This phase I/II trial tests the safety, side effects, and best dose of tazemetostat and umbralisib and whether tazemetostat in combination with umbralisib and ublituximab works to shrink tumors in patients with follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractor). Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Umbralisib may help block the formation of growths that may become cancer. Ublituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving tazemetostat in combination with umbralisib and ublituximab may work better in treating follicular lymphoma.

Start Date01 May 2023

Sponsor / Collaborator

City of Hope National Medical Center

[+1]

NCT04635683 / WithdrawnPhase 1IIT

A Phase I Trial of Lenalidomide, Umbralisib and Ublituximab in Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

This phase I trial studies the safety and how effective the combination of ublituximab, umbralisib, and lenalidomide is in certain types of indolent (slow-growing) non-Hodgkin's lymphoma or mantle cell lymphoma. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide may also stop the growth of non-Hodgkin's lymphoma by blocking blood flow to the cancer. Umbralisib is designed to block a protein called PI3 kinase in order to stop cancer growth and cause changes in the immune system that may allow the immune system to better act against cancer cells. Ublituximab is an antibody that attaches to the lymphoma cells and triggers immune reactions that may result in the death of the targeted lymphoma cells.

Start Date30 Sep 2022

Sponsor / Collaborator

Ohio State University Comprehensive Cancer Center

NCT04692155 / TerminatedPhase 1/2IIT

Phase Ib/II Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL)

This is a single arm, multi-center, open label Phase Ib/II trial in adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). The Diagnosis of MCL (Stage II, III, IV) is supported by histology and over expression of cyclin D1 or by FISH (fluorescent in situ hybridization). In the proposed study, the primary endpoint is to estimate the biological response rate of the combination of Umbralisib at dose 800 mg with Ublituximab (900mg)-Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP), but a phase Ib portion with dose de-escalation at two does level (800 and 600 mg) will be built in to further confirm its safety and tolerability. Treatment will be administered on an outpatient basis in 3-week (21 day) cycles. Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) agreement.

Start Date31 Aug 2021

Sponsor / Collaborator

The University of Alabama at Birmingham

100 Clinical Results associated with Umbralisib Tosylate

100 Translational Medicine associated with Umbralisib Tosylate

100 Patents (Medical) associated with Umbralisib Tosylate

Literatures (Medical) associated with Umbralisib Tosylate

03 Sep 2024·Clinical Cancer Research

PI3K Inhibitors in Hematology: When One Door Closes…

Review

Author: Davids, Matthew S. ; Okkenhaug, Klaus ; Skånland, Sigrid S.

AbstractThe PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan–class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

01 Sep 2024·Critical Reviews in Oncology/Hematology

Safety profile of first-line targeted therapies in elderly and/or comorbid chronic lymphocytic leukaemia patients (unfit subpopulation). A systematic review and network meta-analysis

Review

Author: Stożek-Tutro, Anita ; Reczek, Monika ; Kawalec, Paweł

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton's tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

01 May 2024·Anti-Cancer Agents in Medicinal Chemistry

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021)

Review

Author: Vishakha, S ; Kurmi, Balak Das ; Patel, Preeti ; Navneesh, N ; Jain, Ankit ; Gupta, Ghanshyam Das ; Verma, Sant Kumar

Abstract:New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

News (Medical) associated with Umbralisib Tosylate

19 Sep 2024

·www.prnewswire.com

Mantle Cell Lymphoma Clinical Trial Pipeline Insights Featuring 20+ Companies | DelveInsight

