A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of Abiprubart in Participants With Sjögren's Disease

Primary objective of the study is to evaluate the effect of abiprubart on an established systemic disease activity measure for Sjögren's Disease.

Start Date17 Jul 2024

Sponsor / Collaborator

Kiniksa Pharmaceuticals International Plc

[+1]

NCT05198310

/ CompletedPhase 2

A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor

Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis.

Start Date14 Dec 2021

Sponsor / Collaborator

Kiniksa Pharmaceuticals Ltd.

NCT04497662

/ CompletedPhase 1

A Phase 1 First-in-human Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Intravenous and Subcutaneous Doses of KPL-404 in Healthy Subjects

Phase 1, randomized, double-blind, placebo-controlled first-in-human study to investigate the safety, tolerability, PK and PD properties of single ascending intravenous (IV) and subcutaneous (SC) doses of KPL-404 in healthy subjects

Start Date22 Oct 2019

Sponsor / Collaborator

Kiniksa Pharmaceuticals Ltd.

100 Clinical Results associated with Abiprubart

100 Translational Medicine associated with Abiprubart

100 Patents (Medical) associated with Abiprubart

Literatures (Medical) associated with Abiprubart

01 Feb 2025·THERAPEUTIC DRUG MONITORING

New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review

Review

Author: de Graav, Gretchen N. ; Reinders, Marlies E. J. ; Udomkarnjananun, Suwasin ; Baan, Carla C. ; Hesselink, Dennis A. ; de Winter, Brenda C. M. ; Roodnat, Joke I.

Purpose::

In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents.

Methods::

Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014–2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov.

Results::

Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies.

Conclusions::

The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.

01 Dec 2023·The Journal of pharmacology and experimental therapeutics

First-in-Human Phase 1 Randomized Trial with the Anti-CD40 Monoclonal Antibody KPL-404: Safety, Tolerability, Receptor Occupancy, and Suppression of T-Cell–Dependent Antibody Response

Article

Author: Ziemniak, John ; Samant, Manoj ; Paolini, John F

Blockade of the cluster of differentiation 40 (CD40)-CD40L interaction has potential for treating autoimmune diseases and preventing graft rejection. This first-in-human, randomized, double-blind, placebo-controlled study (NCT04497662) evaluated safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the humanized anti-CD40 monoclonal antibody KPL-404. Healthy volunteers were randomized to one of two single-ascending-dose groups: single intravenous KPL-404 dose 0.03, 0.3, 1, 3, or 10 mg/kg or single subcutaneous KPL-404 dose 1 or 5 mg/kg. There were no dose-limiting or dose-related safety findings. Nonlinear dose-dependent changes in various pharmacokinetic parameters were identified following the range of intravenous doses. At the 10 mg/kg intravenous dose level, the t_1/2 was approximately 7 days, and full receptor occupancy was observed through Day 71, with complete suppression of T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) challenge on Day 1 and rechallenge on Day 29 through Day 57. With KPL-404 5 mg/kg subcutaneously, full receptor occupancy was observed through Day 43, with complete suppression of TDAR through at least Day 29. Antidrug antibodies to KPL-404 were suppressed for 57 days with 10 mg/kg intravenously and for 50 days with 5 mg/kg subcutaneously, further confirming prolonged target engagement and pharmacodynamics. These findings support continued investigation of KPL-404 intravenous and subcutaneous administration in a broad range of indications. SIGNIFICANCE STATEMENT: This first-in-human clinical trial of KPL-404, a fully humanized IgG4 monoclonal antibody, was designed with two independent (by route of administration) placebo-controlled single-ascending-dose-level groups, one with four intravenous single-dose cohorts and another with two subcutaneous single-dose cohorts. The pharmacokinetic profile, duration of full CD40 receptor occupancy, and magnitude and duration of memory immune response suppression observed confirm pharmacodynamic activity regardless of administration route. These data provide evidence that chronic KPL-404 dosing regimens (intravenous or subcutaneous) could be practical.

