A Randomized, Placebo-controlled, Parallel-group, Investigator- and Participant-blinded Phase 2a Study to Investigate the Efficacy, Safety, and Tolerability of DFV890 and MAS825 for Inflammatory Marker Reduction in an Adult Population With Coronary Heart Disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP)

This Phase 2a clinical trial will evaluate the effectiveness, safety, and tolerability of increasing dose strengths of an oral daily medication, DFV890, administered for 12 weeks, or a single s.c. dose of MAS825, to reduce key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 28 people with known coronary heart disease and TET2 or DNMT3A CHIP (VAF ≥2%).

Start Date15 Feb 2024

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

CTIS2022-501406-36-00 / Recruiting

- CDFV890G12101

Start Date14 Dec 2023

Sponsor / Collaborator

Novartis Pharma AG

NCT06031844 / RecruitingPhase 2

A Randomized, Placebo-controlled, Parallel-group, Investigator- and Participant-blinded Phase 2a Study to Investigate the Efficacy, Safety, and Tolerability of DFV890 for Inflammatory Marker Reduction in Adult Participants With Coronary Heart Disease and Elevated hsCRP

This Phase 2a clinical trial will evaluate the effectiveness, safety, and tolerability of increasing dose strengths of an oral daily medication, DFV890, administered for 12 weeks, to reduce key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 24 people with known heart disease and an elevated marker of inflammation, hsCRP.

Start Date16 Oct 2023

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with IFM-2427

100 Translational Medicine associated with IFM-2427

100 Patents (Medical) associated with IFM-2427

Literatures (Medical) associated with IFM-2427

01 May 2024·CTS-Clinical and Translational Science

First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.

Article

Author: Fu, Yunlin ; Junge, Guido ; Denney, Wiliam S ; Sommer, Ulrike ; Gatlik, Ewa ; Voltz, Emilie ; Mehes, Beata ; Lestini, Giulia ; Tritto, Elaine ; Opipari, Anthony ; Pal, Parasar ; Dean, Dennis ; Liu, Xiaoxi ; Velinova, Maria

This first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted: 10-200 mg, once-daily or fed: 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, C_max of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in C_max and AUC_0-last compared with the fasting condition. The median IC₅₀ and IC₉₀ for ex-vivo lipopolysaccharide-stimulated interleukin IL-1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.

01 Jun 2023·Infection

DFV890: a new oral NLRP3 inhibitor—tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function

Article

BACKGROUND:

Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm.

METHODS:

This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety.

FINDINGS:

Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals.

INTERPRETATION:

DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS.

TRIAL REGISTRATION:

ClinicalTrials.gov, NCT04382053.

01 Dec 2021·Cytokine & growth factor reviewsQ2 · MEDICINE

The role and transformative potential of IL-19 in atherosclerosis

Q2 · MEDICINE

Review

Author: Dongming Xing ; Xinlin Liu ; Wujun Chen ; Shuai Wang ; Jiyao Xing

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Traditionally, IL-19 was thought to be expressed in only immune cells, but studies revealed that IL-19 is also expressed in multiple atherosclerotic plaque cell types, but not normal arteries, in humans and mice. IL-19 reduces the development of atherosclerosis via multiple mechanisms, including balancing cholesterol metabolism; enhancing Th2 immune cell polarization; reducing the inflammatory response; and reducing the proliferation, migration and chemotaxis of vascular smooth muscle cells (VSMCs). Clinical and/or animal studies have primarily aimed to achieve regression and/or stabilization of atherosclerotic plaques, with regression in particular indicating a very good drug response. Most antiatherosclerotic drugs in current clinical use, including atorvastatin and alirocumab, target hyperlipidemia. Several other drugs have also been investigated in clinical trials as anti-inflammatory agents; the development of some of these agents has been terminated (canakinumab, darapladib, varespladib, losmapimod, atreleuton, setileuton, PF-04191834, veliﬂapon, and methotrexate), but others remain in development (ziltivekimab, tocilizumab, Somalix, IFM-2427, anakinra, mesenchymal stem cells (MSCs), colchicine, everolimus, allopurinol, and montelukast). Most of the tested drugs have shown a limited ability to reverse atherosclerosis in animal studies. Interestingly, recombinant IL-19 (rIL-19) was shown to reduce atherosclerosis development in a time- and dose-dependent manner. A low dose of rIL-19 (1 ng/g/day) reduced aortic arch and root plaque areas by 70.1% and 32.1%, respectively, in LDLR^-/- mice. At 10 ng/g/day, rIL-19 completely eliminated atherosclerotic plaques. There were no sex differences in the effects of rIL-19 on atherosclerotic mice. Thus, low-dose rIL-19 is an effective antiatherosclerotic agent, in addition to its efficacy in intimal hyperplasia, spinal cord injury, stroke, and multiple sclerosis. We propose that IL-19 is a promising biomarker and target for the diagnosis and treatment of atherosclerosis. This review considers the role and mechanism of action of IL-19 in atherosclerosis and discusses whether IL-19 is a potential therapeutic target for this condition.

