Alsymo aims to treat patients with pulmonary hypertension

Innovation Article published on 13 September 2023 , Updated on 16 January 2024

Many patients suffering from pulmonary arterial hypertension, a rare and incurable disease, progress to treatment failure. To slow the progression of this pathology, a close-knit team of scientists, founders of the start-up Alsymo, are focusing on a drug that acts on pulmonary vascular N-methyl-D-aspartate (NMDA) receptors.

Approximately 50 out of every million adults suffer from pulmonary arterial hypertension (PAH), a rare and incurable disease. This pathology causes an uncontrolled proliferation of vascular cells, which obstructs the small pulmonary vessels and leads to right heart failure. "This is a highly heterogeneous disease, with several subgroups. The causes are poorly understood. In some cases, there is a genetic, inflammatory or drug-related factor. In all cases, the vascular walls are under attack. Our vessels repair themselves every day, but in PAH patients, this repair evolves into chronic vascular remodelling," explains Sylvia Cohen-Kaminsky, a researcher at the Pulmonary hypertension: pathophysiology and novel therapies laboratory (HPPIT - Univ. Paris-Saclay, French National Institute of Health and Medical Research or Inserm) and co-founder of Alsymo. The current therapies available are vasodilators that treat the symptoms, but do not tackle disease progression. In the event of therapeutic failure, heart-lung or double lung transplantation is the last recourse, but is only possible for 50% of patients.

 

The origins of Alsymo

In 2011, biologist Sylvia Cohen-Kaminsky met Mouad Alami, a specialist in medicinal chemistry at the Faculty of Pharmacy, Université Paris-Saclay. A meeting between these two scientists from different disciplines proved decisive: they came up with the idea of designing N-methyl-D-aspartate (NMDA) receptor antagonists that would inhibit the vascular remodelling mechanism. "NMDA receptors (NMDARs) were already known to be essential in the central nervous system for memory, synaptic plasticity and learning. Our recent studies show their involvement in pulmonary vascular remodelling leading to PAH. They are in fact expressed and engaged in proliferating cancer cells, in the same way as in vascular cells in the case of this pathology," develops Sylvia Cohen-Kaminsky. NMDARs are not confined to the central nervous system. They are also present in peripheral organs, including the lungs.

The two scientists continued their studies under the LERMIT Laboratory of Excellence (LabEx), and in 2014 the project was awarded the Medicen label and funding from the French National Research Agency (ANR). The project also won the 1st call for POC-in-Lab Paris-Saclay prematured projects. Two years later, renamed NUTS-MAT, it was selected by SATT (Acceleration Company for Technology Transfer) Paris-Saclay for technological maturation support. The project has benefited from an investment of €652,000. That same year, Alain Pruvost, an engineer in the Drugs and Technologies for Health department (MTS - Univ. Paris-Saclay, Alternative Energies and Atomic Energy Commission or CEA, French National Research Institute for Agriculture, Food and Environment or INRAE) and a specialist in pharmacokinetics and metabolism [DMPK/ADME], joined the team. The start-up, named Alsymo, was created in September 2022. Rémi Delansorne, experienced in biopharmaceutical R&D and corporate strategy, took over as CEO. On 21 December 2022, Alsymo signed an exclusive worldwide license agreement with SATT Paris-Saclay.

 

A selective drug candidate

The project faced a major challenge: ensuring the selectivity of the drug candidate. As Alain Pruvost explains: "If we want to avoid side effects, our molecule must not cross the blood-brain barrier and end up in the central nervous system." And Sylvia Cohen-Kaminsky adds: "We have shown that when our drug candidate is administered in animals, NMDA receptors in other organs are not affected. This is linked to the fact that there are locks in the activity of these receptors. They have to be engaged, the channel has to be open for the drug to enter, which is very selective." The team verified the selectivity of its drug candidate through in vivo and in vitro tests, and confirmed that it does not end up in the brain, but rather in the lung, the target organ.

"Our drug candidate binds to the NMDA receptor in the vascular wall and is able to inhibit this abnormal proliferation of pulmonary vascular cells. Our antagonist is capable of reversing the process, restoring healthy pulmonary arteries in animals and thus lowering pulmonary pressure," adds Mouad Alami. Given the results obtained in the animal model of acute PAH, this drug candidate is proving promising.

 

Working hand in hand with the PAH reference centre

"Our other advantage is that we are backed by the national reference centre for pulmonary hypertension, in conjunction with pulmonologists Marc Humbert, David Montani and Olivier Sitbon of Bicêtre Hospital. They have world-class credentials in this field," explains Sylvia Cohen-Kaminsky. By monitoring patients, the centre's clinicians have identified a sub-group representing 10% of patients who fail to respond to vasodilators, or even develop pulmonary oedema under treatment. These people are, therefore, unmedicated and on the super-urgent lung transplant list. The researcher continues: "Our innovation also lies in having identified these patients, who represent a unique opportunity to test our drug candidate in the absence of any other treatment. We won't have to prove that our molecule is more effective than the vasodilators used in other patients. It's a highly differentiating positioning."

 

Phase II in 2027

While Alsymo was created at an already advanced stage of technological development (TRL 4), the aim now is to pass the regulatory pre-clinical milestones, and then begin Phase I clinical trials in healthy volunteers within 24 to 30 months. "This will be followed by two Phase II trials, one in the most severe form of PAH, called pulmonary veno-occlusive disease, where people have no treatment, and the other in common PAH," explains Mouad Alami. For the project to be successful, the start-up plans to raise funds to finance the preclinical and phase I clinical phases, which require ten million euros. Alsymo's CEO explains: "We don't want to register and market the treatment ourselves. Our aim is to focus on development with a view to achieving clinical proof of concept at the end of phase II, which will enable us to enter into licensing agreements with one or more pharmaceutical companies. They will then carry out phase III trials, which are very costly, and launch the product on the market."

Sylvia Cohen-Kaminsky adds: "We were able to benefit from the entire Paris-Saclay innovation ecosystem, and meet some fantastic people. Our insights, skills and links with the PAH reference centre have enabled us to develop three levels of innovation: the identification of the NMDAR therapeutic target in the vascular remodelling process, the development of the selective NMDAR antagonist drug candidate and the design of clinical trials including, as a priority, the niche of patients with a severe form." And Mouad Alami concludes: "It's a wonderful adventure, combining chemistry and alchemy."

 

Publications:

 

Patents:

  • Novel adamantane and memantine derivatives as peripheral NMDA receptor antagonists - No. WO2017017116 - 02/02/2017
  • Novel dizocilpine derivatives as peripheral NMDA receptor antagonists - No. WO2017017116 - 21/12/2017