Mantle cell lymphoma is a rare and aggressive type of non-Hodgkin lymphoma originating from B-cells in the "mantle zone" of the lymph nodes. The development of novel targeted therapies and immunotherapies, such as Bruton's tyrosine kinase (BTK) inhibitors, is improving treatment outcomes and driving market growth for Mantle cell lymphoma. LAS VEGAS, Sept. 19, 2024 /PRNewswire/ -- DelveInsight's ' Mantle Cell Lymphoma Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mantle cell lymphoma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mantle cell lymphoma pipeline domain. Key Takeaways from the Mantle Cell Lymphoma Pipeline Report DelveInsight's mantle cell lymphoma pipeline report depicts a robust space with 20+ active players working to develop 22+ pipeline therapies for mantle cell lymphoma treatment. Key mantle cell lymphoma companies such as AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others are evaluating new mantle cell lymphoma drugs to improve the treatment landscape. Promising mantle cell lymphoma pipeline therapies such as Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others are under different phases of mantle cell lymphoma clinical trials. In May 2024, AstraZeneca had announced positive interim results from the Phase III ECHO clinical trial, which evaluated Bruton's tyrosine kinase (BTK) inhibitor Calquence (acalabrutinib) in combination with standard chemoimmunotherapy for treating mantle cell lymphoma (MCL). In March 2024, BeiGene, Ltd. announced the presentation of emerging oncology pipeline data at the American Association for Cancer Research (AACR) Annual Meeting. Additional highlights include preclinical characterization data for an investigational BTK degrader, BGB-16673, currently in clinical development for B-cell malignancies, including mantle cell lymphoma In October 2023, Ascentage Pharma announced that it has entered into a clinical collaboration with AstraZeneca Investment. The two companies will jointly conduct a registrational Phase III study of the Bcl-2 inhibitor, APG-2575 (lisaftoclax), in combination with AstraZeneca's Bruton's tyrosine kinase (BTK) inhibitor, CALQUENCE® (acalabrutinib), in treatment-naive patients with first-line chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In January 2023, the FDA granted an orphan drug designation to LP-284, a novel small-molecule, next-generation acylfulvene, for the treatment of mantle cell lymphoma (MCL), a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL), according to an announcement from Lantern Pharma. Request a sample and discover the recent advances in mantle cell lymphoma treatment drugs @ Mantle Cell Lymphoma Pipeline Report The mantle cell lymphoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mantle cell lymphoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mantle cell lymphoma clinical trial landscape. Mantle Cell Lymphoma Overview Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphomas (NHLs) characterized by the (11,14) translocation, leading to overexpression of the cyclin D1 (CCND1) gene. Its various morphological variants can make diagnosis challenging, though some cases are straightforward. Many individuals with MCL are asymptomatic in the early stages, but may later seek medical attention due to persistent, typically painless swelling of lymph nodes, especially in the neck and throat region (e.g., Waldeyer's ring). MCL is marked by a reciprocal chromosomal translocation t(11;14)(q13;q32), which places the cyclin D1 gene next to the immunoglobulin heavy chain gene, causing continuous cyclin D1 expression. This overexpression contributes to tumor cell proliferation through cell cycle dysregulation, chromosomal instability, and epigenetic changes. Rarely, MCL