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Date: 2018-09-20

Type of information: Positive opinion for the granting of a Market Authorisation in the EU

Product name: Venclexta® (US)/Venclyxto® (UE) (venetoclax - RG7601, GDC-0199/ABT-199)

Compound: venetoclax

Therapeutic area: Cancer - Oncology

Action mechanism:

  • protein inhibitor/B-cell lymphoma 2 (BCL-2) inhibitor. Venetoclax (RG7601, GDC-0199/ABT-199 is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). It is believed that blocking BCL-2 may restore the signaling system that tells cancer cells to self-destruct. The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). In collaboration with AbbVie, venetoclax is being evaluated in a robust development program as a single agent or in combination with other medicines. There are ongoing Phase II and III studies for venetoclax in CLL, and Phase I and II studies are also ongoing in several other blood cancers, including indolent NHL, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma (MM).
  • Venetoclax was recently granted Breakthrough Therapy Designation by the FDA for the treatment of previously treated CLL with the 17p deletion.
  • Venclyxto is being co-developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

Company: Genentech, a member of Roche Group (USA - CA - Switzerland) AbbVie (USA -IL)

Disease: chronic lymphocytic leukaemia (CLL)

Latest news:

  • On September 20, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Venclyxto®. The CHMP adopted an extension to the existing indication as follows: “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 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, or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.”
  • • On December 8, 2016, Roche announced that the European Commission has granted conditional marketing approval for Venclyxto™ (venetoclax) for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL without 17p deletion or TP53 mutation in people who have failed both chemo-immunotherapy and a B-cell receptor pathway inhibitor.
  • • On October 13, 2016, the EU Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Venclyxto™ (venetoclax) for the treatment of people with chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation who are unsuitable for or have failed a B-cell receptor pathway inhibitor. Venclyxto® is also recommended for the treatment of people with CLL without 17p deletion or TP53 mutation who have failed both chemo-immunotherapy and a B-cell receptor pathway inhibitor.
  • • On April 11, 2016, the FDA approved Venclexta® (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with 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. 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.
  • Venclexta® is indicated for daily use after detection of 17p deletion is confirmed through the use of the FDA-approved companion diagnostic Vysis CLL FISH probe kit.
  • The most common side effects of Venclexta® include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome. Live attenuated vaccines should not be given to patients taking 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 and marketed by AbbVie and Genentech. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular .
  • • On January 12, 2016, Roche announced the the FDA has accepted the New Drug Application (NDA) and granted Priority Review for venetoclax for the treatment of people with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, including those with 17p deletion. Venetoclax is a small molecule inhibitor of the BCL-2 protein being developed in partnership with AbbVie, and was granted Breakthrough Therapy Designation by the FDA in April 2015 for the treatment of people with previously treated (relapsed or refractory) CLL with 17p deletion. A Marketing Authorization Application (MAA) has also been validated by the European Medicines Agency (EMA).
  • The NDA for venetoclax is based in part on data from the pivotal Phase II M13-982 study. M13-982 (NCT01889186) is a Phase II, open-label, single arm, multicentre study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated chronic lymphocytic leukaemia (CLL) with 17p deletion. The study included 107 patients with relapsed or refractory disease, and all but one had 17p deletion. Additionally, about 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort. The primary endpoint of the study is overall response rate (ORR) as determined by an independent review committee (IRC), and secondary endpoints include complete response (CR), partial response (PR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients. Results from the study were recently presented at the 57th American Society of Hematology (ASH) Annual Meeting showing:
  • • The study met its primary endpoint, with an ORR of 79.4 percent among the 107 patients with relapsed or refractory disease receiving venetoclax, as assessed by IRC. In addition, 7.5 percent of patients achieved a complete response with or without complete recovery of blood counts in the bone marrow (CR/CRi). • Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 patients also had bone marrow assessments and six were MRD-negative. • At one year, 84.7 percent of all responses and 94.4 percent of MRD-negative responses were maintained. The one-year PFS and OS rates were 72 percent and 86.7 percent, respectively. • The most common serious adverse events were fever (7 percent), low red blood cell count as a result of immune response (7 percent), pneumonia (6 percent) and low white blood cell count with fever (5 percent). The most common Grade 3-4 adverse events were low white blood cell count (40 percent), low red blood cell count (18 percent) and low platelet count (15 percent). Grade 3 or higher infection occurred in 20 percent of patients. Laboratory tumour lysis syndrome was reported in five patients; none had clinical consequences.
  • • On May 7, 2015, Roche announced that the FDA has granted breakthrough therapy designation for venetoclax (RG7601, GDC-0199/ABT-199), an investigational medicine being developed in partnership with AbbVie, for the treatment of people who have relapsed or refractory chronic lymphocytic leukemia (CLL) with a genetic abnormality known as 17p deletion.  CLL is a slow-growing cancer of the blood and bone marrow that is generally considered incurable, and is one of the most common adult leukemias worldwide. Most cases of CLL (95 percent) start in white blood cells called B-cells. In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53. The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases. People with 17p deletion CLL have poor results with conventional chemotherapy regimens and a median life expectancy of less than three years.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2016-04-11

UE authorization: 2016-12-05

Favourable opinion UE: 2016-10-13/2018-09-20

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes