific clinical markers for reduction or slowing of disease or disease progression in their trial population and demonstrate patient improvement while on drug therapy;” and
• “With other Alzheimer’s disease products in the pipeline and three receiving breakthrough therapy designation from the FDA, consider head-to-head trials to demonstrate the efficacy of Aduhelm as compared to other impending agents.”
Those pipeline products could add additional pressure on Biogen, asserts Belazi. He points out that there are eight more amyloid beta receptor inhibitor agents in Phase III trials; the three that the FDA has given breakthrough therapy designation to are Eli Lilly and Co.’s donanemab, Biogen and Eisai’s lecanemab and gantenerumab.
“These three competing anti-beta amyloid monoclonal antibodies could be approved by the end of 2023, adding in additional therapy competition for Aduhelm,” he says. “Each of these products will potentially offer enhancements from either a clinical, targeted therapy location or administration perspectives and compete directly with Aduhelm.”
That said, the proposed NCD will directly impact these potential competitors, which are seeking FDA approval based on one similar to that of Aduhelm’s clinical pathway, points out Belazi. “The clinical trials for these agents will need to demonstrate clinical efficacy endpoints that directly demonstrate the product effectiveness in direct measures that limit Alzheimer’s disease progression, objectively measure symptom reduction and/or quantify quality of life measurements,” he says, adding that the trials, including their endpoints and safety measures, “will need to be peer-reviewed to validate their potential and proposed uses.”
“What’s yet to be determined are the outcomes/results of the clinical trials for the other drugs in the pipeline,” points out Rayburg. “If the data is more conclusive of evidence of benefit, will that make any difference in coverage? That’s the burning question.”
According to Studin, the final NCD might not necessarily remain the same for pipeline drugs such as those from Eli Lilly and Roche. “It is plausible either or both could be approved under the accelerated approval program with three preconditions: (1) the Lilly and/or Roche products have strong data and none of the outlier dynamics Biogen had in its trial program; (2) they present post-marketing plans that demonstrate their intent to produce results as expeditiously as possible; and (3) they signal pricing that is acutely sensitive to budget impact.”
Ultimately, says Rayburg, “it is very hard to say” whether the final NCD will remain the same, “as the open comment period allows comments from the company, physicians and patients so all viewpoints can be taken into account. However, CMS’s proposed NCD attempts to address the clinical safety and benefit profile of this controversial drug. There is an unmet need for treatment of this awful progressive disease, but, more importantly, there is a need for a treatment to be both safe and effective as well as affordable. CMS is attempting to better address this with their proposed NCD.”
Contact Belazi via Caroline Chambers at firstname.lastname@example.org, Raffat at email@example.com, Rayburg through Samantha Rideout at SRideout@psgconsults.com,
Studin at firstname.lastname@example.org and Sullivan at email@example.com.