An Open-label Parallel Group Pilot Study to Demonstrate the Safety and Efficacy of Subcutaneous Siplizumab in the Treatment of Hidradenitis Suppurativa

This study is to investigate the efficacy of siplizumab in the treatment of Hidradenitis Suppurativa.

Start Date01 Jan 2025

Sponsor / Collaborator

The University of Alabama at Birmingham

[+1]

NCT06455280 / Not yet recruitingPhase 1IIT

A 12-Month, Open-Label Study Evaluating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Siplizumab as Induction Therapy in Patients With Autoimmune Liver Diseases Undergoing Liver Transplantation (SET-SAIL)

There is a significant unmet need for safe and effective therapeutic approaches to prevent immune-mediated graft injury and its complications in liver transplant (LT) recipients with autoimmune liver disease (AILD) including autoimmune hepatitis and primary sclerosing cholangitis. Siplizumab is an anti-CD2 monoclonal antibody that has demonstrated a favorable safety profile of siplizumab in over 779 human subjects and has been shown to target memory T cells-a key driver in the immune processes surrounding rejection and autoimmunity post LT in AILD. The purpose of this pilot, open-label phase 1 study is to determine the safety of siplizumab for induction in patients with AILD undergoing LT.
Up to eight (8) subjects will receive siplizumab 0.6 mg/kg/dose on the day of transplant (Day 0) and Day 4 post-transplant, for a total of two doses.
All subjects will be followed in the study for 12 months post-LT.

Start Date01 Jun 2024

Sponsor / Collaborator

Columbia University

NCT06453668 / RecruitingPhase 1

A 52-week, Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Trial of Siplizumab in Newly Diagnosed Adult Amyotrophic Lateral Sclerosis (ALS) Patients (AURORA)

The purpose of this study is to investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TCD601 (siplizumab) in newly diagnosed adult ALS patients.

Start Date16 Apr 2024

Sponsor / Collaborator-

100 Clinical Results associated with Siplizumab

100 Translational Medicine associated with Siplizumab

100 Patents (Medical) associated with Siplizumab

Literatures (Medical) associated with Siplizumab

01 Oct 2023·American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

Siplizumab combination therapy with belatacept or abatacept broadly inhibits human T cell alloreactivity in vitro.

Article

Author: Razavi, Ronia ; Berglund, Erik ; Cvetkovski, Filip ; Berglund, David ; Sellberg, Felix

Combined antigen-specific T cell receptor stimulation and costimulation are needed for complete T cell activation. Belatacept and abatacept are nondepleting fusion proteins blocking CD28/B7 costimulation, whereas siplizumab is a depleting antiCD2 immunoglobulin G1 monoclonal antibody targeting CD2/CD58 costimulation. Herein, the effect of siplizumab combination therapy with abatacept or belatacept on T cell alloreactivity in mixed lymphocyte reactions was investigated. In contrast to monotherapy, the combination of siplizumab with belatacept or abatacept induced near-complete suppression of T cell proliferation and increased the potency of siplizumab-mediated T cell inhibition. Furthermore, dual targeting of CD2 and CD28 costimulation enhanced the selective depletion of memory T cells compared with monotherapy. Although siplizumab monotherapy leads to significant regulatory T cell enrichment, high doses of cytotoxic T-lymphocyte-associated antigen 4 and a human IgG1 Fc fragment in the combination therapy reduced this effect. These results support the clinical evaluation of dual costimulation blockade, combining siplizumab with abatacept or belatacept, for the prophylaxis of organ transplant rejection and improvement of long-term outcomes following transplantation. Ongoing investigative research will elucidate when other forms of siplizumab-based dual costimulatory blockade may be able to induce similarly strong inhibition of T cell activation although still allowing for enrichment of regulatory T cells.

01 Jan 2020·Scandinavian journal of immunologyQ4 · MEDICINE

Pharmacokinetic and pharmacodynamic study of a clinically effective anti‐CD2 monoclonal antibody

Q4 · MEDICINE

Article

Author: Berglund, David ; Sykes, Megan ; Berglund, Erik ; Griesemer, Adam ; Fontenot, Jane ; Binder, Christian ; Sachs, David H. ; Hope, James ; Sellberg, Felix

Abstract:

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI‐322 are directed against the CD2 antigen. Siplizumab is species‐specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non‐human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1‐3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI‐322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI‐322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI‐322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI‐322.

