Crigler-Najjar Syndrome

Eli Lilly’s Alzheimer’s drug Kisunla has secured regulatory approval in the UK, but has been rejected for widespread use in NHS. Credit: Michael Vi via Shutterstock. Eli Lilly’s Kisunla (donanemab) will not yet be made available to Alzheimer’s patients in the UK after the National Institute for Health and Care Excellence (NICE) said it doesn’t demonstrate good value for UK’s NHS. On 23 October, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) granted approval to the therapy for the treatment of mild cognitive impairment or mild dementia due to Alzheimer’s disease in some adults. This follows on from the US Food and Drug Administration (FDA)’s green light in July 2024 . However, NICE, which acts as the UK’s price watchdog, said that although the monthly injection slows disease progression by four to seven months, as demonstrated in the Phase III TRAILBLAZER-ALZ 2 (NCT04437511) study, there are “significant uncertainties about how much benefit donanemab provides, and how long this lasts for after stopping treatment”. It also said that more evidence is needed on the clinical and cost-effectiveness of Kisunla. A NICE committee also explained that one-third of patients in the trial had signs of brain swelling or brain bleeding, as determined by amyloid-related imagining abnormalities (ARIAs). Similar concerns were raised in the FDA’s June 2024 advisory committee convened to discuss the drug’s approval. Patients in Lilly’s trial were closely monitored due to this, with MRIs done at four, 12, 24, 52, and 76 weeks in addition to allowing for unscheduled MRIs at investigator discretion. This frequent monitoring can rack up increased costs for payers , as well as bringing up accessibility issues. In the announcement accompanying the decision, Helen Knight, director of medicines evaluation at NICE said: “The cost-effectiveness estimate for donanemab is 5 to 6 times above what NICE normally considers an acceptable use of NHS resources.” See Also: TreeFrog and University of Pittsburgh probe TLS role in immuno-oncology Be Bio raises $82m to advance haemophilia B gene therapy to Phase I/II trial In the US, Kisunla has a price tag $695.65 per vial. This means that the cost of treatment for a six and 12 month-plan would amount to $12,522 and $32,000, respectively. Kisunla isn’t the only Alzheimer’s therapy on the market. Eisai and Biogen ’s Leqembi (lecanemab) secured UK approval in August 2024, but NICE published a separate draft guidance that said it leans against reimbursing the drug. Leqembi has an annual cost of $26,500 per year in the US, and its infusions are administered every two weeks for a minimum of 18 months. In July, Leqembi faced rejection from the European Medicines Agency (EMA) , while the agency is continuing to review Kisunla. Kisunla and Leqembi are monoclonal antibodies that work by targeting and clearing amyloid beta plaques from the brain, aiming to slow early cognitive decline by reducing toxic buildup linked to the disease. It is estimated that around 70,000 adults in England would have been eligible for treatment with Kisunla, according to NICE.

