Idorsia Ltd Announces the Initiation of Phase 3 Registration Study of Antithrombotic Treatment for Use at the Onset of AMI Symptoms

Idorsia Ltd recently announced the initiation of the Phase 3 registration study “SOS-AMI” to evaluate the efficacy and safety of self-administered subcutaneous selatogrel, Idorsia’s P2Y₁₂ receptor antagonist, in suspected acute myocardial infarction (AMI).

An AMI, or heart attack, is a life-threatening condition that occurs when blood flow to the heart muscle (myocardium) is suddenly decreased or completely cut off by a blood clot in one or more of the coronary vessels. An AMI requires immediate treatment, as any delay in intervention can result in irreversible damage to the heart muscle and adverse clinical outcomes. According to the US Centers for Disease Control and Prevention, each year more than 800,000 persons living in the US will suffer a heart attack.

Although the management of AMI has improved in recent decades, morbidity and mortality associated with AMI remain high. The majority of deaths occur outside the hospital. Early action is crucial for survival and to preserve heart muscle.

Besides aspirin, there are no treatment options currently available for the critical time from onset of AMI symptoms to first medical contact. The development of selatogrel in an autoinjector aims to fulfill this medical gap: upon symptoms suggestive of a heart attack, patients would self-inject selatogrel as early as possible and immediately call for emergency medical help.

Martine Clozel, MD, and Chief Scientific Officer at Idorsia, said “From the moment that symptoms start, the clock is ticking. Thrombus formation is progressing, and ischemia is rapidly causing irreversible damage to the heart. In the initial stages of thrombus formation, platelet aggregation dominates – a process in which the platelet P2Y₁₂ receptor plays a key role. If left untreated, the thrombus will become fibrin rich, at which point platelets have a more limited role in thrombus formation. This suggests that a fast-acting P2Y₁₂ receptor antagonist could cut short the thrombus formation in the initial stages of thrombus formation. Our drug discovery team has created a compound with unique properties that might fill this important therapeutic gap.”

Deepak L. Bhatt, MD, MPH, Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital, Professor of Medicine at Harvard Medical School, and Chair of the Steering Committee for SOS-AMI, commented “P2Y₁₂ receptor antagonists have been used in the treatment of millions of patients globally, and their safety and efficacy profiles are well established. Despite the success of chronic treatment with this class and other effective interventions, patients are still suffering recurrent heart attacks. The idea for patients to self-inject early in the onset of symptoms is truly innovative. The subcutaneous route of administration could overcome the onset delay observed with oral compounds from the same class.”

To be effective, any antithrombotic treatment for use at the onset of AMI symptoms should be rapidly absorbed and potent, acting quickly to inhibit thrombus formation at an early stage. Inhibition should be reversed after a few hours to avoid interfering with later patient management decisions. It must also have an appropriate safety profile for use prior to formal diagnosis of AMI. Selatogrel has the potential to satisfy these necessary conditions.

Selatogrel administered subcutaneously is a potent, highly selective, fast-acting, reversible P2Y₁₂ receptor antagonist. Two published Phase 2 studies, one in patients with chronic coronary syndromes and one in patients with AMI showed fast and reversible inhibition of platelet aggregation. Subcutaneous administration of selatogrel 16 mg has demonstrated a rapid onset of action, within 15 minutes, with the magnitude of the effect extending over approximately 8 hours. Selatogrel was safe and well tolerated in both studies.

In late 2019, Idorsia entered into a global development agreement with Antares Pharma, a US-based leader in autoinjector and rescue pen technologies, to design and customize an autoinjector for selatogrel. The Antares autoinjector was selected for its robustness, reliability, ease-of-use, and emergency-ready capabilities – key characteristics necessary due to the nature of AMI. Idorsia has confirmed the usability of the Antares autoinjector through human factor validation studies.

Idorsia is initiating an international, multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to assess the clinical efficacy and safety of 16 mg selatogrel when self-administered (on top of standard-of-care) upon occurrence of symptoms suggestive of an acute myocardial infarction. The primary efficacy endpoint is the occurrence of death from any cause, or non-fatal AMI after any study treatment self-administration. The study will enroll approximately 14,000 patients who are at high risk of recurrent AMI, at around 250 sites in about 30 countries.

A Special Protocol Assessment has been agreed with the FDA. This indicates the FDA is in agreement with the adequacy and acceptability of specific critical elements of overall protocol design (eg, entry criteria, dose selection, endpoints and planned analyses) for a study intended to support a future marketing application.

In December 2020, the FDA designated the investigation of selatogrel for the treatment of a suspected AMI in adult patients with a history of AMI as a “fast-track” development program. This designation is intended to promote communication and collaboration between the FDA and pharmaceutical companies for drugs that treat serious conditions and fill an unmet medical need.

Guy Braunstein, MD, and Head of Global Clinical Development at Idorsia, added “Selatogrel has a pharmacokinetic and pharmacodynamic profile that results in a fast onset, and short duration of action – making it suitable for administration at the onset of symptoms. It is potent and highly selective for the P2Y₁₂ receptor and was well-tolerated in the Phase 2 studies. Further to these properties, selatogrel is suitable for subcutaneous administration, giving rise to the real innovation in SOS-AMI: self-administration as early as possible after onset of symptoms of a suspected AMI. We are now ready to put selatogrel in the hands of patients and I am looking forward to seeing SOS-AMI progress in the course of the next 2-3 years.”

