Clinical Pharmacology Corner: FDA Approves VENCLEXTA™ (venetoclax)

FDA Approves VENCLEXTA™ (venetoclax) for the Treatment of Patients with Chronic Lymphocytic Leukemia with 17p Deletion as Detected by an FDA Approved Test, Who have Received at Least One Prior Therapy

On April 11, 2016, the U.S. Food and Drug Administration (FDA) approved VENCLEXTA (venetoclax) oral tablets under accelerated approval regulations 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. The approved recommended dosage is achieved through a 5-week (WK) ramp-up dosing schedule beginning with 20 mg once daily for 7 days (WK1), followed by a weekly dosage increases (i.e., 50 mg (WK2), 100 mg (WK3), 200 mg (WK4), and 400 mg (WK5)) to the recommended daily dose of 400 mg. This ramp-up is designed to gradually reduce tumor burden (debulk) and decrease the risk of tumor lysis syndrome (TLS). Patient-specific factors for level of risk of TLS should be assessed and prophylactic hydration and anti-hyperuricemics should be provided to patients prior to first dose of VENCLEXTA to reduce the risk of TLS. VENCLEXTA tablets should be taken with a meal and water at approximately the same time each day. VENCLEXTA should be taken until disease progression or unacceptable toxicity is observed. Monitor patients for TLS and neutropenia during the ramp-up and continued phases of treatment and interrupt dosing or reduce dose for toxicities as outlined in the approved product labeling linked below.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)

• MOA: Venetoclax is a selective inhibitor of BCL-2, an anti-apoptotic protein. 
• Dose proportionality: Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg (0.375 to 2 times the approved recommended dosage).
• Absorption: Maximum plasma concentration (Cmax) of venetoclax is reached 5-8 hours after repeat dosing.
• Food effect: Food increases venetoclax exposure by approximately 3-fold (low-fat meal) to 5-fold (high-fat meal).
• Plasma Protein Binding: Greater than 99.9%
• Accumulation: Less than 2-fold
• Terminal half-life: Approximately 26 hours
• Metabolism: Predominantly metabolized by CYP3A4/5 
• Excretion: After single oral administration of venetoclax, greater than 99.9% of the dose was recovered in feces and less than 0.1% of the dose was excreted in urine. Unchanged venetoclax in feces accounted for 20.8% of the administered radioactive dose. 

Drug Interaction Potential

Strong or moderate CYP3A inhibitors

• Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation or during ramp-up phase is contraindicated because the expected increase in venetoclax exposure (i.e., Cmax and AUC) increases the risk for TLS. If a strong CYP3A inhibitor must be used after the ramp-up phase, reduce the VENCLEXTA dose by at least 75% and monitor patients more closely for signs of VENCLEXTA toxicities.
• Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the VENCLEXTA dose by at least 50% and monitor patients more closely for signs of VENCLEXTA toxicities.

Strong or moderate CYP3A inducers: Avoid concomitant use.

P-glycoprotein (P-gp) inhibitors: Avoid concomitant use. If a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50% and monitor patients more closely for signs of VENCLEXTA toxicities.

Narrow therapeutic index P-gp substrates: Avoid concomitant use. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before VENCLEXTA.

Use in Specific Populations

• Renal Impairment: Patients with reduced renal function [Creatinine Clearance (CrCl) less than 80 mL/min] are at increased risk of TLS. These patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA. No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl greater than or equal to 30 mL/min). A recommended dose has not been determined for patients with severe renal impairment (CrCl less than 30 mL/min) or patients on dialysis. 
• Hepatic Impairment: A trend toward increased adverse events was observed in patients with moderate hepatic impairment. Although no dose adjustment is recommended in patients with mild or moderate hepatic impairment, monitor these patients more closely for signs of toxicity during the initiation and ramp-up phase. A recommended dose has not been determined for patients with severe hepatic impairment.
• The following population characteristics were not associated with a clinically meaningful effect on the pharmacokinetics of VENCLEXTA: age (25 to 88 years of age), sex, race, and body weight.

Safety and Efficacy

The efficacy of VENCLEXTA was established in an open-label, single-arm clinical trial of patients with CLL who harbor 17p deletion (missing short arm of chromosome 17) and had received at least one prior therapy (N=106). At the recommended dosage, the efficacy of VENCLEXTA evaluated by ORR as assessed by an Independent Review Committee was 80.2% (95% CI: 71.3%, 87.3%).

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

The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. The most frequent serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, and TLS.

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Full prescribing information is available at http://go.usa.gov/czauz.

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval the Agency's Drugs@FDA website (http://go.usa.gov/cuaZT).

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to the MedWatch Reporting System of the U.S. Food & Drug Administration (FDA) by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov