First BCL-2 inhibitor-Venclexta (venetoclax) approved for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality.

On April 11, 2016, the U. S. Food and Drug Administration approved orphan drug venetoclax  for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.

Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.

According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white blood cell. Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth. This chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.

DESCRIPTION

Venetoclax is a selective inhibitor of BCL-2 protein. It is a light yellow to dark yellow solid with the empirical formula C45 H50 ClN7O7S and a molecular weight of 868.44.

2016-04-12

CLINICAL PHARMACOLOGY

Mechanism of Action

  • Venetoclax is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic protein.
  • Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics.
  • Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases.
  • In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.

INDICATIONS AND USAGE

VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

DOSAGE AND ADMINISTRATION

  • Initiate therapy with VENCLEXTA at 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg.
  • VENCLEXTA tablets should be taken orally once daily with a meal and water. Do not chew, crush, or break tablets.
  • Perform prophylaxis for tumor lysis syndrome.

DOSAGE FORMS AND STRENGTHS

Tablets: 10 mg, 50 mg, 100 mg

SAFETY & EFFICACY

The efficacy of Venclexta was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy. Trial participants took Venclexta orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.

 CONTRAINDICATIONS

Concomitant use of VENCLEXTA with strong inhibitors of CYP3A at initiation and during ramp-up phase is contraindicated.

WARNINGS AND PRECAUTIONS

  • Tumor Lysis Syndrome (TLS): Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases.
  • Neutropenia: Monitor blood counts and for signs of infection; manage as medically appropriate. Immunization: Do not administer live attenuated vaccines prior to, during, or after VENCLEXTA treatment.
  • Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue.

DRUG INTERACTIONS

  • Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors, strong or moderate CYP3A inducers, P-gp inhibitors, or narrow therapeutic index P-gp substrates.
  • If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%.
  • If a strong CYP3A inhibitor must be used after the ramp-up phase, reduce the VENCLEXTA dose by at least 75%.
  • If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before VENCLEXTA.

The FDA granted the Venclexta application breakthrough therapy designation,priority review status, and accelerated approval for this indication. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Venclexta also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Venclexta is manufactured by AbbVie Inc. of North Chicago, Illinois, and marketed by AbbVie and Genentech USA Inc. of South San Francisco, California. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular of Des Plaines, Illinois.

Reference:

  1. FDA News
  2. Prescribing Information