European regulators on Friday recommended against approval of Eisai and Biogen’s Alzheimer's disease drug Leqembi (lecanemab), deeming that the benefits of the anti-amyloid antibody are outweighed by the risk of serious adverse events, particularly amyloid-related imaging abnormalities (ARIAs). The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) noted that while most cases of ARIA seen in clinical trials were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain, which required hospitalisation. The EMA said “the seriousness of this side effect should be considered in the context of the small effect seen with the medicine.”Data supporting the application showed that after 18 months of treatment, Leqembi slowed cognitive decline by 27% in patients with early Alzheimer’s disease, as measured by the CDR-SB dementia rating scale. Eisai’s therapy was associated with an increase in CDR-SB score of 1.21, compared with 1.66 in those who received placebo.The CHMP also raised concerns over a more pronounced risk of ARIA in people who have a certain form of the gene for the protein ApoE4. The committee noted that the risk is highest in those with two copies of the ApoE4 gene, who are known to be at risk of developing Alzheimer’s disease and would therefore be likely to become eligible for treatment with Leqembi.Seek re-examinationIn response to the negative decision, Eisai’s chief clinical officer Lynn Kramer said the company is “extremely disappointed,” with the drugmaker set to seek a re-examination of the opinion. Meanwhile, Biogen’s shares fell more than 7% in premarket trading on Friday.RBC Capital Markets Brian Abrahams estimated that Europe makes up about 20% of the potential market for Leqembi, adding that even if the decision is overturned, a launch in the region would be delayed. Abrahams suggested that the CHMP’s opinion is also “likely to somewhat hamper global perceptions and momentum for the drug and the class.”The CHMP review of Leqembi had been delayed earlier this year after the EMA decided to annul the advice obtained from a previous panel of independent experts due to “procedural reasons.” The scientific advisory group (SAG) met in March to discuss Leqembi’s marketing application, but the panel’s advice was discarded after a court ruling impacted how the EMA handles the competing interests of SAG members.Leqembi is currently marketed in the US, Japan and China, and has also secured approvals in South Korea, Hong Kong and Israel. However, the product’s sales have been slow, reaching only $19 million in the first quarter of the year. Leqembi is also set to face competition in the US, after the FDA recently approved Eli Lilly's amyloid plaque-targeting therapy Kisunla (donanemab-azbt) for adults with early symptomatic Alzheimer's disease. Same fate as Aduhelm?The regulatory stumble for Leqembi in Europe mirrors that of Biogen and Eisai’s earlier attempt with the anti-amyloid antibody Aduhelm (aducanumab). While the therapy was approved in the US – before ultimately being withdrawn due to lacklustre sales – an application was pulled in the EU following a negative recommendation from the CHMP.For related analysis, see Physician Views In-Depth: Though Eli Lilly’s new Alzheimer’s treatment is a fast favourite, Kisunla is unlikely to be kiss of death for Leqembi.

Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT. Moderna’s methylmalonic acidemia candidate, mRNA-3705, will be developed under the FDA’s START pilot program for rare disease, the company announced June 6. It joins therapies from Denali Therapeutics, Neurogene, Grace Sciences and Larimar Therapeutics in the initiative, which aims to do for rare disease drugs what Operation Warp Speed did for the COVID-19 vaccines. Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT, which processes fatty acids. Without it, the acids build up and damage organs. The disease is usually diagnosed within the first few months of life, and there are currently no treatments. MRNA-3705 is an mRNA-based drug that encodes MUT, thereby restoring acid metabolism. It has orphan-drug, fast-track and rare pediatric disease designations from the FDA and is currently being tested in a 63-subject, phase 1/2 clinical trial.  Under START, mRNA-2705 will get extra attention from FDA officials, who will guide Moderna through product development issues like designing studies, choosing control groups and selecting the right patient population. The effort is being carried out by the agency’s Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, which is selecting six participants total for the first iteration of the program, according to a September 2023 announcement from the FDA.  “This selection highlights the promise of Moderna’s innovative mRNA platform beyond vaccines and the potential this novel medicine may have in addressing the serious and unmet medical needs of MMA,” Kyle Holen, M.D., senior vice president and head of development in the therapeutics and oncology unit at Moderna, said in a press release. “Selection for this program will…[result] in acceleration of our development program as we prepare for pivotal study initiation for mRNA-3705 in 2024.” Moderna's other rare disease programs include drugs for propionic acidemia, glycogen storage disorder type 1a, ornithine transcarbamylase deficiency, phenylketonuria, Crigler-Najjar syndrome type 1 and cystic fibrosis. Also picked for the START program is Calico Life Sciences' eIF2B activator fosigotifator, which is under development for Vanishing White Matter disease. The condition is an ultra-rare disease of the brain's white matter caused by variations in an essential enzyme in the cells called eIF2B. This causes a reduction in enzymatic activity that can lead to chronic activation of the integrated stress response.  This causes the white matter to degenerate, causing symptoms such as impaired muscle movement, cognitive decline and seizures. Patients have a shortened life span.  Fosigotifator is being developed in a partnership between Calico and AbbVie through an agreement signed in 2014.