ASH Highlights BTK Inhibitor Pipeline Advancements: Merck Acquires ArQule for $2.7 Billion to Secure Next-Gen Therapy ARQ 531

Today, Merck & Co., Inc. (MSD) announced that it will acquire ArQule, Inc. for $2.7 billion, along with its flagship innovative oral Bruton’s tyrosine kinase (BTK) inhibitor, ARQ 531. At this year’s American Society of Hematology (ASH) Annual Meeting, advances in BTK inhibitor development were among the key focal points of industry interest. Beigene, Eli Lilly and Company (Lilly), AstraZeneca, and Janssen/AbbVie all presented their latest clinical results for respective BTK inhibitors. Why have BTK inhibitors attracted significant R&D investment from multiple major pharmaceutical companies? Where is the next phase of research in this field headed? Today, the WuXi AppTec content team will share the latest developments in BTK inhibitor development, drawing on the most recent clinical data presented by these companies at the ASH Annual Meeting.

BTK—An Important Target in B-Cell Malignancies

The target of BTK inhibitors, BTK, plays a pivotal role in B-cell receptor (BCR) signaling. BCR signaling not only transmits adaptive immune response signals following contact with specific antigens but also serves a fundamental role in B-cell development. Upon antigen induction, a series of protein interactions and the recruitment of signaling molecules lead to the activation of BTK in response to BCR signals, thereby facilitating processes such as B-cell survival, proliferation, differentiation, and antibody production. In the absence of BTK, BCR signaling is insufficient to induce B-cell differentiation. Mutations in BTK can also result in aberrant BCR signaling responses.

▲Multiple roles of BTK in B-cell signaling (Image source: Reference [7])

As BTK activity primarily affects B cells, it has also become an important target for the treatment of B-cell malignancies. In 2013, the first BTK inhibitor was approved for the treatment of mantle cell lymphoma (MCL). It demonstrated remarkable efficacy in various B-cell malignancies, and its indications rapidly expanded to include chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, marginal zone lymphoma (MZL), and chronic graft-versus-host disease. This “first-in-class” covalent BTK inhibitor, known as Imbruvica (generic name: ibrutinib), is a blockbuster targeted therapy for B-cell malignancies and serves as the cornerstone of numerous combination regimens. At this year’s ASH Annual Meeting, Janssen/AbbVie presented long-term efficacy results of ibrutinib in the treatment of patients with CLL.

In the Phase 3 E1912 clinical trial, 354 previously untreated CLL patients under the age of 70 were randomized to receive either a non-chemotherapy combination regimen of Imbruvica and the anti-CD20 antibody rituximab, or a chemoimmunotherapy regimen consisting of chemotherapy and rituximab. At a median follow-up of 48 months, the Imbruvica/rituximab combination reduced the risk of disease progression or death by 61% compared with the control group (HR=0.39; 95% CI, 0.26–0.57; p<0.0001). Furthermore, the non-chemotherapy regimen significantly improved overall survival compared with the control group (HR=0.34; 95% CI, 0.15–0.79; p=0.009).

If there is any drawback to this BTK inhibitor, it is its significant toxicity and side effects. In this clinical trial, treatment-related adverse events (AEs) of grade 3 or higher occurred in 70% of patients. Although this represents an improvement compared to the chemotherapy combination control group, the impact of these toxic side effects on patients’ quality of life may prevent those requiring long-term medication from continuing treatment. This is one of the reasons why pharmaceutical companies such as AstraZeneca and BeiGene are developing next-generation BTK inhibitors.

New-Generation Covalent BTK Inhibitors: Enhancing BTK Specificity

Covalent BTK inhibitors irreversibly inhibit BTK activity by binding to the cysteine residue (C481) on BTK. However, if they bind to other tyrosine kinases, they may also irreversibly inhibit the activity of these other kinases. This is a major reason for the significant toxicity and side effects associated with Imbruvica. Therefore, AstraZeneca and BeiGene have both developed next-generation covalent BTK inhibitors with greater specificity, aiming to reduce the toxicity and side effects of BTK inhibitors. At the ASH Annual Meeting, both companies presented the latest clinical results of their next-generation BTK inhibitors.

Calquence/Obinutuzumab Combination Significantly Improves Progression-Free Survival in Previously Untreated CLL Patients

AstraZeneca’s Calquence was approved last month in the United States, Australia, and Canada for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This covalent BTK inhibitor exhibits higher specificity for BTK compared with Imbruvica. At the ASH Annual Meeting, AstraZeneca presented clinical results from a study evaluating Calquence in combination with the anti-CD20 antibody obinutuzumab for the treatment of previously untreated CLL patients.

