Bayer Submits Regulatory Applications for Aliqopa (copanlisib) Plus Rituximab Combination Therapy in the U.S. and EU for Relapsed Indolent Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL, image source: muhadharaty.com)

June 21, 2021 /BioonBIOON/ --Bayer(Bayer) recently announced that it has submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA), seeking approval for a novel combination therapy of the targeted anticancer drug Aliqopa (copanlisib) and rituximab: (1) in the U.S., for the treatment of relapsed indolent B-cell non-Hodgkin lymphoma (B-iNHL); (2) in the EU, for the treatment of relapsed marginal zone lymphoma (MZL), a subtype of iNHL. The application has been accepted. Previously, Bayer had already received Orphan Drug Designation (ODD) for MZL in the EU. Indolent NHL includes the following subtypes: follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM). In the U.S.,FDACopanlisib has been granted Orphan Drug Designation (ODD) for the treatment of FL, MZL, CLL/SLL, and LPL/WM.

Aliqopa is the only pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor approved in the United States, Israel, and Taiwan, China, for adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. These approvals were based on a single-arm, multicenter Phase IIClinical trialData from (CHRONOS-1). Continued approval for the FL indication will be contingent upon verification and description of clinical benefit in confirmatory trials.In mainland China, the application for Aliqopa for the treatment of FL is under priority review by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) (Acceptance No.: JXHS2100032).

These applications submitted herein are based on the Phase 3 CHRONOS-E trial.`Clinical Trial`results. The study was conducted in patients with relapsed iNHL, and the results showed that the primary endpoint was met: with a median follow-up of 19.2 months,Compared with placebo + rituximab, the Aliqopa + rituximab regimen significantly improved progression-free survival (median PFS: 21.5 months vs 13.8 months) and reduced the risk of disease progression or death by 48% (HR=0.52, p=0.000002).。The risk of disease progression or death was significantly reduced across all prespecified iNHL subtypes, including FL (HR=0.580), MZL (HR=0.475), SLL (HR=0.243), and LPL/WM (HR=0.443).The adverse event (AE) profile of the combination therapy was generally consistent with previously published data for each component, with no new safety signals identified.

Indolent non-Hodgkin lymphoma (iNHL) is a group of heterogeneous malignancies characterized by chronic remission and relapse. For patients with iNHL whose disease has progressed and requires treatment, there are few approved treatment options. Based on the aforementioned data, Aliqopa is the first PI3K inhibitor to demonstrate broad and superior efficacy across all prespecified subtypes, along with a manageable safety profile, when used in combination with rituximab for the treatment of relapsed iNHL. Data from the CHRONOS-3 study were presented at the American Association for Cancer Research (AACR) Annual Meeting 2021 on April 10, 2021, and simultaneously published in the international medical journal *The Lancet*.Tumor》 (The Lancet Oncology).

CHRONOS-3 Study: Primary Endpoint PFS Results

CHRONOS-3 is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of Aliqopa plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). A total of 458 patients were enrolled in the study and randomized in a 2:1 ratio to receive treatment. Histologic subtypes included: follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), and marginal zone lymphoma (MZL).

In addition to the primary endpoint of progression-free survival (PFS), data on the secondary endpoints of overall response rate (ORR) and complete response rate (CR) were also presented at the AACR Annual Meeting. The results showed that,The ORR in the Aliqopa + rituximab treatment group was 80.8%, while the ORR in the placebo + rituximab treatment group was 47.7%, with complete response (CR) achieved in 33.9% and 14.6% of patients in the two groups, respectively.

Among patients with relapsed iNHL enrolled in the trial, 60% had FL, 20.7% had MZL, 10.9% had SLL, and 8.3% had LPL/WM. Subtype analysis showed that,Aliqopa plus rituximab combination therapy significantly improved clinical responses in all pre-specified iNHL subtypes.Compared with placebo plus rituximab treatment,Patients treated with Aliqopa in combination with rituximab also demonstrated early and durable clinical benefit.

In this study, the safety of Aliqopa in combination with rituximab was consistent with the safety previously reported for each drug as monotherapy, demonstrating that Aliqopa can be used in combination with rituximab to treat patients with relapsed iNHL without compromising the overall safety profile of either individual agent.

Molecular structure of copanlisib (Image source: Wikipedia)

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy, the tenth most common cancer type, comprising a highly heterogeneous group of diseases, according toTumorBased on cell proliferation rate and clinical characteristics, NHL can be classified into aggressive NHL (aNHL) and indolent NHL (iNHL). iNHL includes various subtypes such as follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM).

Although this disease is typically slow-growing, it can become more aggressive over time. Despite advances in treatment, improved therapeutic options are still needed for relapsed or refractory disease. Following a response to initial therapy, both response rates and duration of response decline with subsequent lines of treatment, underscoring the unmet medical need among patients with progressed disease.

The active pharmaceutical ingredient of Aliqopa is copanlisib, a novel intravenous pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor that exhibits primary inhibitory activity against the PI3K-α and PI3K-δ isoforms expressed in malignant B cells.The PI3K signaling pathway is involved in cell growth, survival, and metabolism, and dysregulation of this pathway plays a critical role in NHL.Copanlisib has been demonstrated to induce, through apoptosis and inhibition of proliferation of primary malignant B-cell lines,TumorCell death. Copanlisib inhibits several key cellular signaling pathways, including B-cell receptor signaling, CXCR12-mediated chemotaxis of malignant B cells, and NF-κB signaling in lymphoma cell lines.

In the United States, Aliqopa received accelerated approval in September 2017 for adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Data from the open-label, single-arm Phase II CHRONOS-1 trial demonstrated that Aliqopa monotherapy achieved an overall response rate (ORR) of 59% and a complete response (CR) rate of 14% in patients with follicular B-cell non-Hodgkin lymphoma (NHL) who had previously received at least two systemic therapies. Updated data from the CHRONOS-1 study published in the *American Journal of Hematology* in 2020 showed that in the FL patient subgroup, the ORR was 59% and the CR rate was 20%.

Currently, Bayer is conducting a broad clinical development program to evaluate copanlisib in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) who have previously received one or more lines of therapy. In addition to the Phase III CHRONOS-3 study, the Phase III CHRONOS-4 study is evaluating copanlisib in combination with standard immunochemotherapy for the treatment of patients with relapsed iNHL. (Bioon.com)

Original Source:Bayer submits regulatory applications for oncology treatment combination of copanlisib and rituximab in the U.S. and EU