Bayer to Withdraw PI3K Inhibitor Copanlisib (Aliqopa) from U.S. Market Amid Failed Confirmatory Trial

Nov 16, 2023 17:36 CST Updated 17:36

Bayer

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In recent years, the multiple "dilemmas" hovering over PI3K inhibitors have never dissipated.

Whether it will affect the Chinese market remains to be seen.

Recently, Bayer announced the withdrawal of PI3Kα/δ inhibitor Copanlisib (generic name: Copanlisib, trade name: Aliqopa) from the U.S. market due to missing the primary endpoint in the confirmatory trial.

Copanlisib is a PI3K inhibitor administered via intravenous injection, demonstrating inhibitory activity against both PI3K-α and PI3K-δ subtypes expressed in malignant B cells. It induces tumor cell death through apoptosis and the inhibition of malignant B cell proliferation.

In September 2017, Copanlisib was granted accelerated approval by the FDA for marketing based on the positive results of the Phase II clinical trial CHRONOS-1, for the treatment of patients with relapsed follicular lymphoma (FL) who have received at least two prior lines of therapy.

It is reported that CHRONOS-1 is a single-arm, multi-center, open-label Phase II clinical trial. In this trial, a total of 142 patients were evaluated for the efficacy of Copanlisib, including 104 patients with relapsed follicular B-cell non-Hodgkin lymphoma who had relapsed after at least two prior treatments. On days 1, 8, and 15 of each 28-day treatment cycle, patients received 60mg of Copanlisib (administered as a 1-hour intravenous infusion).

The final trial results showed that in patients (n=104) receiving Copanlisib monotherapy, the overall objective response rate (ORR) was 59%, with a complete response (CR) rate of 14% and a partial response (PR) rate of 44%. Updated results after 2 years of follow-up showed that in patients with follicular lymphoma, the ORR was 59%, the CR rate was 20%, and the PR rate was 39%.

Following the accelerated approval of Copanlisib, Bayer conducted the CHRONOS-4 study (n=551) to further validate the drug's efficacy and safety. Unfortunately, before the detailed results were released, Bayer announced that the study did not meet its primary endpoint of significantly extending progression-free survival.

In May this year, Copanlisib was approved for marketing in China and is also used as a third-line therapy for FL patients. As for whether Copanlisib's withdrawal from the U.S. market will affect the Chinese market, it remains to be seen.

Notably, this is not the first setback for Copanlisib. In January this year, Bayer withdrew its marketing application for Copanlisib in the EU for the treatment of marginal zone lymphoma, and in February, it voluntarily withdrew a marketing application for an indication of Copanlisib in China.

PI3K Inhibitors Frequently Encounter Variability

Due to playing a significant role in the fight against various types of cancer, PI3K inhibitors have become a key focus in drug development. What is PI3K? It is an intracellular phosphatidylinositol kinase, belonging to important intracellular signal transduction molecules that participate in regulating physiological processes such as cell proliferation, apoptosis, and differentiation. The dependent signaling pathway plays a crucial role in tumorigenesis. When it is overexpressed due to genetic or epigenetic mutations in major components within the pathway or upstream regulatory factors, it leads to the occurrence and continuous development of tumor cells. Based on its encoding genes, structural characteristics, and substrate specificity,PI3KCan be divided into three types: Ⅰ, Ⅱ, and Ⅲ, with a total of 8 subtypes. The four subtypes most closely related to tumors are those in type Ι, namely PI3Ka, PI3Kβ, PI3Kγ, and PI3Kδ.

As of now, globally, multiple PI3K inhibitors have been approved for marketing, including Bayer's Copanlisib, Gilead's Idelalisib, Novartis' Alpelisib, TG Therapeutics' Umbralisib, Yingli Pharmaceutical's Linperlisib, and Duvrilisib introduced by CSPC Pharmaceutical Group (Copiktra). But most of these approved products have experienced setbacks.

In January this year, Gilead announced the withdrawal of some indications for Idelalisib. As early as 2018, Idelalisib was warned and investigated by the U.S. FDA and EMA due to serious adverse events in clinical trials, with a treatment discontinuation rate as high as 50%; In April, TG Therapeutics voluntarily withdrew the Biologics License Application/Supplemental New Drug Application for Umbralisib in combination with Ublituximab for the treatment of adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma; In September, the FDA Oncologic Drugs Advisory Committee voted against the indication application for Copiktra for third-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In December last year, Copiktra had withdrawn its application for the treatment of relapsed or refractory follicular lymphoma.

On the other hand, the situation of PI3K inhibitors under research is not optimistic either. According to the data from PharmaCube, there are currently 335 PI3K inhibitors in development globally, involving over 100 companies. Only 49.55% of them are in active research and development status, while the rest fall into categories such as "research terminated," "research suspended," or "no further progress reported."

In September this year, Innovent Biologics voluntarily withdrew the domestic marketing application for PI3Kδ inhibitor Parsaclisib in China. This was due to Incyte's adjustment of the overseas development strategy for this product, which led to a significant increase in investment and a substantial extension in the duration of the subsequent confirmatory Phase III clinical study.

Currently, there are multiple companies in China actively developing PI3K inhibitors, including BeiGene, Haihe Biopharma, Hutchmed, and CT Tianqing.

Text | MedValley