TG Therapeutics Ukoniq’s Future In Doubt Amidst Scrutiny Of P13K Inhibitor Accelerated Approvals
Executive Summary
Advisory committee review of combo with ublituximab may provide forum to discuss the Phase III data showing increased risk of death that prompted US FDA safety alert.
TG Therapeutics, Inc.’s Ukoniq (umbralisib) is the latest drug to stumble over the safety issues that have long plagued the phosphatidylinositol 3-kinase (PI3K) inhibitor class. The small group of leukemia and lymphoma therapies are getting a new level of regulatory attention as the US FDA builds out from its 2021 crackdown on “dangling” and “delinquent” accelerated approvals in oncology.
The FDA is “investigating a possible increased risk of death” with Ukoniq, according to a drug safety communication issued on 3 February 2022 – almost exactly one year after the PI3K delta and casein kinase 1 (CK1) epsilon inhibitor’s accelerated approval on 5 February 2021 for two indications: relapsed or refractory marginal zone lymphoma (MZL) patients who received at least one prior anti-CD20-based regimen and relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.
The FDA’s concern about umbralisib safety has been brewing since the agency requested an early analysis of overall survival in the Phase III UNITY-CLL trial, which supports the paired ublituximab BLA and Ukoniq sNDA submitted in March 2021 for chronic lymphocytic leukemia and small lymphocytic lymphoma. UNITY-CLL was “not powered for OS,” TG Therapeutics said, and OS was not part of the primary statistical analysis for the “U2” regimen.
At the September 2021 cut-off date for the FDA-requested OS analysis, TG Therapeutics found an imbalance in favor of the control arm (HR: 1.23) that was not statistically significant, the company said.
An OS hazard ratio above 1.00 “implies potential risk that the investigational therapy is causing harm,” the company noted, pointing out that when the UNITY-CLL survival data were censored for COVID-19-related deaths, the HR dropped to 1.04. (Also see "Bad Times For Breakthrough Drugs Targeting Chemo Complications; Submissions From BMS, Merck" - Pink Sheet, 3 Dec, 2021.)
Nonetheless, “because of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and health professionals that we are re-evaluating this risk against the benefits of Ukoniq for its approved uses,” the FDA stated.
The safety alert followed a partial clinical hold placed on studies of U2 and its components for CLL and non-Hodgkin lymphoma.
“FDA may also hold a future public meeting to discuss these findings and explore the continued marketing of Ukoniq,” the agency continued.
TG Therapeutics has been expecting an advisory committee review of the U2 BLA/sNDA in CLL/SLL in March or April of 2022 – a timeframe that would complicate an FDA decision on the new indication before its 25 March user fee goal.
The two indications under accelerated approval were cleared on the basis of data from the multicohort single-arm Phase II UNITY-NHL study, which included 69 MZL patients who received at least one prior therapy and 117 patients with FL who received at least two prior systemic therapies.
The UNITY-CLL trial that prompted the drug safety alert is not the confirmatory trial for the accelerated approvals. The required confirmatory trial in MZL and FL, which does not appear to have started, will be a Phase III study in relapsed or refractory FL and MZL patients randomized to immunotherapy with or without umbralisib. The primary endpoint should be progression-free survival, FDA review documents indicate.
The Phase III UNITY-CLL trial, in contrast, enrolled 421 treatment-naïve and relapsed or refractory CLL patients who were randomized to the U2 regimen of Ukoniq plus ublituximab or an active control arm of obinutuzumab plus chlorambucil. UNITY-CLL was conducted under a special protocol assessment with the FDA.
TG Therapeutics presented data from UNITY-CLL at the American Society of Hematology annual meeting in December 2020 showing that U2 significantly improved the primary endpoint of PFS over obinutuzumab/chlorambucil (HR=0.54), with consistent PFS improvement across treatment naïve CLL and relapsed or refractory CLL.