SOS-AMI has been designed as a patient-centric study in collaboration with patients. Patients participating in SOS-AMI will be trained by qualified professionals appointed at each study site, on how to recognize AMI symptoms, on how and where to self-inject treatment, and to call for emergency medical help immediately. Trainers will use standardized material mirrored across all countries, which has been developed with the support of education experts, feed-back from post-MI patients, and in alignment with current guidelines. The patient is empowered through focused education to take action. In addition, regular interaction is performed by telephone with the designated site trainer, minimizing the burden on the patient, particularly during times of a global pandemic.

Dr. Mary Mooney, Assistant professor at the School of Nursing and Midwifery, Trinity College Dublin, and Member of the Steering Committee for SOS-AMI, commented “I am passionate about patient education and involving patients in their own care. SOS-AMI pushes the boundaries of heart attack care provision. It puts the patient at the center of the study and empowers them to manage their heart attack symptoms. This means that our success will be heavily dependent on patients’ responses, but I believe patients are ready for this challenge. For our part, we are educating patients on how to recognize the symptoms of AMI, how to use the study autoinjector, and to call emergency services after using the study autoinjector. We should strive for a world where slowing or stopping of a heart attack is as simple as a self-injection. We know the potential is there, we just need to see if it can be realized.”

Jean-Paul Clozel, MD, and Chief Executive Officer, concluded “Self-administration is currently used to treat a number of emergent medical conditions – why not AMI? Anyone can have a good idea, but drug innovation happens when a great team with a great compound, takes a great idea and runs with it. With our integrated drug delivery device, the potential to self-administer selatogrel in the critical time period immediately following onset of suspected AMI symptoms could be revolutionary for patients.”

An AMI, or heart attack, is a life-threatening condition that occurs when blood flow to the heart muscle (myocardium) is suddenly decreased or completely cut off. It is usually caused by a blood clot or blockage in one or more of the coronary vessels supplying blood to the heart muscle. An AMI requires immediate treatment and medical attention, as any delay in intervention can result in irreversible damage to the heart muscle. According to the US Centers for Disease Control and Prevention, each year more than 800,000 persons living in the US will suffer a heart attack. The need for an early intervention has been highlighted by the guidelines of the European Society of Cardiology, which identified the prehospital phase as the most critical for high-risk patients and reiterated that efforts must be made to reduce the delay in initiation of treatment in order to reduce death.^[4,5]

Idorsia has completed a multicenter, double blind, randomized, placebo-controlled study assessing the pharmacodynamics, pharmacokinetics, tolerability and safety of a single subcutaneous injection of selatogrel in adults with chronic coronary syndrome. In this study, 346 patients receiving conventional background oral antiplatelet therapy (eg, acetylsalicylic acid, P2Y₁₂ receptor antagonists) were randomized to receive either selatogrel 8 mg, 16 mg or placebo. The primary objective of the study was to characterize inhibition of platelet aggregation relative to placebo after a single subcutaneous injection of selatogrel either in the thigh or in the abdomen at 2 different doses in patients with chronic coronary syndromes.

Idorsia has also completed a multi-center, open-label, randomized, exploratory study to assess the onset of platelet aggregation inhibition after a single subcutaneous injection of selatogrel in adults with acute myocardial infarction. In this study, 48 patients with confirmed diagnosis of AMI and time from onset of symptoms of more than 30 min and less than 6 hours were randomized to receive either selatogrel 8 mg or 16 mg in addition to conventional antithrombotic treatment (e.g., acetylsalicylic acid, oral P2Y₁₂ receptor antagonists, anticoagulants). The primary objective of the study was to assess the inhibition of platelet aggregation 30 minutes after a single subcutaneous injection of selatogrel in patients with AMI.

Platelet adhesion, activation and aggregation play a pivotal role in atherothrombosis. An essential element in the platelet activation process is the interaction of adenosine diphosphate (ADP) with the platelet P2Y₁₂ receptor. This platelet activation and aggregation can be inhibited by antagonizing the platelet P2Y₁₂ receptor. This prevents the binding of ADP to the receptor, which reduces platelet aggregation and the reaction of platelets to stimuli of thrombus aggregation.

Antares Pharma, Inc. is a specialty pharmaceutical company focused primarily on the development and commercialization of pharmaceutical products and technologies that address unmet needs in targeted therapeutic areas such as urology and endocrinology. The company has a portfolio of proprietary and partnered commercial products with several product candidates in various stages of development, as well as significant strategic alliances with industry leading pharmaceutical companies.

Idorsia Ltd is reaching out for more – We have more ideas, we see more opportunities and we want to help more patients. In order to achieve this, we will develop Idorsia into a leading biopharmaceutical company, with a strong scientific core. Headquartered near Basel, Switzerland – a European biotech-hub – Idorsia is specialized in the discovery, development and commercialization of small molecules to transform the horizon of therapeutic options. Idorsia has a broad portfolio of innovative drugs in the pipeline, an experienced team of professionals covering all disciplines from bench to bedside, state-of-the-art facilities, and a strong balance sheet – the ideal constellation to translate R&D efforts into business success. Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June 2017 and has over 900 highly qualified specialists dedicated to realizing our ambitious targets.