North Chicago, IL (Press Release) – AbbVie (NYSE: ABBV), a research-based global bio­pharma­ceu­tical com­pany, today announced the U.S. Food and Drug Admin­istra­tion (FDA) has placed a partial clin­i­cal hold on all clin­i­cal trials eval­u­ating veneto­clax (VENCLEXTA®/​VENCLYXTO®) for the inves­ti­ga­tional treat­ment of multiple myeloma. The partial clin­i­cal hold follows a review of data from the ongoing Phase 3 BELLINI trial (M14-031), a study in re­lapsed / refractory multiple myeloma, in which a higher proportion of deaths was observed in the veneto­clax arm compared to the control arm of the trial. As a result of this action, no new patients should be enrolled in any studies of veneto­clax for multiple myeloma until a further analysis of the data is com­pleted. Patients who are cur­rently enrolled in studies and receiving benefit from the ther­apy may con­tinue with treat­ment, after consultation with their physician.

This action does not impact any of the approved indi­ca­tions for veneto­clax, such as chronic lym­pho­cytic leukemia (CLL) or acute myeloid leukemia (AML), and is limited to inves­ti­ga­tional clin­i­cal trials in multiple myeloma. AbbVie remains confident in the benefit / risk profile of veneto­clax in those approved indi­ca­tions.

"We are committed to patient safety and are thoroughly analyzing the results observed in the BELLINI trial. We will con­tinue work­ing with the FDA and world­wide regu­la­tory agencies to determine appro­pri­ate next steps for the multiple myeloma pro­gram," said Michael Severino, M.D., vice chairman and pres­i­dent, AbbVie. "We will con­tinue to further the research and devel­op­ment of veneto­clax and other ther­a­pies with the poten­tial to transform the standards of care in blood cancers."

AbbVie has informed clin­i­cal trial investigators involved in the studies eval­u­ating veneto­clax for the treat­ment of multiple myeloma of the results and will work with them to proceed as appro­pri­ate and in the best interest of each patient who may be receiving benefit from veneto­clax and who elects to con­tinue receiving treat­ment. Additional analyses are ongoing, and data will be published in a peer-reviewed journal and/or presented at a future medical meeting.

Venetoclax is being developed by AbbVie and Roche. It is jointly com­mer­cial­ized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About BELLINI

BELLINI is a multi­center, ran­dom­ized, double blind study of bor­tez­o­mib and dexa­meth­a­sone in com­bi­na­tion with either veneto­clax or placebo in patients with re­lapsed or refractory multiple myeloma who have received 1 to 3 prior lines of ther­apy and are sensitive or naïve to pro­te­a­some inhibitors.¹ The BELLINI study met its pri­mary end­point of pro­gres­sion-free survival (22.4 months vs. 11.5 months, hazard ratio [HR] 0.63, 95% con­fi­dence in­ter­val [CI]: 0.44-0.90) and dem­onstrated statistically sig­nif­i­cant im­prove­ments in over­all response rate (82% vs. 68%) and very good partial response or better (59% vs. 36%) in the veneto­clax arm compared to the control arm.

Patients should talk to their doctor im­medi­ately if they are receiving veneto­clax for the treat­ment of multiple myeloma. For medical-related questions, please call: 1-800-633-9110.

The details of the FDA review of the Phase 3 BELLINI study in­cluded the fol­low­ing safety updates:

• In a pre-planned analysis of the primary endpoint and ranked secondary endpoints, in the venetoclax arm 41 out of 194 (21.1%) deaths were observed, among which, 13 (6.7%) were treatment emergent (HR 2.03, 95% CI [1.042 – 3.945]). Of the 13 treatment-emergent deaths in the venetoclax arm, 8 were attributed by the investigator to an event of infection, and more than half were in the setting of refractory or progressive disease.
• In the placebo arm 11 out of 97 (11.3%) deaths were observed, among which, 1 (1.0%) was treatment emergent (occurred less than 30 days after last dose of study drug).
• The incidence of severe, grade 3-5 toxicity (86.5% vs. 87.5%, investigational vs. control arm) and serious adverse events (48.2% vs. 50.0%) was similar between the two arms. The incidence of infections (Infections and Infestation System Organ Class) was 79.8% in the investigational arm and 77.1% in the control arm. The incidence of pneumonia was 20.7% in the investigational arm and 15.6% in the placebo arm.
• Serious adverse events of infection were reported in 28.0% of patients in the investigational arm and 27.1% in the control arm. Serious adverse events of pneumonia were reported in 14.0% of patients in the investigational arm and 12.5% of patients in the placebo arm. Frequent causes of death not related to disease progression identified in the venetoclax arm were: sepsis, pneumonia, and cardiac arrest.

Patients deriving benefit in all ongoing trials eval­u­ating veneto­clax in multiple myeloma can con­tinue treat­ment, in agree­ment be­tween the individual patient and physician.

About VENCLEXTA®/VENCLYXTO® (venetoclax)

VENCLEXTA®/VENCLYXTO® (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lym­phoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apop­tosis.

VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apop­tosis.²

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly com­mer­cial­ized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the com­pa­nies are committed to BCL-2 research and to studying veneto­clax in clin­i­cal trials across several blood and other cancers.

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, in­­clud­ing the U.S. Venetoclax is not approved by any regu­la­tory authority, in any country for the treat­ment of multiple myeloma. AbbVie, in col­lab­o­ration with Roche, is cur­rently work­ing with regu­la­tory agencies around the world to bring this medicine to addi­tional eli­gible patients in need.

Uses and Important VENCLEXTA® (venetoclax) U.S. Safety Information²

Use

VENCLEXTA is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment.
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
• are 75 years of age or older, or
  • have other medical conditions that prevent the use of standard chemotherapy.
  • It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most im­por­tant in­for­ma­tion I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, in­­clud­ing:

Tumor lysis syn­drome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treat­ment, and may lead to death. Your health­care provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treat­ment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive in­tra­venous (IV) fluids into your vein. Your health­care provider will do blood tests to check for TLS when you first start treat­ment and during treat­ment with VENCLEXTA.

It is im­por­tant to keep your appoint­ments for blood tests. Tell your health­care provider right away if you have any symp­toms of TLS during treat­ment with VENCLEXTA, in­­clud­ing fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS.

Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is in­­creased.

Your health­care provider may delay, de­crease your dose, or stop treat­ment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly in­­creased because of the risk of in­­creased TLS.

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
• Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.

Before taking VENCLEXTA, tell your health­care provider about all of your medical con­di­tions, in­­clud­ing if you:

• have kidney problems.
• have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
• have a history of high uric acid levels in your blood or gout.
• are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
• are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
• are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.

What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These prod­ucts may in­­crease the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, in­­clud­ing:

• Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in com­bi­na­tion with ritux­i­mab­ in people with CLL in­clude low white blood cell counts, diarrhea, upper res­pira­tory tract in­fec­tion, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone in people with CLL/SLL in­clude low white blood cell counts; diarrhea; nausea; upper res­pira­tory tract in­fec­tion; low red blood cell counts; tiredness; low platelet counts; muscle and joint pain; swelling of your arms, legs, hands, and feet; and cough.

The most common side effects of VENCLEXTA in com­bi­na­tion with azacitidine, or decitabine, or low-dose cytarabine in people with AML in­clude low white blood cell counts; nausea; diarrhea; low platelet counts; con­sti­pa­tion; fever with low white blood cell counts; low red blood cell counts, in­fec­tion in blood; rash; dizzi­ness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; in­fec­tion in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your health­care provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more in­for­ma­tion, ask your health­care provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact: www.pparx.org for assistance.

The full U.S. pre­scrib­ing in­for­ma­tion, in­­clud­ing Medication Guide, for VENCLEXTA can be found here. Globally, pre­scrib­ing in­for­ma­tion varies; refer to the individual country prod­uct label for com­plete in­for­ma­tion.

Important VENCLYXTO® (venetoclax) EU Safety Information³

VENCLYXTO (venetoclax) Indication

Venclyxto in com­bi­na­tion with ritux­i­mab­ is indicated for the treat­ment of adult patients with chronic lym­pho­cytic leukaemia(CLL) who have received at least one prior ther­apy.

Venclyxto mono­therapy is indicated for the treat­ment of CLL:

• in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell re­cep­tor path­way inhibitor, or
• in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemo immuno­therapy and a B-cell re­cep­tor path­way inhibitor.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is con­tra­in­di­cated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to in­­creased risk for tumor lysis syn­drome (TLS). Concomitant use of preparations con­taining St. John's wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use

Tumor lysis syn­drome (TLS), in­­clud­ing fatal events, has occurred in patients with pre­vi­ously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes con­sis­tent with TLS that require prompt man­agement can occur as early as 6 to 8 hours fol­low­ing the first dose of VENCLYXTO and at each dose in­­crease. Patients should be assessed for risk and should receive appro­pri­ate prophylaxis, monitoring, and man­agement for TLS.

Neutropenia (grade 3 or 4) has been reported and com­plete blood counts should be monitored throughout the treat­ment period. Serious in­fec­tions in­­clud­ing events of sepsis with fatal out­come have been reported. Supportive measures in­­clud­ing antimicrobials for any signs of in­fec­tion should be con­sidered.

Live vaccines should not be admin­istered during treat­ment or there­after until B-cell re­cov­ery.

