Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation

DISEASE BACKGROUND

Myeloproliferative neoplasms (MPN) are clonal stem cell disorders characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They are associated with decreased survival, thromboembolic complications, hemorrhage and an inherent tendency towards leukemic transformation. About 4-6 of 100'000 residents per year are diagnosed with MPN Currently, MPN are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. Between 5-8% of the remaining ET and PMF patients carry mutations in the thrombopoietin receptor (MPL) and in 10-15% of the patient the mutation remains to be determined. Quantitative tests are now available to follow the mutant allele burden of each of the JAK2, CALR and MPL mutant alleles.

THERAPY BACKGROUND

No curative treatment exists for MPN, possibly with the exception of allogeneic hematopoietic stem cell transplantation (HSCT), which is applicable only in a minority of patients. Currently, treatments for MPN are not very effective, or extremely costly. Hydroxyurea has been the standard of care for many decades. A reduction in thrombotic complications can be demonstrated in "high risk" MPN patients (age >60, presence of a previous thrombotic event), but hydroxyurea has no effect on the course of disease (no remission or substantial reduction of the mutant allele burden). Interferon alpha (IFNα) is a promising treatment for early stage PV and is currently being tested in phase III studies. However, IFNα is not always well tolerated and in phase II studies only a proportion of patients showed a substantial response. Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. Allogeneic HSCT is reserved for patients with PMF with a poor prognostic score. These including the recently developed JAK2 inhibitors reduce the symptoms of the disease, but, with the exception of pegylated interferon alpha (peg-IFNα), have little effect on the size of the neoplastic clone and are unable to induce molecular remissions. Thus, the percentage of mutant allele burden in hematopoietic cells does not change much even with successful treatment when considering symptom reduction. It is generally expected that reduction in the size of the malignant clone, as a surrogate marker of treatment success, will have the potential to reduce morbidity and result in prolonged survival of patients.

NOVEL TREATMENT

The beta-3-sympathicomimetic drug Mirabegron is currently available as Betmiga® and indicated to treat hyperactive bladder. It is available as a slow release tablet in a 25 mg and 50 mg formulation. Sympathicomimetic drugs are known to relax the smooth muscle in several areas of the human body and are therefore used for inhalation in patients with asthma or as described for this drug to relax the smooth muscle of the bladder to treat urge incontinence. β3-Adrenoceptors mediate a negative inotropic effect in human ventricular cardiomyocytes, which is opposite to that of β1- and β2-adrenergic receptors. Unlike beta1/2-mimetics, that have significant cardiovascular side effects (including hypertrophy), beta3-mimetics have been reported to protect from hypertrophy and are only associated with some risk of tachycardia and palpitations in some patients.

Sympathicomimetic agonists in patients with JAK2-mutated MPN

RATIONALE FOR PERFORMING THE TRIAL

MPN is initiated and maintained from a mutated hematopoietic stem cell (HSC). The interplay between the MPN HSCs and the stem cell niche is increasingly recognized as crucial for the biology of the disease. Dr. Simon Méndez-Ferrer et al, previously demonstrated that nestin-positive mesenchymal stem cells (nestin+ MSCs) within the bone marrow niche are innervated by sympathetic nerve fibers and are important in regulating normal HSCs. New findings by Dr. Méndez-Ferrer's laboratory show that these nestin+ MSCs are strongly reduced in bone marrow from patients with MPN.

Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. In vivo depletion of nestin+ cells accelerated MPN progression. Conversely, MPN phenotype could be reversed by compensating for the sympathetic neuropathy by the treatment with a beta-3-sympathicomimetic drug. Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. Thus, treatments with a beta-3 sympathicomimetic agonist corrected the damage inflicted by the MPN clone on the stem cell niche and led to a dramatic improvement of the MPN phenotype. Therefore, beta-3 sympathicomimetic agonists represent a promising novel therapeutic approach to MPN by targeting the stem cell niche rather than the MPN clone itself.

Considering the widely used and established safety track record of beta-3-sympathicomimetic drugs, a phase II study has been selected to test the concept of a beneficial effect of beta sympathicomimetic activity on bone marrow niche cells and through this effect on the disease manifestation in MPN patients.