Venetoclax (Venclexta®; Genentech/Roche and AbbVie) in combination with azacitidine (Onureg®Bristol Meyer Squibb) has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with previously untreated intermediate, high- and very high-risk myelodysplastic syndromes (MDS) based on the revised International Prognostic Scoring System (IPSS-R).

Venclexta, which is jointly developed and commercialized by AbbVie and Genentech, is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to help restore the process of apoptosis.

A rare group of blood cancers
Myelodysplastic syndromes are a rare group of blood cancers that gradually affect the ability of the bone marrow to produce normal blood cells. This can lead to weakness, frequent infections, anemia, and debilitating fatigue. In some cases, MDS can also progress into acute myeloid leukemia (AML). Every year in the United States, approximately 10,000 people are diagnosed with MDS, and the median survival for those with higher-risk MDS is approximately 18 months.

There are several classifications of MDS, ranging from very low-risk to very high-risk, determined by the composition of the bone marrow, blood cell counts, and chromosomal alterations. Higher-risk disease is defined as intermediate, high- or very high-risk based on the revised International Prognostic Scoring System (IPSS-R), which is a risk assessment scale that uses five prognostic indicators to predict the course of a patient’s disease. Approximately half (45%) of patients present with higher-risk MDS, which is associated with a poorer prognosis and short life expectancy.

MDS occurs mainly in patients with a median age of about 70 years, and the crude incidence is 4 to 5 cases per 100,000 persons per year. The actual incidence is likely to be higher because of incomplete case assessment and underreporting of MDS in cancer registries, and it may be close to 75 per 100,000 among persons over the age of 70 years.[1]

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“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development.

“We are pleased that the FDA has granted Venclexta its sixth Breakthrough Therapy Designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine,” Garraway added.

M15-531 study
This designation was granted based on interim results from the Phase Ib M15-531, open-label, non-randomized, multicenter, dose-finding study, investigating venetoclax plus azacitidine in people with previously untreated, higher-risk MDS.

The Breakthrough Therapy Designation is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions with preliminary evidence that indicates they may demonstrate a substantial improvement over existing therapies. This is the 38th BTD for Genentech’s portfolio of medicines, and the 11th designation for its hematology portfolio.

Treatment combinations
This most recent designation reinforces the potential of venetoclax-based combinations across several blood cancers, including MDS.

In the United States, venetoclax has been granted six BTDs by the FDA: one for previously untreated chronic lymphocytic leukemia (CLL), two for relapsed or refractory CLL, two for previously untreated AML, and one for MDS.

The drug has already been approved in the United States in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy, and in the European Union in combination with hypomethylating agents, azacitidine and decitabine, for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

Venetoclax is also approved in the United States and European Union in combination with rituximab (Rituxan®; Genentech/Roche) for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with obinutuzumab (Gazyva®; Genentech/Roche) for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of 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.

Clinical trial
A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS) – NCT02942290

Highlights of prescribing information
Venetoclax (Venclexta®; Genentech/Roche and AbbVie)
Azacitidine (Onureg®Bristol Meyer Squibb)
Rituximab (Rituxan®; Genentech/Roche)
Obinutuzumab (Gazyva®; Genentech/Roche)

[1] Cazzola M. Myelodysplastic Syndromes. N Engl J Med. 2020 Oct 1;383(14):1358-1374. doi: 10.1056/NEJMra1904794. PMID: 32997910.

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