Belimumab + Rituximab for Systemic Sclerosis

Overseen By Liza Morales

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Hospital for Special Surgery, New York

Must be taking: Mycophenolate Mofetil

Must not be taking: Anti-fibrotics, Corticosteroids, Biologics, others

Disqualifiers: Severe lung disease, HIV, Hepatitis, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a 52 week, single center, randomized, double-blind, placebo-controlled study. After patients maintain a stable dose of Mycophenolate Mofetil (MMF) for at least 1 month, they will be randomized to treatment with either Belimumab \& Rituximab or placebo.Patients in both groups will be on background MMF for the entirety of the study. Belimumab will be administered subcutaneously and Rituximab intravenously. Placebo injections and infusions will be of normal saline. Randomization will be done in a 2:1 manner to favor the treatment group. It is hypothesized that that Rituximab and Belimumab combination therapy with Mycophenolate Mofetil background therapy will improve fibrosis in SSc skin when compared to treatment with placebo and Mycophenolate Mofetil in a group of patients with early dcSSc.

Will I have to stop taking my current medications?

The trial requires participants to stay on Mycophenolate Mofetil (MMF) throughout the study. If you are taking other medications, especially anti-fibrotic agents or certain biologics, you may need to stop them before joining the trial. The protocol does not specify for all medications, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Belimumab and Rituximab for treating systemic sclerosis?

Research shows that Rituximab may help improve skin and lung function in systemic sclerosis patients, and Belimumab is approved for treating systemic lupus erythematosus, a related autoimmune condition. This suggests potential benefits for systemic sclerosis, although direct evidence is limited. ^{1 2 3 4 5}

Is the combination of Belimumab and Rituximab generally safe for humans?

Belimumab and Rituximab have been studied for safety in conditions like systemic lupus erythematosus and systemic sclerosis. Belimumab is generally considered safe, but like other immune-targeting drugs, it may increase the risk of infections. Rituximab has a long-term safety profile, but it can also increase infection risk and, in rare cases, has been associated with serious brain infections. ^{1 2 6 7 8}

How is the drug combination of Belimumab, MMF, and Rituximab unique for treating systemic sclerosis?

This drug combination is unique because it targets B cells, which are part of the immune system, using two different mechanisms: Belimumab reduces B cell activation, while Rituximab depletes B cells. This dual approach may enhance the treatment's effectiveness in managing systemic sclerosis, a condition with limited standard treatment options. ^{1 2 3 9 10}

Research Team

Robert Spiera, MD

Principal Investigator

Hospital for Special Surgery, New York

Eligibility Criteria

This trial is for adults aged 18-80 with early diffuse cutaneous systemic sclerosis (dcSSc), diagnosed within the last 3 years, and a modified Rodnan Skin Score over 14. Participants must not have used certain drugs like Belimumab or Rituximab before, be free from severe infections or lung disease, and agree to use effective contraception.

Inclusion Criteria

I have been diagnosed with diffuse cutaneous systemic sclerosis.

My first non-Raynaud's symptom appeared less than 3 years ago.

Your skin score is higher than 14.

Exclusion Criteria

I do not have any health conditions that would make it unsafe for me to take a new drug.

My condition has been diagnosed for over 3 years.

I haven't taken any anti-fibrotic drugs like colchicine or tyrosine kinase inhibitors in the last month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Belimumab and Rituximab or placebo, with background Mycophenolate Mofetil for 48 weeks

48 weeks

Weekly subcutaneous injections and two infusions two weeks apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Belimumab
• MMF
• Placebo Infusion
• Placebo Subcutaneous Injection
• Rituximab

Trial Overview The study tests if combining Belimumab and Rituximab improves skin fibrosis in dcSSc patients compared to placebo. All participants will continue their Mycophenolate Mofetil (MMF) treatment. The active drugs or placebos are given via subcutaneous injections and intravenous infusions over a year.

Participant Groups

Group I: MMF + Rituximab + Belimumab Experimental Treatment 3 Interventions

Two infusions of 1000 mg of Rituximab, two weeks apart, weekly subcutaneous injections of 200 mg of Belimumab, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

Group II: MMF + Placebo + Placebo Placebo Group 3 Interventions

Two placebo infusions of normal saline, two weeks apart, weekly saline placebo subcutaneous injections, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

Belimumab is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Benlysta for:

• Systemic lupus erythematosus (SLE)

Approved in European Union as Benlysta for:

• Systemic lupus erythematosus (SLE)

Approved in Canada as Benlysta for:

• Systemic lupus erythematosus (SLE)

Approved in Japan as Benlysta for:

• Systemic lupus erythematosus (SLE)

Who Is Running the Clinical Trial?

Hospital for Special Surgery, New York

Lead Sponsor

Trials

257

Recruited

61,800+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

In a 52-week pilot study involving 20 patients with early diffuse cutaneous systemic sclerosis (dcSSc), treatment with belimumab alongside mycophenolate mofetil (MMF) showed a greater median decrease in skin thickness (MRSS) compared to placebo, although this difference was not statistically significant.

