BioArctic AB’s (publ) (Nasdaq Stockholm: BIOA B) partner Eisai has made a major move in the fight against Alzheimer’s disease today, submitting a marketing authorization application for lecanemab (Brand Name in the U.S.: LEQEMBI™) to the European Medicines Agency (EMA). This investigational anti-amyloid beta (Aβ) protofibril antibody is intended to treat early Alzheimer’s disease, such as mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. The application is based on the positive results of the Phase 3 Clarity AD study and the Phase 2b clinical study, which both showed that lecanemab could reduce clinical decline in early AD. Upon successful validation, BioArctic will receive a milestone payment of MEUR 5.
The groundbreaking Clarity AD study has delivered highly statistically significant results on its primary endpoint (CDR-SB: Clinical Dementia Rating-Sum of Boxes) and all key secondary endpoints. The most common adverse events seen in the lecanemab group were infusion reactions, ARIA-H, ARIA-E, headache and falls. In November 2022, the results of the Clarity AD study were unveiled to the world at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, and simultaneously published in the New England Journal of Medicine, one of the most prestigious peer-reviewed medical journals.
On January 6, 2023, Eisai received a major boost in its fight against Alzheimer’s disease (AD) after the U.S. Food and Drug Administration (FDA) granted accelerated approval for its lecanemab drug. In addition, Eisai has submitted a Supplemental Biologics License Application (sBLA) to the FDA for approval under the traditional pathway. To further its reach, Eisai has also initiated submission of data for a BLA in China to the National Medical Products Administration (NMPA) in December 2022. Finally, the company has plans to submit a marketing authorization application in Japan by the end of the first quarter 2023.
Eisai is taking the lead on the development and regulatory submissions of lecanemab, while jointly commercializing and promoting the product with Biogen, and maintaining final decision-making authority. Meanwhile, BioArctic has the right to commercialize the product in the Nordic region under certain conditions, and is now gearing up for commercialization there in partnership with Eisai.
BioArctic AB (publ) is pleased to announce the release of its new information, in compliance with the EU Market Abuse Regulation. This news was made public on January 11, 2023, at 00.30 a.m. CET and is sure to have a positive impact on the market.
INDICATION, DOSAGE AND ADMINISTRATION, AND IMPORTANT SAFETY INFORMATION IN THE U.S
LEQEMBI is an exciting new treatment for those with Alzheimer’s disease. It has been approved for patients with mild cognitive impairment or mild dementia, the population that it was tested in clinical trials. If you have been diagnosed with Alzheimer’s, LEQEMBI may be the perfect option for you – its approval is based on the reduction in amyloid beta plaques observed in patients who take it. To ensure that LEQEMBI continues to be a viable treatment option, further clinical trials are taking place to verify its clinical benefit.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Amyloid Related Imaging Abnormalities
MRI studies of patients taking BACE inhibitors such as LEMQEMBI have revealed a worrying side effect: amyloid-related imaging abnormalities like ARIA-E and ARIA-H. ARIA-E can be seen as brain edema or sulcal effusions, while ARIA-H appears as microhemorrhage and superficial siderosis. Although usually asymptomatic, these conditions can cause serious and even life-threatening events like seizures and status epilepticus. Those affected may experience headaches, confusion, visual changes, dizziness, nausea, and difficulty with balance and movement. Thankfully, the symptoms associated with ARIA usually resolve over time.
ARIA monitoring and dose management guidelines
- Before beginning treatment with LEQEMBI, it is essential to obtain recent brain magnetic resonance imaging (MRI) within the last year. An MRI should be obtained prior to the 5th, 7th, and 14th infusions to ensure the best possible outcomes.
- The decision on how to dose patients with ARIA-E and ARIA-H should be based on their clinical symptoms and radiographic severity. Depending on the severity of ARIA, clinicians should use their clinical judgment to decide whether to continue dosing, keep up treatment, or permanently discontinue LEQEMBI.
- Patients receiving LEQEMBI should be monitored closely for the first 14 weeks, as they may be at risk of developing ARIA. If any symptoms arise, a thorough clinical evaluation should be conducted and an MRI may be necessary. If ARIA is observed on the MRI, a careful clinical evaluation should be performed before continuing treatment.
- Patients who have continued dosing through symptomatic ARIA-E or through asymptomatic, but radiographically severe ARIA-E, have no experience to draw on. However, there is limited experience in those who have continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There is also limited data regarding dosing patients who have experienced recurrent ARIA-E.
Incidence of ARIA
- In Study 1 (Phase 2b), LEQEMBI treatment was associated with symptomatic ARIA-E in 3% (5/161) of patients. Fortunately, clinical symptoms associated with ARIA were successfully resolved in 80% of patients during the period of observation.
- Patients in the LEQEMBI group experienced a higher rate of ARIA, including asymptomatic cases, than the placebo group (12% vs 5%). Additionally, the LEQEMBI group experienced a higher rate of ARIA-E (10% vs 1%) and a similar rate of ARIA-H (6% vs 5%) compared to the placebo group. No increase in isolated ARIA-H was observed in the LEQEMBI group compared to the placebo group.
