Last update 24 Dec 2024

Garadacimab

Last update 24 Dec 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Anti-FXIIa monoclonal antibody, Immunoglobulin G4, anti-(human blood-coagulation factor viia) (human monoclonal CSL312 gamma4-chain), disulfide with human monoclonal CSL312 lambda-chain, dimer, CSL-312

+ [1]

Target

F12 x Factor XIIa

Mechanism

F12 inhibitors(Coagulation factor XII inhibitors), Factor XIIa inhibitors(Factor XIIa inhibitors)

Therapeutic Areas

Immune System DiseasesCardiovascular DiseasesCongenital Disorders+ [3]

Active Indication

Hereditary AngioedemaIdiopathic Pulmonary Fibrosis

Inactive Indication

COVID-19NeoplasmsUpper Extremity Deep Vein Thrombosis

Originator Organization

CSL Behring LLC

Active Organization

CSL Behring LLC

CSL Ltd.CSL Behring GmbH

Inactive Organization-

Drug Highest PhaseNDA/BLA

First Approval Date-

RegulationOrphan Drug (EU), Orphan Drug (AU), Orphan Drug (US)

Gene Sequence

Sequence Code 318415073H

Source: *****

Sequence Code 318415074L

Source: *****

Clinical Trials associated with Garadacimab

NCT05819775 / Active, not recruitingPhase 3

A Phase 3 Open-label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema in Pediatric Subjects 2 to 11 Years of Age

The purpose of this study is to investigate the safety, PK / PD, and efficacy of SC CSL312 for prophylactic treatment of pediatric subjects with HAE.

Start Date30 May 2023

Sponsor / Collaborator

CSL Behring LLC

NCT05306275 / CompletedPhase 1

A Phase 1, Randomized, Open-label, Parallel-group Study to Compare the Pharmacokinetic Properties of CSL312 Administered by Subcutaneous Prefilled Syringe Assembled to Autoinjector to Prefilled Syringe Assembled to Needle Safety Device in Healthy Adult Subjects

This is an open-label, parallel-group, phase 1, single center study to assess the relative bioavailability of CSL312 administered subcutaneously via a prefilled syringe assembled to an autoinjector compared to a prefilled syringe assembled to a needle safety device in healthy, adult subjects.

Start Date04 Apr 2022

Sponsor / Collaborator

CSL Behring LLC

NCT05130970 / CompletedPhase 2

A Randomized, Double-blind, Placebo-controlled, Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Garadacimab in Subjects With Idiopathic Pulmonary Fibrosis

This is a prospective, phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of garadacimab in subjects with idiopathic pulmonary fibrosis (IPF).

Start Date03 Feb 2022

Sponsor / Collaborator

CSL Behring LLC

100 Clinical Results associated with Garadacimab

100 Translational Medicine associated with Garadacimab

100 Patents (Medical) associated with Garadacimab

Literatures (Medical) associated with Garadacimab

01 Dec 2024·CLINICAL AND EXPERIMENTAL ALLERGY

Timing of Onset of Garadacimab for Preventing Hereditary Angioedema Attacks

Article

Author: Lawo, John‐Philip ; Tachdjian, Raffi ; Craig, Timothy J. ; Hakl, Roman ; Staubach, Petra ; Wieman, Lolis ; Li, H. Henry ; Aygören‐Pürsün, Emel

01 Oct 2024·JOURNAL OF INTERNAL MEDICINE

Targeting factor XIIa for therapeutic interference with hereditary angioedema

Review

Author: Cohn, Danny M. ; Renné, Thomas

Abstract:

Hereditary angioedema (HAE) is a rare, potentially life‐threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)‐driven kallikrein–kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first‐line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa‐targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long‐term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE.

01 Oct 2024·STRUCTURE

Structural basis for the inhibition of βFXIIa by garadacimab

Article

Author: Quek, Adam J ; Panousis, Con ; Kapp, Eugene A ; Pelzing, Matthias ; Ghai, Rajesh ; Nash, Andrew D ; Ow, Saw Yen ; Drulyte, Ieva ; Wilson, Michael J

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

News (Medical) associated with Garadacimab

13 Dec 2024

·www.prnewswire.com

CSL Receives Positive CHMP Opinion for Garadacimab in Hereditary Angioedema (HAE)