In the Phase 3 ELEVATE clinical trial, with a median follow-up of 28.3 months, Calquence/obinutuzumab combination therapy and Calquence monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively, compared with the chemotherapy/obinutuzumab control group.

▲Key Efficacy Data from the ELEVATE Clinical Trial (Image source: Reference [6])

In terms of adverse events, 11.2% of patients receiving Calquence combination therapy discontinued treatment due to treatment-related side effects.

BeiGene Announces Latest Results from Phase 1/2 Clinical Trial of Zanubrutinib

Brukinsa (zanubrutinib), developed by BeiGene, became the first domestically originated anti-cancer drug from China to receive FDA approval in November this year. Although the approved indication is for mantle cell lymphoma, BeiGene is already conducting multiple clinical trials using Brukinsa to treat patients with CLL/SLL.

Brukinsa is a next-generation oral covalent BTK inhibitor, optimized by BeiGene for enhanced BTK specificity and absorption. At the ASH Annual Meeting, BeiGene presented the latest results from the Phase 1/2 clinical trial of Brukinsa in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The results demonstrated an overall response rate of 95.9% (118/123) at a median follow-up of 29.5 months. Among these responses, the complete response rate was 16.3% (20/123), the partial response rate was 73.2% (90/123), and the partial response rate with lymphocytosis was 6.5% (8/123).

In terms of safety and tolerability, 61.8% of patients experienced at least one grade ≥3 adverse event (AE), and only five patients discontinued treatment due to AEs.

Another challenge facing covalent BTK inhibitors is their requirement to bind to cysteine 481 (C481) in BTK, thereby achieving irreversible inhibition of BTK activity. If a mutation occurs at the C481 site of the BTK protein, the efficacy of covalent BTK inhibitors will be significantly compromised. The C481 mutation is one of the important reasons for acquired resistance in B-cell malignancies. To address this challenge, several companies have begun developing BTK inhibitors capable of overcoming the C481 mutation. At the ASH Annual Meeting, Eli Lilly and ArQule presented preliminary clinical results of their respective investigational BTK inhibitors.

Reversible BTK Inhibitors—Overcoming Acquired Resistance

Eli Lilly and Company presented interim results from its Phase 1/2 clinical trial of the BTK inhibitor LOXO-305 in patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the ASH Annual Meeting. The data demonstrated that LOXO-305 induced objective responses across multiple dose levels in patients who had received various prior therapies and exhibited diverse acquired resistance mechanisms.

LOXO-305 is a highly specific, non-covalent BTK inhibitor acquired by Eli Lilly and Company through its acquisition of the star precision therapy company Loxo Oncology. LOXO-305 can reversibly bind to BTK, maintaining its anticancer activity even in the presence of the C481 acquired resistance mutation, while avoiding off-target effects.

▲Introduction to LOXO-305 (Image source: Eli Lilly and Company official website)

In the Phase 1/2 BRUIN clinical trial, a total of 28 patients were enrolled in five cohorts to receive dose-escalating LOXO-305. The cohort included 16 patients with chronic lymphocytic leukemia (CLL), 8 patients with mantle cell lymphoma (MCL), and patients with other B-cell malignancies. Patients with CLL had received a median of four prior systemic therapies, and 75% had been treated with at least one Bruton’s tyrosine kinase (BTK) inhibitor. Patients with MCL had received at least three prior lines of therapy, and 88% had been treated with at least one BTK inhibitor.

Trial results showed that among 13 evaluable patients with chronic lymphocytic leukemia (CLL), 10 patients responded (8 with partial response and 2 with partial response accompanied by lymphocytosis), achieving an overall response rate of 77%. Patients who achieved response included those who were resistant or intolerant to prior BTK inhibitor therapy, or resistant to prior BCL-2 inhibitor therapy.

▲Efficacy Results of LOXO-305 in the Treatment of B-Cell Malignancies (Image source: Eli Lilly and Company website)

Among the 6 evaluable patients with mantle cell lymphoma (MCL), 1 patient achieved complete response and 2 achieved partial response, resulting in an overall response rate of 50%. Notably, two of the responding patients had previously experienced disease progression following treatment with other BTK inhibitors.

“LOXO-305 has exceeded our expectations,” said Jacob Van Naarden, Chief Operating Officer of Loxo Oncology, a subsidiary of Eli Lilly. “The wide therapeutic index of LOXO-305 enables us to pursue an ambitious development program, including building combination therapies that leverage the drug’s high selectivity.”

