Biogen Sees Rocky 2022 Finish with Further Aduhelm, Lecanemab Scrutiny

2023-01-03

临床3期加速审批临床结果上市批准

Courtesy of John Tlumacki/The Boston Globe via Getty Biogen experienced a turbulent end to a turbulent 2022. Last week, two documents came to light: one the results of a congressional investigation into the approval of its Alzheimer’s drug Aduhelm (aducanumab), the second a revised informed consent form calling into question the safety of lecanemab, which could receive accelerated approval this week. On Friday, Science revealed Biogen’s development partner Eisai updated the consent form for the Phase III Clarity AD trial warning participants that combining lecanemab with blood clot medications could lead to fatal brain hemorrhages. The revision was made in a July 14 version of the consent form, Science reported. In part, Eisai wrote the “risk is estimated to be more than 1 in 100 people, but less than 5 in 100 people.” This follows reports of two trial participant deaths allegedly associated with lecanemab. In a presentation at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference, Marwan Sabbagh, M.D., a behavioral neurologist at the Barrow Neurological Institute, said the two fatalities were associated with cerebral microhemorrhages in the open-label extension phase of the study. Libby Holman, senior director of product communications at Eisai U.S. referred BioSpace to a statement that reads in part, "Eisai promptly communicates important safety information to the DSMBs, regulatory agencies, sites, investigators and patients through a variety of appropriate mechanisms, including... Informed Consent Form (ICF) revisions." The company additionally expressed confidence that the informed consents used in its studies accurately describe the known risks associated with lecanemab. The PDUFA date for lecanemab is Friday, January 6. If Biogen and Eisai do receive accelerated approval this week, the price point for the antibody must be set at lower than $20,600 a year to be cost-effective, according to the Institute for Clinical and Economic Review (ICER). The Watchdog further calculated the drug’s clinical benefits at between $8,500 and $20,600 per year. In September, the partners announced lecanemab reduced clinical decline by 27% compared to placebo after 18 months. The initial price for Aduhelm, which in June 2021 became the first drug approved to treat Alzheimer’s in 18 years, was $56,000 per patient, per year. Following a spate of controversy and insurers refusing to cover the drug, Biogen slashed the price to $28,200 in December 2021. At the time of Aduhelm’s approval, ICER recommended a price point of between $2500 and $8300 per patient per year, alleging “insufficient efficacy”. Results from the Phase III Emerge and Engage trials were mixed, and Biogen and Eisai initially made the decision to discontinue both trials due to futility. Congressional Investigation Reveals “Atypical Processes” Almost immediately after the green light, the U.S. House of Representatives launched an investigation into the regulatory review and approval, pricing and marketing of Aduhelm. The final report, prepared by the Committees on Oversight and Reform, and Energy and Commerce, was published Thursday. The report points to a joint briefing document prepared and presented by Biogen and the FDA to the regulator’s Peripheral and Central Nervous Systems Drugs Advisory Committee in November 2020 – a joint process that had previously been used only for cancer drugs “under circumstances of broad consensus”. The adcomm overwhelmingly voted against traditional approval for Aduhelm. While the report ultimately concluded the interactions between the FDA and Biogen prior to the PCNS adcomm were appropriate, it highlighted “atypical processes.” Among these, the investigators found: Documents showing Biogen and the FDA engaged in at least 115 meetings, calls and substantive email exchanges over a 12-month period beginning in July 2019. According to the report, the regulator’s own internal review of the approval process found the extent of collaboration was “atypical” and “exceeded the norm in some respects.” The FDA and Biogen “inappropriately collaborated on a joint briefing document for the PCNS advisory committee that did not adequately represent differing views within FDA.” “Biogen set an unjustifiably high price for Aduhelm to ‘Make History’ for the company despite the impact on patients and the Medicare program.” The report specifically highlighted a September 2020 presentation to Biogen’s board where the company stated its ambition was to make history and “establish Aduhelm as one of the top pharmaceutical launches of all time.” On this last point, only time – possibly three days – will tell if Biogen heeds the lessons provided it by insurers and Medicare itself – on the pricing of lecanemab.