June 23, 2017

AbbVie Announces Pivotal Phase 2 Trial Evaluating VENCLYXTO™ (venetoclax) in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) with 17p Deletion to be Presented at 22nd European Hematology Association (EHA) Annual Congress

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- First oral presentation of full Phase 2 trial results with overall response rate (ORR), inclusive of complete and partial remission rates(1)

- Results also presented from a separate investigational Phase 1b study in CLL/small lymphocytic leukemia (SLL) patients receiving venetoclax in combination with rituximab after at least one prior therapy(2)

NORTH CHICAGO, Illinois, June 23, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the presentation of results from the pivotal Phase 2 study of VENCLYXTO™ (venetoclax), a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor. VENCLYXTO monotherapy responses in 158 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and 17p deletion showed that 77 percent (95% confidence interval [CI]: 69.9, 83.5) achieved an overall response rate (ORR = complete remission [CR] + complete remission with incomplete marrow recovery [Cri] + partial remission [PR] + nodular partial remission [nPR]) (primary endpoint),1 18 percent achieved a complete remission (CR +CRi) (secondary endpoint), 53 percent achieved a partial remission (PR), 6 percent achieved an nPR,3 and 27 percent achieved blood minimal residual disease (MRD) negativity, as measured by flow cytometry (exploratory endpoint).1 These results, which were based on an investigator assessment, will be presented in an oral session on Sunday, June 25, at the 22nd European Hematology Association (EHA) Annual Congress in Madrid.

VENCLYXTO monotherapy was granted conditional marketing authorization in the EU 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; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.3 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.

"These response rates associated with venetoclax treatment in patients with CLL and 17p deletion who relapsed or were refractory to prior treatments were evaluated in one of the two pivotal studies that were included in the EU summary of product characteristics for VENCLYXTO for use in this patient population," said Prof. Dr. Stephan Stilgenbauer of the Department of Internal Medicine at Ulm University in Germany, who will present the study results at the EHA Annual Congress. "In addition, we are encouraged by the results of the secondary and exploratory endpoints included in this Phase 2 trial."

Design and Results of Pivotal Phase 2 Study Presented at EHA Congress
In the pivotal Phase 2 study, patients with relapsed/refractory CLL harboring 17p deletion received VENCLYXTO 400 mg daily following a four to five-week dose titration phase until they experienced progressive disease or discontinued due to other reasons.1 Assessment of minimal residual disease (MRD) in peripheral blood was performed with the first clinical assessment of complete remission (CR) or partial remission (PR) with nodes less than 2 cm and then every 12 weeks until MRD negativity.1 This means fewer than one CLL cell in 10,000 leukocytes (white blood cells) could be detected.4 A total of 158 study participants had received a median of two prior therapies, and 11 percent had previously received a B-cell receptor signaling inhibitor.1 The median age of study participants was 67 years, and the median duration of VENCLYXTO therapy was 16.7 months (range: 0-34.4).1

An initial analysis of results from 107 patients by an independent review committee showed that VENCLYXTO resulted in an overall response rate (ORR = CR + CRi + PR +nPR) of 79 percent (95% confidence interval [CI]: 70.5, 86.6), a CR +CRi rate of 7 percent, a PR rate of 69 percent, and an nPR rate of 3 percent.3 Subsequently, 51 additional patients were enrolled in a safety expansion cohort.1 Results of the full study cohort of 158 patients showed the investigator-assessed ORR was 77 percent (95% CI: 69.9, 83.5),1 the CR +CRi rate was 18 percent, the PR rate was 53 percent, and the nPR rate was 6 percent.3 Among 18 patients who had received prior BCR inhibitor treatment, the ORR was 61 percent and the CR rate was 11 percent.1 Among the full trial cohort of 158 patients, 27 percent demonstrated MRD negativity (exploratory endpoint) in peripheral blood by flow cytometry.1 A total of 101 patients were evaluable for blood MRD by flow cytometry.1 Progression-free survival (PFS) and overall survival (OS) (secondary endpoints) over 24 months were estimated to be 52 percent and 72 percent, respectively.1

In the study, the most commonly reported adverse events were neutropenia (42 percent), nausea (37 percent), diarrhea (37 percent), anemia (24 percent) and fatigue (22 percent).1 The most common grade 3-4 adverse events were neutropenia (39 percent), thrombocytopenia (15 percent) and anemia (14 percent). Infection rate (77 percent all grades, 22 percent grade 3-4) and spectrum were consistent with the underlying disease.1 The rate of laboratory tumor lysis syndrome (TLS) was 5 percent, with no cases of clinical TLS.1

Phase 1b Venetoclax Data Presented at EHA Congress
Results from an ongoing Phase 1b investigational study of venetoclax were also presented at the EHA Congress. This open-label, multicenter study is evaluating the safety and tolerability of venetoclax in combination with rituximab in patients with relapsed CLL/small lymphocytic leukemia (SLL).5 The primary objectives of this study are to assess the safety profile, determine the maximum tolerated dose, and establish the recommended Phase 2 dose of venetoclax when administered in combination with rituximab.5

This analysis evaluated responses in 49 patients with previously-treated CLL/SLL who were treated with venetoclax and rituximab therapy.2 Patients who achieved CR or MRD negativity could stop therapy and remain on the study. Patients who manifested progressive disease (per iWCLL criteria) while off therapy could re-initiate venetoclax and subsequent rituximab therapy. A total of 21 patients discontinued the study.2 A total of 12 had progressive disease while on therapy (five with Richter's transformation and seven with CLL progression).2 The other nine patients either withdrew consent (five), failed to report for follow-up evaluations (one), discontinued due to adverse events related to venetoclax (one with tumor lysis syndrome and one with worsening peripheral neuropathy) or discontinued due to adverse events considered not related to therapy (one).2 A total of 16 patients stopped venetoclax per protocol.2

In the Phase 1b study, the most commonly reported adverse events were upper respiratory tract infection, neutropenia and mild GI issues. Grade 3-4 adverse events were reported for 37 patients (76 percent); the most common were neutropenia (53 percent), thrombocytopenia (16 percent) and anemia (14 percent).2

As of April 5, 2017, the ORR was 86 percent. 51 percent of patients had achieved an investigator-assessed CR/CRi, 35 percent had achieved PR/nPR, and 59 percent had achieved MRD negativity.2

"We are encouraged by the early results from this Phase 1b study of continuous venetoclax in patients with relapsed/refractory CLL/SLL and in those who received venetoclax in combination with rituximab," said Gary Gordon, M.D., Ph.D., vice president, oncology clinical development, AbbVie. "We remain committed to developing and delivering therapies that address unmet needs in certain patients with CLL."

About VENCLYXTO™ (venetoclax)
VENCLYXTO™ (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukaemia (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; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.3 It is also being evaluated for the treatment of patients with various blood cancer types.3,6,7,8,9  The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.3 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.3

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 with venetoclax, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL and frontline CLL, along with studies in several other cancers.

Venetoclax is currently approved in several countries in Europe, as well as in Argentina, Australia, Mexico, Puerto Rico, Israel, USA, and Canada.  AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Important VENCLYXTO (venetoclax) EU Safety Information

Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase. Concomitant use of preparations containing St. John's wort.

Special Warnings & Precautions for Use
Tumour lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumour 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 for TLS.  Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including IV hydration, frequent monitoring and hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. 

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 were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS. 

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations 
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. 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://abbvieoncology.com.

About AbbVie
AbbVie is a global, research-driven 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 or LinkedIn.

AbbVie Forward-Looking Statements
Some statements in this news release may be 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," in AbbVie's 2016 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.

1 Stilgenbauer S, et al. Venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) with 17p deletion: outcome and minimal residual disease from the full population of the pivotal M13-982 trial. Presented at the 2017 European Hematology Association Congress, June 25, 2017.
2 Anderson MA, et al. Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab. Poster at the 2017 European Hematology Association Congress, June 23, 2017.
3 Summary of Product Characteristics for VENCLYXTO, December 2016.
4 EMA (2014) Guidelines on the use of MRD endpoint in CLL. Accessed June 2017.
5 Clinicaltrials.gov. NCT01682616: A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Accessed June 2017.
6 Clinicaltrials.gov. NCT01994837: A Phase 2 Study of ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed October 2016.
7 Clinicaltrials.gov. NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed October 2016.
8 Clinicaltrials.gov. NCT01328626: A Phase 1 study evaluating the safety and pharmacokinetics of ABT-199 in subjects with relapsed or refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma. Accessed October 2016.
9 Clinicaltrials.gov. NCT01889186: A study of the efficacy of ABT-199 in subjects with relapsed or refractory chronic lymphocytic leukemia with the 17p deletion. Accessed October 2016.


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