This study is a survey in Japan of recombinant ADAMTS13 used to treat or to prevent participants with congenital thrombotic thrombocytopenic purpura (cTTP). The study sponsor will not be involved in how the participants are treated but will provide instructions on how the clinics will record what happens during the study.
The main aim of the study is to check for side effects related from recombinant ADAMTS13 and to check if recombinant ADAMTS13 improves or prevents cTTP.
During the study, participants with cTTP will take recombinant ADAMTS13 intravenous injection according to their clinic's standard practice. The study doctors will check for side effects from recombinant ADAMTS13 for 18 months.

Start Date30 May 2024

Sponsor / Collaborator-

NCT05714969 / RecruitingPhase 2

A Phase 2b, Multicenter, Randomized, Double-blind Study of Safety and Efficacy of TAK-755 (rADAMTS13) With Minimal to No Plasma Exchange (PEX) in the Treatment of Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)

This is a study of TAK-755 in adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP). The main aim of this study is to determine the percentage of participants with a clinical response without plasma exchange during the study. Participants who have an acute attack of iTTP will receive TAK-755 and immunosuppressive therapy during their stay at the hospital until they achieve a clinical response. Participants will also be treated with TAK-755 for an additional time of up to 6 weeks after the acute phase. In total, participants will stay in the study for approximately 3 months.

Start Date21 Mar 2023

Sponsor / Collaborator

Takeda Pharmaceutical Co., Ltd.

[+1]

JPRN-jRCT2031220348 / RecruitingPhase 3

A Phase 3b, prospective, open-label, multicenter, single treatment arm, continuation study of the safety and efficacy of TAK-755 (rADAMTS-13, also known as BAX 930/SHP655) in the prophylactic and on-demand treatment of subjects with severe congenital thrombotic thrombocytopenic purpura (cTTP; Upshaw-Schulman Syndrome, or hereditary thrombotic thrombocytopenic purpura)

Start Date29 Sep 2021

Sponsor / Collaborator-

100 Clinical Results associated with Apadamtase alfa /Cinaxadamtase alfa

100 Translational Medicine associated with Apadamtase alfa /Cinaxadamtase alfa

100 Patents (Medical) associated with Apadamtase alfa /Cinaxadamtase alfa

185

Literatures (Medical) associated with Apadamtase alfa /Cinaxadamtase alfa

29 Dec 2023·Modern rheumatology case reports

Thrombotic thrombocytopenic purpura that developed 3 years after systemic lupus erythematosus had remitted with rituximab therapy

Article

Author: Shinoda, Koichiro ; Tobe, Kazuyuki ; Kawataka, Masatoshi ; Yamazaki, Miho ; Kobiyama, Aoi ; Asano, Ryoko ; Tsuda, Reina ; Kido, Toshiki ; Hounoki, Hiroyuki ; Okada, Ikuma

ABSTRACT:

Patients with systemic lupus erythematosus (SLE) occasionally develop thrombotic thrombocytopenic purpura (TTP), which can be fatal. Here, we report a case of TTP developing 3 years after SLE remitted with rituximab (RTX) therapy. A 50-year-old woman was treated with RTX for marked immune thrombocytopenic purpura and autoimmune haemolytic anaemia due to SLE relapse. After induction of remission, she was treated with prednisolone alone without maintenance therapy with RTX. Approximately 3 years later, she was readmitted with marked thrombocytopenia and severe renal dysfunction. On admission, she was diagnosed with TTP for the first time based on severe reduction in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and detection of ADAMTS13 inhibitors. CD19+ B cells in the patient’s serum increased to 34%, suggesting that B cells had reactivated once the effect of RTX had subsided. The patient was successfully treated with plasmapheresis, glucocorticoid pulse therapy, and RTX. There are no previous reports of newly diagnosed TTP with ADAMTS13 inhibitor production after having achieved remission of SLE with RTX. Therefore, our report also discusses the potential mechanisms of production of new autoantibodies after B-cell depletion therapy.

01 Dec 2023·International journal of hematology

Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice

Article

Author: Hosoda, Chihiro ; Tatsumi, Kohei ; Onodera, Yu ; Mori, Ryota ; Mitani, Seiji ; Shima, Midori ; Ohshima, Chiaki ; Takabayashi, Yoko ; Kawasaki, Ryohei ; Soejima, Kenji ; Sugimoto, Mitsuhiko ; Nishio, Kenji ; Sakata, Asuka ; Mackman, Nigel

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel-Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf^-/-, Adamts13^-/-) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf^-/- mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

01 Apr 2024·Journal of thrombosis and haemostasis : JTH

Targeted ADAMTS-13 replacement therapy for thrombotic thrombocytopenic purpura

Review

Author: Arnold, Donald M ; Moroniti, Jonathan J ; Vrbensky, John R ; Nazy, Ishac

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach.

