In short
Recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1 is an investigational protein-based substance being developed for the treatment of myasthenia gravis. It is a solution for infusion given intravenously and has no marketing authorisation. One clinical trial is registered in the EU Clinical Trials Information System: a Phase 1/2 first-in-human study in generalised myasthenia gravis involving 55 participants.
Key points
- Phase 1/2 first-in-human trial in generalised myasthenia gravis
- 55 participants planned in a double-blind, randomised, placebo-controlled design
- Given as an intravenous solution for infusion
- Main goal: safety and tolerability, including immune-related adverse events
- Trial status: authorised in the EU registry
- Substance has orphan designation from the European Medicines Agency
What is recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1?
Recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1 is an investigational protein-based substance. It is classified as a protein of non-chemical origin and is being developed as a potential treatment for myasthenia gravis. The substance has no marketing authorisation in the product records and is therefore not an approved medicine.
The European Medicines Agency granted orphan designation EU/3/19/2187 on 25 July 2019 to Toleranzia AB, Sweden, for this substance in the treatment of myasthenia gravis. Orphan designation is given to medicines intended for rare diseases; at the time of designation myasthenia gravis affected approximately 1.7 in 10,000 people in the European Union, equivalent to around 88,000 people.
How does recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1 work?
Myasthenia gravis is an autoimmune disorder in which the immune system attacks and damages acetylcholine receptors on muscle cells. For a muscle to contract, a substance called acetylcholine is released from a nerve and attaches to the acetylcholine receptors on the muscle cells. In myasthenia gravis, because of the damage to these receptors, the muscles cannot contract normally.
The recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1 is designed as an immune tolerising agent. The aim of this approach is to induce immune tolerance, meaning the immune system becomes less reactive to the acetylcholine receptor, rather than broadly suppressing the immune system. The registered trial describes the substance as TOL2, an immune tolerising agent.
Which conditions is it used or studied for?
- Generalised myasthenia gravis — the only condition in the registered trial. This is a long-term autoimmune disease causing muscle weakness and tiredness, and it may be life-threatening when the muscles involved in breathing are affected.
How is recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1 given?
The substance is formulated as a solution for infusion and is given by intravenous administration. In the registered trial, the substance is administered intravenously alongside other medicines including prednisolone tablets, normal human immunoglobulins for intravascular administration, glucose solutions, and albumin.
What do the clinical trials show?
One trial is registered in the EU Clinical Trials Information System under the number 2024-515627-10-00. It is a double-blind, randomised, placebo-controlled, first-in-human Phase 1/2a multi-centre trial designed to assess safety, tolerability, and immune response of single and multiple ascending doses of TOL2 in patients with generalised myasthenia gravis.
The trial plans to enrol 55 participants and its status is authorised. The primary outcomes focus on safety: the incidence and severity of adverse events using Common Terminology Criteria for Adverse Events version 5.0, with special attention to exacerbation of myasthenia gravis or myasthenic crisis, immune-complex related adverse reactions, and cytokine release syndrome, which are considered adverse events of special interest. Other primary outcomes include local tolerability reactions at the infusion site, signs of vascular toxicity, changes in vital signs, electrocardiogram findings, safety laboratory parameters, physical examination findings, and use of concomitant medications including rescue medication.
The trial specifically targets AChR antibody seropositive myasthenia gravis patients. Because the trial is first-in-human, no efficacy results are available yet; the main purpose is to establish safety and tolerability in people.
What side effects are known?
Because the substance is still in early clinical development, no side effect profile has been established from completed trials. The registered trial is designed to detect adverse events of special interest, including exacerbation of myasthenia gravis or myasthenic crisis, immune-complex related adverse reactions, and cytokine release syndrome. The published research article describes the substance as a promising new drug candidate for treatment of myasthenia gravis but does not report a side effect profile from human trials.