01 Apr 2022·The Journal of pharmacology and experimental therapeuticsQ3 · MEDICINE

Preclinical Immunopharmacologic Assessment of KPL-404, a Novel, Humanized, Non-Depleting Antagonistic Anti-CD40 Monoclonal Antibody

Q3 · MEDICINE

Article

Author: Muralidharan, Sujatha ; Garron, Tracy ; Njenga, Moses ; Paolini, John F ; Bondensgaard, Kent

The CD40/CD40L pathway plays a major role in multiple inflammatory processes involving different immune and stromal cells. Abnormal activation of this pathway has been implicated in pathogenesis of complex autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, Graves' disease, and Sjogren's Syndrome. We completed in vitro and in vivo preclinical characterization of KPL-404, a novel humanized anti-CD40 IgG4 monoclonal antibody, to demonstrate its potency, efficacy, and pharmacokinetic profile; safety was also assessed. In vitro, KPL-404 bound recombinant human and cynomolgus monkey CD40 with comparable affinity in the nanomolar range. KPL-404 binding to cell surface CD40 did not induce antibody- or complement-mediated cytotoxicity of CD40-expressing cells. Pharmacological antagonistic activity of KPL-404 was demonstrated in vitro by inhibition of CD40-mediated downstream NF-kB activation. In the in vivo study with cynomolgus monkeys, KPL-404, administered intravenously as a single dose (10 mg/kg) or two monthly doses of 1 or 5 mg/kg, did not elicit observable safety findings, including thrombocytopenia over 8 weeks. KPL-404 engaged CD40 expressed on peripheral B cells for 2 and 4 weeks after a single administration of 5 or 10 mg/kg IV, respectively, without depletion of peripheral B cells. At 5 mg/kg IV, KPL-404 blocked both primary and secondary responses to T-cell dependent antibody responses to test antigens, KLH, and tetanus toxoid. These data illustrated the relationship between KPL-404 serum concentration and pharmacodynamic effects of CD40-targeting in circulation and in lymphoid tissues. These data support clinical development of KPL-404 in autoimmune diseases. SIGNIFICANCE STATEMENT: We aimed to develop a potent and efficacious CD40 antagonist. In vitro and in vivo findings show that KPL-404 blocks the anti-CD40 antibody that potently inhibits primary and secondary antibody responses at pharmacologically relevant concentrations, has a favorable pharmacokinetic profile, and does not deplete B cells by antibody-dependent cellular cytotoxicity or apoptosis ("nondepleting"). These findings support clinical development of KPL-404 as a potential therapeutic in autoimmune diseases.

News (Medical) associated with Abiprubart

11 Aug 2025

·www.fiercebiotech.com

Novartis scores double phase 3 win in Sjögren\'s syndrome, succeeding where rivals failed

