A randomized, double-blind, placebo controlled, dose finding study to assess the efficacy and safety of SAR443122 in adult patients with moderate to severe ulcerative colitis - RESOLUTE

Start Date20 Jun 2023

Sponsor / Collaborator

Sanofi-Aventis Recherche & Développement SA

NCT05588843

/ RecruitingPhase 2

A Randomized, Double-blind, Placebo Controlled, Dose-finding Study to Assess the Efficacy and Safety of SAR443122 in Adult Patients With Moderate to Severe Ulcerative Colitis

This is a randomized, double-blind, placebo controlled, dose-ranging Phase 2 study. The primary objective is to evaluate the efficacy and safety of SAR443122 compared to placebo in participants with moderate to severe UC. Dose selection for further clinical development will be based on the multiple efficacy, safety and PK parameters.
The study consists of 4 parallel arms (3 dose groups of SAR443122 vs placebo) to assess the efficacy and safety of SAR443122 in participants with moderate to severe UC. All participants will receive a total of 52 weeks (a 12-week induction treatment phase and a 40-week maintenance phase) of study treatment, except if treatment should be discontinued per investigator's assessment.
At the end of the first 12 weeks of induction treatment, all participants in clinical response or remission will be offered study treatment up to 40 weeks and will continue with the same blinded treatment that was assigned. Participants who do not achieve clinical response or remission at the end of the initial 12 weeks induction treatment will roll over in an open-label treatment arm and will be treated with SAR443122 at the highest tested dose.
In addition, participants from the maintenance treatment that lose clinical efficacy at any time up to V10/Week 40 (Week 28 of maintenance) will be offered to roll over in the open-label treatment arm with SAR443122 at the highest dose.

Start Date25 Nov 2022

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with Eclitasertib

100 Translational Medicine associated with Eclitasertib

100 Patents (Medical) associated with Eclitasertib

Literatures (Medical) associated with Eclitasertib

01 Aug 2025·ADVANCES IN THERAPY

A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants

Article

Author: Badalamenti, Salvatore ; Kruger, Annie J ; Lin, Yong ; Pomponio, Robert J ; Clot, Pierre-Francois ; Krahnke, Tillmann ; Staudinger, Heribert ; Farenc, Christine

INTRODUCTION:

Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1.

METHODS:

This 2-part Phase I trial enrolled healthy participants aged 18-55 years. Part 1 consisted of 2 sub-parts. Part 1a was a double-blind, randomized, single ascending dose (SAD) study with 6 cohorts of 8 participants each randomized 3:1 to single oral dose of eclitasertib (10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or placebo. Part 1b was an open-label, randomized, three-sequence, cross-over design study to evaluate the relative bioavailability of the prototype formulation versus the drug substance and the effect of food in an independent cohort of 10 participants. Part 2 was a double-blind, randomized, multiple ascending dose study (MAD) with 4 cohorts of 10 participants each randomized 4:1 to receive eclitasertib (50 mg, 100 mg, 200 mg, or 600 mg once daily) or placebo orally for 14 days. Incidence of adverse events (AEs; primary outcome), PK (secondary outcome), and PD properties (exploratory outcome; assessed by reduction in levels of S166 phosphorylated RIPK1) were evaluated.

RESULTS:

Single and multiple oral doses of eclitasertib were well tolerated, with no study drug-related severe or serious AEs reported. Medical device-site reactions (includes AEs classified as device-site reaction, vessel puncture-site hematoma/pain, catheter-site pain/hematoma and catheter-site-related reactions) and headache were the most commonly reported AEs in both parts. Overall, the median T_max ranged from 3 to 4 h. C_max and AUC increased sub-dose proportionally. Administration of eclitasertib 100 mg following a high-fat meal did not significantly impact its bioavailability. At doses of 100 mg and above, > 90% inhibition of RIPK1 phosphorylation in human peripheral blood mononuclear cells was observed with eclitasertib at 12 h post-dose in both SAD and MAD studies.

CONCLUSIONS:

Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation.

TRIAL REGISTRATION:

EudraCT 2019-001350-25.

