CK1ε

New York-based TG Therapeutics voluntarily withdrew its pending Biologics License Application (BLA) and supplemental New Drug Application (sNDA) for its combination of ublituximab and Ukoniq (umbralisib), dubbed U2, for adults with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The company indicates the withdrawal was due to recently updated overall survival (OS) data from the Phase III Unity-CLL trial “that showed an increasing imbalance in OS.” The trial compared U2 to an active control arm of Obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory CLL. That trial hit the primary endpoint, with U2 significantly prolonging assessed progression-free survival (PFS) compared to the control arm. Based on that study, a BLA and sNDA were submitted to the U.S. Food and Drug Administration for CLL/SLL. The FDA informed TG Therapeutics in November 2021 that it was going to run an Oncologic Drug Advisory Committee (ODAC) meeting over the review to discuss the benefit-risk pro Ukoniq in its approved indications. There were several concerns, apparently, but the FDA’s primary issue seemed to be from an early ad hoc analysis of OS in the Unity-CLL study. OS was only a secondary efficacy endpoint of the trial but was not part of the primary analysis as part of the trial’s statistical analysis plan agreed upon by way of a Special Protocol Assessment (SPA) the company had with the FDA. As a result, it wasn’t analyzed or part of the BLA/sNDA. Also, the trial wasn’t designed to be powered for OS. But the FDA requested an early analysis of OS from the trial as part of an ongoing review of the regulatory submissions. The first analysis of OS leveraged a cut-off date of September 2021. There was an imbalance in favor of the control arm. But because of the ad hoc nature of the analysis, about 15% of patients weren’t included in the survival data, or the data was outdated. When the company excluded deaths associated with COVID-19, the two arms were about equal. Then, in February 2022, TG Therapeutics submitted updated OS data with the same September 2021 cut-off date but had fewer missing data and more OS events. These demonstrated improvements from the previous OS data, but neither were viewed as statistically significant. The FDA then requested more data. This demonstrated an increasing imbalance favoring the control arm, which didn’t correlate with the data they provided the FDA in February 2022. Based on the new information, TG Therapeutics decided to withdraw the BLA/sNDA for U2 to treat CLL/SLL. The FDA also is canceling the ODAC meeting. TG also expects the FDA to withdraw the accelerated approval for Ukoniq. “We were very disappointed to see that the recently updated overall survival data showed an increasing survival imbalance in favor of the control arm,” stated Michael S. Weiss, TG’s chairman and CEO. “Accordingly, we and our advisors determined that we should withdraw the BLA/sNDA for U2 in CLL. Additionally, we made the difficult decision to withdraw Ukoniq from sale for the approved indications in MZL/FL. We want to thank the patients, families and practitioners who worked with us in our search for novel treatment options for patients with B-cell malignancies.” Ukoniq is the first and only oral inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. It was indicated for adults with r/r marginal zone lymphoma (MZL) who received at least one previous anti-CD20-based therapy and for adults with r/r follicular lymphoma (FL) who had at least three previous lines of systemic therapy. Weiss went on to say that it will now focus its resources on its multiple sclerosis and autoimmune platform. Ublituximab is currently under review by the FDA for relapsing forms of multiple sclerosis with a target action date of September 28, 2022. This leaves the company currently with no products to market. In February, the FDA reported it was investigating a potential increased death risk for Ukoniq. It informed physicians and patients of the investigation and went back to evaluate the Unity trial. It also suspended enrollment of new patients in other trials of the drug while it reviewed the Unity findings Ukoniq first entered the market in February 2021 when the FDA granted it Accelerated Approval for r/r MZL and FL. At TG's 2021 annual report on March 1, the company reported 2021 product revenue of $6.537 billion, with $152 million in license revenue. As of December 31, 2021, it held $350.3 million in cash, cash equivalents and investment securities. It reported a net loss for the year of $348.1 million.

