• FDA removed the partial clin­i­cal hold based upon agree­ment on revisions to the CANOVA study protocol, in­clud­ing new risk mitigation measures, protocol-specified guidelines and updated futility criteria
• The t(11;14) genetic bio­marker is among the most common and routinely tested genetic ab­nor­mal­i­ties in patients with multiple myeloma¹

North Chicago, IL (Press Release) – AbbVie (NYSE: ABBV), a research-based global bio­pharma­ceu­tical com­pany, today announced that the U.S. Food and Drug Admin­istra­tion (FDA) has lifted the partial clin­i­cal hold placed on CANOVA (M13-494), a Phase 3 trial eval­u­ating veneto­clax (VENCLEXTA® OR VENCLYXTO®) for the inves­ti­ga­tional treat­ment of re­lapsed / refractory multiple myeloma. The CANOVA trial eval­u­ates veneto­clax in com­bi­na­tion with dexa­meth­a­sone versus poma­lido­mide in com­bi­na­tion with dexa­meth­a­sone in patients with re­lapsed / refractory multiple myeloma pos­i­tive for the translocation (11;14) ab­nor­mal­ity. The t(11;14) genetic bio­marker is among the most common and routinely tested genetic ab­nor­mal­i­ties in patients with multiple myeloma.¹

The FDA removed the partial clin­i­cal hold based upon agree­ment on revisions to the CANOVA study protocol, in­clud­ing new risk mitigation measures, protocol-specified guidelines and updated futility criteria. Enrollment in the CANOVA trial may resume as de­ter­mined by each par­tic­i­pant site based on the approved protocol.

All other clin­i­cal trials eval­u­ating veneto­clax in patients with multiple myeloma remain on partial clin­i­cal hold while next steps con­tinue to be eval­u­ated with the agency. The partial clin­i­cal hold does not impact any of the approved indi­ca­tions for veneto­clax, such as chronic lym­pho­cytic leukemia (CLL) or acute myeloid leukemia (AML). AbbVie remains confident in the benefit / risk profile of veneto­clax in those approved indi­ca­tions.

"We are pleased to move for­ward with the CANOVA study which, with the t(11;14) bio­marker test, can help identify patients who may respond better to treat­ment and add clarity for physicians when choosing a ther­apy, if approved," said Mohamed Zaki, M.D., Ph.D., global head of hematology devel­op­ment, AbbVie. "We are work­ing closely with regu­la­tory author­i­ties world­wide to con­tinue our efforts to under­stand the poten­tial of veneto­clax for patients with multiple myeloma while continuing to ad­vance research in patients with the t(11;14) genetic ab­nor­mal­ity."

Results from the Phase 3 BELLINI trial eval­u­ating patients with re­lapsed / refractory multiple myeloma were presented at the 24th European Hematology Association (EHA) Annual Congress during the late-breaking oral presentation session on Sunday, June 16. Additional data will be presented at a future congress or published in a medical journal.²

In March 2019, AbbVie announced the FDA placed a partial clin­i­cal hold on all trials eval­u­ating veneto­clax for the inves­ti­ga­tional treat­ment of multiple myeloma, fol­low­ing a review of data from the Phase 3 BELLINI trial of veneto­clax with bor­tez­o­mib and dexa­meth­a­sone (Ven + Vd) versus placebo (placebo + Vd) in patients with re­lapsed / refractory multiple myeloma, in which a higher proportion of deaths (41/194 (21%)) was observed in the veneto­clax arm com­pared to the control arm of the trial (11/97 (11%) — over­all survival hazard ratio (HR) 2.027, 95% con­fi­dence in­ter­val (CI): [1.042, 3.945]). Progressive disease was the most common cause (45%) of death. The rates of serious adverse events (AEs) (48% vs 50%) and serious in­fec­tions (28% vs 27%) were com­parable be­tween arms.²

Venetoclax is not approved by any regu­la­tory authority, in any country, for the treat­ment of multiple myeloma.