01 Nov 2024·BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

Article

Author: Hornyánszky, Gábor ; Éles, János ; Greiner, István ; Kálomista, Ildikó ; Eszter Szabó, Judit ; Linke, Nikolett ; Gábor Vass, Csaba ; Bana, Péter ; Levente Petró, József ; Katalin Szalai, Krisztina

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.

01 Aug 2021·European journal of medicinal chemistryQ1 · MEDICINE

Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors

Q1 · MEDICINE

Article

Author: Chen, Haihu ; Xu, Lijuan ; Yao, Zhengguang ; Zhang, Wannian ; Zhuang, Chunlin ; Xia, Chunnian

Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC₅₀ values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.

News (Medical) associated with Eclitasertib

15 Oct 2024

·www.outsourcing-pharma.com

Sanofi abandons phase 2 trial of Denali’s multiple sclerosis candidate

The K2 trial tested oditrasertib’s safety and ability to reduce the blood levels of neurofilament light chain, a biomarker of neuronal damage in multiple sclerosis. However, the trial failed to meet its primary and undisclosed key secondary endpoints, according to a filing . Multiple sclerosis is a degenerative and progressive disorder where the immune system attacks the insulation around nerve cells, leading to the death of the cells and to increasing disability in people with the condition, which number around 2.8 million . Oditrasertib is designed to block a protein called receptor-interacting protein kinase 1 (RIPK1), which is involved in cell death. Blocking RIPK1 could make nerve cells more resistant to the pathology and slow down the disease. Denali obtained oditrasertib in 2016 when it took over the previous developer Incro Pharmaceuticals. Sanofi then got in on the action when it inked a $1 billion strategic collaboration with Denali in 2018 to develop candidates for the treatment of immunological and neurological conditions. Numerous setbacks The partnership has faced numerous obstacles in the last few years. Another of the RIPK1 inhibitors in the deal flopped in a phase 1b trial for the treatment of Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) in 2020, leading the partners to focus on oditrasertib. In February this year, however, oditrasertib failed in a phase 2 trial for the treatment of ALS and Sanofi discontinued the trial. Another RIPK1 inhibitor in the sights of the partners is eclitasertib, which cannot penetrate the central nervous system and is in phase 2 development for the treatment of ulcerative colitis. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Denali Therapeutics raised $500 million in a private placement in February this year and its main candidate, an enzyme replacement therapy to treat the rare disease mucopolysaccharidosis type II, is in a phase 2/3 trial set to complete enrollment this year. The growing prevalence of multiple sclerosis is set to drive the global market for treatments, which was worth $21.3 billion in 2023 and is projected to grow by 7.9% to $38.9 billion by 2032. Getting a RIPK1 blocker to the market is proving difficult for many players, with a candidate developed by GlaxoSmithKline showing no efficacy signs in clinical results in patients with ulcerative colitis published in 2021. Some of the most advanced RIPK1 contenders include phase 1-stage programs by China’s GenFleet Therapeutics, Roche’s U.S. company Genentech, and a compound developed by Eli Lilly and Rigel Pharmaceuticals.

Phase 2Drug ApprovalPhase 1Acquisition

10 Oct 2024

·endpts.com

Sanofi discontinues Denali-partnered MS trial after Phase 2 failure

Sanofi is ending a Phase 2 clinical trial that’s testing a drug from Denali for multiple sclerosis, putting a stop to the development plan. Denali said in an SEC filing Thursday that Sanofi notified the company that the drug, oditrasertib, did not meet primary or key secondary endpoints in the study. The drug looked to block RIPK1, a signaling protein that when overstimulated can drive neuroinflammation and cell death, root causes of diseases like multiple sclerosis. A Sanofi spokesperson said the company has no other planned studies. The new data are the latest in a string of disappointing readouts since the collaboration got off the ground. Sanofi paid Denali $125 million upfront back in 2018 with more than $1 billion in potential milestone payments, a huge bet on the RIPK1 target that oditrasertib was aimed at. In February, oditrasertib failed a Phase 2 ALS study , after failing to improve patient symptoms as measured by the ALS Functional Rating Scale. Another drug that headlined the 2018 deal, DNL747, was fully halted in 2020 after the companies got a peek at Phase 1b data in patients with Alzheimer’s and ALS. A third asset, DNL758, is still in the middle of a Sanofi-run Phase 2 study for patients with ulcerative colitis. But the company discontinued an earlier study in October 2023 after the drug was found to not be effective in patients with cutaneous lupus erythematosus. Despite the pared-back collaboration, Denali entered the third quarter with $1.35 billion in cash, equivalents and marketable securities as of the end of June. That funding will help pay for advancing the company’s mid- to late-stage pipeline, including a potential treatment for Hunter syndrome that Denali is teeing up for an accelerated approval application. The company said last month that it had a successful meeting with the FDA about a surrogate endpoint and plans to submit the application in early 2025.