cases without this translocation may involve CCND2 or CCND3 translocations. Hypothetical molecular subtypes, based on the cell of origin, correlate with clinical phenotypes: classical or aggressive MCL arises from naive B cells lacking or having limited iGVH mutations and expressing SOX11, a neural transcription factor inhibiting terminal B cell differentiation. The indolent variant originates from antigen-experienced B cells with IGVH somatic hypermutations, typically SOX11-negative and genetically stable. Diagnosis of MCL involves detailed patient history, thorough clinical evaluation, and specialized tests, including biopsy of an affected lymph node or bone marrow. These tests confirm the NHL type and subtype, assess disease extent, and determine appropriate treatments. Treatment for MCL is multifaceted and tailored to each patient, often including chemotherapy, immunotherapy drugs like rituximab, targeted therapies such as ibrutinib, and stem cell transplants, particularly for aggressive disease or younger patients. Radiation therapy may target specific lymphoma areas. Participation in clinical trials can offer new treatment options. Treatment plans are developed collaboratively by healthcare professionals and patients, considering disease stage, overall health, and personal preferences. Regular monitoring and follow-up care are essential to track treatment response and manage side effects effectively. Find out more about mantle cell lymphoma treatment drugs @ Drugs for Mantle Cell Lymphoma Treatment A snapshot of the Mantle Cell Lymphoma Pipeline Drugs mentioned in the report: Learn more about the emerging mantle cell lymphoma pipeline therapies @ Mantle Cell Lymphoma Clinical Trials Mantle Cell Lymphoma Therapeutics Assessment The mantle cell lymphoma pipeline report proffers an integral view of the mantle cell lymphoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Mantle Cell Lymphoma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Parenteral, Intravenous, Subcutaneous, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Apoptosis stimulants, Proto-oncogene protein c-bcl-2 inhibitors, Proteasome inhibitors, Immunologic cytotoxicity, T lymphocyte replacements, Agammaglobulinemia tyrosine kinase inhibitors Key Mantle Cell Lymphoma Companies: AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others Key Mantle Cell Lymphoma Pipeline Therapies: Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others Dive deep into rich insights for new drugs for mantle cell lymphoma treatment, visit @ Mantle Cell Lymphoma Drugs Table of Contents For further information on the mantle cell lymphoma pipeline therapeutics, reach out @ Mantle Cell Lymphoma Treatment Drugs Related Reports B-Cell Lymphoma Epidemiology B-Cell Lymphoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology as well as the B-cell lymphoma epidemiology trends. B-Cell Lymphoma Market B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including Vincerx Pharma, Ubix Therapeutics, Biomea Fusion Inc, Shanghai Hengrui Pharmaceutical, BeiGene, Hanmi Pharmaceutical, among others. Diffuse Large B-Cell Lymphoma Pipeline Diffuse Large B-Cell Lymphoma Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key DLBCL companies, including Genmab, Roche, Acerta Pharma, Autolus, Xynomic Pharmaceuticals, Genentech, Celgene, AbbVie, Mabion, among others. Diffuse Large B-Cell Lymphoma Market Diffuse Large B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including AbbVie, Genmab, Merck, Roche, Xencor and Janssen, Denovo Biopharma, Calithera Biosciences, IMV, Biogen, Autolus Therapeutics, Allogene Therapeutics, Novartis, Miltenyi Biomedicine, Regeneron Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 3ImmunotherapyOrphan Drug

