Shanghai: Friday, October 30, 2015: Hutchison MediPharma Limited (“HMP”) today announces that it has successfully completed its first-in-human Phase I clinical trial of HMPL‑523. HMPL‑523 is a novel, highly selective and potent small molecule inhibitor targeting spleen tyrosine kinase, also known as Syk, a key component in B-cell receptor signaling.
The first-in-human Phase I study of HMPL‑523 was a dose-escalating study conducted to assess the safety, tolerability and pharmacokinetics of both single and repeat doses of HMPL‑523 in healthy volunteers in Australia. The study began in June 2014, and completed ten single dose cohorts, with eight subjects per cohort, from 5mg single dose through 800mg single dose. In April 2015, we began the multiple ascending dose section of the Phase I study in which HMPL‑523 was administered once daily for 14 consecutive days. We have now completed four dose cohorts, again with eight subjects per cohort, from 200mg multiple dose through to 400mg multiple dose. At 400mg daily, HMPL‑523 drug exposures are well above the predicted efficacious dose level and consequently, we do not intend to escalate further in healthy volunteers.
The preliminary safety profile of HMPL‑523 was in-line with our expectations. Importantly, the off-target side effects such as hypertension, severe diarrhea and neutropenia that were encountered by first generation small molecule Syk inhibitors (e.g. fostamatinib) were not observed with HMPL‑523 in this study. Furthermore, HMPL‑523 exhibited a linear pharmacokinetic profile and a dose dependent suppression of B-cell activation. Full results of the Phase I study will be published in due course.
Christian Hogg, CEO of Hutchison China MediTech Limited said, “We have now established what we believe will be a safe and effective Phase II dose range for the further development of HMPL‑523. This will now allow us to move this important, potentially first-in-class, compound into global Phase II proof-of-concept studies against multiple indications both in autoimmune diseases and oncology.”
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 (“RA”), 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 (“mAb”) 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.
HMPL‑523 is an oral small molecule therapy targeting Syk, a major component in the B-cell signaling pathway. If proven safe and effective, we believe HMPL‑523 will be more attractive due to its convenience of use as compared to the intravenous B-cell receptor blocking mAb rituximab (Roche) and the TNFα blocking mAb drugs like infliximab (Janssen), adalimumab (AbbVie) and etanercept (Amgen/Pfizer). Furthermore, oral small molecules, such as HMPL‑523, are generally cleared more quickly from the body as compared to mAbs thereby reducing the risk of infections which result from sustained suppression of the immune system.
The four mAb therapies discussed above accounted for over $20 billion in aggregate sales in 2014, according to the annual reports of the Companies marketing these drugs, and represented an important part of the total market for RA drugs, which is predicted to reach US$38.5 billion in 2017, according to Visiongain.
About small molecule B-cell signaling pathway inhibitors in immunology
Clinical efficacy in RA has been established by a first generation small molecule Syk inhibitor, fostamatinib (Rigel/AstraZeneca). Unfortunately, poor kinase selectivity, linked to critical off-target side effects such as hypertension, severe diarrhea, and neutropenia limited fostamatinib’s dose and led to failure in Phase III studies and ultimately discontinuation in RA.
We designed HMPL‑523 to be highly selective to eliminate these off-target toxicities thereby creating the opportunity for safe combination with other therapies to maximize efficacy. Furthermore, the pharmacokinetic properties of HMPL‑523 are unique, with pre-clinical studies indicating extensive tissue distribution. We believe high tissue distribution is important, particularly in tissue-oriented autoimmune diseases, and research on HMPL‑523 has confirmed this by demonstrating strong efficacy in RA and lupus pre-clinical models with relatively low plasma concentrations. Consequently, in addition to our planned global Phase II development in RA, we intend to evaluate HMPL‑523 as a treatment for lupus.
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) both received Breakthrough Therapy designation and accelerated approval from the FDA in the U.S. in hematological cancer indications. Given the important role of B-cell receptor signaling in hematological cancer, we intend to initiate a Phase I study in Australia in hematological cancer patients in late 2015.
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.