Sept. 21, 2021 16:36 UTC First study of RP7214, a DHODH inhibitor, in Covid-19 patients with mild, symptomatic disease on the background of promising preclinical efficacy & Phase 1 healthy volunteer safety Randomized, placebo-controlled Phase 2 study is designed to evaluate the effect of RP7214 on viral load & clearance, disease biomarkers and clinical improvement in patients’ status along with the tolerability and immunomodulatory activity of RP7214. RP7214 is expected to function by inhibiting the DHODH enzyme on host cells and limit their ability to support viral replication. This unique mechanism of action, if successful in the clinic, is expected to be complementary to other antiviral drugs that directly inhibit the virus. Future plans may include testing RP7214 in partially/fully vaccinated patients with breakthrough covid-19 infections as part of a broader clinical development program. As infections continue to persist and spread despite increasing vaccinations, there is growing need for a convenient oral anti-viral treatment option that patients can potentially self-administer at home while will in turn reduce burden on the healthcare infrastructure and allow resumption of economic activity. BASEL, Switzerland--(BUSINESS WIRE)-- Rhizen Pharmaceuticals S.A. a clinical-stage oncology & inflammation-focussed biopharmaceutical company, today announced that the first patient has been dosed in a Phase 2 clinical trial of RP7214, a small molecule oral dihydroorotate dehydrogenase (DHODH) Inhibitor. The randomized, double-blind, placebo-controlled, Phase 2 study will evaluate the efficacy & safety of oral RP7214, in covid-19 patients with mild, symptomatic disease with an underlying risk factor on the background of promising preclinical efficacy & phase 1 healthy volunteer safety. The study is being conducted in India across 12 centres in coordination with Rhizen’s India affiliate, Incozen Therapeutics Pvt ltd., and is designed to enrol up to 204 patients across both study arms. Viral replication involves a huge demand for building blocks and relies on nucleotides derived from host cells. DHODH is a rate-limiting enzyme in the pyrimidine biosynthesis pathway, inhibition of which leads to depletion of host nucleotide pools required for viral replication. RP7214 is a small molecule potent inhibitor of human DHODH with low nanomolar potency with demonstrated selective activity on SARS-COV-2 replication in a preclinical setting without any effect on the host cells. The known anti-inflammatory potential of DHODH inhibitors along with RP7214’s high oral bioavailability and wide safety window as demonstrated in a healthy volunteer Phase-1 study provides compelling rationale for testing RP7214 in mild COVID patients. With a pro fundamentally addresses replication of the viral genome, RP7214 is expected to be agnostic to the mutational status of SARS-COV-2 in patients thereby offering a potential means to avoid disease progression and hospitalizations. “DHODH inhibition is an interesting therapeutic approach that has broad application across oncology, inflammation & anti-infectives. In addition to our development efforts with RP7214 in AML, we are pleased that Rhizen has been able to respond to this pandemic by progressing the development of this program in Covid-19. In this study, we expect to get a read on the ability of RP7214 to inhibit the viral replication & clearance and induce an anti-inflammatory response” said Swaroop Vakkalanka, Ph.D., Founder & CEO of Rhizen Pharma. Swaroop also added that “Given the orthogonal nature of this host-directed mechanism of RP7214, we expect that RP7214 will eventually also combine well with direct acting antiviral agents, across a broad range of RNA-viral indications. If therapeutically active, we expect RP7214 will play a major role in mitigating & reducing the severity of de novo and breakthrough infections in both unvaccinated and vaccinated individuals, thereby becoming an important public health tool that can help reduce the burden on healthcare systems and allow economic activity to resume.” RP7214 was earlier studied in a Phase I first-in-human healthy volunteer study in the US under an IND across both single-dose, multiple-dose and fed-fasted conditions and was found to be very well-tolerated across all doses tested, with high bioavailability and dose-proportional plasma concentrations. About Rhizen Pharmaceuticals AG.: Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology & inflammation therapeutics. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways. Rhizen has proven expertise in the PI3K modulator space with the discovery of our first PI3Kδ & CK1ε asset Umbralisib that has been successfully developed & commercialized in MZL & FL by our licensing partner TG Therapeutics (TGTX) in USA. Beyond this, Rhizen has a deep oncology & inflammation pipeline spanning discovery to Phase 2 clinical development stages. Rhizen is headquartered in Basel, Switzerland. For additional information, please visit Forward-looking statements This press release may contain certain forward-looking statements relating to the company and its business. Although the company believes its expectations are based on reasonable assumptions, all statements other than statements of historical fact included in this press release about future events are subject to (i) change without notice and (ii) factors beyond the company’s control. These statements may include, without limitation, any statements preceded by, followed by, or including words such as “target,” “believe,” “expect,” “aim,” “intend,” “may,” “anticipate,” “estimate,” “plan,” “project,” “will,” “can have,” “likely,” “should,” “would,” “could”, and other words and terms of similar meaning or the negative thereof. Forward-looking statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the company to be materially different from those expressed or implied by such statements. 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