08 Aug 2024

·www.echemi.com

Regulatory Challenges of Gene Therapy and Cancer Drugs: Industry Trends Behind the Withdrawal of Zydelig and FDA's Response

In 2022, Gilead announced that it would voluntarily withdraw Zydelig from the U.S. market for two lymphoma treatments, a full six years after it suspended the trial due to patient deaths. A Gilead spokesperson clarified that the withdrawal was not due to safety concerns, but rather because of insurmountable obstacles to recruiting subjects for additional research trials required by the FDA. Nevertheless, Zydelig retains its eligibility for the treatment of chronic lymphocytic leukemia and remains on the market for patients. Notably, the withdrawal of Zydelig coincides with the withdrawal of several other PI3K inhibitors used to treat follicular lymphoma: Secura Bio's duvelisib (trade name Copiktra) withdrawn in December 2021, TG's umbralisib (trade name Ukoniq) withdrawn in 2022 (here may be a clerical error, read "February" or adjusted to another month), Bayer's copanlisib (trade name Aliqopa) also withdrew from the market in November 2023. Together, these events outline an industry trend. A study published in JAMA Internal Medicine reveals an interesting data point: Before Gilead decided to withdraw some uses of Zydelig from the U.S. market, its global sales had reached a staggering $842 million. This reflects the wide application and high recognition of the drug in the market, although it ultimately failed to fully meet all expectations for various reasons. Interestingly, the pharmaceutical industry sometimes employs a series of ingenious strategies to speed up the process of bringing a product to market. Eli Lilly, for example, successfully used all four avenues of acceleration to bring oncology product Lartruvo to market in 2016. The key clinical data for the product is based only on the results of a trial involving 133 patients, and while the results showed a possible positive impact on survival outcomes for sarcoma, a cancer that affects muscles and other soft tissues, the specific effect on slowing cancer growth is unclear. However, just over two years later, a larger study revealed that Lartruvo had no significant impact on patient survival, and Eli Lilly had to withdraw it from the market. Despite this, Lartruvo still managed to achieve a whopping $500 million in sales during its short market life. Among the many drugs approved for accelerated marketing, oncology products have become the hardest hit by ineffective drugs. However, as the development of therapies continues to deepen and progress, new questions continue to emerge and are presented to the FDA. In particular, advanced therapies represented by cell and gene therapies, when they meet with the accelerated approval system, have brought unprecedented challenges to this "old revolution". Given the complexity of cell and gene therapies and the relative lack of understanding of their safety, once ineffective advanced therapies are released to the market, the consequences and impacts will be far beyond the scope of small molecule ineffective drugs. For example, the tragic death of a three-year-old boy in a clinical trial of Pfizer's fordadistrogene movaparvovec, a gene therapy for Duchenne muscular dystrophy, highlights the shortcomings and limitations of researchers in predicting the potential for serious adverse events. As vectors of ssRNA (single stranded RNA), viruses (such as AAV) play a critical role in gene therapy, but can also cause a series of serious adverse events including cardiopulmonary failure, myocarditis, thrombotic microangiopathy, and acute liver failure. These potential risks have forced the FDA to be more cautious and rigorous in approving gene therapies. Speaking at the annual meeting of the American Society for Gene and Cell Therapy, CBER director Peter Marks said speeding up the withdrawal of approved gene therapies could be easier and faster than for small-molecule therapies. At the same time, he stressed that "accelerated approval of gene therapy is not a get-out-of-jail-free ticket." The FDA will not hesitate to withdraw accelerated approval of rare disease gene therapies if they fail subsequent confirmatory trials." Marks further points out that the "one-size-fits-all" nature of gene therapy makes confirmatory studies easier to follow and monitor patients over time. It also makes for greater clarity and clarity on the question of whether to withdraw gene therapy. In contrast, there may be more controversy and disagreement in the decision process of withdrawing cancer therapy. Marks, however, said the FDA would only withdraw gene therapy if it was clear that the patient benefit was likely to be "minimal" but the side effects were significant. He cited a case in which Bluebird Bio's sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) caused patients to develop myelodysplastic syndrome and leukemia during treatment. The product was approved by the FDA in December 2023 with a boxed warning about hematologic malignancies. Marks said it is unclear whether these malignancies are related to the preconditioning regimen associated with Lyfgenia treatment, the underlying disease, or the gene therapy itself. In addition, the case of drug manufacturers refusing to voluntarily withdraw the market is not unique in the history of FDA accelerated approval. Everything from the withdrawal of Makena, a drug that reduced the risk of preterm birth, after 12 years on the market, to the legal battle between Pepaxto and the FDA highlights the complexity and seriousness of the issue. In the face of these challenges, FDA has to seek the support of legislation to strengthen its regulatory power and capability. Fortunately, the introduction of the FDORA (Comprehensive Food and Drug Reform Act) bill provides the FDA with greater flexibility and autonomy to act without public hearings.

