Chord focuses on clinical-stage programs based on molecules that are well understood and have a history of clinical testing and use in human patients.
The active substance in our lead medicinal product candidate CRD1 is cladribine. Cladribine’s mode of action and safety are well studied and understood. The safety and efficacy of cladribine has been studied in thousands of patients with autoimmune and oncologic diseases.
Cladribine reduces the number of B and T lymphocytes in the body. The reduction of lymphocytes, in particular of memory B cells, is long-term, which is considered to relate to cladribine’s efficacy. The long-term treatment effects are achieved with only a few cladribine administrations.
Cladribine has very limited activity against innate immune cells - another set of white blood cells - which remain available to fight infections. This is thought to avoid immune suppression in patients treated with cladribine. The effect of cladribine is mainly directed towards lymphocytes. The relative selectivity for B and T lymphocytes is due to cladribine’s mode of action.
Cladribine seems particularly suitable for the treatment of diseases that are mediated by a pathological activity of B cells. A pronounced B cell-mediated pathology is the common theme in the rare disorders Chord Therapeutics selected for the development of CRD1.
The safety of cladribine is well studied and does not require extensive monitoring.
Immune reconstitution is a theoretical therapeutic concept where pathogenic auto-reactive B and T cells are removed from the body to allow a more naive immune system to grow back.
The promise of this concept is long-term remission and potentially a partial immune-reset.
The experience from use of cladribine in other autoimmune and oncologic disorders where long-term treatment benefit was seen after short-term treatment, which is compatible with the mode of action of Cladribine, gives reason to believe that cladribine might act as an immune reconstitution therapy.
We hope to be able to transfer this therapeutic concept to the cladribine treatment of neuromyelitis optica spectrum disorders and myasthenia gravis.
In the clinical development program we plan to perform with CRD1 we aim at confirming potential key benefits for the patient.
Treatment with CRD1 will will be very convenient for the patient
CRD1 is an oral drug, there are no injections or infusions required.
CRD1 will be administered for only few days per year, despite resulting in a long-term treatment effect expected to cause disease remission.
Patients can focus on what matters most to them, instead of thinking about the treatment of their disease. Being free from drug for most of the year provides opportunity & flexibility for the patient, like for example planning pregnancy - an important consideration, given that most NMOSD and MG patients are young women.
Cladribine is extremely well-studied in a large patient population
The active substance in CRD1, cladribine, has been studied in several thousand patients with autoimmune and oncologic disorders.
The extensive previous experience in a similar patient population makes it reasonable to assume that the known safety and tolerability attributes of cladribine will translate to other indications treated with CRD1.
Indications are carefully selected to build on cladribine's mode of action
The well-characterised mode of action of cladribine suggests promise for efficacy of CRD1 in diseases with B-cell driven pathology, like NMOSD and MG.
The prospect for potential immune reconstitution with cladribine holds promise of durable treatment benefit.
The active substance in our lead medicinal product candidate CRD1 is cladribine.
Cladribine is a lymphocyte depleting agent, a chlorinated analog of the natural occurring substance deoxyadenosine. Like adenosine, cladribine is taken up by the cell via specialised transporters. Inside the cell, adenosine is either used for energy metabolism or for building DNA and protein.
Adenosine is either broken down by an enzyme called ADA (adenosine deaminase) to be used for the creation of DNA and protein, or activated for use in energy metabolism by an enzyme called DCK (deoxycitidine kinase). DCK adds phosphate groups to make adenosine triphosphate (ATP), the universal energy currency of the cell.
This process of activation is counter-balanced by an enzyme that removes phosphate groups, called 5’-NT (5’-nucleotidase).
As lymphocytes produce a lot of DNA and protein and need a lot of energy, they have high levels of ADA and DCK activity, while 5’-NT activity is low in lymphocytes. Cladribine is resistant to break-down by ADA. Cladribine therefore accumulates in lymphocytes where it is activated by DCK. The high level of activated cladribine is cytotoxic to dividing and resting lymphocytes. The key to selectivity - the prefrential activity of cladribine to deplete lymphocytes - lies in the high ratio of DCK/5’-NT activity unique to lymphocytes.
Cladribine is a chlorinated analog of the natural occurring substance deoxyadenosine.
Cladribine is a lymphocyte depleting agent. The high ratio of DCK vs 5’-NT enzymatic activity makes B & T lymphocytes particularly sensitive to cladribine.