Phase 2Accelerated ApprovalClinical Trial Failure

20 Feb 2024

·www.fiercebiotech.com

Sanofi stumbles in HIMALAYA trial, chalking up phase 2 ALS fail in another blow to Denali alliance

Shares in Denali Therapeutics fell 7.3% to $17.02 Friday. Sanofi’s HIMALAYA adventure has ended in failure, dealing another blow to its RIPK1 collaboration with Denali Therapeutics. The phase 2 study randomized 305 people with amyotrophic lateral sclerosis (ALS) to receive SAR443820, a RIPK1 inhibitor also known as DNL788, or placebo orally twice a day. After 24 weeks, Sanofi assessed the change from baseline on an ALS severity scale, ALSFRS-R. The clinical trial also features an open-label extension designed to measure the combined assessment of the function and survival score at Week 52. In a financial filing, Denali revealed the HIMALAYA study failed to meet the ALSFRS-R primary endpoint. Sanofi will share detailed safety and efficacy results at an upcoming scientific forum. For now, the only information is that the study missed its primary endpoint. Sanofi is continuing to study SAR443820 in a phase 2 multiple sclerosis trial. That study began dosing 13 months ago, triggering a $25 million milestone payment to Denali, and finished enrolling its 174 subjects by the end of 2023. The primary completion date is September 2025, according to ClinicalTrials.gov. The multiple sclerosis study is part of a dwindling list of opportunities open to the Sanofi-Denali RIPK1 collaboration. Sanofi paid $125 million to buy into the program in 2018, 11 months after Denali raised $250 million in the biggest biotech IPO of 2017. However, the project hit an early bump in the road when the partners switched to a backup compound in response to chronic toxicity data on their lead asset. In parallel, the partners worked on another RIPK1 inhibitor that, unlike SAR443820, is designed not to penetrate the central nervous system. That drug, eclitasertib, is being studied in peripheral inflammatory diseases but has suffered setbacks. Sanofi stopped work on cutaneous lupus erythematosus last year in response to phase 2 efficacy data, although it is continuing to run a midstage study in ulcerative colitis. Other companies have shared Sanofi’s interest in RIPK1. Eli Lilly paid Rigel Pharmaceuticals $125 million for an inhibitor of the kinase in 2021 and began a phase 2 rheumatoid arthritis study last year. GSK, which previously dropped a RIPK1 cancer candidate, offloaded an asset to Boston Pharmaceuticals in 2021. Bristol Myers Squibb removed a phase 1 RIPK1 inhibitor from its pipeline last year. Shares in Denali fell 7.3% to $17.02 over the course of Friday's trading.

Phase 2Phase 1IPOFinancial Statement

100 Deals associated with Eclitasertib

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	United States	Piramal Pharma Limited	25 Nov 2022
Colitis, Ulcerative	Phase 2	United States	Sanofi	25 Nov 2022
Colitis, Ulcerative	Phase 2	China	Sanofi	25 Nov 2022
Colitis, Ulcerative	Phase 2	Japan	Sanofi	25 Nov 2022
Colitis, Ulcerative	Phase 2	Japan	Piramal Pharma Limited	25 Nov 2022
Colitis, Ulcerative	Phase 2	Argentina	Sanofi	25 Nov 2022
Colitis, Ulcerative	Phase 2	Argentina	Piramal Pharma Limited	25 Nov 2022
Colitis, Ulcerative	Phase 2	Chile	Sanofi	25 Nov 2022
Colitis, Ulcerative	Phase 2	Chile	Piramal Pharma Limited	25 Nov 2022
Colitis, Ulcerative	Phase 2	Czechia	Piramal Pharma Limited	25 Nov 2022

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