Another PI3K Inhibitor Will Be Withdrawn From U.S. Market

Reprinted with AIS Health permission from the December 2023 issue of Radar on Specialty Pharmacy*

Bayer recently revealed that it will work with the FDA to voluntarily withdraw the New Drug Application (NDA) for its cancer drug Aliqopa (copanlisib). The therapy is the latest phosphoinositide 3-kinase — also called phosphatidylinositol 3-kinase — (PI3K) inhibitor/indication with accelerated approval to treat a hematologic malignancy to be pulled from the U.S. market, potentially spurring payers to take a closer look at these agents.

The agency gave Aliqopa accelerated approval on Sept. 14, 2017, for the treatment of adults with relapsed follicular lymphoma (FL) who have received at least two systemic therapies. Approval was based on the CHRONOS-1 Phase II clinical trial. In the confirmatory study, CHRONOS-4, adding Aliqopa to standard immunochemotherapy regimens did not meet the primary endpoint of progression-free survival (PFS) vs. the standard immunochemotherapy control arm. Bayer says it will publish the trial results “in a timely manner.”

Other PI3K inhibitors given accelerated approval for hematologic malignancies have had their indications withdrawn from the U.S. market.

The first was Secura Bio, Inc.’s Copiktra (duvelisib), which was given accelerated approval on Sept. 24, 2018, for the treatment of adults with relapsed or refractory FL after at least two systemic therapies. On Dec. 3, 2021, the manufacturer disclosed that it was voluntary withdrawing the agent.

Then on Jan. 14, 2022, Gilead Sciences, Inc. revealed that it was voluntarily withdrawing two indications for Zydelig (idelalisib): for the treatment of relapsed FL and small lymphocytic leukemia (SLL), both of which were given accelerated approval on July 23, 2014.

Finally, on April 15, 2022, TG Therapeutics, Inc. said that it voluntarily withdrew its pending Biologics License Application (BLA)/supplemental NDA (sNDA) for the combination of ublituximab and Ukoniq (umbralisib) for the treatment of adults with chronic lymphocytic leukemia (CLL) and SLL*.* The company also said that it voluntarily withdrew Ukoniq from sale for two indications: (1) for adults with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen, and (2) for adults with FL who have received at least three prior systemic therapies. The FDA gave the drug accelerated approval for those indications on Feb. 5, 2021.

A couple of months before TG Therapeutics withdrew the pending BLA/supplemental NDA and approved indications, the FDA issued a drug safety communication about the possible increased risk of death with Ukoniq based on the agency’s review of the Phase III UNITY trial of people with CLL. “The results showed a possible increased risk of death in patients receiving the combination of Ukoniq and the monoclonal antibody compared to the control arm. Those receiving the combination of Ukoniq and the monoclonal antibody also experienced more serious adverse events than those in the control arm,” said the agency on Feb. 3, 2022. It noted that while the drug was not approved for CLL, “the FDA believes these findings have implications for” its MZL and FL indications.


A little more than two months later, the FDA’s Oncologic Drugs Advisory Committee (ODAC) held an April 21 meeting to discuss PI3K inhibitors in hematologic malignancies. The committee initially had scheduled a second meeting for April 22 to discuss the BLA/sNDA for ublituximab and Ukoniq and Ukoniq’s MZL and FL indications, but it canceled that meeting following TG Therapeutics’ move to withdraw those.

In its briefing document for the April 21 meeting, ODAC noted that “there are several central issues relating to the development of PI3K inhibitors in hematologic malignancies: concerning trends in overall survival (OS) in multiple randomized controlled trials (RCTs), toxicities of the PI3K inhibitor class, inadequate dose optimization, and trial design considerations regarding the limitations of single-arm trials.”

More specifically, “six randomized trials evaluating a PI3K inhibitor have demonstrated a higher rate of death or concerning OS results suggesting potential harm to patients. The randomized trials demonstrated or suggested a favorable effect on PFS and other efficacy parameters such as ORR [overall response rate]. Therefore, the adverse effect on OS is likely driven by PI3K inhibitor toxicity.

“The observation of a potential detriment in OS across this many randomized trials is unprecedented in oncology,” stated ODAC. “For each trial, there is a low number of observed OS events (as low as 3% to 20% of the planned sample size without a pre-specified plan for evaluating OS), leading to uncertainty of the specific OS estimate. However, based on the confidence intervals for the HRs, potential harm to patients cannot be ruled out. Taken together, these are not isolated observations, but rather repeated observations across multiple trials of different PI3K inhibitors in patients with indolent lymphoid malignancies.”

ODAC subsequently voted 16-0, with one abstention, in favor of requiring randomized controlled data to support the approval of PIK3 inhibitors given the observed toxicities with the class.

The committee did not discuss Novartis Pharmaceuticals Corp.’s PI3K inhibitor Piqray (alpelisib), which is approved for certain people with breast cancer.


“This class has shown a concerning trend in decrease in OS, a high rate of severe adverse events and subsequent patient discontinuation,” says Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. Bayer’s withdrawal of Aliqopa’s NDA “will likely impact other PI3K inhibitors with additional review and caution, given these current safety and efficacy signals. Additionally, this will likely keep the available PI3K therapies as a later line option after exhausting other available therapies with more robust randomized clinical studies and more established safety profiles.”

He comments that “it is interesting to note that Bayer withdrew their marketing application [for Aliqopa] to the European Medicines Agency in December 2021.”

He tells AIS Health, a division of MMIT, that the issue with PI3K inhibitors is likely due to “a combination of factors.” In trials, the drugs have shown durable ORR and PFS improvements, he notes, but lower OS. “The single-arm trial design which led to the approvals was not supported by the subsequent randomized clinical trial data.…The randomized trials have shown higher rates of Grade 3 or higher fatal and serious adverse events (ADRs) than in the single arm studies. This may be a reflection of the drug itself, the toxicities inherent with the PI3K class, potential nonoptimal dose being identified that would assist with optimizing the efficacy and minimizing the ADRs of the drug and/or having nonrandomized trial design for the accelerated approval process.”

Asked about how developments within the class could impact PI3K inhibitors being developed, Szczotka points to the ODAC vote requiring randomized data. “Other PI3K inhibitors in development will need to submit data that includes this type of trial design and ensure that OS is demonstrated, in addition to having durable ORR and PFS, while minimizing the ADRs in comparison to the prior marketed PI3K inhibitors in larger patient populations. This will likely extend their clinical trials and delay submission to the FDA for approval.”

In addition, he says, because of the known toxicities, clinical trials for the drugs “will need to ensure that the proper optimal dosing regimen is identified that will minimize the ADR seen with this class of agents to a larger number of patients in the clinical trial. This would assist with addressing the known safety issues and OS.”

Moving forward, payers are likely to evaluate accelerated approvals for other drugs within the class “to ensure that randomized control trial design with [an] adequate number of study participants over a longer time period would be a cornerstone for payer review. Additionally, studies will need to have relevant standard-of-care therapies included in the placebo or control arm of the study, especially in those diseases with current multiple therapy options. While payers will evaluate the available approved clinical trials and their design, they can influence manufacturers to ensure that their submitted clinical trial designs will move towards these targets and have safe and effective therapy available at the time of FDA approval.”

Contact Szczotka via Caroline Chambers at

By Angela Maas

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