Breakthrough Clinical Results
AbbVie announced that the Phase 3 VERONA trial evaluating venetoclax in combination with azacitidine for newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) did not meet its primary endpoint of overall survival. The hazard ratio was 0.908 (p=0.3772). No new safety signals were observed. The results will be presented at a future medical congress or publication. This outcome does not affect the currently approved indications for venetoclax. VERONA is a global, randomized, controlled trial comparing venetoclax plus azacitidine to azacitidine plus placebo in newly diagnosed HR-MDS patients. Venetoclax is a BCL-2 inhibitor that promotes apoptosis in cancer cells.
Key Highlights
- VERONA trial failed to meet the primary endpoint of overall survival in HR-MDS patients.
- No new safety signals were observed with the venetoclax and azacitidine combination.
- Results will be presented at a future medical congress or publication.
- Current approved indications for venetoclax remain unaffected.
Incidence and Prevalence
Global Incidence and Prevalence of Myelodysplastic Syndromes (MDS)
Determining precise global incidence and prevalence of MDS is challenging due to variations in diagnostic criteria, underreporting, and underdiagnosis. Studies using different methodologies and data sources yield varying estimates. Here's a summary of information gleaned from several sources:
Incidence:
- SEER Data (US): Early SEER data (2001-2003) indicated an age-adjusted incidence of 3.3 per 100,000 per year, rising to 4.9 per 100,000 per year for 2007-2011. This increase was likely due to improved reporting awareness rather than a true rise in incidence. Later SEER data analysis (2001-2013) found an overall lower rate of secondary AML (sAML) developing from MDS, but still showed worse survival for those who developed sAML. Age was a significant factor, with younger patients having a shorter transformation interval to sAML. Specific rates for MDS itself were not provided in this later analysis.
- Active Case-Finding Studies: Studies using active case-finding methods, such as electronic pathology report searches, suggest a higher incidence, ranging from 5.3 to 13.1 per 100,000.
- Medicare Claims Data (US, age 65+): Estimates based on Medicare claims data are considerably higher, ranging from 75 to 162 per 100,000. This likely reflects the increased incidence of MDS with age.
- Düsseldorf MDS Registry (Germany): A smaller, regional registry reported a crude incidence rate of 4.15 per 100,000 per year.
- UK Study: One study mentioned that the incidence of MDS observed in their US cohort was 4-5 times greater than that reported for the UK. However, no specific UK incidence rate was provided.
Prevalence:
- US Estimates: Older estimates placed MDS prevalence in the US at 2.9%, based on ICD codes. A more recent study (2006-2019) found a prevalence of 5.2% in a US cohort, nearly double the previous estimates. This study also highlighted the highest prevalence among Hawaiian and Pacific Islander groups (7.6%), followed by Native American and Hispanic groups.
- US Estimates (General): Broader US prevalence estimates range from 60,000 to 170,000 cases, with projections of growth.
- Düsseldorf MDS Registry (Germany): This registry reported a point prevalence of 7 per 100,000 persons.
Key Observations:
- Age: MDS incidence and prevalence increase significantly with age.
- Sex: Men generally have a higher incidence of MDS than women.
- Race/Ethnicity: Data suggests varying prevalence across racial and ethnic groups, with higher rates observed in some populations (e.g., Hawaiian/Pacific Islander in one US study).
- Data Source Variability: Estimates derived from different data sources (e.g., cancer registries, claims data, active case-finding) can vary substantially.
- Underestimation: Many sources acknowledge that the true incidence and prevalence of MDS are likely underestimated due to underdiagnosis and underreporting.
It's important to consider the limitations of each data source and the potential for underestimation when interpreting these figures. Further research and standardized reporting are needed to improve the accuracy of global MDS burden estimates.
Mechanism of Action
The provided text discusses approved drugs for various conditions, including acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS). It does not offer information on the mechanisms of action of drugs in trials that have not been approved for myelodysplastic syndrome.
One article mentions two hypomethylating agents (HMAs), azacitidine (AZA) and decitabine (DAC), used for AML and HR-MDS. These drugs work by inhibiting DNA methyltransferase, leading to hypomethylation of DNA and potentially reactivating tumor suppressor genes. However, this information pertains to approved drugs, not those in trials that failed to gain approval.
Another article discusses the high failure rate (97%) of oncology drug-indication pairs in clinical trials. It highlights that some drugs thought to act through a specific mechanism actually kill cells via off-target effects. While this information is relevant to drug development in oncology, it doesn't specify the mechanisms of action for failed MDS drugs.
To find the three most common mechanisms of action in trials for drugs not approved for MDS, one would need to consult other resources like clinical trial databases or review articles specifically addressing this topic.
Drug used in other indications
Venetoclax in combination with azacitidine is primarily used for treating acute myeloid leukemia (AML), especially in older patients or those ineligible for intensive chemotherapy. Several studies and trials explore its use in other contexts:
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Relapsed/Refractory AML: Venetoclax + azacitidine is being investigated as a salvage therapy for patients with relapsed or refractory AML who have failed initial treatment. Studies show overall response rates ranging from 33-46%, with a significant portion achieving less stringent overall response criteria. While remissions are often short-lived (under a year), they can bridge patients to allogeneic stem cell transplant.
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High-Risk Myelodysplastic Syndromes (MDS): Venetoclax-based combinations are being explored in high-risk MDS, showing a complete remission rate of 39% in treatment-naive patients and 5-14% in those who have failed hypomethylating agents (HMAs).
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Blast-Phase Myeloproliferative Neoplasm: Venetoclax has demonstrated activity in blast-phase myeloproliferative neoplasm, with a 25% complete remission rate and additional patients meeting less stringent response criteria.
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Pediatric MDS/AML: Limited preclinical data exists for pediatric MDS/AML. Single-center experiences suggest venetoclax + azacitidine is safe and promising, warranting further exploration in late-phase clinical trials.
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Post-Transplant Maintenance: A study investigated low-dose decitabine + venetoclax as maintenance therapy after allogeneic hematopoietic stem cell transplantation for high-risk AML/MDS. Results showed promising 2-year overall survival (85.2%) and event-free survival (84.7%) rates, with manageable adverse events.
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Combination with other agents: Studies are exploring venetoclax in combination with other targeted agents like FLT3 inhibitors and IDH inhibitors, showing improved clinical outcomes. One study combined venetoclax with gilteritinib in two AML patients with FLT3-ITD mutation unresponsive to venetoclax + azacitidine, with promising results.
Intervention Models:
The intervention models in these trials vary depending on the specific disease and patient population. Common approaches include:
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Combination with HMAs: Venetoclax is frequently combined with azacitidine or decitabine, typically administered subcutaneously or intravenously.
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Combination with Low-Dose Cytarabine (LDAC): Venetoclax + LDAC is another explored combination, often administered subcutaneously.
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Combination with Intensive Chemotherapy: Studies are investigating the addition of venetoclax to standard induction chemotherapy regimens.
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Post-Transplant Maintenance: Venetoclax-based combinations are being evaluated as maintenance therapy after allogeneic stem cell transplantation.
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Monotherapy: In some cases, venetoclax is used as a single agent, particularly in patients refractory to other treatments.
The specific dosing and scheduling of venetoclax and other agents vary across trials and depend on factors like patient age, disease status, and prior therapies.