The United Kingdom medicines authority approved the Alzheimer’s disease drug Kisunla (donanemab) last week for certain patients. This follows the Unites States Food and Drug Administration granting marketing authorization in July of this year. However, in the U.K. Kisunla is likely to face major reimbursement challenges after the cost-effectiveness watchdog, the National Institute for Health and Care Excellence, declared the drug “cannot currently be considered good value for the taxpayer.”
For NICE to be able to authorize a medical technology for population-wide reimbursement across the National Health Service the product must provide benefits to patients that justify the price premium being paid over and above standard existing care. In other words, it must represent a cost-effective use of NHS resources and taxpayers’ money. In the case of Kisunla, the cost-effectiveness estimate calculated by NICE was five to six times higher than the threshold which the agency typically uses. Products calculated as having such high incremental costs in relation to their benefits are usually not reimbursed.
NICE will issue its final recommendation on Kisunla once a consultation period ends later this month, after which the independent committee will consider all responses and additional analyses at a second meeting. The product’s manufacturer, Eli Lilly, and the NHS have been asked to furnish more information to address “areas of uncertainty” in the currently available evidence.
Donanemab works by removing a sticky protein, beta amyloid plaque, from the brain. Such plaque build-up is hypothesized to be a cause of Alzheimer’s disease. Tau plaque is also thought to contribute to Alzheimer’s disease. And in a phase 3 trial, Kisunla was shown to be effective at clearing both beta amyloid and tau plaque in the brain.
Among 1,700 trial participants with early symptomatic Alzheimer’s disease and amyloid and tau pathology, donanemab slowed the rates of cognitive and functional decline. Specifically, 47% of those who received the drug, compared to 29% who were given a placebo, showed no signs of cognitive decline after one year of treatment.
We observed a similar narrative unfold this past summer when Leqembi (lecanemab) was approved by the British regulatory authority in August, but NICE soon after opposed reimbursing the drug. Leqembi has fairly comparable safety and efficacy numbers. Its dosing regimen is different, however, as it’s an infusion once every two weeks rather than four, which is the case with Kisunla. At the time, the Telegraph quoted from a spokesperson for NICE who said that the “costs of providing the treatment, including fortnightly infusions in hospital and intensive monitoring for side effects, combined with the relatively small benefits it provides to patients means it cannot be considered good value for the taxpayer. Lecanemab provides on average four to six months slowing in the rate of progression from mild to moderate Alzheimer’s disease, but this is just not enough benefit to justify the additional cost to the NHS.”
U.S. Insurance Coverage Of Leqembi And Kisunla
NICE’s evaluations reveal that thus far beta amyloid-directed monoclonal antibodies have shown limited cost-effectiveness. This can pose a direct access challenge, particularly in countries with single payers or healthcare systems in which a (quasi)-government authority makes reimbursement decisions on behalf of multiple insurers.
The U.S. situation is quite different. There is no single payer or NICE informing decisions by a lone government insurer. Generally, payers in both the public markets, such as Medicare and Medicaid, as well as insurers in the commercial sector, each make coverage decisions.
Nonetheless, in the case of biologics targeting Alzheimer’s disease in early stage patients, such as first-in-class Aduhelm (aducanumab) and later Leqembi and Kisunla, Medicare—the predominant payer for Alzheimer’s disease-related medical technologies—decided to take the unusual step of conducting a National Coverage Determination. It’s not entirely clear what triggered the NCD, but the story of Aduhelm’s controversial path to regulatory approval likely played a role. Furthermore, clinical trial data suggested a large degree of uncertainty regarding safety and efficacy. And with millions of Medicare beneficiaries potentially eligible for treatment, cost may have also factored into the decision to pursue an NCD. The now moribund Aduhelm’s original annual price was $56,000 (later cut in half to $28,000); Leqembi’s list price per year is $26,500; and a 12-month course of Kisunla in the U.S. can cost annually about $32,000.
In April 2022, the Centers for Medicare and Medicaid Services issued an NCD which severely restricted access to all such products unless they had regular, as opposed to accelerated, approval by the FDA and were deemed to offer at least some clinically meaningful benefit.
Almost immediately following the regular approval by the FDA of Leqembi, CMS announced it will cover most patients eligible for the therapeutic. This includes persons with mild cognitive impairment or mild dementia and confirmed amyloid plaques.
CMS requires that Medicare beneficiaries who take Leqembi and Kisunla enroll in a patient registry to collect more data on the drugs. The patient registry requirement is also a prerequisite for reimbursement.
While sales of Leqembi have climbed this year, they’re still well below initial expectations. Perhaps in some ways this is a reflection of their perceived value to patients and doctors.
In the U.S., there is a lack of consensus among neurologists on whether to recommend beta amyloid-directed monoclonal antibodies like Kisunla and Leqembi to their patients. Some question whether the degree to which the drug slows cognitive deterioration is clinically meaningful to patients.
There are also persistent safety worries which were highlighted when the FDA initially denied approval of donanemab. The agency questioned the drug’s long term safety, noting a relatively higher rate of treatment discontinuation due to adverse events such as amyloid-related imaging abnormalities, ARIA, that can lead to brain hemorrhage and swelling among those on Kisunla compared to placebo.
Notably, the labeled indication in the U.K. is “mild cognitive impairment and mild Alzheimer’s disease-related dementia in patients who have only one copy of the apolipoprotein E ε4 allele or who don’t carry it at all.” This is narrower than the label granted in the U.S. The FDA recommends testing ApoE ε4 status prior to initiation of treatment to inform the risk of developing ARIA. Eli Lilly announced this week that in a phase 3 trial an adjusted dosing regimen successfully reduced the risk of brain swelling.
Leqembi also triggered ARIA characterized by edema in about 12% of clinical trial participants. Most cases were asymptomatic, but occasional severe reactions occurred, including three deaths from brain bleeding and swelling. Two deaths possibly linked to the use of lecanemab have been reported since the drug’s regulatory approval.
All in all, in light of the issues cited in the U.S. and U.K. regarding safety, effectiveness and cost-effectiveness, uptake challenges will likely persist for the amyloid plaque-busting treatments indicated for early stage Alzheimer’s disease patients.
