Efgartigimod for Antibody-Mediated Rejection

(Shamrock Trial)

Recruiting at 12 trial locations

Overseen By Sabine Coppieters, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: argenx

Must be taking: Immunosuppressants

Disqualifiers: T-cell rejection, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

30 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

No, you will not have to stop taking your current medications. Participants must stay on their standard background immunosuppression therapy, including tacrolimus, mycophenolate mofetil, and steroids, during the treatment period.

What data supports the idea that Efgartigimod for Antibody-Mediated Rejection is an effective treatment?

The available research does not provide specific data on the effectiveness of Efgartigimod for Antibody-Mediated Rejection. Instead, it discusses other treatments like intravenous immunoglobulin (IVIG) and rituximab, which have been used to treat this condition. These treatments have shown some success in managing antibody-mediated rejection in kidney transplants. Without direct data on Efgartigimod, we cannot conclude its effectiveness for this condition based on the provided information. ^{1 2 3 4 5}

What safety data is available for efgartigimod treatment?

Efgartigimod has been evaluated for safety in multiple clinical trials, primarily for generalized myasthenia gravis. In the phase 3 ADAPT trial, efgartigimod was generally well tolerated, with most adverse events being mild to moderate in severity. The ongoing ADAPT+ extension trial also supports its safety profile, showing consistent clinically meaningful improvements with a similar tolerability profile. Efgartigimod has been approved in several countries for the treatment of generalized myasthenia gravis, indicating a recognized safety profile by regulatory authorities. ^{6 7 8 9 10}

Is the drug Efgartigimod PH20 SC a promising treatment for Antibody-Mediated Rejection?

Yes, Efgartigimod PH20 SC is a promising drug because it has shown success in treating autoimmune diseases by reducing harmful antibodies and improving patients' quality of life. It has been effective in conditions like myasthenia gravis and immune thrombocytopenia, suggesting it could be beneficial for Antibody-Mediated Rejection as well. ^{7 8 9 11 12}

What is the purpose of this trial?

The purpose of this study is to assess the safety, tolerability, and efficacy of efgartigimod PH20 SC given by a prefilled syringe in participants with Antibody-Mediated Rejection (AMR) after kidney transplantation. After a screening period of up to 6 weeks, eligible participants will be randomized in a 1:1:1 ratio. The study drug will be administered subcutaneously while patients remain on their standard background immunosuppression therapy (tacrolimus, mycophenolate mofetil, steroids) during the treatment period (48 weeks). At the end of the treatment period, the participants will enter an observational/follow-up period (approximately 24 weeks). The participants will be in the study for up to 78 weeks.

Eligibility Criteria

This trial is for kidney transplant recipients aged 18-80 with Antibody-Mediated Rejection (AMR) who have had their transplant at least 6 months ago. Participants must be on stable doses of mycophenolate mofetil and tacrolimus, with a low steroid dose for specific periods before the study.

Inclusion Criteria

I have been taking mycophenolate mofetil for at least 20 weeks.

I have been on a stable dose of mycophenolate mofetil and tacrolimus for at least 4 weeks.

I had a kidney transplant more than 6 months ago.

Exclusion Criteria

Confirmed T-cell or mixed rejection at time of the study

I have recently changed my immunosuppressive medication.

Any other medical condition that, in the investigator's opinion, would interfere with the results of the study or put the participant at undue risk

Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 6 weeks

Treatment

Participants receive Efgartigimod PH20 SC or placebo subcutaneously while on standard background immunosuppression therapy

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

approximately 24 weeks

Treatment Details

Interventions

• Efgartigimod PH20 SC

Trial Overview The trial tests Efgartigimod PH20 SC's safety and effectiveness against AMR in kidney transplant patients. It compares efgartigimod to a placebo, both given by prefilled syringe alongside standard immunosuppression drugs over a treatment period of 48 weeks followed by observation.

