SHANGHAI – Beijing-based Beigene Co. Ltd. has shared positive phase I results for BGB-3111, a targeted small-molecule BTK inhibitor to treat B-cell malignancies that Beigene execs believe has the potential to become best in class, beating out ibrutinib (Imbruvica, Pharmacyclics Inc./Johnson & Johnson), the only BTK inhibitor currently on the market in the U.S. and Europe.

Beigene first became well known for its lucrative out-licensing deals with Merck KGaA for BGB-283, a second-generation BRAF inhibitor, and BGB-290, a PARP inhibitor. But BGB-3111 is Beigene's own program. Given that Beigene announced recently the intention to raise $100 million on the Nasdaq, this is a crucial time for the company with a lot at stake. (See BioWorld Today, Oct. 21, 2015.)

The trial data presented at the American Society of Hematology Annual Meeting in Orlando, Fla., came from studies conducted in Australia, a common first stop for innovative Chinese companies seeking to gather clinical data quickly. But Beigene has plans for more than its home market in China and intends to study BGB-3111 in the U.S. as well. (See BioWorld Today, June 24, 2015.)

According to the company, BGB-3111 has higher selectivity against BTK than ibrutinib, which is approved for mantle cell lymphoma and chronic lymphocytic leukemia (CLL) and is currently being evaluated in a phase III trial forWaldenstrom’s Macroglobulinemia patients. If successful, Pharmacyclics LLC and Janssen Biotech Inc., the two companies responsible for developing and commercializing Imbruvica, will gain approval to treat a much wider patient population that currently only has chemotherapy as a treatment option. (See BioWorld Today, Dec. 8, 2015.)

An orally active inhibitor, BGB-3111 covalently binds to the cysteine Cys-481 of BTK, resulting in irreversible inactivation of the kinase. There are nine other kinases in the human genome with a similar cysteine residue, ITK, EGFR and JAK3 to name a few, but BGB-3111 is highly selective against BTK.

Activity against these other kinases is implicated in ibrutinib-associated toxicities such as diarrhea, bleeding and atrial fibrillation. In biochemical and cellular assays, BGB-3111 was more selective than ibrutinib and it is hoped will lead to less severe side effects in patients.

Summing up the importance of the phase I study results, Lai Wang, head of discovery biomarkers and in vivo pharmacology, told BioWorld Today they are operating under three beliefs for BGB-3111. First, that it is highly active in a number of lymphoid malignancies with a favorable safety and tolerability profile to date. Second, that is a very potent BTK inhibitor in the clinic in target suppression, as a result of high drug exposure.

Third, and most important, the study shows sustained and complete BTK inhibition by BGB-3111 in deep disease-relevant tissues, which has not been shown for other BTK inhibitors.

"We believe that better target inhibition in the tissues could potentially lead to improved efficacy," according to Wang.

The trial included a total of 39 patients: 25 from the initial dose escalation component and 14 patients enrolled before Aug. 1 from the ongoing dose-expansion component. The second expansion cohort plans to enroll a total of 100 patients, with 70 patients already dosed as of Nov. 30.

The trial tested BGB-3111 in patients with CLL, mantle cell lymphoma, Waldenström's macroglobulinemia, diffuse large B-cell lymphoma, indolent non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's-like lymphoma.

In the data presented at ASH, no dose-limiting toxicities (DLT) were encountered, and the maximum tolerated dose (MTD) was not reached. BGB-3111 achieved high plasma exposure and complete and sustained BTK inhibition in both circulating and nodal lymphocytes as a single therapy.

Based on the pharmacokinetics, pharmacodynamics, safety and efficacy of BGB-3111 in the dose-escalation phase, 320 mg once daily and 160 mg twice daily are being further explored in the ongoing dose-expansion trial.

There were no drug-related serious adverse events according to Beigene.

"BGB-3111 has demonstrated complete and sustained BTK inhibition in circulating and nodal lymphocytes with a favorable tolerability and safety profile. It has produced rapid and durable responses as a monotherapy in different types of B-cell malignancies," commented Constantine Tam, consultant hematologist at Peter MacCallum Cancer Centre in Australia, and coordinating principal investigator of the study.

The data show that 29 objective responses were observed: three complete responses, one very good partial response and 25 partial responses, as of Oct. 19. All patients who have achieved an objective response remain in the study, free of progression.

However, eight patients discontinued BGB-3111 including six due to disease progression and two due to adverse events related to their underlying malignancy.

Three patients died during the study as a result of disease progression or complications of disease progression.

Beigene is a proponent of taking a combined therapy, and Wang said there are plans to test BGB-3111 in combination with Gazyva (obinutuzumab), a humanized monoclonal antibody and their own internal PD-1 antibody, BGB-A317, in late 2015 or early 2016. They are also looking at expanding the study to further indications.

The abstract Beigene presented has been chosen to be a part of 2016 Highlights of ASH, and the data will be presented in a roadshow of six cities across the U.S. and Canada.

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