News (Medical) associated with IFM-2427

13 Mar 2024

·www.pharmamanufacturing.com

Novartis buys IFM unit, picking up STING inhibitors

Novartis has exercised its option to acquire all the outstanding capital stock of IFM Due, a subsidiary of Boston-based IFM Therapeutics. IFM Due and Novartis entered into an option and collaboration agreement back in September 2019 . Now, per the deal, IFM will receive $90 million upfront and will be eligible for up to $745 million in milestone payments, adding up to $835 million in total consideration. IFM Due was launched in February 2019, with a focus on developing small molecules that inhibit the cGAS-STING pathway. The recent acquisition provides Novartis with full rights to IFM Due’s portfolio of STING antagonists, which have the potential to treat an array of serious inflammation-driven diseases characterized by excessive interferon and other pro-inflammatory cytokine signaling. This is Novartis' second acquisition of an IFM Therapeutics subsidiary.In April 2019 Novartis paid $310 million upfront for subsidiary IFM Tre, shortly after Tre had dosed an initial subject with its first-in-class NLRP3 antagonist, IFM-2427. The molecule was the first of Tre's three unique development candidates to enter the clinic, all of which are intended to block only the inflammation driven by the NLRP3 pathway.

Acquisition

28 Mar 2019

·www.biospace.com

IFM Therapeutics Announces Dosing of First Subjects in Phase 1 Healthy Volunteer Study of Lead NLRP3 Antagonist, IFM-2427