If approved, garadacimab will be the first and only once-monthly treatment inhibiting factor XIIa to prevent attacks in HAE patients – a community CSL has been serving for more than 40 years MARBURG, Germany, Dec. 13, 2024 /PRNewswire/ -- Global biotechnology leader CSL (ASX:CSL; USOTC:CSLLY) today announced the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending granting a marketing authorization for garadacimab as a once-monthly prophylactic treatment for hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older. Garadacimab is a monoclonal antibody that targets activated factor XII (factor XIIa), a plasma protein that plays a key role in attacks of swelling in people with HAE, thereby inhibiting the HAE cascade at the top to prevent HAE attacks. The final European Commission (EC) decision is expected in Q1 2025. "CSL has a longstanding and relentless patient-focused approach to developing transformational medicines in areas of unmet need. This CHMP decision brings us closer to offering an innovative treatment to patients living with HAE, which is a debilitating and potentially life-threatening condition," said Emmanuelle Lecomte-Brisset, Senior Vice President and Head of Global Regulatory Affairs, CSL. "We look forward to making this therapy available to patients in Europe." Attacks of HAE are often painful and can spread to multiple sites of the body, including the abdomen, larynx, face, and extremities. Current HAE preventive therapies work at various downstream steps in the cascade, but none prevent the cascade at its start. The CHMP positive opinion is based on data from the pivotal placebo-controlled Phase 3 VANGUARD trial and its open-label extension study, both evaluating the efficacy and safety of garadacimab. The pivotal study met its primary endpoint and showed that garadacimab led to 62 percent of patients achieving attack-free status throughout the treatment period, reduced the median number of HAE attacks to zero and reduced the mean number of HAE attacks per month by 86.5 percent compared to placebo. Interim analysis of the ongoing open-label extension study (median garadacimab exposure 13.8 months) showed that garadacimab has a favorable long-term safety profile and provides sustained HAE attack reduction. The full results from VANGUARD were published in The Lancet (April 2023) and the primary results of the ongoing open-label extension study were published in Allergy (October 2024). If granted, the centralized marketing authorization of garadacimab would be valid in all EU member states. The final opinion was published in the CHMP meeting highlights on the EMA website. About HAE HAE is a rare and potentially life-threatening genetic condition that occurs in about 1 in 10,000 to 1 in 50,000 people. HAE is caused by deficient or dysfunctional C1-INH, a protein in the blood that helps to control inflammation. Inadequate amounts of properly functioning C1-INH can lead to the accumulation of fluid in body tissues, causing considerable swelling referred to as angioedema. HAE attacks can affect many parts of the body and can spread to multiple sites, including the face, abdomen, larynx, and extremities. Patients who have abdominal attacks of HAE can experience extreme pain, diarrhea, nausea, and vomiting caused by swelling of the intestinal wall. HAE attacks that involve the face or throat can result in airway closure, asphyxiation and, if left untreated, death. About CSL CSL (ASX:CSL; USOTC:CSLLY) is a global biotechnology company with a dynamic portfolio of lifesaving medicines, including those that treat haemophilia and immune deficiencies, vaccines to prevent influenza, and therapies in iron deficiency and nephrology. Since our start in 1916, we have been driven by our promise to save lives using the latest technologies. Today, CSL – including our three businesses: CSL Behring, CSL Seqirus and CSL Vifor – provides lifesaving products to patients in more than 100 countries and employs 32,000 people. Our unique combination of commercial strength, R&D focus and operational excellence enables us to identify, develop and deliver innovations so our patients can live life to the fullest. For inspiring stories about the promise of biotechnology, visit CSLBehring.com/Vita and follow us on Twitter.com/CSL. For more information about CSL, visit . Media Contact Valerie Bomberger, CSL Office: +1 610-291-5388 Mobile: +1 267-280-3829 Email: [email protected] Stephanie Fuchs, CSL Behring Mobile: +49 151 58438860 Email: [email protected] In Australia: Jimmy Baker, CSL Mobile: +61 450 909 211 Email: [email protected] Chris Cooper, CSL Mobile: +61 455 022 740 Email: [email protected] SOURCE CSL Behring WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 3Clinical ResultDrug Approval

02 Jun 2024

·www.fiercebiotech.com

Intellia ups the ante in HAE dosing battle, showcasing durability of one-and-done option

