Validating a revolutionary therapy against lethal haemorrhage 

Blood cells

A public-private consortium formed by the biotech Hemostatics, based at the Barcelona Science Park, the Clínica Universidad de Navarra (CUN) and the Institute of Chemical Research of Catalonia (ICIQ), has received €2.5 million from the Spanish Research Agency (AEI), under the call for grants for Public-Private Collaboration Projects, to accelerate the development of an innovative treatment aimed at controlling disabling and lethal haemorrhage. 

The aim of the project is the preclinical and clinical development of the antifibrinolytic agent CM-352, a first-in-class drug that represents a pioneering therapeutic approach to control severe bleeding in unmet medical needs, such as those associated with major surgery, trauma or intracranial haemorrhage (ICH).

The CM-352 compound is the result of a long research process led by Dr Josune Orbe (CSO of Hemostatics), Head of the CIMA’s Atherothrombosis research group, and Dr José Antonio Páramo (CMO) of the Haematology Service of the Clínica Universidad de Navarra and member of the Spanish Society of Thrombosis and Haemostasis (SETH).

Until now, the total capital raised to develop the compound amounts to €3 million, including €0.3 million from the CDTI’s Neotec programme received in 2022, plus other private funds.  

A global health and economic issue

Haemorrhage accounts for up to 50% of trauma deaths occurring worldwide within 24 hours of traumatic injury, according to SEMICYUC-Spanish Society of Intensive and Critical Care Medicine and Coronary Units, and up to 80% of intraoperative trauma mortality. It is a very common complication in cardiovascular patients, or patients with certain rare genetic diseases, as well as in different clinical situations, such as surgeries, or postpartum haemorrhage, which is estimated to affect 14 million women each year and represents the world’s leading cause of maternal death, according to WHO, with some 70,000 deaths annually. 

“The socio-economic cost of acute bleeding in trauma cases alone is enormous and causes more than six million deaths per year (more than all communicable diseases combined, including Covid-19, malaria, tuberculosis, HIV/AIDS, etc), and is responsible for a total cost of over $670 billion in the United States alone. However, an antihaemorrhagic agent, that can address the unmet medical needs of severe haemorrhagic processes and minimise the risk of possible side effects in the face of less severe haemorrhagic episodes, has not yet been found,” said Nicolas Saglio. “Our compound, CM-352, in addition to reducing this major burden of morbidity and mortality, will significantly reduce the healthcare cost of annual expenditure on blood and transfusion-related activities.” 

Public-private partnership to create a next generation antifibrinolytic

CM-352 is a drug with a completely innovative mechanism of action, as it targets cessation of bleeding by inhibiting matrix metalloproteinases (MMPs), a revolutionary pharmacological strategy that promises to be more effective and safer than the current standard antifibrinolytics (TXA and EACA) used in clinical practice to control acute bleeding. 

The regulatory preclinical phase will be coordinated by Hemostatics and will involve the integration of the efforts of the Atherothrombosis Research Group (CIMA), led by Dr Josune Orbe, the UT Health University of Houston and other organisations. 

“We already have experimental results indicating that CM-352 is highly effective in all major bleeding scenarios, with no signs of toxicity, thrombosis, or off-target adverse effects. We will now complete efficacy, toxicity, pharmacodynamic and pharmacokinetic studies in several preclinical models required by regulatory agencies. Obtaining these results will allow us to reach a key milestone of the project: approval from the health authorities to test CM-352 in a Phase I clinical trial. Our initial focus will be on the US FDA. Subsequently, we will also go to the EMA in Europe, and everything will be done in close collaboration with the Spanish agency, the AEMPS,” Saglio explained. 

Through the Innovation and Valorisation Laboratory and the High Throughput Experimentation (HTE Laboratory), the ICIQ will address the identification and optimisation of a CM-352 synthesis route that improves the efficiency and reduces the cost of the production process of the molecule. The team involved in the project will be led by Dr Fernando Bravo, Manager of the Knowledge and Technology Transfer Department (KTT) and Industrial Projects, and Dr Xisco Caldentey, Manager of HTE. 

“The current synthesis route of CM-352 has enabled us to obtain sufficient compound quantities to progress through the preclinical phases, and ICIQ’s involvement will focus on developing a synthetic process with a new optimised synthesis route, which also allows for robust, reproducible scaling with safety guarantees. This objective will be addressed through a combination of intelligent catalyst design and high-performance parallelisation techniques for reaction optimisation. In this regard, techniques involving the screening of hundreds of reactions using automated analysis systems will be applied, such as the one available at ICIQ’s HTE Laboratory, a unique facility in Spain, with few similar models worldwide. The selection of the final synthetic route for obtaining CM-352 will be based on techno- economic criteria (cost/kg), including the relative cost of purification processes, efficiency, safety, and minimisation of environmental impact, thereby facilitating its future industrialisation and commercialisation,” said Dr Bravo. 

Finally, the CM-352 Phase I trial will involve the active participation of CUN, with technical support from CIMA and will focus on severe haemorrhage in traumatology, where there is no treatment with proven clinical efficacy. The study will be carried out by the Haemostasis and Thrombosis Unit of the Haematology Department and the Department of Orthopaedic Surgery, under the coordination of Dr José Antonio Páramo. 

“Our objective will be to evaluate the tolerance and safety of CM-352 in patients undergoing scheduled total knee replacement surgery (total knee arthroplasty) to prevent possible haemorrhagic complications, which constitute a serious associated adverse event. This represents a very important milestone in the compound’s development since, in existing literature, no clinical study has reported the use of MMP inhibitors to treat haemorrhages. The absence of toxicity and secondary effects after treatment with CM-352 will also represent the first time such results are obtained for an MMP inhibitor in humans, allowing us to move to a Phase II focused on severe haemorrhages in traumatology, where there is currently no treatment with proven clinical efficacy,” noted Dr Páramo. 

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