Participant Groups

Group I: Treatment arm 2 Experimental Treatment 2 Interventions

Participants receiving Efgartigimod PH20 SC on top of optimized standard background immunosuppression therapy (tacrolimus, mycophenolate mofetil, and optionally steroids) up to week 24 followed by placebo PH20 SC on top of optimized standard background immunosuppression therapy from weeks 24 to 48

Group II: Treatment arm 1 Experimental Treatment 1 Intervention

Participants receiving Efgartigimod PH20 SC on top of optimized standard background immunosuppression therapy (tacrolimus, mycophenolate mofetil, and optionally steroids)

Group III: Treatment arm 3 Placebo Group 1 Intervention

Participants receiving Placebo PH20 SC on top of optimized standard background immunosuppression therapy (tacrolimus, mycophenolate mofetil, and optionally steroids)

Efgartigimod PH20 SC is already approved in European Union, United States, Japan, China for the following indications:

Approved in European Union as VYVGART for:

• Generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive

Approved in United States as VYVGART Hytrulo for:

• Generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive
• Chronic inflammatory demyelinating polyneuropathy (CIDP)

Approved in Japan as VYVDURA for:

• Generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive

Approved in China as Efgartigimod alfa injection (subcutaneous injection) for:

• Generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive

Who Is Running the Clinical Trial?

argenx

Lead Sponsor

Trials

76

Recruited

11,500+

Tim Van Hauwermeiren

argenx

Chief Executive Officer since 2008

B.Sc. and M.Sc. in Bioengineering from Ghent University, Executive MBA from The Vlerick School of Management

Dr. Peter Ulrichts

argenx

Chief Medical Officer since 2023

MD from Maastricht University, PhD in Molecular Immunology from Maastricht University

Findings from Research

In a pilot study involving six pediatric renal transplant recipients with chronic antibody-mediated rejection (CAMR), treatment with high-dose intravenous immunoglobulin (IVIG) and rituximab led to a significant improvement in kidney function, as indicated by an increase in glomerular filtration rate (GFR) after 6 months.

The treatment was well tolerated, suggesting it is a safe option for managing CAMR, and four out of six patients showed improvement or stabilization of their kidney function, highlighting the potential efficacy of this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Billing, H., Rieger, S., Ovens, J., et al.[2022]

In a study of 39 renal transplant recipients with antibody-mediated rejection (ABMR), treatment with intravenous immunoglobulin (IVIG) significantly improved renal function compared to those receiving only methylprednisolone (MP).

The improvement in glomerular filtration rate (GFR) for the IVIG group was notable, with a change in slope from -0.72 to -0.03 mL/min/month post-treatment, indicating a positive effect of IVIG on graft function over 12 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Pooled Immunoglobulin as Treatment of Active Antibody-Mediated Rejection of Transplanted Kidney. Furmańczyk-Zawiska, A., Urbanowicz, A., Perkowska-Ptasińska, A., et al.[2019]

In a study of 43 patients with chronic active antibody-mediated rejection (CAMR), the combination therapy of rituximab and intravenous immunoglobulin (IVIg) showed a 3-year allograft survival rate of 60.5%, with better outcomes in patients with low proteinuria (69.2%) compared to those with high proteinuria (47.1%).

The therapy effectively reduced the decline in kidney function (eGFR) in both groups, particularly in those with low proteinuria, indicating that lower protein levels at treatment are predictive of better allograft survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcome of Rituximab and Intravenous Immunoglobulin Combination Therapy in Kidney Transplant Recipients with Chronic Active Antibody-Mediated Rejection. Ban, TH., Yu, JH., Chung, BH., et al.[2019]

In a study involving four patients with acute antibody-mediated rejection (ABMR) of kidney transplants, the combination of double filtration plasmapheresis (DFPP) and semi-selective immunoadsorption (IA) showed significant effectiveness in reducing ABMR severity and improving kidney function in early cases.

The results suggest that DFPP + IA can be a valuable rescue treatment for severe ABMR in high-risk patients, particularly when other treatments have failed, although responses may vary in later cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Double Membrane Filtration Immunoadsorption in Severe C1q-Binding Donor-Specific Antibody-Positive Acute Humoral Kidney Allograft Rejection: A Case Series. Russwurm, M., Maier-Giebing, T., Kortus-Goetze, B., et al.[2023]

In a study of 112 endomyocardial biopsies from 25 heart transplant patients, C4d positivity was identified as a key indicator of acute antibody-mediated (humoral) rejection, which can lead to serious complications like graft loss.