News (Medical) associated with Apadamtase alfa /Cinaxadamtase alfa

31 May 2024

·firstwordpharma.com

CHMP nods for haemophilia B gene therapy, chikungunya vaccine lead decisions from May meeting

At its May meeting, the European Medicines Agency's drug advisory body recommended 14 new medicines for approval, including one biosimilar and five generics, while it also backed extended labelling for seven treatments. In addition, the Committee for Medicinal Products for Human Use (CHMP) confirmed a negative opinion following a re-examination, and there were two marketing application withdrawals. All of the decisions can be found detailed below.Positive recommendations on new medicines: Takeda’s enzyme replacement therapy Adzynma (rADAMTS13) for the treatment of children and adult patients with congenital thrombotic thrombocytopenic purpura. SIFI’s Akantior (polyhexanide) for the treatment of acanthamoeba keratitis. CStone Pharmaceuticals’ anti-PD-L1 monoclonal antibody Cejemly (sugemalimab) for the treatment of adults with metastatic non-small-cell lung cancer (NSCLC). Pfizer’s gene therapy Durveqtix (fidanacogene elaparvovec) for the treatment of haemophilia B. AstraZeneca’s Fluenz (influenza vaccine [live attenuated, nasal]) for the prophylaxis of influenza in children and adolescents from 24 months to <18 years of age. Eckert & Ziegler’s GalliaPharm (germanium [68Ge] chloride / gallium [68Ga] chloride) for radiolabelling of various kits used for positron emission tomography (PET) imaging. Valneva’s Ixchiq (chikungunya vaccine [live]) to protect adults against disease caused by Chikungunya virus transmitted to humans by infected mosquitoes. Novo Nordisk’s Zegalogue (dasiglucagon) for the treatment of severe hypoglycaemia in adults, adolescents and children aged six years and over with diabetes mellitus. Bio-Thera Solutions’ biosimilar version of Avastin (bevacizumab), named Avzivi, for the treatment of carcinoma of the colon or rectum, breast cancer, NSCLC, renal cell cancer, epithelial ovarian, fallopian tube or primary peritoneal cancer, and carcinoma of the cervix. Five generic medicines also received a positive opinion: Apexelsin (paclitaxel) for the treatment of metastatic breast cancer; Dasatinib Accord Healthcare (dasatinib) for the treatment of chronic myelogenous leukaemia; and generic versions of pomalidomide from Accord Healthcare, Krka and Zentiva for treatment of multiple myeloma.Positive recommendations on extensions of therapeutic indication: Sanofi/Regeneron’s Dupixent (dupilumab) as an add-on maintenance treatment in adults with uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils. Bristol Myers Squibb/Pfizer’s Eliquis (apixaban) to include the treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in paediatric patients from 28 days to <18 years of age. Calliditas Therapeutics/Stada’s Kinpeygo (budesonide) for the treatment of adults with primary immunoglobulin A nephropathy (IgAN). Mirum Pharmaceuticals’ Livmarli (maralixibat) to include progressive familial intrahepatic cholestasis in patients 3 months of age and older. AbbVie’s Skyrizi (risankizumab) for the treatment of adults with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional or biologic therapy. AstraZeneca’s Tagrisso (osimertinib) in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adults with advanced NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. BeiGene’s Tevimbra (tislelizumab) alone for the treatment of adults with locally advanced or metastatic NSCLC after prior platinum-based therapy; in combination with pemetrexed and platinum‑containing chemotherapy for the first-line treatment of certain adults with non-squamous NSCLC whose tumours have PD-L1 expression on ≥50% of tumour cells with no EGFR or ALK positive mutations; and in combination with carboplatin and either paclitaxel or nab-paclitaxel for the first-line treatment of certain adults with squamous NSCLC.Negative opinions on new medicines: The CHMP confirmed its initial recommendation to refuse the granting of a marketing authorisation for Neuraxpharm and Minoryx Therapeutics’ Nezglyal (leriglitazone) for the treatment of cerebral adrenoleukodystrophy.Withdrawal of applications: Cytokinetics pulled a filing seeking approval of Kinharto (omecamtiv mecarbil) for the treatment of adults with symptomatic chronic heart failure and reduced ejection fraction. The decision was based on feedback from the EMA that supporting results were not sufficient to conclude that the benefits of the cardiac myosin activator outweigh the risks. Cytokinetics recently outlined plans to conduct another study of Kinharto. Clinuvel withdrew an application to expand use of Scenesse (afamelanotide) into adolescents with erythropoietic protoporphyria. The drug has been approved in this indication in the EU since 2014 for adults. However, the company determined that it was not possible to provide the comprehensive safety and efficacy data expected by the EMA in the expanded population.