Drug ApprovalGene Therapy

13 May 2024

·www.biospace.com

Cut or Keep Running? How Companies Respond to Failed Confirmatory Trials

Pictured: An arrow splitting toward pills and money, or pills and headstones/Taylor Tieden for BioSpace It’s been a little over a month since Amylyx Pharmaceuticals announced it would withdraw its amyotrophic lateral sclerosis drug Relyvrio from the market after it failed to meet the primary endpoints in a Phase III trial. Relyvrio received approval in 2022 after a positive Phase II study and the company had vowed to pull it if the second trial was not successful. Relyvrio isn’t the first drug to be withdrawn from the market after additional trials have failed to reaffirm earlier studies supporting the efficacy and safety of novel therapies. Conversely, some drugs stay on the market for years after confirmatory trials don’t deliver the expected results. For example, Jazz Pharmaceuticals and PharmaMar’s Zepzelca remains on the market for small cell lung cancer despite not meeting overall survival endpoints. Even for drugs that have yet to reach the market, companies can be faced with tough decisions when late-stage trials do not yield the expected results. BrainStorm Cell Therapeutics, for example, continues to develop its cell therapy NurOwn for ALS even after a Phase III trial failed to meet its primary endpoint and an FDA advisory committee voted against approval last year. Market withdrawal and pipeline decisions after late-stage failures depend on a number of factors, including the details of the study’s data. “The first thing that comes to mind is, why did the trial fail? Is it related to efficacy, safety, or both?” Nicolas Schmitz, a senior market analyst at KBI Biopharma, told BioSpace in an email. “The nature of the failure (statistical significance, side effects or patient recruitment challenges) will obviously play a crucial role in the future of the drug candidate and the company that owns it.” Not Cut and Dry In the last few years, there have been a handful of approved drugs withdrawn from the market. TG Therapeutics received accelerated approval for Ukoniq in February 2021 but voluntarily withdrew the lymphoma drug in 2022 after updated data showed a possible increased risk of death. Gilead Sciences’ Zydelig for lymphoma and small lymphocytic leukemia received accelerated approval in 2014 but was voluntarily withdrawn in 2022 after enrollment challenges hindered its confirmatory trial. And Genentech’s Tecentriq won accelerated approval in 2016 for urothelial carcinoma but failed to meet its overall survival endpoint in a Phase III trial the following year for patients with locally advanced or metastatic urothelial cancer who had been treated with platinum chemotherapy. It was withdrawn from the market in 2021 for this indication, with additional indications being pulled in 2022. Failed trials play a key role in earlier development decisions too. For example, a failed Phase III study can cause some companies to shutter entire development programs, while others will continue pushing forward with additional studies, perhaps with different trial designs or targeting different patient populations. In September 2023, when the FDA’s Cellular, Tissue and Gene Therapies advisory committee voted 17-1 against recommending NurOwn for approval, the company decided to continue developing the therapy. “We’re heartened and encouraged by the support of the community, but it really comes back to the evidence that we have which drives us,” Co-CEO Stacy Lindborg told BioSpace. The advisory committee had been critical of the company’s manufacturing plan and questioned the greater mortality rate in the experimental group. Moreover, the primary endpoint of BrainStorm’s Phase III trial—the proportion of participants experiencing an improvement of 1.25 points per month post-treatment on the ALSFRS-R vs. placebo—did not meet statistical significance. However, this endpoint was achieved in a subset of patients. “At face value, we took the endpoints, and our first inclination was that this is a failed trial,” Lindborg said, adding that all companies have a responsibility to trial participants to understand what they have learned. “When we started seeing that the cells had done what we expected, we started to ask additional questions.” Indeed, the team saw in the trial data improvements in neurofilament light and other markers of neurodegenerative disease, Lindborg said. BrainStorm came to an agreement with the FDA on the design of a Phase IIIb trial for NurOwn in February 2024. Lindborg is optimistic that the trial will succeed, but would not comment on what action the company would take if the new endpoints are not met. Sarepta Therapeutics is also looking to move forward with a therapy that hasn’t delivered as expected in clinical trials. The FDA accepted Sarepta’s supplemental Biologics License Application (sBLA) for full approval and to expand the label of its Duchenne muscular dystrophy gene therapy Elevidys earlier this year, despite its failing a confirmatory trial in October 2023. The company expects a decision on or before June 21. Financial Factors Finances also play a role in whether companies pursue additional trials in the face of less-than-ideal results. A larger company might have more freedom to pursue further development following a failure than a small company would. Schmitz pointed to Eli Lilly’s solanezumab, which failed to meet endpoints in multiple trials before being dropped in 2023, as an example. Lilly earned more than $34 billion in revenue in 2023, with 63% of that coming from a handful of drugs. In comparison, Amylyx earned $380 million in revenue in 2023, with Relyvrio its only marketed product. If a company is “struggling with cash” with no alternative products, a failed trial “might certainly be the end of the adventure” for that company, he said. “The key tenets of every product are cycle time, cost and value,” Lindborg said. “Is there an appropriate need, such that what you’re investing can be recouped and that you’re able to continue to do research in the future?” Companies may also sell drug programs that failed in clinical trials to companies with the resources to continue research and development, Schmitz said. Lindborg added that partnerships between companies could help cost-effectiveness and efficiency by sharing capacity and headcount across organizations. Whether or not a drug is withdrawn from the market or development is halted ultimately affects whether trial participants and other patients can access that drug. A study examining cancer drugs that failed clinical trials after receiving accelerated approval found that multiple drugs were still recommended by the National Comprehensive Cancer Network even after negative results were available. Amylyx will continue to make Relyvrio available for free to patients who believe the drug is helping them, a decision that was commended by The ALS Association, according to The Washington Post. “We try to boil every question down to, what’s best for people with the disease, what’s best for the families, what’s best for the community,” Amylyx Co-CEO Justin Klee told BioSpace last month. “We ran a large, randomized control trial. It was a very well-done trial, and the benefit was uncertain.” Nadia Bey is a freelance reporter in North Carolina. Her work and contact information can be found at nadiabey.com.