Both treatment groups experienced significant improvements in MRSS, and belimumab treatment was associated with a notable reduction in profibrotic gene expression, suggesting its potential mechanism of action in reducing fibrosis in dcSSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Gordon, JK., Martyanov, V., Franks, JM., et al.[2023]

Belimumab is a fully-humanized monoclonal antibody that effectively inhibits B-lymphocyte stimulator, and it has been approved for treating adults with autoantibody-positive systemic lupus erythematosus (SLE), showing a favorable safety profile in phase III trials.

Rituximab, a chimeric anti-CD20 monoclonal antibody, is also used in SLE treatment, and the review discusses its safety and efficacy alongside belimumab, providing insights into their use in both adult and pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. Hui-Yuen, JS., Nguyen, SC., Askanase, AD.[2017]

Rituximab therapy significantly improved skin scores and disease severity in 20 patients with diffuse systemic sclerosis over a follow-up period of approximately 48.5 months.

The treatment also helped preserve lung function, with 85.7% of patients showing stable forced vital capacity (FVC) and over 80% maintaining stable lung imaging scores, indicating its potential as a modifying therapy for early diffuse systemic sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Bosello, SL., De Luca, G., Rucco, M., et al.[2016]

Rituximab treatment in 15 patients with systemic sclerosis led to a significant decrease in CD4+IL4+ T cells in both skin and peripheral blood, indicating a potential mechanism for its effects on skin fibrosis and lung function.

The study found that while CD4+IL4+ T cells decreased significantly after rituximab treatment compared to standard treatment, other T cell subpopulations (CD4+INFγ+ and CD4+IL17+) did not show significant changes, suggesting a targeted effect of rituximab on specific immune pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis. Antonopoulos, I., Daoussis, D., Lalioti, ME., et al.[2021]

In a study of 24 patients with progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD), rituximab (RTX) significantly improved lung function after one year, with an increase in %pFVC by 8.8% and %pDLCO by 4.6%.

RTX also allowed for a reduction in prednisone dosage, with 25% of patients able to stop taking it altogether, indicating its potential as a safe and effective add-on therapy for patients who did not respond to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression. Narváez, J., LLuch, J., Molina-Molina, M., et al.[2021]

In a study involving 364 patients with systemic lupus erythematosus (SLE), long-term treatment with belimumab combined with standard therapy demonstrated a stable or declining incidence of adverse events over 4 years, indicating a favorable safety profile.

The most common side effects were mild, such as arthralgia and upper respiratory infections, and serious infusion reactions were rare, suggesting that belimumab can be safely administered for extended periods in SLE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Merrill, JT., Ginzler, EM., Wallace, DJ., et al.[2013]

Rituximab was found to be safe and well tolerated in a pilot study involving 15 patients with diffuse cutaneous systemic sclerosis (dcSSc), with only minor adverse events reported.

While rituximab effectively depleted B cells in the skin and circulation, it did not significantly improve skin thickness or show clear benefits for other organ involvement, indicating limited efficacy in treating dcSSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Lafyatis, R., Kissin, E., York, M., et al.[2022]

Rituximab, a B cell-targeted biologic used for autoimmune diseases, has a low incidence of serious infections, but there is a rare risk of progressive multifocal leucoencephalopathy, occurring in about 5 out of 100,000 patients, with no proven causal link established.

Repeated use of rituximab can lead to hypogammaglobulinaemia, which increases the risk of serious infections, highlighting the need for careful monitoring of patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B Cell Therapies, Approved and Emerging: a Review of Infectious Risk and Prevention During Use. Md Yusof, MY., Vital, EM., Buch, MH.[2022]

The BLISS-BELIEVE study is a 104-week trial involving 200 adults with systemic lupus erythematosus (SLE) that aims to compare the efficacy and safety of belimumab alone versus belimumab combined with rituximab, focusing on disease control and remission rates.

The primary goal is to determine the proportion of patients achieving disease control at week 52, with safety monitored through the incidence of adverse events, highlighting the potential for enhanced treatment outcomes through combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. Teng, YKO., Bruce, IN., Diamond, B., et al.[2020]

In an open-label study of 8 patients with diffuse cutaneous systemic sclerosis (dc-SSc), rituximab effectively depleted B-cells and significantly improved skin sclerosis scores after 24 weeks (p<0.001).

Rituximab treatment also led to notable improvements in skin histopathology, including reduced collagen content and myofibroblast numbers, while being well tolerated with only two serious adverse events deemed unrelated to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Smith, V., Van Praet, JT., Vandooren, B., et al.[2022]

References

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

Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. [2017]

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

Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. [2016]

4. Germany pubmed.ncbi.nlm.nih.gov

B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis. [2021]

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

Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression. [2021]

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

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. [2013]

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

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. [2022]

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

B Cell Therapies, Approved and Emerging: a Review of Infectious Risk and Prevention During Use. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. [2022]