Last week’s on-time opening of a government portal for collecting real-world evidence on Alzheimer’s drugs may have surprised some. But the timely roll-out has done little to staunch criticism of a requirement that patients and their doctors need to be part of the registry to qualify for Medicare coverage.

The data-collection requirement was just one of a number of factors that analysts expect will weigh on the sales of newly arriving antibody drugs that target amyloid for treating Alzheimer’s disease and temper the drugs’ initial uptake.

The Food and Drug Administration granted traditional approval to Eisai and Biogen’s Leqembi this month in patients with mild cognitive impairment (MCI) or the mild dementia stage of Alzheimer’s disease, following a unanimous vote by outside advisors that a confirmatory study conducted by Eisai had verified Leqembi’s clinical benefit. Further FDA decisions on additional therapies in the same class are on the way. 

Leqembi demonstrated a 27% decline in early disease progression in a trial of 1,795 patients after 18 months. The FDA granted accelerated approval for Leqembi in January, allowing the manufacturers to launch the $26,500 treatment based on preliminary evidence. A similar treatment from Eli Lilly – donanemab – showed a 35% decline in a study of 1,736 patients after 18 months. 

Both therapies are considered by many to be the most promising breakthroughs seen against the memory-stealing disease in two decades. Despite encouraging signs that approval and coverage hurdles for the drugs are finally falling, though, expressions of concern about the burden of data collection have only increased. 

Hand-wringing over the portal began early this year but intensified on June 1. That’s when the Centers for Medicare and Medicaid Services reiterated plans to provide reimbursement for anti-amyloid drugs only if the patient has a physician participating in a registry and upon their full FDA approval. 

Some viewed the CMS update as a net positive, given the prospect of immediate coverage for a drug class that had been hampered by an earlier national coverage determination (NCD) limiting public coverage to patients taking part in clinical trials. However, analysts also said the registry requirement would likely add a hurdle for patients to gain and maintain coverage of these drugs.

The update “represents a big step towards reimbursement for the class, but registry requirement is suboptimal,” wrote J.P. Morgan analyst Chris Schott in an investor note at the time. 

CMS says the goal is to find out, through real-world evidence, whether this class of drugs slows cognitive decline and function for patients in broad community practice and to gather more insight into side effects associated with their use, like brain hemorrhage and edema. The agency also wants to find out if benefits and harms change over time.

Researchers may also want to suss out gender differences. According to a subgroup analysis, Leqembi slowed cognitive decline in women by 12% versus 43% in men, but the difference wasn’t found to be statistically significant. 

That data-gathering will pose “at least somewhat of a burden for patients and doctors to both enroll and then regularly provide patient data,” Schott noted. “As we have seen with REMS programs in other therapeutic areas, this will likely slow initial uptake as physicians better understand what is needed to ensure continued coverage.”

Patient groups have also derided the plan. The Alzheimer’s Association stated that making coverage conditional upon a registry is “an unnecessary and potentially harmful barrier.” The requirement “will almost inevitably make it difficult for the vast majority of patients…to access new medicines that delay the progression of this awful disease,” added Sue Peschin, president & CEO of Alliance for Aging. 

And UsAgainstAlzheimer’s called on CMS administrator Chiquita Brooks-LaSure to clarify how the website “will increase access to treatments and not create barriers to care.” The Pharmaceutical Researchers and Manufacturers of America (PhRMA) has also gone on record expressing its disappointment.

Deborah Williams, founder of consultancy Health Policy Insights, says the registry may not have become such a big bone of contention had manufacturers reassured investors. 

“If Biogen and Eisai had said, ‘Hey, we’ve got this; it’s going to be OK,’ it might have been a different outcome,” she said. “A lot of the quality metrics CMS asks for, physicians believe are very burdensome. If they can find another way of doing these registries so it’s more of a pass-through, that would be a lot better.”