- After one treatment of LEQEMBI, there was a report of an intracerebral hemorrhage larger than 1 cm in diameter in one patient, while no such events were reported in patients taking the placebo. Other studies have also reported events of intracerebral hemorrhage, some of them fatal, in patients taking LEQEMBI.
Apolipoprotein E ε4 (ApoE ε4) carrier status and risk of ARIA
In Study 1 (Phase 2b), ApoE ε4 homozygotes were found to be at a higher risk of developing ARIA when treated with LEQEMBI compared to heterozygotes and noncarriers. Of the 5 LEQEMBI-treated patients who had symptomatic ARIA, 4 were ApoE ε4 homozygotes, 2 of whom experienced severe symptoms. This increased incidence of ARIA in ApoE ε4 carriers has been reported in other studies as well, highlighting the importance of ApoE ε4 testing when deciding to initiate treatment with LEQEMBI. Despite the increased risk, however, the recommendations for the management of ARIA remain the same for ApoE ε4 carriers and noncarriers alike.
ARIA-E and ARIA-H events were observed in patients receiving treatment with LEQEMBI, with the majority of radiographic events occurring early in treatment. Of those affected, 4% experienced mild ARIA-E and ARIA-H, while 1% experienced severe ARIA-E and ARIA-H. Notably, 62% of ARIA-E patients experienced resolution of symptoms on MRI scans within 12 weeks, increasing to 81% by 21 weeks and 94% overall. In 1 of the 10 patients with ARIA-H, mild superficial siderosis was observed.
Concomitant antithrombotic medication and other risk factors for intra-cerebral hemorrhage
- Patients who were taking anticoagulant medications were excluded from enrollment in Study 1 (Phase 2b). However, those taking antiplatelet medications such as aspirin and clopidogrel were allowed to participate. If anticoagulant medication use was due to a short-term medical event and lasted for four weeks or less, treatment with LEQEMBI was temporarily suspended.
- With a majority of exposures to antithrombotic medications being to aspirin, the risk of ARIA or intracerebral hemorrhage in patients taking other antiplatelet drugs or anticoagulants is limited due to the few patients exposed to these medications. However, additional caution should be taken when considering the administration of antithrombotics or a thrombolytic agent, such as tissue plasminogen activator, to a patient already being treated with LEQEMBI, as intracerebral hemorrhages >1 cm in diameter have been observed in such cases.
- Patients with a history of cerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, superficial siderosis, evidence of vasogenic edema, evidence of cerebral contusion, aneurysm, vascular malformation, infective lesions, multiple lacunar infarcts or stroke involving a major vascular territory, and severe small vessel or white matter disease were excluded from enrollment in Study 1 (Phase 2b). Therefore, extra precaution should be taken when considering the use of LEQEMBI for patients with these risk factors.
- Patients treated with LEQEMBI had an infusion-related reaction rate of 20% (32/161), compared to only 3% (8/245) in the placebo group. Nearly all (88%) of these reactions occurred with the first infusion and were mild (56%) or moderate (44%) in severity. Although these reactions caused discontinuations in 2% (4/161) of patients, the symptoms were generally manageable, including fever, flu-like symptoms (chills, aches, shaky feeling and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.
- LEQEMBI treatment resulted in a noticeable change in blood cell counts: 38% of patients experienced a decrease in lymphocyte counts to less than 0.9 x109/L, compared to only 2% of those on placebo. Meanwhile, 22% of LEQEMBI-treated patients had an increase in neutrophil counts to greater than 7.9 x109/L, compared to just 1% of the placebo group. These changes were only temporary, but still demonstrate the power of LEQEMBI as a treatment option.
- If an infusion-related reaction occurs, the infusion rate can be decreased or stopped, and the necessary treatment can be applied. To prevent future reactions, prophylactic measures such as antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids may be taken prior to future infusions.
- In Study 1 (Phase 2b), LEQEMBI-treated patients were nearly three times more likely than placebo-treated patients to discontinue study treatment due to an adverse reaction. The most frequently reported cause of discontinuation was infusion-related reactions, which affected 2% of LEQEMBI-treated patients compared to 1% of placebo-treated patients.
- Patients treated with LEQEMBI in Study 1 (Phase 2b) experienced more frequent adverse reactions than those given placebo, with 20% reporting infusion-related reactions, 14% reporting headache, 10% reporting ARIA-E, 9% reporting cough and 8% reporting diarrhea. In contrast, only 3%, 10%, 1%, 5%, and 5% of placebo patients reported infusion-related reactions, headache, ARIA-E, cough, and diarrhea, respectively.
LEQEMBI™, the brand name for the innovative monoclonal antibody Lecanemab, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) on January 6, 2023. This breakthrough treatment was developed as a result of a strategic research alliance between BioArctic and Eisai, and is indicated for the treatment of Alzheimer’s disease (AD) in the U.S. When used in mild cognitive impairment or mild dementia stage of the disease, LEQEMBI has been demonstrated to reduce Aβ plaques in clinical trials, thus providing a promising step forward in the fight against AD. Eisai has now submitted a sBLA in the USA for LEQEMBI based on the data from the Phase 3 confirmatory Clarity AD clinical trial, in the hope of verifying its clinical benefit and securing continued approval.
