Otsuka announces new results from OASIS-HAE and OASISplus studies of investigational medicine donidalorsen in people with hereditary angioedema

Windsor, United Kingdom, 3rd June 2024 — Otsuka Pharmaceutical Europe Ltd. 

(Otsuka) today announced new results from Ionis’ Phase 3 OASIS-HAE and OASISplus studies of donidalorsen (80 mg) via subcutaneous injection every four (Q4W) or eight 

(Q8W) weeks in people with hereditary angioedema (HAE). Results were presented in three late-breaking oral presentations at the 2024 European Academy of Allergy and Clinical Immunology (EAACI) Annual Meeting in Valencia, Spain (31 May – 3 June 2024). The OASIS-HAE results have also been published in The New England Journal of Medicine (NEJM). 

The OASIS-HAE study demonstrated an 81% lower monthly HAE attack rates with donidalorsen Q4W (n=45) compared to placebo (n=22) over weeks 1 to 25 (p<0.001), and a 55% reduction with donidalorsen Q8W (n=23) versus placebo (p=0.004).1,2 Following completion of the placebo-controlled treatment period in OASIS-HAE, 94% 

(n=83) of eligible patients rolled over to the open-label extension (OLE) cohort of the OASISplus study.3  

Of the patients that enrolled in the OASISplus OLE cohort with up to 53 weeks of treatment with donidalorsen Q4W or Q8W, ≥92% experienced a reduction in mean monthly HAE attack rates when compared to OASIS-HAE baseline.3 

The OASISplus study also included a prospective cohort to assess patients switching from both newer oral and injectable long-term prophylactic treatments to donidalorsen. A total of 64 patients who switched to donidalorsen were included in the OASISplus switch cohort. Results showed a further reduction of 62% in mean monthly HAE attack rates at week 17 compared to baseline, and 84% (n=55) of patients reported a prefer-ence for donidalorsen over their previous prophylactic treatment.4,5    

Donidalorsen was well-tolerated across all studies. There were no serious treatment emergent adverse events (TEAEs) related to donidalorsen, and most adverse events 

(AEs) were mild or moderate in severity. Upper respiratory tract infections, influenza, in-jection site reactions and headache were amongst the most common AEs.1,2,3,4,5

HAE is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face and/or throat.6,7,8,9,10 Donidalorsen is an investigational RNA-targeted prophylactic medicine designed to reduce the production of prekallikrein (PKK), interrupting the pathway that leads to HAE attacks.11 

Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam

University Medical Center said, “These promising results are a positive step forward for people living with HAE who want a further improvement in disease control. High frequency of HAE attacks impacts health-related quality of life and is an unmet need for this patient population.”   

“Results from the Phase 3 OASIS-HAE study and OASISplus cohorts are encouraging,” said Andy Hodge, CEO, Otsuka Pharmaceutical Europe. “Despite the availability of other prophylactic treatments, there is still a high unmet need with a considerable number of patients with HAE reporting that they do not have control of their condition.”  

Otsuka has exclusive rights to commercialise donidalorsen in Europe and is preparing to submit a Marketing Authorisation Application to the European Medicines Agency 

(EMA). Ionis is preparing to submit a New Drug Application with the US Food and Drug Administration (FDA). Donidalorsen has received Orphan Drug Designation in the USA and the EU.12,13

About OASIS-HAE Study 

The global, multicentre, randomised, double-blind, placebo-controlled Phase 3 OASIS-HAE study enrolled 91 participants, aged 12 years and above, with HAE-1 and HAE-2 hereditary angioedema.14 Participants were randomised in a 2:1 ratio to either a 4-week dosing interval or an 8-week dosing interval. Within each dosing interval group, patients were randomly assigned again in a 3:1 ratio to receive subcutaneous injection of 80 mg donidalorsen or placebo. Forty-five patients received donidalorsen Q4W, 23 received donidolorsen Q8W and 22 received placebo.1  

The primary endpoint was the time-normalised number of investigator-confirmed HAE attacks per four weeks from week 1 to week 25 compared to placebo. More than 90% of patients completed the OASIS-HAE study.14 Following completion of the treatment period, over 94% (n=83) of eligible patients entered the Phase 3 OASISplus open-label extension study.2  

The study demonstrated an 81% lower monthly HAE attack rate with donidalorsen Q4W (n=45) compared to placebo (n=22) over weeks 1 to 25 (p<0.001), and a 55% reduction with donidalorsen Q8W (n=23) versus placebo (p=0.004).1 In a key secondary endpoint, at weeks 5 to 25, donidalorsen Q4W dosing (n=45) significantly reduced mean monthly HAE attack rates by 87% (p<0.001) compared to placebo.1 In the same time frame, treatment with donidalorsen reduced moderate to severe attacks per month by 89% for Q4W dosing (n=45) (p<0.001) compared to placebo (n=22).1 Donidalorsen also reduced HAE attacks per every four weeks that required acute therapy by 92% for Q4W dosing (n=45) (p<0.001) compared to placebo (n=22).2 The Q8W dosing arm decreased attack rates by 60% versus placebo from weeks five to 25 (p=0.004), and decreased the rate of attacks requiring acute therapy by 67% (p=0.004).

