A literature review of the patent publications on venetoclax – a selective Bcl-2 inhibitor: discovering the therapeutic potential of a novel chemotherapeutic agent

ABSTRACT

Introduction: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies.

Areas covered: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations, in vitro and in vivo efficacy as well as the therapeutic application of venetoclax.

Expert opinion: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.

KEYWORDS:

• Apoptosis
• bcl-2
• bcl-2 inhibitor
• cancer therapy
• combinational therapy
• venetoclax

Article highlights

• In 2016, the U.S. Food and Drug Administration (FDA) approved venetoclax for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have been previously treated with at least one other therapy and in June 2018, for patients with CLL or small lymphocytic lymphoma (SLL) regardless of 17p deletion, who have received at least one prior therapy. The indications expanded further in November 2018 for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, in combination with azacitidine or decitabine or low-dose cytarabine. Furthermore, venetoclax is approved by the FDA for the treatment of adult patients with CLL or SLL as a first line treatment as of May 2019.

• Bcl-2 protein is an anti-apoptotic protein, which can be overexpressed in malignant cells, prolonging their lifespan, and has been linked to increased relative resistance to multiple chemotherapeutic drugs.

• Combinational treatment with various therapeutic agents: bromodomain inhibitors, Notch pathway inhibitors, vascular disrupting agents, cyclin-dependent kinase (CDK) inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, interleukin receptor-associated kinase-1 (IRAK1) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, phosphoinositide 3-kinase (PI3K) modulators, TRAIL receptor agonist proteins, parvovirus, BH3 peptides, antibodies, and antibody-drug conjugates can be found in patents.

• Combinational treatment has shown a synergistic effect and has proven useful in some cases of drug-resistant cancers.

• Treatment of systemic lupus erythematosus or lupus nephritis with venetoclax delayed the onset of severe proteinuria and significantly prolonged survival of spontaneous murine models of lupus.

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Authors’ contributions

The concept of the manuscript was performed by both authors as well as the design, analysis, interpretation and critical revision. The manuscript was drafted by N Žigart. Both authors agree to be accountable for all aspects of the work.

Declaration of interest

N Žigart was supported by a Ph.D. scholarship from Lek/Sandoz. Z Časar is employed by Lek/Sandoz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This document does not represent an opinion of a patent professional and/or Sandoz entity, and is not to be understood as an evaluation of the validity or protective scope of the patents, or patentability or protective scope of the patent applications, respectively, mentioned therein.

Reviewer disclosure

A reviewer on this manuscript has disclosed that they are an employee of the Walter and Eliza Hall Institute which receives royalty payment from Genentech for venetoclax. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by Lek/Sandoz.