Announcement marks first human trial for an NLRP3 antagonist BOSTON, March 28, 2019 /PRNewswire/ -- IFM Therapeutics (IFM), a privately held biopharmaceutical company focused on developing therapies that modulate novel targets in the innate immune system, today announced that the first subjects have been dosed in a Phase 1 healthy volunteer trial of IFM-2427. IFM-2427, the lead program from IFM's subsidiary IFM Tre, is a first-in-class systemic NLRP3 (NOD-, LRR- and pyrin domain-containing 3) antagonist that can potentially block the inflammatory responses underlying a variety of serious diseases. "Initiating this Phase 1 trial of IFM-2427 – less than a year after IFM Tre was launched – is a meaningful achievement for IFM and reflective of our team's ability to efficiently advance product candidates from discovery to clinical development," said Gary D. Glick, Ph.D., Chief Executive Officer and Co-Founder of IFM Therapeutics. "Further, this first-in-human study of a systemic NLRP3 inhibitor reinforces our leadership in innate immune system biology. We are committed to exploiting the full therapeutic potential of NLRP3 inhibition through the advancement of chemically-distinct molecules with varying mechanisms of action and across a breadth of indications." NLRP3 is an intracellular innate immune signaling receptor that allows immune cells to detect the presence of pro-inflammatory foreign or endogenous molecules that signal infection, tissue damage or metabolic derangements. These conditions trigger the assembly of a multi-protein complex called an inflammasome, which then initiates an immune response. While this response can be useful for fending off foreign pathogens, abnormal or chronic activation of the NLRP3 inflammasome is known to cause negative downstream effects and the onset and progression of numerous diseases. IFM-2427 is the first of IFM Tre's three unique development candidates to enter the clinic, all of which are intended to block only the inflammation driven by the NLRP3 pathway, leaving other immune pathways unsuppressed and free to produce inflammatory responses to confront harmful pathogens. IFM-2427 is a first-in-class small molecule designed to inhibit the activity of NLRP3 outside the central nervous system by directly binding to the protein, thereby blocking its activation that leads to the maturation of the pro-inflammatory cytokines IL-1, IL-18 along with pyroptosis, an inflammatory form of cell death. The Phase I clinical study of IFM-2427 is being carried out in up to 90 subjects and is expected to complete in the fourth quarter of 2019. About IFM Tre IFM Tre, a subsidiary of IFM Therapeutics (IFM), is a biopharmaceutical company developing a suite of small-molecule antagonists targeting inappropriate inflammatory responses of the innate immune system via the NLRP3 pathway, which is believed to underlie a variety of serious diseases. The Company is developing chemically distinct systemic, gut-directed and CNS-penetrant drug candidates to address a breadth of indications triggered by NLRP3, including metabolic, fibrotic, autoimmune, autoinflammatory, and neurodegenerative diseases. About IFM Therapeutics IFM Therapeutics (IFM) is a privately held biopharmaceutical company based in Boston, Massachusetts. The Company was founded by an international group of preeminent scientists and physicians following the sale of IFM Therapeutics, Inc (originally founded by Gary Glick and Atlas Venture) to Bristol-Myers Squibb. IFM's team has discovered and developed small molecules that modulate novel targets in the innate immune system as next-generation therapies for cancer, auto-immunity, and inflammatory disorders. In addition to IFM Tre, IFM owns and operates IFM Due, a subsidiary company launched in February 2019 that is developing small-molecule antagonists and inhibitors targeting aberrant inflammatory responses of the innate immune system triggered by the cGAS-STING pathway, which is believed to underlie a variety of serious diseases. For more information, please visit . View original content to download multimedia: SOURCE IFM Therapeutics, LLC

First in ClassSmall molecular drug

100 Deals associated with IFM-2427

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Coronary Disease	Phase 2	US	Novartis Pharmaceuticals Corp.	16 Oct 2023
Coronary Disease	Phase 2	CA	Novartis Pharmaceuticals Corp.	16 Oct 2023
Familial cold urticaria	Phase 2	US	Novartis Pharmaceuticals Corp.	20 Sep 2021
Familial cold urticaria	Phase 2	FR	Novartis Pharmaceuticals Corp.	20 Sep 2021
Familial cold urticaria	Phase 2	DE	Novartis Pharmaceuticals Corp.	20 Sep 2021
Osteoarthritis, Knee	Phase 2	US	Novartis Pharmaceuticals Corp.	20 Sep 2021
Osteoarthritis, Knee	Phase 2	AR	Novartis Pharmaceuticals Corp.	20 Sep 2021
Osteoarthritis, Knee	Phase 2	CZ	Novartis Pharmaceuticals Corp.	20 Sep 2021
Osteoarthritis, Knee	Phase 2	DE	Novartis Pharmaceuticals Corp.	20 Sep 2021
Osteoarthritis, Knee	Phase 2	HU	Novartis Pharmaceuticals Corp.	20 Sep 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04382053 (Pubmed) Manual	Phase 2	COVID-19 \| Respiratory Insufficiency	143	SoC+IFM-2427	pkwqunwpod(kratunozjk) = cmouuyewge aehuspgzks (nfgxparfje, 1.06) View more	Negative	14 Sep 2022
				SoC	pkwqunwpod(kratunozjk) = snasonvxkw aehuspgzks (nfgxparfje, 1.05) View more
NCT04382053 (CTgov)	Phase 2	COVID-19 \| Respiratory Insufficiency	143	Standard of Care (SoC)+DFV890 (DFV890 + SoC)	deziuefwzn(cyosmstxsj) = mkkawebufz lcrphvverw (tvjouequno, jbtoxcwfnc - yyjjerxeba) View more	-	30 Nov 2021
				Standard of Care (SoC) (Standard of Care (SoC))	deziuefwzn(cyosmstxsj) = ftqlapybpt lcrphvverw (tvjouequno, loppnkinfg - hrwgrasrev) View more

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