Drug ApprovalVaccineClinical Result

17 May 2024

·www.sciencedaily.com

Clinicians report success with first test of drug in a patient with life-threatening blood clotting disorder

A recombinant form of human ADAMTS13 approved for a different condition helped to save the life of a young mother with immune thrombotic thrombocytopenic purpura. A team led by investigators from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, used a new drug to save the life of a patient with immune thrombotic thrombocytopenic purpura (iTTP), a rare disorder characterized by uncontrolled clotting throughout the small blood vessels. The group describes the first clinical use of the drug for iTTP in the New England Journal of Medicine. "The drug is a genetically engineered version of the missing enzyme in iTTP, and we showed that it was able to reverse the disease process in a patient with an extremely severe form of this condition," said lead author Pavan K. Bendapudi, MD, an investigator in the Division of Hematology and Blood Transfusion Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School. iTTP results from an autoimmune attack against an enzyme called ADAMTS13 that is responsible for cleaving a large protein involved in blood clotting. The current mainstay of therapy for this life-threatening blood disorder is plasma exchange, which removes the harmful autoantibodies and provides extra ADAMTS13. Plasma exchange induces a clinical response in most patients but can restore at best only about half of normal ADAMTS13 activity. By contrast, a recombinant form of human ADAMTS13 (rADAMTS13) offers the possibility of greatly increased ADAMTS13 delivery. rADAMTS13 was recently approved for patients with congenital thrombotic thrombocytopenic purpura, which occurs in patients born with complete loss of the ADAMTS13 gene. It's questionable whether rADAMTS13 could be effective in iTTP given the presence of inhibitory anti-ADAMTS13 autoantibodies, but Bendapudi and his colleagues received permission from the US Food and Drug Administration to utilize rADAMTS13 donated from the manufacturer under a compassionate use protocol in a dying patient with treatment-resistant iTTP. "We found that rADAMTS13 rapidly reversed this patient's disease process despite the current dogma that inhibitory autoantibodies against ADAMTS13 would render the drug useless in this condition," said Bendapudi. "We were the first physicians to use rADAMTS13 to treat iTTP in the United States, and in this case it helped to save the life of a young mother." Bendapudi noted that the infused rADAMTS13 overwhelmed the inhibitory autoantibodies in the patient and reversed the thrombotic effects of iTTP. This impact was observed almost immediately upon administration of rADAMTS13, after daily plasma exchange had failed to induce remission. "I think rADAMTS13 has the potential to replace the current standard of care in acute iTTP. We will need larger, well-designed trials to evaluate this possibility," said Bendapudi. A phase 2b randomized clinical trial of rADAMTS13 in iTTP was recently initiated.

