Britain's NICE says Alzheimer's drug Kisunla is not cost-effective

The UK Medicines Agency last week approved the Alzheimer's drug Kisunla (donanemab) for certain patients. This follows the granting of marketing authorization by the US Food and Drug Administration in July this year. However, Kisunla is likely to face major reimbursement problems in the UK after cost-effectiveness watchdog the National Institute for Health and Care Excellence said the drug “cannot currently be considered good value for the taxpayer”.

For NICE to approve a medical technology for population-wide reimbursement across the NHS, the product must provide benefits to patients that justify the price premium paid over existing standard 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 the agency normally uses. Products whose additional costs are so high in relation to their benefits are generally not reimbursed.

NICE will make its final recommendation on Kisunla once a consultation period ends later this month. The independent committee will then consider all responses and additional analyzes at a second meeting. The product's manufacturer, Eli Lilly, and the NHS have been asked to provide further 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 formation is suspected to be a cause of Alzheimer's disease. Tau plaque is also thought to contribute to Alzheimer's disease. And in a phase 3 study, Kisunla was shown to be effective in clearing both beta-amyloid and tau plaque in the brain.

In 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% of those who received a placebo showed no signs of cognitive decline after one year of treatment.

We saw a similar development 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 comparable safety and effectiveness numbers. However, the dosing schedule is different as it is an infusion every two weeks and not every four weeks as is the case with Kisunla. That was back then telegraph quoted a NICE spokesperson as saying 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 offers to patients, “Lecanemab slows the rate of progression of mild to moderate Alzheimer's disease by four to six months on average, but this benefit is simply not enough to offset the additional cost to the NHS justify.”

US insurance coverage for Leqembi and Kisunla

The NICE evaluations show that monoclonal antibodies directed against beta-amyloid have so far shown limited cost-effectiveness. This can pose a challenge for direct access, particularly in countries with single-payer or health systems where a (quasi-)governmental authority makes reimbursement decisions on behalf of multiple insurers.

The situation in the USA is completely different. There is no single payer or NICE making decisions from a single government insurer. In general, both payers in the public markets, such as Medicare and Medicaid, and insurers in the commercial sector each make their coverage decisions.

Still, in the case of biologics that target early-stage Alzheimer's disease, such as the first-in-class Aduhelm (aducanumab) and later Leqembi and Kisunla, Medicare – the primary payer for medical technologies related to Alzheimer's disease – chose the unusual step Step to implement 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. In addition, data from clinical trials suggested a high degree of uncertainty regarding safety and effectiveness. And since millions of Medicare beneficiaries may be eligible for treatment, cost may also have played a role in the decision to undergo NCD treatment. The now dying Aduhelm's original annual price was $56,000 (later halved to $28,000); Leqembi's list price per year is $26,500; and a 12-month Kisunla course in the US can cost around $32,000 annually.

In April 2022, the Centers for Medicare and Medicaid Services issued an NCD that severely restricted access to all such products unless they had regular, rather than accelerated, FDA approval and would provide at least a clinically meaningful benefit .

Almost immediately after the regular FDA approval of Leqembi, CMS announced that it would cover most patients eligible for the therapeutic. This includes people with mild cognitive impairment or mild dementia and confirmed amyloid plaques.

CMS requires that Medicare beneficiaries taking Leqembi and Kisunla enroll in a patient registry to collect additional data on the drugs. The obligation to register patients is also a prerequisite for reimbursement.

Although Leqembi's sales have increased this year, they are still well below original expectations. Perhaps this in some way reflects their perceived value to patients and physicians.

In the United States, there is no consensus among neurologists about whether to recommend beta-amyloid-targeting monoclonal antibodies such as Kisunla and Leqembi to their patients. Some question whether the extent to which the drug slows cognitive decline is clinically meaningful for patients.

There are also ongoing safety concerns, which became apparent when the FDA initially refused to approve donanemab. The agency questioned the long-term safety of the drug, noting that treatment discontinuations are relatively higher due to adverse events such as amyloid-related imaging abnormalities (ARIA), which can cause brain bleeding and swelling in patients on Kisunla compared to placebo.

In particular, the indication in the UK 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 do not carry it at all.” This is narrower than that in Label granted to the USA. The FDA recommends testing ApoE ε4 status before starting treatment to determine the risk of developing ARIA. Eli Lilly announced this week that an adjusted dosing regimen successfully reduced the risk of brain swelling in a Phase 3 trial.

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 from cerebral hemorrhage and swelling. Since the drug's regulatory approval, two deaths have been reported that may be related to the use of lecanemab.

Overall, given the safety, efficacy and cost-effectiveness issues cited in the US and UK, there will likely continue to be challenges in the acceptance of the amyloid plaque-destroying treatments indicated for patients with early-stage Alzheimer's disease.