CD11b

The original FDA full approval decision date was 15 October, but this has been delayed. Credit: Tada Images via Shutterstock. Intercept Pharmaceuticals will have to keep waiting for a decision about Ocaliva (obeticholic acid) after the US Food and Drug Administration (FDA) has asked for more time to determine whether to grant the drug full approval. It’s been a rocky ride for the rare liver disease drug, and now its subsidiary is also facing delays despite the original Prescription Drug User Fee Act (PDUFA) date for the drug’s supplemental New Drug Application (sNDA) being on 15 October. The treatment is only available to primary biliary cholangitis (PBC) patients through accelerated approval in the US. The FDA did not provide a new anticipated action date, however, Intercept’s president Vivek Devaraj said: “We will continue to engage with the FDA regarding our pending application.” Bologna, Italy-based Alfasigma inherited the drug as part of its $794m acquisition of Intercept Pharmaceuticals in September 2023 and the company has continued operating as a subsidiary of Alfasigma. However, the treatment has faced a series of setbacks since its 2016 accelerated approval. In 2018, the FDA had to add a boxed warning after Ocaliva was being incorrectly dosed as a daily treatment, instead of a weekly treatment. A September 2024 FDA advisory committee (AdCom) recommended against full approval for Ocaliva by a 13-1 vote, concluding that confirmatory evidence did not verify the treatment provided clinical benefit. In a separate vote, panellists voted 10-1 that the benefits of Ocaliva did not outweigh its risks, with three abstentions. In the same month, the European Commission (EC) withdrew Ocaliva’s conditional marketing authorisation as a second-line treatment for patients with PBC. This followed a June recommendation from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use, which reassessed the benefit-risk profile of the drug. In a surprise decision just days later, the President of the General Court of the European Union overruled the decision, allowing Ocaliva to remain on the market. See Also: Testosterone by M et P Pharma for Male Hypogonadism: Likelihood of Approval Integrin Alpha M drugs in development, 2024 PBC is a chronic autoimmune disease where the immune system attacks the small bile ducts in the liver, causing bile buildup, liver inflammation, and eventually scarring or cirrhosis. Ocaliva activates the farnesoid X receptor (FXR) to reduce bile acid production and promote its removal. Ocaliva now faces competition in the PBC space. In August 2024, the FDA granted accelerated approval to Gilead’s Livdelzi (seladelpar), a drug it inherited as part of the $4.3bn CymaBay Therapeutics deal in March 2024. According to GlobalData forecasts, Livdelzi is set to generate $558m in 2030. Before it was acquired by Alfasigma, Ocaliva earned $285.7m in 2022, as per Intercept’s financials. GlobalData is the parent company of Pharmaceutical Technology. In September 2024, the EC gave Ipsen’s Iqirvo (elafibranor) the green light for the treatment of PBC in combination with ursodeoxycholic acid in adults who do not respond adequately to ursodeoxycholic acid alone. The decision in Europe follows an accelerated approval granted by the FDA in June this year.

JENA, Germany, Sept. 03, 2024 (GLOBE NEWSWIRE) -- InflaRx N.V. (Nasdaq: IFRX), a biopharmaceutical company pioneering anti-inflammatory therapeutics targeting the complement system, today announced the presentation of preclinical data for the company’s novel oral C5aR inhibitor, INF904, at the 2024 European Meeting on Complement in Human Diseases (EMCHD) being held in Lübeck, Germany, September 2 – 6, 2024. Members of InflaRx leadership also participated in a satellite symposium highlighting the role of the C5a/C5aR1 axis in driving inflammation and served as the biopharma industry representative on a panel focused on the relevance of targeting C3 and C5. InflaRx also hosted a lunch seminar focused on C5a/C5aR inhibition in human disease with best-in-class compounds. Camilla Chong, MD, Chief Medical Officer of InflaRx, commented: “We welcome the opportunity to demonstrate our commitment to advancing the science of complement inhibition and progress toward our goal of developing first-in-class and best-in-class anti-inflammatory therapies via inhibition of C5a and C5aR. The preclinical findings presented at EMCHD 2024 from multiple in vivo and ex vivo models provide strong evidence of INF904’s significant anti-inflammatory properties and strong pharmacokinetic properties, further supporting our belief that INF904 may have differentiating advantages as a member of the C5aR inhibitor drug class.” Preclinical pharmacological