“Overall survival was not part of the primary analysis in the secondary [endpoints] … because it was not powered to be tested … and it was pretty early in terms of information available,” TG Therapeutics CEO Michael Sean Weiss told the JP Morgan conference on 10 January.
“Nevertheless, we did run that analysis for the FDA the best that we could at the time. There was clearly missing information, but we gave them everything that we had. And as it turns out, there was an imbalance in favor of the control arm in overall survival.”
Class-Wide Toxicity Concerns
Weiss highlighted U2’s side effect profile, reporting that in UNITY-CLL, “about 14% of the patients came off drug for tolerability issues, which we think is pretty good and in line with … drugs for treatment of these diseases.” In the PI3K inhibitor class in particular, “you’re going to see significantly higher rates of discontinuation due to AEs.”
“Clinical trials of other medicines in the same PI3 kinase inhibitor class as Ukoniq have shown similar safety concerns,” the FDA safety alert reports, linking to a 2016 alert about increased rates of AEs including death in trials of Gilead Sciences, Inc.’s Zydelig (idelalisib) in combination with other cancer medicines.
Gilead announced plans to voluntarily withdraw third-line indications in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) on 14 January 2022, almost seven years after receiving accelerated approval in 2014. The company cited difficulties finding patients for the confirmatory postmarketing study, reporting that less than half the patients had been enrolled.
Zydelig remains available under a regular approval in combination with rituximab for relapsed CLL.
Incyte Corporation said on 25 January that it had pulled the FDA filing for its PI3K-delta inhibitor candidate parsaclisib in FL, MZL and mantle cell lymphoma (MCL), after determining that it would be unable to complete confirmatory studies “within a time period that would support the investment.”
But Incyte also characterized the withdrawal was a business decision and unrelated to changes in parsaclisib’s safety or efficacy. (Also see "Keeping Track Of Withdrawals: Libtayo, Parsaclisib Applications Pulled Due To Postmarketing Issues" - Pink Sheet, 28 Jan, 2022.)
Incyte’s announcement followed by a day Bayer AG’s decision to withdraw applications for its pan-PI3K inhibitor Aliqopa (copanlisib) for subtypes of indolent B-cell non-Hodgkin lymphoma (iNHL) in multiple countries, including the US. Bayer said it will conduct additional analyses of data from ongoing studies to address specific questions it has received from the regulatory authorities in countries where it had filed for approval based on the Phase III CHRONOS-3 trial. (Also see "Bayer Pulls Aliqopa Combo Filings In EU, US & Other Markets – But May Resubmit" - Pink Sheet, 25 Jan, 2022.)
Secura Bio, Inc. is voluntarily pulling a third-line FL indication for Copiktra (duvelisib), the company announced in December 2021. Copiktra, which targets PI3K-delta and PI3K-gamma, received the accelerated approval in September 2018, but the confirmatory trial was never started. After Secura Bio acquired Copiktra from Verastem in 2020, the company decided to voluntarily withdraw the third-line FL indication because the FL treatment landscape in the US no longer supported investing in the postmarketing requirements.
CLL and SLL indications remain on Copiktra’s label under regular approval. (Also see "‘Dangling’ Cancer Indications In US: New Year Brings New Withdrawals Of Accelerated Approvals" - Pink Sheet, 18 Jan, 2022.)
Will Ukoniq’s Troubles Derail Ublituximab Outside Of Cancer?
While the prospects of FDA action on the Ukoniq/ublituximab sNDA/BLA in the big CLL market have been dimmed by the FDA’s safety alert regarding Ukoniq’s safety in the pivotal UNITY-CLL trial, the company is also pursuing a BLA for ublituximab on its own as a treatment for relapsing multiple sclerosis.
The RMS application has a user fee goal date of 28 September 2022 – hopefully leaving enough time for some resolution of the survival data concerns that spurred the FDA safety alert and partial clinical hold on umbralisib in hematologic cancers.