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Background The OSMO study assessed the efficacy of switching to mepolizumab in patients with severe eosinophilic asthma that was uncontrolled whilst receiving omalizumab. The objective of this analysis was to assess the proportion of patients achieving pre-defined improvements in up to four efficacy outcomes and the relationship between patient baseline characteristics and treatment response. Methods This was a post hoc analysis of OSMO study data (GSK ID:204471; ClinicalTrials.gov No. NCT02654145). Patients with severe eosinophilic asthma uncontrolled by high-dose inhaled corticosteroids, other controller(s) and omalizumab subcutaneously (≥ 4 months) were switched to mepolizumab 100 mg administered subcutaneously. Endpoints included the proportion of responders—i.e. patients achieving a pre-defined clinical improvement in ≥ 1 of the following outcomes: (1) Asthma Control Questionnaire (ACQ)-5 score (≥ 0.5-points), (2) St George’s Respiratory Questionnaire (SGRQ) total score (≥ 4-points), (3) pre-bronchodilator forced expiratory volume in 1s (FEV 1 ; ≥ 100 mL), all at Week 32, and (4) annualised rate of clinically significant exacerbations (≥ 50% reduction). Results Of the 145 patients included, 94%, 83%, 63% and 31% were responders for ≥ 1, ≥ 2, ≥ 3 and 4 outcomes, respectively; 75% and 78% were ACQ-5 and SGRQ score responders, and 50% and 69% were FEV 1 and exacerbation responders. Subgroup analyses demonstrated improvements irrespective of baseline blood eosinophil count, prior omalizumab treatment regimen/duration, comorbidities, prior exacerbation history, maintenance oral corticosteroid use, ACQ-5 and SGRQ scores, and body weight/body mass index. Conclusions After switching to mepolizumab, almost all patients with uncontrolled severe eosinophilic asthma on omalizumab achieved a beneficial response in ≥ 1 clinical outcome. Improvements were observed regardless of baseline characteristics. Trial registration This manuscript is a post hoc analysis of data from the OSMO study. ClinicalTrials.gov, NCT02654145. Registered January 13, 2016.

Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.

Relapsed/refractory (R/R) disease is a major hurdle to long‐term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)‐based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC‐resistant AML cell lines, primary AML patient samples, and patient‐derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c‐MYC and MCL‐1, inducing AraC‐resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two‐drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10‐fold reduction of VEN concentration. The roles of MCL‐1 and c‐MYC in the three‐drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC‐resistant AML by downregulating c‐MYC and MCL‐1 and to a lesser extent cellular respiration.