characterization of INF904, an oral small molecule antagonist to complement 5a receptor1 (C5aR1)Rui Liu, Zhongli Xu, Ophelia Chen, Bruce P. Burnett, Maria Habel, Renfeng Guo Overall, this study demonstrated that INF904 is a highly selective and potent inhibitor of C5aR1 with promising pharmacokinetic (PK) properties, while also exhibiting strong efficacy potential in vivo. Both INF904 and avacopan were evaluated through a series of cell-based, ex vivo, and in vivo assays. In a hamster neutropenia model, INF904 inhibited C5a-induced neutropenia by 96.5% compared to 51.1% for the same dose of avacopan. INF904 also demonstrated a more favorable PK profile with 2- to 5-fold higher exposure than avacopan across all tested animal species. The data also indicated that INF904 is a much weaker inhibitor of CYP3A4/5, with an IC50 value of 62 µM, compared to 1.7 µM for avacopan. CYP3A4/5 enzymes play an important role in the metabolism of a variety of drugs, including glucocorticoids. INF904, a novel oral C5a receptor 1 (C5aR1) antagonist, shows promising therapeutic effects in inflammatory disease modelsZhongli Xu, Rui Liu, Ophelia Chen, Bruce P. Burnett, Maria Habel, Renfeng Guo Results from in vitro and in vivo inflammatory disease models indicated that INF904 acts by reducing neutrophil activation. In two in vitro whole blood disease models, INF904 effectively blocked CD11b upregulation on neutrophils in a dose-dependent manner. Further, in three hamster models used to assess INF904’s therapeutic effects after oral dosing, significant anti-inflammatory effects were noted, including reduced influx of neutrophils, significant reductions in plasma levels of CREA and BUN, and histological improvements. About INF904 INF904 is an orally administered, small molecule inhibitor of the C5a receptor that has shown anti-inflammatory therapeutic effects in several pre-clinical disease models. Further, in contrast to the marketed C5aR inhibitor, in vitro experiments demonstrated that INF904 has minimal inhibition of the cytochrome P450 3A4/5 (CYP3A4/5) enzymes, which play an important role in the metabolism of a variety of metabolites and drugs, including glucocorticoids. Reported results from a first-in-human study demonstrated that INF904 is well tolerated in treated subjects and exhibits no safety signals of concern in single doses ranging from 3 mg to 240 mg or multiple doses ranging from 30 mg once per day (QD) to 90 mg twice per day (BID) for 14 days. Pharmacokinetic / pharmacodynamic data support best-in-class potential of INF904 with a ≥90% blockade of C5a-induced neutrophil activation achieved over the 14-day dosing period. About InflaRx InflaRx (Nasdaq: IFRX) is a biopharmaceutical company pioneering anti-inflammatory therapeutics by applying its proprietary anti-C5a and anti-C5aR technologies to discover, develop and commercialize highly potent and specific inhibitors of the complement activation factor C5a and its receptor C5aR. C5a is a powerful inflammatory mediator involved in the progression of a wide variety of inflammatory diseases. InflaRx’s lead product candidate, vilobelimab, is a novel, intravenously delivered, first-in-class, anti-C5a monoclonal antibody that selectively binds to free C5a and has demonstrated disease-modifying clinical activity and tolerability in multiple clinical studies in different indications. InflaRx is also developing INF904, an orally administered, small molecule inhibitor of the C5a receptor. InflaRx was founded in 2007, and the group has offices and subsidiaries in Jena and Munich, Germany, as well as Ann Arbor, MI, USA. For further information, please visit www.inflarx.com. InflaRx GmbH (Germany) and InflaRx Pharmaceuticals Inc. (USA) are wholly owned subsidiaries of InflaRx N.V. (together, InflaRx). Contacts: InflaRx N.V.MC Services AGJan Medina, CFAVice President, Head of Investor RelationsEmail: IR@inflarx.deKatja Arnold, Laurie Doyle, Dr. Regina LutzEmail: inflarx@mc-services.eu Europe: +49 89-210 2280U.S.: +1-339-832-0752 FORWARD-LOOKING STATEMENTSThis press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “estimate,” “believe,” “predict,” “potential” or “continue,” among others. Forward-looking statements appear in a number of places throughout this release and may include statements regarding our intentions, beliefs, projections, outlook, analyses, current expectations and the risks, uncertainties and other factors described under the heading “Risk Factors” and “Cautionary statement regarding forward looking statements” in our periodic filings with the U.S. Securities and Exchange Commission. These statements speak only as of the date of this press release and involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law.