The presence of C4d in biopsies was associated with slower recovery in patients, suggesting that humoral rejection can persist even when cellular rejection signs diminish, potentially worsening allograft vasculopathy regardless of the patient's age or time since transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

C4d-the witness of humoral rejection. de Gouveia, RH., Vitorino, E., Ramos, S., et al.[2009]

Efgartigimod, a human IgG1 antibody, significantly improved symptoms in patients with generalized myasthenia gravis, with 68% of treated patients showing a meaningful response compared to only 30% in the placebo group, indicating strong efficacy.

The treatment was well tolerated, with similar rates of adverse events between efgartigimod and placebo groups, suggesting it is a safe option for patients, with no deaths reported during the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Howard, JF., Bril, V., Vu, T., et al.[2022]

Efgartigimod alfa is the first neonatal Fc receptor antagonist approved for treating generalized myasthenia gravis (gMG), showing significant and rapid improvements in muscle strength and quality of life in a phase 3 trial with a placebo group.

The treatment was generally well tolerated, with most side effects being mild to moderate, indicating a favorable safety profile for patients with gMG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use. Heo, YA.[2023]

Efgartigimod, a first-in-class neonatal Fc receptor antagonist, received its first approval in the USA in December 2021 for treating generalized myasthenia gravis in adults who are positive for anti-acetylcholine receptor antibodies.

The drug is also being evaluated for other autoimmune diseases and has been approved in Japan for generalized myasthenia gravis patients regardless of antibody status, indicating its potential broad application in autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efgartigimod: First Approval. Heo, YA.[2022]

Efgartigimod was found to be safe and well-tolerated in a phase 2 study involving 24 patients with generalized myasthenia gravis, with no serious adverse events reported.

The treatment led to a significant reduction in pathogenic IgG autoantibodies and resulted in a rapid and long-lasting improvement in disease symptoms for 75% of patients, suggesting its potential as an effective therapy for myasthenia gravis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Howard, JF., Bril, V., Burns, TM., et al.[2020]

Intravenous immunoglobulin (IVIG) combined with rituximab has been shown to effectively reduce anti-HLA antibodies, improving transplantation success rates for highly sensitized patients who were previously considered poor candidates.

The combination therapy also provides a strong anti-inflammatory effect, which is beneficial in treating antibody-mediated rejection, and advancements in detection methods allow for earlier intervention to prevent allograft loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in management of the highly HLA-sensitized and ABO-incompatible transplant recipients. Jordan, SC., Peng, A., Vo, AA.[2015]

Efgartigimod is a promising new treatment for primary immune thrombocytopenia (ITP) that works by binding to the neonatal Fc receptor (FcRn), which leads to increased degradation of IgG antibodies that cause platelet destruction.

This therapy offers a novel mechanism of action compared to existing treatments, potentially providing an effective option for patients who may not respond well to traditional therapies like corticosteroids or IVIgG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efgartigimod alfa for the treatment of primary immune thrombocytopenia. Broome, C.[2023]

Efgartigimod, an FcRn inhibitor, has shown potential in reducing harmful autoantibodies and alleviating symptoms in autoimmune diseases like myasthenia gravis and primary immune thrombocytopenia.

The neonatal crystallizable fragment receptor (FcRn) plays a crucial role in immune regulation by controlling the recycling of IgG antibodies and facilitating antigen presentation, making it a promising target for autoimmune therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roles of FcRn in Antigen-Presenting Cells during Autoimmunity and a Clinical Evaluation of Efgartigimod as an FcRn Blocker. Zhou, Y., Jiang, S.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Human Pooled Immunoglobulin as Treatment of Active Antibody-Mediated Rejection of Transplanted Kidney. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Clinical Outcome of Rituximab and Intravenous Immunoglobulin Combination Therapy in Kidney Transplant Recipients with Chronic Active Antibody-Mediated Rejection. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of Double Membrane Filtration Immunoadsorption in Severe C1q-Binding Donor-Specific Antibody-Positive Acute Humoral Kidney Allograft Rejection: A Case Series. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

C4d-the witness of humoral rejection. [2009]

6. England pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Efgartigimod: First Approval. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic strategies in management of the highly HLA-sensitized and ABO-incompatible transplant recipients. [2015]

11. England pubmed.ncbi.nlm.nih.gov

Efgartigimod alfa for the treatment of primary immune thrombocytopenia. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Roles of FcRn in Antigen-Presenting Cells during Autoimmunity and a Clinical Evaluation of Efgartigimod as an FcRn Blocker. [2023]