Novartis hailed the win as the “first ever global phase 3 trials to demonstrate statistically significant reduction in disease activity for Sjögren\'s disease.”\n Novartis may have abandoned one Sjögren\'s syndrome asset this year, but it looks like the drugmaker has a winner on its hands with another candidate.The Swiss pharma had been evaluating ianalumab, a dual-mechanism, B-cell-depleting antibody that targets the protein BAFF-R, in a pair of phase 3 studies dubbed Neptunus 1 and 2, which in total enrolled 779 patients with the systemic autoimmune disease.Both studies hit their primary endpoint of demonstrating an improvement in disease activity as measured on the EULAR Sjögren\'s syndrome disease activity index at 52 weeks compared to placebo, Novartis announced in an Aug. 11 release. The drug was also well tolerated and demonstrated a favorable safety profile, according to the pharma.The company hailed the win as the “first ever global phase 3 trials to demonstrate statistically significant reduction in disease activity for Sjögren\'s disease.” For now, Novartis is holding back the data for a future medical conference, while referencing plans to take the results to global regulators with the aim of bringing the first targeted treatment for the autoimmune disease to market.“Sjögren\'s disease is a serious, progressive, systemic autoimmune disease, often unrecognized or misdiagnosed with a significant detrimental impact to quality of life, with very limited treatment options and an established unmet need,” Novartis Chief Medical Officer Shreeram Aradhye, M.D., said in the release.“Both phase 3 trials demonstrate that ianalumab improves disease activity in patients with Sjögren\'s disease,” Aradhye added. “These phase 3 studies mark a significant milestone. We look forward to engaging with health authorities to discuss these findings in the near future.”It’s a big win for Novartis, which started the year dropping its anti-CD40 antibody iscalimab after becoming doubtful of its competitive profile. That left ianalumab as Novartis’ last and best hope for the disease.Ianalumab had already shown \"meaningful differences in patients with this very difficult-to-treat disease” in phase 2, Novartis executives pointed out at the time.Iscalimab was only the latest Big Pharma prospect to fail to make the grade in Sjögren\'s. Last year, Sanofi crossed off Sjögren’s from the list of targeted indications for its CD40L monoclonal antibody frexalimab after seeing phase 2 efficacy data, while, more recently, Kiniksa Pharmaceuticals ended work on its own Sjögren\'s prospect abiprubart. While Novartis had always sounded positive about the potential of ianalumab in the automimmune disease, the therapy has faced its own clinical setbacks. Only last month, the company reported that the B-cell-depleting antibody had failed to hit the efficacy threshold in a phase 2 study for a painful skin condition called hidradenitis suppurativa.Ianalumab\'s story begins with Novartis’ collaboration with MorphoSys, before the Big Pharma went on to buy the biotech last year. The therapy is also being investigated for other B cell-driven autoimmune diseases like immune thrombocytopenia, systemic lupus erythematosus, lupus nephritis, warm autoimmune hemolytic anemia and diffuse cutaneous systemic sclerosis.

$Novartis scores double phase 3 win in Sjögren\'s syndrome, succeeding where rivals failed$

Phase 3Phase 2Clinical ResultClinical Trial Failure

26 Feb 2025

·www.biospace.com

Kiniksa Axes Sjögren’s Program, AstraZeneca-Licensed Antibody in Cardio Pivot

iStock, cagkansayin Kiniksa will now focus its development efforts on the IL-1 blocker KPL-387, which it is testing for recurrent pericarditis with Phase II/III trials planned for mid-2025. Kiniksa Pharmaceuticals will no longer move forward with its Sjögren’s syndrome drug development program and will walk away from an investigational antibody licensed from AstraZeneca, the London-based biotech announced on Tuesday. In Sjögren’s, Kiniksa was testing abiprubart, a monoclonal antibody that targets the CD40 protein, which is highly expressed in specific types of immune cells. In autoimmune diseases such as Sjögren’s, this mode of action could potentially disrupt pathological pathways that would otherwise culminate in a defective immune response that attacks healthy cells. Before being shelved, abiprubart was one of Kiniksa’s most mature assets. In July 2024, the biotech kicked off its Phase IIb study for the asset, testing biweekly and monthly dosing schedules in approximately 200 patients. The decision to discontinue abiprubart is in line with Kiniksa’s “strategic reprioritization of its portfolio and certain capital allocation considerations,” the biotech wrote in an SEC filing dated Feb. 21. The company will “immediately” stop enrollment into abiprubart’s mid-stage study and start winding down activities linked to the asset, while looking for strategic alternatives. Abiprubart’s termination has already cost Kiniksa $19 million, and the biotech expects to incur around $14 million to $17 million more in discontinuation expenses, mostly attributed to “contract termination costs” for existing supply agreements. Kiniksa expects to wrap up wind-down activities for abiprubart by the end of the year. Other players in the Sjögren’s syndrome space include J&J and Horizon Therapeutics , which reported respective mid-stage wins in June 2024 and January 2023. Also on Tuesday, Kiniksa announced it is terminating its licensing deal with AstraZeneca’s MedImmune for the GM-CSF blocker mavrilimumab. The asset, also a monoclonal antibody, was being tested for the chronic autoimmune disease giant cell arteritis and COVID-19-related acute respiratory distress syndrome. Kiniksa entered its licensing deal with MedImmune in December 2017, paying $23 million in upfront, pass-through and certain clinical milestone payments. At the time, the London biotech also promised up to $57.5 million in future milestones for the first two programs covered by the contract, plus up to $15 million for additional indications. In January 2024, however, Kiniksa announced it had slowed down investment into mavrilimumab and was in the process of looking for potential development partners for the asset. With abiprubart and mavrilimumab discontinued, Kiniksa is down to a completely cardiovascular pipeline —though the indication for its most immature candidate, the IL-1 antagonist KPL-1161, has yet to be disclosed. As per its Tuesday press release, Kiniksa will now focus its development efforts on KPL-387, also an IL-1 blocker, for recurrent pericarditis. The biotech is gearing up for a Phase II/III trial of the asset in mid-2025.