– DSP-5336, an Investigational Menin and Mixed-lineage Leukemia Inhibitor, is Being Evaluated in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a mixed lineage leukemia rearrangement (MLLr) or nucleophosmin mutation (NPM1m) – MARLBOROUGH, Mass., July 15, 2024 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation to DSP-5336 for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with a KMT2A rearrangement, also known as, mixed lineage leukemia rearrangement (MLLr) or nucleophosmin mutation (NPM1m). DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction, which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2,3 FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. "For patients and families facing a diagnosis of relapsed or refractory acute myeloid leukemia, significant unmet medical needs remain – and we share in their urgency to identify and advance new treatment pathways," said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. "We are encouraged by FDA's decision and look forward to working closely with the agency as we continue our clinical development of DSP-5336." Updated data from the ongoing open-label, dose escalation and optimization portion of the Phase 1/2 study for DSP-5336 were presented at the European Hematology Association (EHA) 2024 Hybrid Congress, building on preliminary data presented at the 2023 American Society of Hematology (ASH) Annual Meeting. Objective response was observed in 57% (12/21) of patients, which included responses in patients with both Nucleophosmin 1 (NPM1) mutation and KMT2A (MLL) rearrangement. The proportion with complete remission or complete remission with partial hematologic recovery (CR/CRh) was 24% (5/21 patients). To date, DSP-5336 remains well-tolerated with no dose limiting toxicity (DLT) observed and no significant cardiac signal nor treatment-related discontinuations or deaths. No significant drug-drug interactions with azoles have been identified and repeat dosing results in minimal to no pharmacokinetic accumulation. Importantly, no differentiation syndrome (DS) prophylaxis was needed, and the three cases of DS reported (5%) were manageable and did not result in intensive care unit (ICU) stays or discontinuation of DSP-5336. "Management of AML continues to be challenging with limited options for which there are currently no approved targeted therapies to treat AML with KMT2A (MLL) rearrangements or NPM1 mutations, leaving a serious unmet medical need," said Jatin Shah, M.D., Chief Medical Officer – Oncology at SMPA. "DSP-5336 has shown promising clinical activity, and menin inhibitors have tremendous potential to impact the outcomes of these types of acute leukemia. We are excited by these early results and FDA Fast Track Designation, and look forward to working closely with the agency and our collaborators to rapidly advance this program with the goal of providing a well-tolerated and effective targeted treatment option for patients with relapsed or refractory acute myeloid leukemia." Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells, in the bone marrow. Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.4 Approximately 30% of AML patients have NPM1 mutations6 and 5-10% of AML patients have KMT2A (MLL) rearrangements.5 About DSP-5336 DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.1,3 DSP-5336 reduced the expression of the leukemia-associated genes HOXA9 and MEIS1, and increased the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.7,8 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. The FDA granted Fast Track Designation for DSP-5336 for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in June 2024. About Sumitomo Pharma Sumitomo Pharma Co., Ltd. is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.) and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women's health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, and in-house advanced technology capabilities, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website or follow us on LinkedIn. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. © 2024 Sumitomo Pharma America, Inc. All rights reserved. References Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL Interaction. Future Med Chem. 2014; 6(4):447-462. doi:10.4155/fmc.13.214. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8):394-402. doi:10.1016/j.tibs.2013.05.005. Kuhn MWM, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181. doi:10.1158/2159-8290.CD-16-0237. Chennamadhavuni A, Lyengar V, Mukkamalla SKR, et al. Leukemia. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: . Borkin D, Klossowski S, Pollock J, et al. Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction. J Med Chem. 2018;61(11):4832-4850. doi:10.1021/acs.jmedchem.8b00071. Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev. 2021;42(2):133-170. doi:10.1210/endrev/bnaa031 Eguchi K, Shimizu T, Kato D, et al. Preclinical Evaluation of a Novel Orally Bioavailable Menin-MLL Interaction Inhibitor, DSP-5336, for the Treatment of Acute Leukemia Patients with MLL-Rearrangement or NPM1 Mutation. Blood 2021; 138 (Supplement 1): 3339. Available at: . Daver N, Zeidner JF, Yuda J, et al. Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia. Blood 2023; 142 (Supplement 1): 2911. Available at: . SOURCE Sumitomo Pharma America