Otsuka is applying for marketing authorization for donidalorsen (Dawnzera) for the treatment of hereditary angioedema.

13.01.2025 14:03

Otsuka Pharmaceutical Europe Ltd. has submitted a marketing authorization application for the RNA-directed drug donidalorsen to the European Medicines Agency (EMA). Donidalorsen is intended for the routine prophylactic treatment of hereditary angioedema (HAE). The EMA has accepted the application.

„We believe that donidalorsen has the potential to advance long-term prophylactic treatment for people with HAE. The acceptance of our EU marketing authorization application is an important milestone on the path to better care for HAE patients in Europe,“ said Pontus Billstam, Managing Director of Otsuka Pharma in the D/A/CH region.

Donidalorsen received orphan drug designation in February 2024. [1] If approved by the European Commission, donidalorsen would be the first RNA-directed drug for the treatment of HAE and would represent a new treatment option for this rare, potentially life-threatening disease. Donidalorsen was developed by Ionis Pharmaceuticals, Inc. (Ionis), and Otsuka holds the exclusive marketing rights in Europe. In November 2024, Ionis applied for marketing authorization in the US from the FDA. Donidalorsen had already received orphan drug designation there in 2023. [2]

„Besides disease control, it is particularly important in chronic diseases like HAE to minimize the burden on patients and maintain their mental health. Otsuka has around 30 years of experience in the field of mental health and is committed to making this expertise available to doctors and patients alongside the new therapy option,“ Pontus Billstam continues.

The submission of the marketing authorization application to the EMA is based on the positive results of the Phase 3 OASIS-HAE and OASISplus trials (including the open-label extension of the OASISplus trial and a separate switch cohort who switched from other long-term therapies to donidalorsen) as well as the Phase 2 trials. Donidalorsen demonstrated a significant and sustained reduction in the rate of HAE attacks in the clinical trials. [3-7]

In the Phase 3 OASIS-HAE and OASISplus trials, improvements in various disease factors were observed with donidalorsen: A significant and sustained reduction in the mean monthly rate of HAE attacks was observed [3,5,8], and a further improvement in the attack rate over more than 90 % was seen in the four-week (Q4W) and eight-week (Q8W) dosing groups [5]. A clinically significant improvement in quality of life was also observed in patients in the Q4W group, as measured by the Angioedema Quality-of-Life Questionnaire (AE-QoL). [3] Furthermore, 91 % of patients in the Q4W group receiving donidalorsen achieved good disease control, as measured by the Angioedema Control Test (AECT). [3]

The results of the prospective OASISplus study showed a further reduction in the mean rate of monthly HAE attacks by 62 % compared to baseline in patients who had previously switched to donidalorsen from another prophylactic treatment. 84 % of the patients reported that they preferred donidalorsen to their previous prophylactic treatment. [4,9]

The results of the ongoing Phase 2 extension study showed a mean reduction in the rate of HAE attacks of 96 % after up to two years of treatment with donilarosen. [7]

Across all studies, donidalorsen was well tolerated and showed an acceptable safety profile. There were no serious treatment-related adverse events (TEAEs) associated with donidalorsen. [3,4,7] Most adverse events (AEs) were mild or moderate [3-7], and injection site reactions were the most common. [3,4,7]