Despite the avail­a­bil­ity of multiple myeloma ther­a­pies, there is no optimal treat­ment sequence.³ Nearly all multiple myeloma patients eventually relapse, which is asso­ci­ated with poor out­comes, and each remission is typically shorter than the pre­vi­ous one.⁴ Patients with multiple myeloma have an average life ex­pec­tancy of approx­i­mately five to six years after diag­nosis.⁵ It is the second most common blood cancer with nearly 140,000 cases ex­pec­ted to be diag­nosed world­wide this year.^6,7

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 CANOVA

CANOVA is a Phase 3, multi­center, ran­dom­ized, open label study of either veneto­clax or poma­lido­mide in com­bi­na­tion with dexa­meth­a­sone in patients with t(11;14)-positive re­lapsed / refractory multiple myeloma.⁸

About BELLINI

BELLINI is a multi­center, ran­dom­ized, double blind study of either veneto­clax or placebo in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone in patients with re­lapsed / refractory multiple myeloma who have received 1 to 3 prior lines of ther­apy and are sensitive or naïve to pro­te­a­some inhibitors. The study in­cluded 291 patients with 194 in the veneto­clax arm and 97 in the placebo arm.⁹

The BELLINI trial met its pri­mary end­point of im­proved pro­gres­sion-free survival (PFS) (22.4 months vs. 11.5 months, [hazard ratio=0.63, p=0.01]), with a median follow-up of 18.7 months, and dem­onstrated statistically sig­nif­i­cant im­prove­ment in over­all response rate (ORR) (82% vs. 68%, p<0.01) and very good partial or better response (59% vs. 36%, p<0.01) in the veneto­clax arm com­pared to the control arm. Median over­all survival was not reached (HR 2.027, 95% CI (1.042, 3.945)).²

Safety analyses showed the majority of deaths in the veneto­clax arm were related to in­fec­tion and progressive disease. There were 52 deaths in the study pop­u­la­tion, 41 (21%) in the veneto­clax arm and 11 (12%) in the placebo arm, with progressive disease the most common cause (45%). The rates of serious AEs (48% vs 50%) and serious in­fec­tions (28% vs 27%) were com­parable be­tween arms.²

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.¹⁰

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 Information¹⁰

Uses

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.
• Infections. Death and serious in­fec­tions such as pneu­monia and blood in­fec­tion (sepsis) have hap­pened during treat­ment with VENCLEXTA. Your health­care provider will closely monitor and treat you right away if you have a fever or any signs of in­fec­tion 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 obinutuzumab or ritux­i­mab­ or alone in people with CLL or SLL in­clude low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper res­pira­tory tract in­fec­tion; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

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.

Use and Important VENCLYXTO® (venetoclax) EU Safety Information¹¹

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.

Important VENCLYXTO (venetoclax) EU Safety Information

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, com­pe­ti­tion from other prod­ucts, chal­lenges to intellectual property, 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. Anderson, K. C. (2014). Multiple myeloma: NCCN clin­i­cal practice guidelines in on­col­ogy (NCCN Guidelines®).
2. Kumar, et al. EHA 2019 Abstract #LBA2601.
3. Costello, C., & Mikhael, J. R. (2018). Therapy sequencing strategies in multiple myeloma: Who, what and why? Future Oncology, 14(2), 95-99.
4. Myeloma UK. Infopack for re­lapsed and/or refractory myeloma patients. https://www.myeloma.org.uk/wp-content/uploads/2018/03/Myeloma-UK-Infopack-for-relapsed_refractory-myeloma-patients.pdf [ONLINE] Accessed June 14, 2019.
5. SEER Cancer Stat Facts: Myeloma. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/mulmy.html. [ONLINE] Accessed, June 14, 2019.
6. Kazandjian D. Multiple myeloma epidemiology and survival, a unique malig­nan­cy. Semin Oncol. 2016; 43(6): 676-681.
7. Cowan AJ, Allen C, Barac A, et al. Global burden of multiple myeloma: a sys­tematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018; 4(9): 1221-1227.
8. Clinicaltrials.gov (2018). NCT 03539744: A Study of Venetoclax and Dexamethasone Compared With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (CANOVA). Accessed June 14, 2019.
9. 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.
10. VENCLEXTA (venetoclax) [Package Insert]. North Chicago, IL.: AbbVie Inc.
11. Summary of Product Characteristics for VENCLYXTO (venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

Source: AbbVie.