Indeed, a registry’s impact is not to be underestimated. Jenifer Ehreth, principal at consultancy International Market Access, who’s done extensive work on creating databases on utilization of healthcare services, says when collecting information from Alzhemer’s patients, it’s necessary to “triangulate” the data from more than one source, such as family or caregivers, due to patient memory lapses.

Although this can be expensive, Ehreth noted, the alternative might mean the data collected is unreliable. Much of the discussion she’s heard so far about the registry, she said, has been “naïve” to expectations about the data’s accuracy. 

CMS has signaled that it’s open to use of other portals. And Schott wrote that he expects the agency will ultimately revise the NCD to allow for full Medicare Part B coverage without the need for a registry. 

“This is supported by two clearly positive phase 3 studies for Leqembi and donanemab that help substantiate anti-amyloid medications in Alzheimer’s along with a clear unmet need and broad public support,” the analyst argued.

Other challenges that could prove to be a drag on the launch of Leqembi and other anti-amyloid antibodies include both the diagnostic infrastructure, as well as the limited availability of infusion centers for receiving the bi-monthly IV drug. 

Step one to diagnosing MCI is a cognitive test, usually administered by the physician. Leqembi’s label recommends, but doesn’t require, genetic testing for ApoE4 status, which is associated with Alzheimer’s disease. 

The FDA also noted that the presence of the ApoE4 allele increases the risk of a kind of brain swelling and bleeding known as amyloid-related imaging abnormalities (ARIA), with greater risk observed in homozygotes than heterozygotes. Currently, there is no FDA-authorized test for its detection, and available ones vary in accuracy.

The physician would then sit down with the patient to determine whether to proceed to the next phase of testing, confirming the presence of beta amyloid in the brain. That’s done either through positron emission tomography (PET) imaging, cerebrospinal fluid (CSF) collection or a blood test. 

PET, which requires use of a radioactive tracer, is limited by the number of imaging centers – roughly 2,000 in the U.S. offer it. Besides being an invasive test, a spinal tap can be challenging to conduct among people of dementia age. 

To confirm amyloid’s presence, “A blood-based test is more ubiquitous,” said Masoud Toloue, CEO of testing firm Quanterix, whose Simoa pTau-181 lab assay for detecting elevated tau in blood or spinal fluid has been used in many of the clinical trials involving anti-amyloid drugs. “Ninety percent of people in the U.S. live near a blood draw center.” 

Once those results are in, the physician and patient would sit down and determine whether it makes sense to start treatment. Patients will need ongoing monitoring to varying degrees based on their ApoE4 status, concomitant use of blood-thinning drugs, and if they have a condition called cerebral amyloid angiopathy (CAA), which may increase ARIA risk.

“It’s a multistep journey and will be very complicated now that there is a treatment,” added Toloue.

He argues that blood testing is the “only way to scale testing and access” to the new treatments. “We firmly believe this is an incredibly urgent need,” he said. “A rapid infrastructure has to be built globally.”

Quanterix is running a clinical trial to get to what he described as the “holy grail” in the industry, determining whether a multiple blood biomarker test can replace PET and CSF in the future.

Analysts predict a slower sales trajectory in the near-term for both Leqembi and donanemab, as physicians work to properly identify and support patients on the medications, with estimates increasing in later years. 

“We continue to expect a slow ramp in 2023 and acceleration moving into 2024,” for Leqembi, wrote SVB Securities analyst Marc Goodman in an investor note this month. 

Goodman added that the development of a subcutaneous formulation and potential maintenance dosing could “really differentiate this product” from donanemab, as well as ease administration burdens.

Eisai has said Leqembi could generate $7 billion in annual sales globally by 2030, and many analysts think the figure could be higher. Goldman Sachs analyst Salveen Richter forecasts $16 billion in worldwide Leqembi sales.

Schott’s team forecasts a $25 billion market opportunity for the anti-amyloid antibody class as a whole. 

“Further, we see potentially meaningful upside for these drugs in the prevention setting, where Lilly believes AB-antibodies will show even greater efficacy.”