The US Food and Drug Administration has approved the drug Kisunla (donanemab) for Alzheimer’s disease … [+]
The United Kingdom Medicines Authority approved the drug Kisunla for Alzheimer’s disease (donanemab) last week for certain patients. This follows the US Food and Drug Administration granting marketing authorization in July this year. In Britain, however, Kisunla is likely to face major reimbursement challenges after cost-effectiveness watchdog the National Institute for Health and Care Excellence said the drug “cannot currently be considered good value for the taxpayer considered.”
In order for NICE to authorize a medical technology for population-wide reimbursement within the National Health Service, the product must provide benefits to patients that justify the price premium paid over and above standard existing care. In other words, it must represent a cost-effective use of NHS resources and taxpayers’ money. In Kisunla’s case, the cost-effectiveness estimate calculated by NICE was five to six times higher than the agency’s typical threshold. Products that are calculated to have such high costs relative to their benefits are generally not reimbursed.
NICE will issue its final advice on Kisunla once a consultation period ends later this month, after which the independent commission will consider all responses and additional analysis at a second meeting. The product’s manufacturer, Eli Lilly, and the NHS have been asked to provide more information on “areas of uncertainty” in the currently available evidence.
Donanemab works by removing a sticky protein called beta-amyloid plaque from the brain. Such plaque buildup is believed to be a cause of Alzheimer’s disease. Tau plaque is also believed to contribute to Alzheimer’s disease. And in a phase 3 study, Kisunla was found to be effective clean up both beta-amyloid and tau plaque in the brain.
Among 1,700 study participants with early symptomatic Alzheimer’s disease and amyloid and tau pathology, donanemab slowed the rate of cognitive and functional decline. Specifically, 47% of those who received the drug, compared to 29% who received a placebo, showed no signs of cognitive decline after one year of treatment.
We saw a similar story unfold last summer when Leqembi (lecanemab) was approved by the UK regulator in August, but NICE opposed reimbursement for the drug shortly afterwards. Leqembi has fairly similar safety and efficacy numbers. However, the dosing schedule is different as it is an infusion once every two weeks instead of four as is the case with Kisunla. At the time the Telegraph quoted from a NICE spokesperson who said that the “cost of providing the treatment, including fortnightly infusions in hospital and intensive monitoring for side effects, combined with the relatively small benefits it brings to patients, means it is not considered good value for the taxpayer can be considered. Lecanemab on average delays the progression of mild to moderate Alzheimer’s disease by four to six months, but this is simply not enough benefit to justify the additional cost to the NHS.”
US insurance coverage from Leqembi and Kisunla
NICE’s evaluations show that beta-amyloid-targeted monoclonal antibodies have shown limited cost-effectiveness to date. This can pose an immediate access challenge, especially in single-payer countries or healthcare systems in which a (quasi)governmental entity makes reimbursement decisions on behalf of multiple insurers.
The American situation is very different. There is no single payer or NICE making decisions from a single government insurer. In general, payers in both the public markets, such as Medicare and Medicaid, and insurers in the commercial sector each make coverage decisions.
Nevertheless, Medicare – the main payer of Alzheimer’s disease-related medical technologies – decided in the case of biologics that target Alzheimer’s disease in early-stage patients, such as the first-in-class Aduhelm (aducanumab) and later Leqembi and Kisunla , to take the unusual step of conducting a National Coverage Determination. It’s not entirely clear what prompted the NCD, but the story of Aduhelm’s controversial path to regulatory approval likely played a role. In addition, clinical trial data indicated a high degree of uncertainty regarding safety and efficacy. And since millions of Medicare beneficiaries may be eligible for treatment, cost may also have played a role in the decision to pursue an NCD. The original annual price of the now dying Aduhelm was $56,000 (later halved to $28,000); Leqembi’s list price per year is $26,500; and a twelve-month Kisunla treatment in the US can cost approximately annually $32,000.
In April 2022, the Centers for Medicare and Medicaid Services issued an NCD that severely limited access to all such products unless they received regular, rather than accelerated, approval from the FDA and were deemed to provide at least some clinically meaningful benefit .
Almost immediately after Leqembi’s regular FDA approval, CMS announced it will cover this most patients are eligible for the therapeutic agent. This includes individuals with mild cognitive impairment or mild dementia and confirmed amyloid plaques.
CMS requires Medicare beneficiaries taking Leqembi and Kisunla to enroll in a patient registry to collect more data about the drugs. The requirement for patient registration is also a condition for reimbursement.
Although Leqembi sales have increased this year, they are still well below initial expectations. Perhaps this is in some ways a reflection of their perceived value to patients and physicians.
There is one in the US lack of consensus among neurologists about whether beta-amyloid-targeted monoclonal antibodies such as Kisunla and Leqembi should be recommended to their patients. Some wonder whether the extent to which the drug slows cognitive decline is clinically meaningful for patients.
There are also lingering safety concerns raised during the FDA’s first phase approval of donanemab denied. The agency questioned the long-term safety of the drug and noted a relatively higher rate of treatment discontinuation due to side effects such as amyloid-related imaging abnormalities, ARIA, which can lead to brain hemorrhages and swelling in those taking Kisunla compared with placebo.
Specifically, the labeled indication in Britain is “mild cognitive impairment and mild dementia associated with Alzheimer’s disease in patients who have only one copy of the apolipoprotein E ε4 allele or who do not carry it at all.” This is narrower than the label assigned by the FDA in the US recommends testing ApoE ε4 status before starting treatment to inform the risk of developing ARIA. Eli Lilly announced this week that in a phase 3 trial, a modified dosing regimen successfully reduced the risk of brain swelling.
Leqembi also caused ARIA characterized by edema in approximately 12% of clinical trial participants. Most cases were asymptomatic, but serious reactions occasionally occurred, including: three deaths against brain haemorrhages and swellings. There have been two deaths possibly related to the use of lecanemab reported since the drug’s regulatory approval.
Overall, in light of the issues raised in the US and UK regarding safety, effectiveness and cost-effectiveness, the challenges in acceptance of the amyloid plaque-fighting treatments indicated for patients with amyloid plaque disease Early stage Alzheimer’s is likely to persist.