License out/inPhase 2Phase 1

25 Feb 2025

·www.fiercebiotech.com

Kiniksa adds to Sjögren\'s exodus with trial termination, axes AstraZeneca asset

In the wake of its recent pipeline decisions, Kiniksa is evaluating strategic alternatives for abiprubart.\n Kiniksa Pharmaceuticals is stopping development of a midphase autoimmune asset and returning a drug candidate to AstraZeneca as it doubles down on its cardiovascular disease pipeline.The asset licensed from AstraZeneca, GM-CSF antagonist mavrilimumab, was already on the back-burner, but the termination of the midphase autoimmune program comes as more of a shock. Six weeks ago, Kiniksa chief medical officer John Paolini, M.D., told investors the company was “certainly very excited” about a phase 2b trial of abiprubart in Sjögren’s syndrome. Today, Kiniksa said it is stopping the study.Kiniksa, which is evaluating strategic alternatives for abiprubart, framed the decision to end the trial as a result of a “strategic reprioritization of its portfolio and certain capital allocation considerations.” The action will cost $33 million to $37 million, Kiniksa said, but will free the biotech from the cost of funding a study that was scheduled to run into 2027.Abiprubart, an antibody that inhibits the signaling between CD40 and CD154, was in development in a competitive niche but Kiniksa had previously presented that as a positive. Last month, Kiniksa CEO Sanj Patel told investors “there has been some external derisking of the mechanism through other assets,” but he said abiprubart was differentiated through its monthly subcutaneous dosing.Amgen’s CD40L antagonist fusion protein, dazodalibep, is ahead of abiprubart in the race to market, with the big biotech starting phase 3 trials in Sjögren’s last year. But that drug is given intravenously.The high-concentration liquid formulation of abiprubart opened up the option of subcutaneous dosing. The list of rivals that Kiniksa believed may be able to offer subcutaneous dosing has thinned in recent years. Novartis axed its rival subcutaneous anti-CD40 antibody in Sjögren’s last month after assessing the risks and benefits of the molecule. Sanofi reached a similar decision in April, when it crossed Sjögren’s off the list of potential indications for its anti-CD40L prospect. Bristol Myers Squibb terminated a phase 1 trial of its CD40 candidate in Sjögren’s in 2023 because of “insufficient enrollment.” Kiniksa disclosed the winddown of its Sjögren’s trial, which it expects to complete by the end of the year, alongside the news that it is terminating development of mavrilimumab. The biotech licensed the asset from AstraZeneca’s MedImmune in 2017, paying $23 million in upfront and subsequent payments. But by early last year, the company was evaluating potential partnership opportunities to advance the molecule.The hunt for a partner ended last week, when Kiniksa told MedImmune it was stopping development of the asset and terminating the license agreement. Kiniksa’s actions leave it focused on a cardiovascular disease pipeline led by the IL-1 antagonist KPL-387. The program is targeting recurrent pericarditis, the same indication as Kiniksa’s approved drug Arcalyst, and a phase 2/3 trial is set to start this year.