Phase 3Phase 2Accelerated Approval

100 Deals associated with Umbralisib Tosylate

External Link

KEGG	Wiki	ATC	Drug Bank
D11322 D11323	Umbralisib Tosylate	L01XE	DB14989

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Follicular Lymphoma	Preclinical	US	TG Therapeutics, Inc.	05 Feb 2021
Marginal Zone B-Cell Lymphoma	Preclinical	US	TG Therapeutics, Inc.	05 Feb 2021
Chronic Lymphocytic Leukemia	Preclinical	IT	TG Therapeutics, Inc.	19 Nov 2015
Chronic Lymphocytic Leukemia	Preclinical	GB	TG Therapeutics, Inc.	19 Nov 2015
Chronic Lymphocytic Leukemia	Preclinical	RU	TG Therapeutics, Inc.	19 Nov 2015
Chronic Lymphocytic Leukemia	Preclinical	US	TG Therapeutics, Inc.	19 Nov 2015
Chronic Lymphocytic Leukemia	Preclinical	PL	TG Therapeutics, Inc.	19 Nov 2015
Chronic Lymphocytic Leukemia	Preclinical	ES	TG Therapeutics, Inc.	19 Nov 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02742090 (CTgov)	Phase 2	Chronic Lymphocytic Leukemia	51	Umbralisib	dwalkhbbzp(zvvdagcmeq) = nwekbbjwdf lyxijzsxmp (tkvcxnngxl, hzlflevarq - lgqoosctgz) View more	-	03 Jul 2024
NCT02612311 (UNITY-CLL, CTgov)	Phase 3	Chronic Lymphocytic Leukemia	603	Ublituximab+Umbralisib (Experimental: Arm A: Ublituximab + Umbralisib)	clmeeznftl(chxtlsdjuv) = jhnbylqheb opnsxymeav (fmfaerjawo, ifzeksdwge - gteopsopqe) View more	-	07 May 2024
				Obinutuzumab+Chlorambucil (Active Comparator: Arm B: Obinutuzumab + Chlorambucil)	clmeeznftl(chxtlsdjuv) = ybuomsrylw opnsxymeav (fmfaerjawo, jzaoturysm - pqjvlxzbpk) View more
NCT03801525 (ULTRA-V, CTgov)	Phase 2/3	Chronic Lymphocytic Leukemia \| Small Lymphocytic Lymphoma	277	Ublituximab+Venetoclax+Umbralisib (Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V))	srawdtanps(eqjhrqyqeq) = dbvmwzlvwt tdbqfeeacp (cndefoodix, sxucbrvjex - xebdrjihdb) View more	-	19 Apr 2024
				Ublituximab+Venetoclax+Umbralisib (Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V))	dvpybjkhof(momhhyyvlv) = jeudfdlrwo vsrkfzofkx (onyqrerehz, ambtfxuymn - qjrlifjzpj) View more
NCT04624633 (ASH2023)	Phase 2	Chronic Lymphocytic Leukemia	29	Acalabrutinib	(pziqrhobky) = xtnymcpjmz zrnxebbiay (bnmggxfccn ) View more	-	09 Dec 2023
				Umbralisib	(pziqrhobky) = dwxhpvihby zrnxebbiay (bnmggxfccn ) View more
NCT04783415 (CTgov)	Phase 2	Mantle-Cell Lymphoma	12	Ublituximab+Acalabrutinib+Umbralisib	grlypjmgxn(vehpdbdmhz) = memxpuxltc cxfhegcicx (fgoxcfuuoy, bwpojhhgct - tfrefmmrqm) View more	-	18 Nov 2023
NCT04508647 (CTgov)	Phase 2	Follicular Lymphoma \| Marginal Zone B-Cell Lymphoma	4	Ublituximab (Ublituximab Only)	vdczwncxij(niuhahkcre) = csuyvrlook clvjnxyhpl (vsndntvtet, vnwndxektj - cdyvzyrtdf) View more	-	09 Nov 2023
				Ublituximab+Umbralisib (Ublituximab First, Then Ublituximab and Umbralisib)	cpazuzzaea(rbrxktzqsg) = weognncipb nxfffbgshp (zthvpzzcie, ztjkxzthho - qhgadbrbrl) View more
NCT04692155 (CHOP U2, CTgov)	Phase 1/2	Mantle-Cell Lymphoma	1	Ublituximab+Umbralisib	xbuwowecja(ntphxvvpyh) = gvtwsosqvy gflxqeeuob (mpmosvuate, fwtvtfjcqu - pukftvzgjs) View more	-	28 Sep 2023
NCT04016805 (CTgov)	Phase 2	Chronic Lymphocytic Leukemia	41	Ibrutinib+Ublituximab+Umbralisib (Ublituximab + Umbralisib + Ibrutinib)	cdpqdisofs(swxcyqicvc) = eqbwnbqpnw qzlsosnddk (mzoibilkvt, hnnybladey - mtfjzdducm) View more	-	24 Jul 2023
				Ublituximab+Venetoclax+Umbralisib (Ublituximab + Umbralisib + Venetoclax)	cdpqdisofs(swxcyqicvc) = picnbaiuea qzlsosnddk (mzoibilkvt, uvojuajezn - gwwgoeatij) View more
NCT03828448 (CTgov)	Phase 2	Follicular Lymphoma \| Small Lymphocytic Lymphoma	34	Ublituximab+Umbralisib	gfrqbdmqfn(xmgqasemek) = ifbaqdxqco xxejdxrvfs (qprocemuwm, zgtoprgeou - oqqnjjkwak) View more	-	24 Jul 2023

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