Shanghai: Friday, January 15, 2016: Hutchison MediPharma Limited (“HMP”) today announces that it has initiated a Phase I trial in Australia in patients with hematological malignancies. HMPL-523 is a novel, highly selective and potent small molecule oral inhibitor targeting spleen tyrosine kinase, also known as Syk, a key component in B-cell receptor signaling. Preparations and site selection began in late 2015 and the first patient was dosed on January 13, 2016. This trial follows the successful completion of a first-in-human Phase I clinical trial in healthy volunteers in October 2015.
The new study is a Phase I, open-label, dose escalation study of HMPL-523 as monotherapy administered orally to patients with relapsed or refractory hematological malignancies who are unable to tolerate standard therapy or for whom there is no effective therapy. Two stages for this study are planned: a dose escalation stage and a dose-expansion stage. The primary objectives of the study are to evaluate safety and tolerability, and to determine the maximum tolerated dose and/or recommended Phase II dose of HMPL-523 in this patient population. Other objectives include the evaluation and characterization of the pharmacokinetics of HMPL-523 and its metabolites, and to make preliminary assessments of the anti-tumor activity of HMPL-523 in certain sub-populations in the dose expansion phase of the trial.
The successful completion of the first-in-human study in healthy volunteers in 2015 has established the safety profile of HMPL-523. HMP now hopes that this Phase I study in hematological malignancies could provide clinical proof-of-concept that modulation of the B-cell signaling pathway through inhibition of Syk will provide patients with a clinical benefit.
About B-cell signaling
As one of the major cellular components of the immune system, B-cells play pivotal roles in several immune system related diseases, such as autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and allergy, as well as hematological cancers (i.e. B-cell malignancies) including lymphoma and leukemia. Targeted B-cell receptor signaling therapies, including monoclonal antibodies and small molecules, have been proven to be clinically effective for the treatment of rheumatoid arthritis as well as B-cell malignancies, leading to scientific and commercial success.
Syk is a key protein involved in the B-cell signaling pathway.
About hematological cancers
Hematological cancers are classified as leukemia (affecting blood and bone marrow), lymphoma (affecting the lymphatic system) and myeloma (affecting bone marrow). According to Frost & Sullivan, there were approximately 954,000 new cases of hematological cancers worldwide in 2014, which is expected to increase to approximately 1.1 million new cases annually by 2020. The global market for hematological cancer treatments is projected to grow from approximately $19.2 billion in 2014 to $25.7 billion by 2020. Treatment of hematological cancers is determined on a case-by-case basis and primarily involves chemotherapy, radiation, targeted therapy and/or stem cell transplantation and, more recently, immunotherapy and gene therapy.
About small molecule B-cell signaling pathway inhibitors in hematological cancer
The advantages of small molecule B-cell receptor signaling therapy has driven research and development by major pharmaceutical companies. Notable success has been achieved in B-cell malignancies in oncology, such as lymphoma and leukemia, where small molecule inhibitors are now being used to target kinases down-stream from Syk in the B-cell signaling pathway, namely Bruton’s tyrosine kinase (“BTK”) and PI3Kδ. In 2013 and 2014, ibrutinib (BTK/AbbVie) and idelalisib (PI3Kδ/Gilead) respectively both received Breakthrough Therapy designation and accelerated approval from the U.S. Food and Drug Administration in hematological cancer indications.
In early clinical studies in hematological cancer, where off-target toxicities are less limiting, several small molecule Syk inhibitors have begun to show promise. Fostamatinib, entospletinib (Gilead) and TAK-659 (Takeda) have all exhibited efficacy against various sub-types of non-Hodgkin’s lymphoma, in either a single agent or combination setting, thereby indicating that Syk is a relevant target for these diseases.
About the HMPL-523 Phase I study in healthy volunteers
HMPL-523 is an oral small molecule therapy targeting Syk. A first-in-human, dose-escalating, Phase I study to assess safety, tolerability and pharmacokinetics of HMPL-523 was completed in healthy volunteers in Australia. HMPL-523 was administered up to 800mg as a single dose and up to 400mg multiple dose in 14 cohorts. The treatment was generally well tolerated without material off-target toxicities. HMPL-523 exhibited a linear pharmacokinetic profile and a dose dependent suppression of B-cell activation.
HMP is a novel drug R&D company focusing on discovering, developing and commercialising innovative therapeutics in oncology and autoimmune diseases. With a team of over 280 scientists and staff, its pipeline is comprised of novel oral compounds for cancer and inflammation in development in North America, Europe, Australia and Greater China. HMP is a subsidiary of Chi-Med. For more information, please visit: www.hmplglobal.com.