With Intellia showing the potential to provide a one-and-done option, the game is officially on in HAE. The future of hereditary angiodema treatment seems to be coming down to how many shots it takes to reduce attacks. Gene editing biotech Intellia Therapeutics is the latest to reveal updated data for its candidate, showing that a single dose of NTLA-2002 provided a durable reduction in the swelling attacks that define the disease. Intellia showcased a 98% mean reduction in monthly attack rate and a 99% mean reduction in moderate to severe attacks after just one dose of NTLA-2002. The results of the in vivo CRISPR-based gene editing therapy were presented at the 2024 European Academy of Allergy and Clinical Immunology Annual Congress in Valencia, Spain, this weekend. From week one to 16, patients experienced a 90% reduction in attacks, a number that rose to 92% between weeks five and 16 and then to 98% during the on-study period, Intellia said. The results compare to a similar cut from the 10 patients presented at the same conference last year, which showed a 95% mean reduction in monthly attack rate. Now, Intellia has found that eight out of the 10 patients remain attack-free after that 16-week observation period through the latest follow-up, which had a cut-off date in February of this year. The average follow-up for the patients is 20 months. All of the patients who discontinued prophylaxis treatment after receiving NTLA-2002 have not had to resume. “We are thrilled to see that the majority of patients have been attack-free for over 18 months or longer. These remarkable attack rate reductions have been consistent, even in patients with the most severe symptoms,” Intellia CEO John Leonard said in a statement. As for safety, NTLA-2002 was well tolerated with mild adverse events mostly including infusion-related reactions and fatigue. There have been no dose-limiting toxicities, serious adverse events or grade 3 or higher adverse events. Intellia’s presentation came a few days after Ionis debuted data showing the RNA-targeting prophylactic therapy donidalorsen spurred an 81% lower monthly rate of swelling attacks in patients who received the drug every four weeks. Analysts from Willian Blair heralded donidalorsen’s “highly competitive” profile and said it could have an edge over CSL Behring’s garadacimab, which is already under review but requires more frequent injections and an initial in-office loading dose. With Intellia showing the potential to provide a one-and-done option, the game is officially on in HAE.

Clinical ResultGene Therapy

31 May 2024

·www.fiercebiotech.com

Ionis reveals an oasis for HAE patients as RNA med reduces attacks in phase 3

In the OASISplus study, an open-label extension and switch trial, attack rates continued to improve over time, with 93% and 92% improvements from baseline in the four-week and eight-week groups. We can now envision the oasis that Ionis Pharmaceuticals saw with its hereditary angioedema data. Earlier this year, the company announced that donidalorsen had met the primary endpoint of a phase 3 study, but now we know it’s because the treatment spurred an 81% lower monthly rate of swelling attacks in patients who received the drug every four weeks. Data from the OASIS-HAE and OASISplus studies also showed that 84% of patients who switched from previous prophylactic treatment preferred Ionis’ offering. Patients can administer the treatment themselves via auto-injector. The therapy had a favorable safety profile, according to Ionis’ Friday announcement. The data will be presented at the 2024 European Academy of Allergy and Clinical Immunology Annual Congress in Valencia, Spain. Ionis is taking the data to regulators to support an approval in HAE, a life-threatening condition that causes random swelling attacks to parts of the body. Donidalorsen is an RNA-targeting prophylactic therapy that reduces the production of prekallikrein, thereby interrupting the pathway that leads to HAE attacks. “These data underscore the potential of donidalorsen to continually improve HAE attack rates and quality of life over time, positioning donidalorsen as an attractive potential treatment option,” said Ionis CEO Brett Monia, Ph.D. “In our prospective switch cohort, patients switched to donidalorsen from another prophylactic without increased breakthrough attacks and achieved greater disease control. In fact, a majority of patients who switched reported a preference for donidalorsen.” Ionis previously reported in January that the OASIS-HAE study met its primary endpoint, with the rate of angioedema attacks at both the four-week and eight-week regimens of donidalorsen lower than the placebo cohorts. The study featured patients receiving 80 mg of donidalorsen every four weeks or every eight weeks or placebo, with a total of 90 people across the cohorts. In the four-week cohort, which featured 45 patients, donidalorsen significantly reduced monthly attacks by 87% compared to placebo, which was a key secondary endpoint. The drug also reduced severe to moderate attacks per month by 89% in the same time frame and reduced attacks that required acute therapy by 92%. At week 25, 91% of patients taking the drug in this group had well-controlled disease. While Ionis did not provide detailed data on the eight-week group, the company said patients had a similar benefit. In the OASISplus study, an open-label extension and switch trial, attack rates continued to improve over time, with 93% and 92% improvements from baseline in the four-week and eight-week groups, respectively. Patients also had improved quality of life. In a group of patients who previously switched over to donidalorsen, there was a 62% improvement in monthly attacks compared to baseline. Patients also managed the transition without breakthrough attacks. William Blair analysts said donidalorsen has showcased a “highly competitive” profile with the latest cut of data. An approval in 2025 is expected as Ionis is planning to submit a new drug application soon. “Ultimately, we see donidalorsen’s profile as generally superior to current prophylactic options, with less frequent dosing and at-home autoinjector dosing potential being further differentiators,” William Blair’s analysts wrote Friday morning. The profile is comparable to CSL Behring’s garadacimab, which is under review for the indication with a decision expected by year end. However, garadacimab requires a loading dose administered in-office followed by monthly injections, whereas patients can self-administer donidalorsen, with the possibility of dosing every eight weeks. Ionis is behind CSL Behring, but William Blair believes the market can handle multiple options. If Ionis captures a conservative 15% of the market, revenue could reach $450 million in the U.S. in 2030. “We view today’s updates as positive for Ionis, with the current donidalorsen clinical profile appearing as good or better overall than available and other late-stage options, which is reinforced in data from the switch study showing a strong patient preference,” the analysts said.