credentials

1. European Medicines Agency. EU/3/24/2898 – orphan designation for treatment of hereditary angioedema. Available at: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-2898 [Last accessed January 2025]
2. US Food and Drug Administration. Donidalorsen Orphan Drug Designation. Available at: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=961723 [Last accessed: January 2025]
3. Riedl MA, et al. Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med 2024;391(1):21-31.
4. Riedl MA, et al. Self-reported treatment preferences of patients switching from prior prophylactic therapies to donidalorsen for the treatment of hereditary angioedema: Results from the phase 3 OASISplus study. EAACI Congress. 2024.
5. Tachdjian R, et al. Long-term safety of donidalorsen for the treatment of hereditary angioedema: Results from the phase 3 open-label extension OASISplus study. EAACI Congress. 2024.
6. Fijen LM, et al. Inhibition of prekallikrein for hereditary angioedema. N Engl J Med 2022;386(11):1026-1033.
7. Petersen RS, et al. A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema. Allergy. 2024;79(3):724-734.
8. ClinicalTrials.gov. OASIS-HAE: A study to evaluate the safety and efficacy of donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in participants with hereditary angioedema (HAE). Available at: https://www.clinicaltrials.gov/study/NCT05139810 [Last accessed: January 2025]
9. Riedl MA, et al. Treatment of hereditary angioedema: safety, efficacy, and patient preference after switching to donidalorsen (OASISplus study). Annals of Allergy, Asthma & Immunology. 2024;133(6):S37.
10. Manning ME. Recognition and Management of Hereditary Angioedema: Best Practices for Dermatologists. Dermatol Ther (Heidelb) 2021;11(5):1829-1838.
11. Valerieva A, et al. Therapeutic management of hereditary angioedema: past, present and future. Balkan Med J 2021;38(2):89–103.
12. Santacroce R, et al. The Genetics of Hereditary Angioedema: A Review. J Clin Med. 2021;10(9):2023.
13. Pines JM, et al. Recognition and Differential Diagnosis of Hereditary Angioedema in the Emergency Department. J Emerg Med 2021;60(1):35–43.
14. Maurer M, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update World Allergy Organ J. 2022;15(3):100627.
15. Ghazi A, Grant JA. Hereditary angioedema: epidemiology, management, and role of icatibant. Biologics. 2013;7:103–113.
16. Sabharwal G, Craig T. Pediatric hereditary angioedema: an update. F1000Research. 2017; 6:1205.

About hereditary angioedema (HAE)

HAE is a rare and potentially life-threatening genetic disorder characterized by recurrent episodes of severe swelling (angioedema) in various parts of the body, such as the hands, feet, genitals, stomach, face, and/or throat. [10-15] In many cases, the disease manifests during adolescence, and the worldwide prevalence of this rare disease is estimated at 1 in 50,000. [14-16]

About Donidalorsen

Donidalorsen is an investigational ligand-conjugated antisense RNA (LICA) drug that targets the production of prekallikria (PKK), which plays a key role in activating inflammatory mediators associated with acute attacks of hereditary angioedema (HAE). By reducing PKK production, donidalorsen could be an effective prophylactic approach to preventing HAE attacks.

About Otsuka

Otsuka Pharmaceutical is a global healthcare company with the corporate philosophy: „Otsuka – people creating new products for better health worldwide.” Otsuka researches, develops, manufactures, and markets innovative products, focusing on medicines for areas of high unmet medical need and nutritional supplements to support health in everyday life. In the pharmaceutical field, Otsuka is a leader in the challenging area of mental health and has research programs for several diseases with unmet medical needs, including tuberculosis, a significant global public health problem.

Otsuka Europe employs approximately 500 people and focuses on psychiatric and neurological disorders, infectious diseases, nephrology, oncology, rare diseases, and digital medicine. Otsuka Pharmaceutical Europe Ltd. is part of Otsuka Pharmaceutical Company Ltd., a subsidiary of Otsuka Holdings Co. Ltd., headquartered in Tokyo, Japan.

Otsuka Group companies employ 34,388 people worldwide, with total sales of approximately €13.27 billion and research and development expenditures of €2 billion in 2023. Further information about Otsuka can be found at [website address]. www.otsuka.de.

About Ionis Pharmaceuticals, Inc.

For three decades, Ionis has been developing medicines to offer people with serious illnesses a better future. Ionis currently has five marketed medicines and a promising pipeline of drugs in late-stage clinical development, particularly in the areas of cardiovascular medicine and neurology. As a pioneer in RNA-directed therapies, Ionis continues to advance this innovation and is also developing new approaches in gene editing. A deep understanding of disease biology and industry-leading technologies drive Ionis' work, coupled with the passion and necessity to deliver life-changing improvements for patients. For more information about Ionis, please visit [website address]. Ionispharma.com.