Drug Interactions

CYP3A inhibitors may in­­crease VENCLYXTO plasma con­cen­tra­tions. At initiation and dose-titration phase: Strong CYP3A inhibitors are con­tra­in­di­cated due to in­­creased risk for TLS and mod­er­ate CYP3A inhibitors should be avoided. If mod­er­ate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose ad­just­ment recom­men­da­tions. At steady daily dose: If mod­er­ate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose ad­just­ment recom­men­da­tions.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may de­crease VENCLYXTO plasma con­cen­tra­tions. Avoid coadministration with strong or mod­er­ate CYP3A inducers. These agents may de­crease veneto­clax plasma con­cen­tra­tions.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

The most commonly occurring adverse reac­tions (>=20%) of any grade in patients receiving veneto­clax in the com­bi­na­tion study with ritux­i­mab­ were neu­tro­penia, diarrhea, and upper res­pira­tory tract in­fec­tion. In the mono­therapy studies, the most common adverse reac­tions were neu­tro­penia/neutrophil count de­creased, diarrhea, nausea, anemia, fatigue, and upper res­pira­tory tract in­fec­tion.

The most frequently occurring serious adverse reac­tions (>=2%) in patients receiving veneto­clax in com­bi­na­tion with ritux­i­mab­ or as mono­therapy were pneu­monia, febrile neu­tro­penia and TLS.

Discontinuation due to adverse reac­tions occurred in 16% of patients receiving veneto­clax plus ritux­i­mab­ and 9% receiving veneto­clax mono­therapy. Dosage ad­just­ments due to adverse reac­tions occurred in 15% of patients receiving veneto­clax plus ritux­i­mab­ and 2% receiving veneto­clax mono­therapy. Dose inter­rup­tions occurred in 71% of patients treated with the com­bi­na­tion of veneto­clax and ritux­i­mab­.

Specific Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal im­pair­ment (CrCl <30 mL/min) or on dialysis has not been estab­lish­ed, and a recommended dose for these patients has not been determined. VENCLYXTO should be admin­istered to patients with severe renal im­pair­ment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to in­­creased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when admin­istered to a pregnant woman. Advise nursing women to dis­con­tinue breastfeeding during treat­ment.

This is not a com­plete summary of all safety in­for­ma­tion. See VENCLYXTO full summary of prod­uct char­ac­ter­istics (SmPC) at www.ema.europa.eu. Globally, pre­scrib­ing in­for­ma­tion varies; refer to the individual country prod­uct label for com­plete in­for­ma­tion.

About AbbVie in Oncology

At AbbVie, we strive to discover and develop medicines that deliver transformational im­prove­ments in cancer treat­ment by uniquely combining our deep knowledge in core areas of biology with cutting-edge tech­nolo­gies, and by work­ing together with our partners – scientists, clin­i­cal experts, industry peers, advocates, and patients. We remain focused on delivering these transformative ad­vances in treat­ment across some of the most debilitating and widespread cancers. We are also committed to exploring solu­tions to help patients obtain access to our cancer medicines. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and devel­op­ment efforts, and through col­lab­o­rations, AbbVie's on­col­ogy portfolio now consists of marketed medicines and a pipe­line con­taining multiple new molecules being eval­u­ated world­wide in more than 200 clin­i­cal trials and more than 20 dif­fer­en­t tumor types. For more in­for­ma­tion, please visit http://www.abbvie.com/oncology.

About AbbVie

AbbVie is a global, research and devel­op­ment-based bio­pharma­ceu­tical com­pany committed to devel­op­ing inno­va­tive ad­vanced ther­a­pies for some of the world's most complex and critical con­di­tions. The com­pany's mission is to use its expertise, dedicated people and unique ap­proach to inno­va­tion to markedly im­prove treat­ments across four pri­mary thera­peutic areas: immunology, on­col­ogy, virology and neuroscience. In more than 75 countries, AbbVie employees are work­ing every day to ad­vance health solu­tions for people around the world. For more in­for­ma­tion about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram.

Forward-Looking Statements

Some state­ments in this news release are, or may be con­sidered, forward-looking state­ments for pur­poses of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "antici­pate," "project" and similar ex­pres­sions, among others, generally identify forward-looking state­ments. AbbVie cautions that these forward-looking state­ments are subject to risks and un­cer­tain­ties that may cause actual results to differ ma­teri­ally from those indicated in the forward-looking state­ments. Such risks and un­cer­tain­ties in­clude, but are not limited to, chal­lenges to intellectual property, com­pe­ti­tion from other prod­ucts, dif­fi­culties in­her­ent in the research and devel­op­ment process, adverse litigation or gov­ern­ment action, and changes to laws and reg­u­la­tions appli­­cable to our industry. Additional in­for­ma­tion about the economic, competitive, gov­ern­mental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2018 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Com­mis­sion. AbbVie under­takes no obli­ga­tion to release publicly any revisions to forward-looking state­ments as a result of sub­se­quent events or devel­op­ments, except as required by law.

References

1. Clinicaltrials.gov (2018). NCT02755597: A study eval­u­ating venetoclax (ABT-199) in multiple myeloma subjects who are receiving bor­tez­o­mib and dexa­meth­a­sone as standard ther­apy. Accessed March 2019.
2. VENCLEXTA (venetoclax) [Package Insert]. North Chicago, IL.: AbbVie Inc.
3. Summary of Product Characteristics for VENCLYXTO (venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

Source: AbbVie.