01 Jan 2020·American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant SurgeonsQ1 · MEDICINE

Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro

Q1 · MEDICINE

Article

Author: Obradovic, Aleksandar ; Shonts, Brittany ; Berglund, David ; Sellberg, Felix ; Binder, Christian ; Waffarn, Elizabeth ; DeWolf, Susan ; Ho, Siu-Hong ; Sykes, Megan ; Danzl, Nichole ; Podestà, Manuel A

Siplizumab, a humanized anti-CD2 monoclonal antibody, has been used in conditioning regimens for hematopoietic cell transplantation and tolerance induction with combined kidney-bone marrow transplantation. Siplizumab-based tolerance induction regimens deplete T cells globally while enriching regulatory T cells (Tregs) early posttransplantation. Siplizumab inhibits allogeneic mixed-lymphocyte reactions (MLRs) in vitro. We compared the impact of siplizumab on Tregs versus other T cell subsets in HLA-mismatched allogeneic MLRs using PBMCs. Siplizumab predominantly reduced the percentage of CD4⁺ and CD8⁺ effector memory T cells, which express higher CD2 levels than naïve T cells or resting Tregs. Conversely, siplizumab enriched proliferating CD45RA^- FoxP3^HI cells in MLRs. FoxP3 expression was stable over time in siplizumab-containing cultures, consistent with enrichment for bona fide Tregs. Consistently, high-throughput TCRβ CDR3 sequencing of sorted unstimulated and proliferating T cells in MLRs revealed selective expansion of donor-reactive Tregs along with depletion of donor-reactive CD4⁺ effector/memory T cells in siplizumab-containing MLRs. These results indicate that siplizumab may have immunomodulatory functions that may contribute to its success in tolerance-inducing regimens. Our studies also confirm that naïve in addition to effector/memory T cells contribute to the allogeneic MLR and mandate further investigation of the impact of siplizumab on alloreactive naïve T cells.

News (Medical) associated with Siplizumab

14 Sep 2023

·www.pharmaceutical-technology.com

FDA accepts Madrigal’s liver disease therapy NDA for review

Resmetirom will target crucial underlying causes of NASH in the liver. Credit: crystal light / Shutterstock.com. The US Food and Drug Administration (FDA) has accepted for review Madrigal Pharmaceuticals ’s new drug application (NDA) for resmeritom, a liver disease therapy. Resmetirom is indicated for treating adult patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Recommended Reports Reports LOA and PTSR Model - Siplizumab in Liver Transplant Rejection GlobalData Reports LOA and PTSR Model - Aldafermin in Liver Cirrhosis GlobalData View all Companies Intelligence Madrigal Pharmaceuticals Inc Nash S.r.L. View all The regulator has granted priority review and set a Prescription Drug User Fee Act date of 14 March 2024. Resmetirom is a once-daily, oral, thyroid hormone receptor (THR)-β selective agonist that targets crucial underlying causes of NASH in the liver. Its clinical development programme consists of 18 clinical studies: 12 trials in Phase I, two in Phase II and four in Phase III. The company is seeking approval to treat patients with NASH and liver fibrosis under the FDA’s accelerated approval pathway. Madrigal CEO Bill Sibold stated: “NASH with liver fibrosis represents a significant unmet need in healthcare today: the disease has a serious impact on patients and, without treatment, it can lead to increased risk of cirrhosis, liver failure, liver cancer and premature mortality. “Resmetirom is a liver-directed therapy that has demonstrated the potential to treat the liver fibrosis that is associated with these negative outcomes, while resolving the underlying steatohepatitis that drives the disease.” NASH, which is a major cause of mortality related to the liver, is an advanced form of nonalcoholic fatty liver disease.