ARQ 531, developed by ArQule, Inc., is an oral, potent, and reversible BTK inhibitor capable of inhibiting both wild-type BTK and BTK harboring the C481S mutation. In the Phase 1 clinical trial, a total of 47 patients with relapsed/refractory B-cell malignancies received ARQ 531 at various doses. The dose-escalation study identified 65 mg once daily (65 mg QD) as the recommended dose for Phase 2 clinical trials. At doses >65 mg QD, 8 out of 9 evaluable patients with chronic lymphocytic leukemia (CLL) achieved partial response; among these 8 responders, 7 carried the BTK-C481S mutation. Furthermore, 100% (5/5) of CLL patients who underwent a third scan assessment achieved durable partial responses and remained on treatment.

▲Efficacy of ARQ 531 in Patients with CLL (Image source: Reference [9])

In addition to demonstrating superior efficacy in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), ARQ 531 has also shown promising anticancer activity in the treatment of Richter syndrome, follicular lymphoma, and diffuse large B-cell lymphoma. This innovative BTK inhibitor has also attracted the attention of Merck & Co., Inc. (known as MSD outside the United States and Canada). In a press release announcing the acquisition of ArQule, Inc., Dr. Roger M. Perlmutter, President of Merck Research Laboratories, stated that the acquisition would expand Merck’s research and development pipeline, highlighting ARQ 531 as a compelling investigational therapy for B-cell malignancies.

Conclusion

BTK is a well-validated target for B-cell malignancies. The approval trajectories of Imbruvica, Calquence, and Brukinsa have outlined a clear pathway for indication development, progressing from mantle cell lymphoma (MCL) to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and subsequently to other B-cell malignancies. Advances in the development of next-generation BTK inhibitors indicate that these agents must not only demonstrate robust efficacy but also exhibit improved safety and tolerability profiles, thereby reducing treatment discontinuation due to adverse effects. In addition to enhancing the specificity of covalent irreversible BTK inhibitors, the development of novel reversible BTK inhibitors may represent a promising strategy to overcome acquired resistance (including C481 mutations) while mitigating toxicity.

Patients with B-cell malignancies will be the ultimate beneficiaries of the development and iteration of BTK inhibitors, as they will have more treatment options.

References:

[1] ArQule Announces Final Phase 1 Clinical Data for Its Reversible BTK Inhibitor, ARQ 531, at the American Society of Hematology 2019 Annual Meeting. Retrieved December 9, 2019, from https://www.businesswire.com/news/home/20191209005198/en

[2] Merck to Acquire ArQule, Advancing Leadership in Oncology. Retrieved December 9, 2019, from https://www.businesswire.com/news/home/20191209005234/en

[3] Lilly Presents Interim Clinical Data from LOXO-305 Dose Escalation Trial in B-Cell Leukemias and Lymphomas at the American Society Hematology Annual Meeting. Retrieved December 9, 2019, from https://investor.lilly.com/news-releases/news-release-details/lilly-presents-interim-clinical-data-loxo-305-dose-escalation

[4] BeiGene Announces Clinical Data on BRUKINSA™ (Zanubrutinib) at the 61st American Society of Hematology (ASH) Annual Meeting. Retrieved December 9, 2019, from https://www.globenewswire.com/news-release/2019/12/08/1957589/0/en/BeiGene-Announces-Clinical-Data-on-BRUKINSA-Zanubrutinib-at-the-61st-American-Society-of-Hematology-ASH-Annual-Meeting.html

[5] IMBRUVICA® (ibrutinib) Combination Therapy Data From Two Studies and Long-Term Integrated Analysis Presented at ASH 2019 Show Efficacy and Safety in First-Line Treatment of Chronic Lymphocytic Leukemia. Retrieved December 9, 2019, from https://www.janssen.com/imbruvica-ibrutinib-combination-therapy-data-two-studies-and-long-term-integrated-analysis

[6] CALQUENCE Significantly Prolonged the Time Patients Lived Without Disease Progression or Death in Previously Untreated Chronic Lymphocytic Leukemia. Retrieved December 9, 2019, from https://www.businesswire.com/news/home/20191207005030/en

[7] Sabine Ponader, et al., (2014). Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies. J Clin Oncol, 10.1200/JCO.2013.53.1046

[8] Results from the First-in-Human, Proof-of-Concept Phase 1 BRUIN Trial in Pretreated B-Cell Malignancies for LOXO-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor. Retrieved December 9, 2019, from https://www.loxooncology.com/docs/presentations/LOXO-305-ASH2019-Phase1-8DEC2019-Final-V3.pdf

[9] Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies. Retrieved December 9, 2019, from https://www.arqule.com/wp-content/uploads/ARQ531_ASH2019_vfinal-1.pdf

Original Title: ASH | BTK Inhibitors in Full Bloom: Eli Lilly and BeiGene Announce Latest Results, MSD Acquires Next-Generation Investigational Therapy for $2.7 Billion

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