$Kiniksa adds to Sjögren\'s exodus with trial termination, axes AstraZeneca asset$

License out/inPhase 2Phase 3Clinical Trial Termination

100 Deals associated with Abiprubart

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Sjogren's Syndrome	Phase 2	-	Kiniksa Pharmaceuticals Ltd.	09 Jul 2024
Rheumatoid Arthritis	Phase 2	United States	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021
Rheumatoid Arthritis	Phase 2	Bulgaria	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021
Rheumatoid Arthritis	Phase 2	Czechia	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021
Rheumatoid Arthritis	Phase 2	Hungary	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021
Rheumatoid Arthritis	Phase 2	Poland	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021
Rheumatoid Arthritis	Phase 2	South Africa	Kiniksa Pharmaceuticals Ltd.	14 Dec 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05198310 (CTgov)	Phase 2	Rheumatoid Arthritis	145	KPL-404 (Cohort 2 KPL-404 5 mg/kg q2wk)	ouvnwhqfny = zebuvihygc srcfugsaum (eqppfhjxoh, jytvwvsfil - wyfwqgerns) View more	-	22 Jul 2025
				KPL-404 (Cohort 3 KPL-404 5 mg/kg Qwk)	wiklblgnmy(axjuoqygha) = qpiohaqvrm wqcwnkesxy (pyzkcsjsbe, 0.216) View more
NCT05198310 (EULAR 12024 \| EULAR 22024) Manual	Phase 2	Rheumatoid Arthritis	78	Abiprubart 5mg/kg SC qwk	mtsmcmpjki(shwyjvnpbc) = lhrbvadcho mfntbrnjut (ryaszsahzx, -2.62 to -1.80)	Positive	12 Jun 2024
				Abiprubart 5mg/kg SC q2wk	mtsmcmpjki(shwyjvnpbc) = ldhirwgfja mfntbrnjut (ryaszsahzx, -2.43 to -1.58)
NCT05198310 (GlobeNewswire) Manual	Phase 2	Rheumatoid Arthritis	51	Abiprubart (Cohort 4:400 mg SC monthly dose group)	nincxijqbe(audaxoglzq) = bggdvnqjyg piaduykbyb (dulvdgbqwh, -2.54 to -1.21)	Positive	02 Apr 2024
				Placebo	nincxijqbe(audaxoglzq) = yyydujyysc piaduykbyb (dulvdgbqwh, -1.98 to -0.62)
NCT05198310 (GlobeNewswire) Manual	Phase 2	Rheumatoid Arthritis	129	Abiprubart (pooled group)	mnndvceyhx(cxhjipgabw) = fsyezslmxv qfrpswenko (qavusbdxgy, -2.34 to -1.74)	Positive	02 Apr 2024
				Placebo	mnndvceyhx(cxhjipgabw) = vurvpoegem qfrpswenko (qavusbdxgy, -1.88 to -1.16)
NCT05198310 (GlobeNewswire) Manual	Phase 2	Rheumatoid Arthritis	-	Abiprubart (Cohort 1)	-	Positive	02 Apr 2024
				Abiprubart (Cohort 2)
NCT05198310 (Biospace) Manual	Phase 2	Rheumatoid Arthritis Rheumatoid Factor	-	Abiprubart 2 mg/kg SC biweekly dosing (Cohort 1)	uzcfustpbs(bhrgnglhce) = xbtkgaxcre onbviwhowo (vnjudqvrwu ) View more	Positive	04 Jan 2024
				Abiprubart 5 mg/kg SC biweekly dosing (Cohort 2)	uzcfustpbs(bhrgnglhce) = xwpptfxoys onbviwhowo (vnjudqvrwu ) View more

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