TG Therapeutics is seeking accelerated approval in the U.S. for its investigational oral therapy umbralisib to treat patients with marginal zone lymphoma (MZL) and follicular lymphoma (FL) who failed to respond to prior treatments or whose disease returned thereafter.
The company initiated a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), which means it will file sections of the application as they’re completed, rather than waiting until all NDA sections are completed before applying, as it’s normally done. This is possible due to umbralisib’s prior designation as breakthrough therapy for adult patients with MZL.
The FDA allowed TG to combine the application for both marginal zone and follicular lymphoma in a single NDA. The submission is expected to be completed in the first quarter of 2020.
“We are extremely pleased to have initiated our first NDA submission for umbralisib and to have received guidance from the FDA to include both MZL and FL in a single NDA,” Michael S. Weiss, executive chairman and CEO of TG Therapeutics, said in a press release. “This is an extremely important milestone for us, as it brings us one step closer to potentially offering a novel treatment option to patients with previously treated MZL and FL.”
Umbralisib (formerly TGR-1202) is an oral, once-daily treatment that works by inhibiting the proteins PI3K-delta and CK1-epsilon. PI3K delta is an enzyme important for many cell activities, but is mainly involved in the signaling, development, and survival of immune B-cells, and often implicated in lymphomas mediated by this type of cell, including MZL and FL.
CK1-epsilon is involved in the regulation of signaling pathways also implicated in cancer development. Blocking CK1-epsilon is thought to have anti-cancer effects and to help avoid the immune-related side effects that are seen with other PI3K inhibitors.
Umbralisib has demonstrated anti-cancer effects in preclinical models of blood cancer as well as in clinical studies.
The open-label UNITY-NHL Phase 2b trial (NCT02793583) is currently evaluating umbralisib, alone or in combination with other drugs, for treating non-Hodgkin’s lymphomas including MZL and FL.
The study enrolled 72 patients with MZL who failed to respond to at least one prior treatment with an anti-CD20 targeted therapy, and 118 FL patients previously treated with at least two lines of therapy, including an anti-CD20 regimen and an alkylating agent.
Its primary efficacy measure is overall response rate — the proportion of patients responding favorably to the therapy — as determined by an independent committee.
According to TG Therapeutics, the proportion of patients with FL who experienced a positive response to umbralisib alone was above the established threshold of 40%, with the trial meeting its primary goal for this patient population.
The company also presented preliminary efficacy data from the first 42 patients with MZL given umbralisib as a single agent. All of these patients failed to respond to prior CD20 targeted therapy, but 52% of them responded to umbralisib, and an additional 36% attained stable disease, for a clinical benefit rate of 88%.
Treatment with umbralisib was well-tolerated, with a safety profile similar to other trials, the company reports.
“I want to thank the patients, their families and the research teams who participated in these important trials and helped advance umbralisib,” Weiss said. “And the TG team for working tirelessly to initiate this NDA submission. This is the beginning of an impactful 2020 as we look forward to topline Phase 3 data from both the UNITY-CLL trial and the ULTIMATE I & II trials in multiple sclerosis, as well as potential regulatory submissions based off these data.”
The FDA’s accelerated approvals program targets new treatments intended for serious conditions and for filling an unmet medical need. During its review, the treatment’s therapeutic effects are measured using a surrogate endpoint, a marker (e.g. lab measurement, radiographic image, or physical sign) that is not a direct measure of clinical benefit but is thought to be a good predictor of it. Using a surrogate endpoint can shorten the time the FDA takes to approve the therapy.
If the treatment is approved, companies are still required to conduct additional studies to confirm its clinical benefits. If so, the FDA then grants standard approval to the therapy.