Priority ReviewPhase 2NDAPhase 3

14 Aug 2023

·www.pharmaceutical-technology.com

vTv announces Phase III plans for type 1 diabetes drug cadisegliatin

Phalguni Deswal @Phalguni_GD Image Credit: Shutterstock/antoniodiaz vTv Therapeutics plans to initiate a Phase III clinical trial for cadisegliatin for treating type 1 diabetes (T1D) by the end of 2023 before filing for marketing approval with the US Food and Drug Administration (FDA). Cadisegliatin is a liver-selective glucokinase activator that is used as an adjunct therapy with insulin. It received a breakthrough therapy designation (BTD) based on its Phase II trial (NCT03335371) , which showed a 40% decrease in the frequency of severe and symptomatic hypoglycaemic events along with a decrease in serum and urine ketone events in the treatment group. Recommended Reports Reports LOA and PTSR Model - Siplizumab in Type 1 Diabetes (Juvenile Diabetes) GlobalData Reports LOA and PTSR Model - Golimumab in Type 1 Diabetes (Juvenile Diabetes) GlobalData View all Companies Intelligence vTv Therapeutics Inc Cantex Pharmaceuticals Inc VTV View all The Phase III trial will assess the reduction in the number of hypoglycaemic events with cadisegliatin, compared to placebo. This primary endpoint for the trial is recommended by the FDA as part of the approval data for T1D drugs. vTv plans to expand the drug indications for cadisegliatin to potentially include type 2 diabetes, chronic obstructive pulmonary disease, renal disease, primary mitochondrial myopathy, glioblastoma and other cancer, and related conditions. Hypoglycaemia is a significant concern for patients with T1D, as insulin treatment causes hypoglycaemia in these patients. Other drugs currently in development for treating insulin-induced hypoglycaemia include Zucara Therapeutics’ ZT-01 . vTv’s other drug azeliragon is currently in Phase II/III of development for triple-negative breast cancer by its partner, Cantex Pharmaceuticals. Azeliragon is a receptor for advanced glycation end products (RAGE) inhibitor which is being investigated for multiple indications including Alzheimer’s disease , Covid-19 complications, brain metastasis, glioblastoma, inflammatory lung disease, and other cancer indications. The company’s cash reserves stand at $12.6m as of 30 June 2023. vTv now has until 18 December 2023 to comply with Nasdaq’s Minimum Bid Requirement, which requires a company’s ordinary shares to have a value of at least $1 for a minimum of ten business days. The value of vTv’s share stands at $0.72, as of the market close on 11 August, with a market cap of $58.75m.

Phase 2Breakthrough TherapyPhase 3Clinical Result

100 Deals associated with Siplizumab

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KEGG	Wiki	ATC	Drug Bank
D05847	Siplizumab	-	DB06371

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia, Sickle Cell	Phase 2	US	Itbmed ABStartup	28 Sep 2023
Diabetes Mellitus, Type 1	Phase 2	BE	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	FR	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	DE	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	IT	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	PL	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	ES	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	SE	Itbmed ABStartup	23 Jan 2023
Diabetes Mellitus, Type 1	Phase 2	GB	Itbmed ABStartup	23 Jan 2023
Plaque psoriasis	Phase 2	US	MedImmune LLC	01 Mar 2001

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01780454 (CTgov)	Phase 1/2	Kidney Failure, Chronic	2	Thymic Irradiation+MEDI-507+Rituximab	yrbavrcunn(pqjehfdjet) = msdmchrkpt mrxepxfnvv (pyhthamdse, fwjanuinck - qvxzsrvpek) View more	-	23 Sep 2020
Pubmed	Phase 1	Peripheral T-Cell Lymphoma	-	Siplizumab	xdkpnxgwqu(eursxosjzw) = wiqhqmfctq ugrndpwrwu (zbhddywhvy )	-	03 Jun 2018
NCT00801632 (CTgov)	Phase 2	Kidney Failure, Chronic	5	steroid+MEDI-507+methylprednisolone+Cyclophosphamide+Prednisone+tacrolimus+rituximab	xhxcuygxai(fgtmnmwfnj) = wvluatnkln vwwyaydhgb (evipheryqx, kharpwsgbq - fzavazrfrh) View more	-	12 May 2015
ASCO2005	Phase 1	Lymphoproliferative Disorders	9	Siplizumab	bgqtgfayjp(tqqtaongsf) = vanowbidwe ovfxvxxfju (qgtzlfjzfg, 24–99) View more	-	01 Jun 2005

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