Eisai has made incredible progress in the fight against Alzheimer’s disease. In July of 2020, they launched the Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical Alzheimer’s. This study, funded by the National Institute on Aging, has already seen success, as the company has completed a LEQEMBI subcutaneous bioavailability study and is currently evaluating subcutaneous dosing in the Clarity AD open label extension study. With these breakthroughs, Eisai is leading the charge to a future free of Alzheimer’s.
The Tau NexGen clinical study is now underway and exploring exciting new combination therapies for Dominantly Inherited Alzheimer’s Disease (DIAD) with lecanemab as a background anti-amyloid treatment. Led by the Washington University School of Medicine in St. Louis, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is spearheading this groundbreaking research since January 2022. Join us in our mission to bring new hope to those affected by DIAD.
About Phase 2b (Study 201) study and Phase 3 Clarity AD study
A groundbreaking Phase 2b clinical study tested the efficacy of lecanemab, a promising new treatment for early Alzheimer’s Disease (AD). 856 participants took part in a double-blind, parallel-group, dose-finding study over the course of 18 months. Results showed a dose-dependent reduction in PET SUVR, a measure of amyloid-β accumulation in the brain, when compared to placebo, as well as significant reductions in clinical decline (ADCOMS, CDR-SB, and ADAS-cog14) of up to 47.2% for the 10 mg/kg bi-weekly treatment. Unfortunately, the study did not achieve its primary outcome measure at 12 months of treatment. The most commonly reported side effects were infusion reactions, headache, ARIA-E, cough, diarrhea, dizziness, and cerebral microhemorrhages.
The Phase 3 Clarity AD study was a groundbreaking placebo-controlled, double-blind, parallel-group, randomized study of lecanemab 10 mg/kg or placebo administered bi-weekly for 18 months in 1,795 people living with early AD. Incredible results were seen; the mean change of CDR-SB from baseline at 18 months was 1.21 for lecanemab and 1.66 for placebo, significantly reducing clinical decline on the global cognitive and functional scale by -0.45 (95% CI: -0.67, -0.23; P=0.00005), representing a 27% slowing of decline. This effect was seen as early as six months (difference: -0.17 [95% CI: -0.29, -0.05]; P<0.01) and was reinforced by all key secondary endpoints (P<0.001). This trial was a revolutionary step forward in the treatment of early AD.
Patients treated with lecanemab experienced more frequent infusion reactions, ARIA-H, ARIA-E, headache, and falls compared to those on placebo. Although the majority of infusion reactions were mild-to-moderate (grade 1-2: 96%), they still occurred frequently on the first dose (75%).
The study revealed that while 0.7% and 0.8% of participants in the lecanemab and placebo groups respectively passed away, there were no deaths related to lecanemab or ARIA in the 18-month double-blind study period. Moreover, 14.0% and 11.3% of participants in the lecanemab and placebo groups respectively experienced serious adverse events. Additionally, 88.9% and 81.9% of participants in the lecanemab and placebo groups respectively experienced treatment-emergent adverse events, with 6.9% and 2.9% of participants in the lecanemab and placebo groups respectively experiencing drug withdrawal.
Lecanemab treatment was associated with an ARIA incidence profile that was consistent with what was seen in the Phase 2 trial results. Most cases of ARIA-E were mild to moderate in severity, asymptomatic, and resolved within four months of detection. Of those with symptomatic ARIA-E, the most commonly reported symptoms were headache, visual disturbance and confusion. There was no significant difference observed in the incidence of isolated ARIA-H between lecanemab and placebo groups. All in all, lecanemab was found to be a safe and effective treatment.
About the collaboration between BioArctic and Eisai
BioArctic and Eisai have had a long-term collaboration since 2005 to develop and commercialize drugs for the treatment of Alzheimer’s disease. The most significant agreements are the Development and Commercialization Agreement for the lecanemab antibody signed in 2007, and the Development and Commercialization agreement for the BAN2401 back-up antibody in 2015. In 2014, BioArctic and Biogen also joined forces to develop and commercialize lecanemab. Eisai is in charge of the clinical development and market approval as well as commercialization of the products for Alzheimer’s disease, while BioArctic has the right to commercialize lecanemab in the Nordic countries. BioArctic is also entitled to payments in connection with regulatory filings, approvals, and sales milestones, as well as royalties on global sales.
About BioArctic AB
BioArctic AB is a Swedish biopharma company that is dedicated to developing disease-modifying treatments for neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and ALS. Founded in 2003, BioArctic is committed to finding novel treatments to address high unmet medical needs. Its collaborations with universities are key to the company’s success, and it works closely with its strategic partner, Eisai, in the Alzheimer’s field. BioArctic’s portfolio is a blend of projects funded by global pharmaceutical companies and its own in-house projects, which have significant market and out-licensing potential. Its Class B share is listed on the Nasdaq Stockholm Mid Cap (ticker: BIOA B).