Clinical ResultPhase 3siRNA

100 Deals associated with Garadacimab

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15629

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Hereditary Angioedema	NDA/BLA	US	CSL Ltd.	14 Dec 2023
Hereditary Angioedema	NDA/BLA	EU	CSL Behring GmbH	14 Dec 2023
Idiopathic Pulmonary Fibrosis	Phase 2	US	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	AU	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	AT	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	BE	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	CA	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	DK	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	DE	CSL Behring LLC	03 Feb 2022
Idiopathic Pulmonary Fibrosis	Phase 2	IT	CSL Behring LLC	03 Feb 2022

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05130970 (CTgov)	Phase 2	Idiopathic Pulmonary Fibrosis	81	Garadacimab (Garadacimab)	hpcbfsdwzd(vtpsuzpldy) = gsedaxxhfz vvpudyvlen (clmwetccwi, jxrjcjbzfn - plrokespfe) View more	-	13 Dec 2024
				Placebo (Placebo)	hpcbfsdwzd(vtpsuzpldy) = sxfjtdjbgg vvpudyvlen (clmwetccwi, khetgvyskm - rpgjaxlwzb) View more
AAAAI2024	Phase 2/3	Hereditary Angioedema activated factor XII	172	Garadacimab 75 mg	hzecyucqax(ovumcfennj) = The most common garadacimab-related TEAEs were mild/moderate injection-site reactions kqkgcrqsqu (gvpyuhsalh )	Positive	23 Feb 2024
				Garadacimab 200 mg
AAAAI2024	Phase 1	-	132	Garadacimab 200 mg via Autoinjector/Pre-filled Pen	quhjcysgpi(imfviyqtec) = uekpyyucoo hizwkoalwk (mbsxfgktce ) View more	Positive	23 Feb 2024
				Garadacimab 200 mg via Needle Safety Device	quhjcysgpi(imfviyqtec) = qzpaqdovln hizwkoalwk (mbsxfgktce ) View more
NCT04656418 (CTgov)	Phase 3	Hereditary Angioedema	64	CSL312 (CSL312)	cryeiipzkw(fejcucpbko) = hqnjtxwatv prpwzknawz (jcdvhszkpg, pmsqgasair - ymhhxjmodi) View more	-	29 Jun 2023
				Placebo (Placebo)	cryeiipzkw(fejcucpbko) = uggpzvzusc prpwzknawz (jcdvhszkpg, aslkicolfx - dhqxrnqbnp) View more
NCT03712228 (CTgov)	Phase 2	Hereditary Angioedema	44	Placebo (Placebo)	tqgpwmzbea(ssleplqwhb) = wjghjlfzke ycovljeywp (ttndpoqjcr, ktsmieogek - quaolqkmcy) View more	-	08 Nov 2022
				Factor XIIa antagonist monoclonal antibody (CSL312 (Low))	tqgpwmzbea(ssleplqwhb) = lbfnegbgfy ycovljeywp (ttndpoqjcr, prfvgyavlf - lczusisarx) View more
ERS2022	Not Applicable	COVID-19 aPTT \| FXII levels \| FXIIa-mediated kallikrein activity (FXIIa-mKA)	124	Garadacimab (GAR) 700 mg IV	syaaorhuxx(uobqwfrljn) = ilkubvagpp aiollifaii (wyjwkznsld ) View more	Negative	04 Sep 2022
				Placebo (PL) plus standard of care (SOC)	syaaorhuxx(uobqwfrljn) = pjdtajqozq aiollifaii (wyjwkznsld ) View more
NCT04656418 (PRNewswire) Manual	Phase 3	Hereditary Angioedema	-	Garadacimab	pjqoukxvwp(lhfbrmgnby) = The study met its primary and secondary efficacy objectives and also demonstrated favorable safety and tolerability wqjwolpsqa (iunvmybtzo )	Positive	17 Aug 2022
				Placebo
NCT04409509 (CTgov)	Phase 2	COVID-19	124	Placebo (Placebo)	zsltzioxcb(lhxxpvjjsh) = uoknriazui wvogqbmafe (pztlwezqou, bkytrctula - cohdrneazq) View more	-	24 Jan 2022
				Garadacimab, Factor XIIa Antagonist Monoclonal Antibody (CSL312)	zsltzioxcb(lhxxpvjjsh) = tplfwvnuze wvogqbmafe (pztlwezqou, aisqwypbky - wghlwvxeau) View more

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