Phase 2Drug Approval

19 Apr 2024

·www.pharmaceutical-technology.com

FDA approves Takeda’s ENTYVIO SC for Crohn’s disease

The safety profile of Takeda’s TENTYVIO SC in the trial was aligned with the IV formulation. Credit: Michael Vi via Shutterstock. The US Food and Drug Administration (FDA) has granted approval for Takeda’s ENTYVIO subcutaneous (SC) administration as a maintenance therapy to treat adults with moderately to severely active Crohn’s disease (CD). ENTYVIO SC is intended for usage as maintenance treatment in moderately to severely active CD patients following induction therapy using intravenous (IV) ENTYVIO. In September 2023, the FDA approved the SC administration of ENTYVIO as a maintenance treatment in adults with moderately to severely active ulcerative colitis patients and is available as a single-dose prefilled pen (ENTYVIO Pen) in the US. The latest approval is based on the findings from the double-blind, randomised, placebo-controlled Phase III VISIBLE 2 Study analysing the safety and efficacy of ENTYVIO SC. Trial data showed that a significant 48% of patients receiving ENTYVIO SC every two weeks achieved long-term clinical remission, compared to 34% of those on placebo. See Also: SGN-1 by Guangzhou Huajin Pharmaceutical Technology for Solid Tumor: Likelihood of Approval SGN-1 by Guangzhou Huajin Pharmaceutical Technology for Peritoneal Cancer: Likelihood of Approval ENTYVIO SC’s safety profile in the trial was in line with the IV formulation, with injection site reactions noted as an adverse reaction. Takeda US gastroenterology senior vice-president and head Brandon Monk said: “The approval of subcutaneous ENTYVIO in Crohn’s disease delivers on our goal of providing treatment options that can help patients achieve remission of their ulcerative colitis or Crohn’s disease, while also providing them flexibility and choice of route of administration. “With ENTYVIO Pen, patients have the option of administering their maintenance treatment at home or on the go. “Our development of a subcutaneous option demonstrates Takeda’s commitment to meeting the very real needs of those living with gastrointestinal diseases.” Last month, the Japanese Ministry of Health, Labour and Welfare approved the company’s ADZYNMA Intravenous Injection 1500 to treat congenital thrombotic thrombocytopenic purpura.

Clinical ResultPhase 3Drug Approval

100 Deals associated with Apadamtase alfa /Cinaxadamtase alfa

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R&D Status

Approved

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Indication	Country/Location	Organization	Date
Congenital Thrombotic Thrombocytopenic Purpura	US	Takeda Pharmaceuticals U.S.A., Inc.	09 Nov 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	US	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	AR	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	AT	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	GR	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	IT	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	PL	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	ES	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Thrombotic Thrombocytopenic Purpura, Acquired	Phase 2	GB	Takeda Pharmaceutical Co., Ltd.	21 Mar 2023
Anemia, Sickle Cell	Phase 1	US	Shire Plc	21 Oct 2019
Purpura, Thrombotic Thrombocytopenic	Phase 1	US	Baxalta, Inc.	30 Sep 2014

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03393975 (phase 3, Pubmed)	Phase 3	Congenital Thrombotic Thrombocytopenic Purpura ADAMTS13	48	Recombinant ADAMTS13	lscrjjvpzk(cbgufivcbj) = yciwkkdyrx deuqwciyad (pzuycxqqjm ) View more	Positive	02 May 2024
				Standard Therapy (plasma-derived products)	suirxgwmwq(ejnpjsczoi) = fzdflmocmj brnmzerwbi (pklpyldmwi ) View more
NCT03997760 (CTgov)	Phase 1	Anemia, Sickle Cell	19	Placebo	dhgeqoitxe(gthjtjjxkz) = urixhblemf bmhtyqtfmk (fuydritevw, vlcghzpzjg - hwchskupxx) View more	-	23 Apr 2024
NCT03997760 (ASH2023)	Phase 1	Anemia, Sickle Cell	19	rADAMTS13	itthqgmpgx(kpeaxfeede) = uogktkodpr tohrogwzyj (liovygjqwp ) View more	Positive	09 Dec 2023
FDA Manual	Not Applicable	Congenital Thrombotic Thrombocytopenic Purpura	86	ADZYNMA	dfxarljxqc(ahcaoixzpo) = ivpikbuxwq gzvngzsuuo (brlkufjgwh ) View more	Positive	09 Nov 2023
				Plasma-Based Therapies	dfxarljxqc(ahcaoixzpo) = tghqfrisot gzvngzsuuo (brlkufjgwh, 0.304) View more
NCT03922308 (EHA2023)	Phase 2	Thrombotic Thrombocytopenic Purpura, Acquired	28	Placebo	jnzwnounmi(hooquvfvdj) = ntmnosvyvw ngcnlwbaqm (dosnlwyfic )	-	08 Jun 2023
				rADAMTS13 40 IU/kg IV	jnzwnounmi(hooquvfvdj) = ewigqliyow ngcnlwbaqm (dosnlwyfic )
NCT03922308 (CTgov)	Phase 2	Thrombotic Thrombocytopenic Purpura, Acquired	28	Placebo (Standard of Care (SoC) + Placebo)	vyhlddjwpy(qiyobetwxg) = ukqkfvrutz gxqfrwxprk (aqlotunics, gdvcxvpilj - qtzpbylhwi) View more	-	01 Dec 2022
				Placebo+SHP655 (SoC + SHP655 + Placebo)	vyhlddjwpy(qiyobetwxg) = phcsubuwhp gxqfrwxprk (aqlotunics, gynulzaadf - hzxmuwrmes) View more

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