At week 25, 91% of donidalorsen Q4W patients were well-controlled as measured by the Angioedema Control Test (AECT). Donidalorsen resulted in clinically significant im-provement in quality of life as measured by the Angioedema Quality of Life Question-naire (AE-QoL).1 AE-QoL scores improved by 25 points (Q4W) (p <0.001) compared to placebo. An improvement of six points is considered clinically meaningful. Similarly, the Q8W dosing arm improved AE-QoL total score from baseline to week 25 by 20 points 

(p=0.010).1,2 

Donidalorsen was well-tolerated, with no serious TEAEs related to donidalorsen. Most AEs were mild or moderate in severity, and injection site reactions were the most com-mon AE. One patient in the donidalorsen Q8W group discontinued based on investiga-tor recommendation due to patient noncompliance and a TEAE.1,2 

Eligible patients rolled over into the OASISplus study, which consisted of two patient cohorts: an OLE cohort, and a switch cohort.  

About OASISplus Study – Open-Label Extension Cohort  

The Phase 3 OASISplus OLE study is a 53-week global, multicentre study of donidalorsen administered by subcutaneous injection every four weeks (80mg) or every eight weeks (80mg) in patients completing the OASIS-HAE study. These are patients aged 12 years and above, with HAE-1 and HAE-2 hereditary angioedema. The study is designed to evaluate the safety and efficacy of extended dosing of donidalorsen following completion of the Phase 3 OASIS-HAE study.15  

Following completion of the placebo-controlled treatment period in OASIS-HAE, 94% 

(n=83) of eligible patients rolled over to the OLE cohort of the OASISplus study.3 Partici-pants from the Q4W and Q8W dosing groups of the placebo-controlled study continued to receive treatment with donidalorsen via subcutaneous injection dosed at intervals of either Q4W (n=69) or Q8W (n=14).3  

Of the patients that enrolled in the OASISplus OLE cohort with up to 53 weeks of treat-ment with donidalorsen Q4W or Q8W, ≥92% experienced a reduction in mean monthly HAE attack rates when compared to OASIS-HAE baseline.3 

Continued treatment resulted in further improved quality of life measures and high levels of disease control in this cohort. At week 25, 91% (42/46) of patients in the Q4W arm and 100% (9/9) of patients in the Q8W arm reported well-controlled disease as meas-ured by the AECT. AE-QoL scores improved by 28 points (Q4W) and 24 points (Q8W) at week 25 compared to baseline in OASIS-HAE. An improvement of six points is con-sidered clinically meaningful.3 

Safety results were consistent with findings from OASIS-HAE, with no serious safety concerns and no patient discontinuations due to TEAEs. Influenza was the most com-mon AE in this cohort.3  

About OASISplus Study – Switch Cohort 

The OASISplus study also included a prospective cohort to assess patients switching from both newer oral and injectable long-term prophylactic treatments to donidalorsen.4 

The OASISplus switch cohort evaluated the safety and efficacy of long-term dosing of donidalorsen every four weeks in patients (n=64) who were previously treated with an-other prophylactic HAE medication (lanadelumab, berotralstat or C1-esterase inhibitor) for at least 12 weeks prior to entering the OASISplus study. Patients followed a pre-de-fined specific protocol to transition from their prior therapy to donidalorsen.5  

Results from a pre-defined endpoint of 17 weeks demonstrated that patients experi-enced a further 62% reduction in mean monthly HAE attack rate at week 17 compared to baseline over their previous prophylactic treatment.5 Eighty-four percent (n=55) of pa-tients who switched reported a preference for donidalorsen over their previous treat-ment, citing disease control, time to administer, and injection site pain or reactions.5 

Quality of life measures also showed continued improvement, with 93% of patients re-porting well-controlled disease compared to 67% at baseline with prior prophylactic treatment.5 Results also demonstrated ≥8-point improvement in AE-QoL scores.  Safety results were consistent with findings from OASIS-HAE, with no serious safety concerns. One patient discontinued due to a TEAE not related to donidalorsen. Upper respiratory tract infection was the most common AE in this cohort.5 

About hereditary angioedema (HAE)  

HAE is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face and/or throat.6,7,8,9,10 In most cases the disease onset occurs during the teenage years, and the worldwide prevalence of this rare disease is estimated to be one in 50,000.10,16 

About donidalorsen11 

Donidalorsen is an RNA investigational ligand-conjugated antisense (LICA) medicine designed to target the production of prekallikrien (PKK), which plays an important role in activating inflammatory mediators associated with acute attacks of hereditary angioedema (HAE). By reducing the production of PKK, 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 pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs in several under-addressed diseases including tuberculosis, a significant global public health issue. 

Otsuka Europe employs around 500 people and focuses on psychiatric and neurologic disorders, nephrology and immunology, haemato-oncology, and digital therapeutics. Otsuka Pharmaceutical Europe Ltd. is a part of Otsuka Pharmaceutical Company, Ltd., a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan.   

The Otsuka group of companies employ approximately 34,400 people worldwide with consolidated sales of approximately €16 billion and a spend of €2 billion on research and development in 2023. For further information on Otsuka, please visit www.otsuka-europe.com.  

About Ionis Pharmaceuticals, Inc. 

For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels Ionis’ work, coupled with a passion and urgency to deliver life-changing advances for patients. For further information on Ionis, please visit Ionispharma.com.