JSP191 for Chronic Granulomatous Disease

Overseen By Sandra Anaya-O'Brien, R.N.

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: Pregnant, HIV positive, Uncontrolled seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

38 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the idea that JSP191 for Chronic Granulomatous Disease (also known as: JSP191, AMG 191) is an effective treatment?

The available research does not provide specific data on JSP191 for treating Chronic Granulomatous Disease. Instead, it discusses other treatments like hematopoietic stem cell transplantation (HSCT), which has shown improved survival rates of over 84-90%. It also mentions gene therapy as a promising future approach. Without specific data on JSP191, we cannot compare its effectiveness to these treatments. ^{1 2 3 4 5}

What safety data exists for JSP191 treatment in Chronic Granulomatous Disease?

The provided research does not contain specific safety data for JSP191 or AMG 191 in the treatment of Chronic Granulomatous Disease. The articles focus on the quality of life, immunological aspects, and treatment options like hematopoietic stem cell transplantation and gene therapy for CGD, but do not mention JSP191 or AMG 191. ^{3 6 7 8 9}

Is the drug JSP191 a promising treatment for Chronic Granulomatous Disease?

The provided research articles do not contain information about JSP191 or its effectiveness for Chronic Granulomatous Disease. Therefore, I cannot determine if JSP191 is a promising treatment based on the given data. ^{10 11 12 13 14}

What is the purpose of this trial?

Background: Chronic granulomatous disease (CGD) is a rare immune disorder that can cause serious infections throughout the body. The only cure for CGD is a stem cell transplant. Transplants from a sibling are best, but many people must get transplants from unrelated donors. However, these transplants can cause serious complications in people with CGD. Objective: To see if a study drug (JSP191) can help improve the success rates of stem cell transplants for people with CGD from an unrelated donor. Eligibility: People aged 4 to 65 years with CGD who require a transplant. Design: Participants will be screened. Part of the screening will help to identify the best match to a transplant donor. Participants will have a physical exam, including dental and eye exams. They will have blood and urine tests. They will have tests of their breathing and heart function. A bone marrow sample will be taken. They will have their stem cells collected. Participants will have a catheter inserted into a vein in their chest. It will remain in place for the entire period of transplant and recovery. Participants will be in the hospital 40 to 50 days for the transplant. This will include a conditioning phase, to prepare their body for the procedure, as well as the transplant and recovery phases. As part of the conditioning phase, participants will receive JSP191 through a vein for 1 hour. After discharge, participants will have follow-up visits 2 times a week for 100 days. Additional follow-up visits will continue for 5 years....

Research Team

Elizabeth M Kang, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

This trial is for people aged 4-65 with Chronic Granulomatous Disease (CGD) needing a stem cell transplant and have an unrelated matched donor. Participants must be able to stay near the NIH for 3 months post-transplant, use contraception, and not have major illnesses or organ failure that could affect survival after the transplant.

Inclusion Criteria

Has an unrelated matched donor available (but no matched related donor available)

If of childbearing potential, must agree to consistently use contraception from 1 month prior to baseline, throughout study participation, and for 1 year after receiving transplanted cells. Acceptable forms of contraception are: Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA-approved contraceptive method; Male partner has previously undergone a vasectomy

If able to impregnate a partner, must agree to consistently use contraception from the time of enrollment through 3 months post-transplant. Acceptable forms of contraception are: Male condom with spermicide

Exclusion Criteria

I have seizures that are not controlled by medication.

Transaminases > 5x upper limit of normal based on the individual s clinical situation and at the discretion of the investigator

CRP > 100 mg/dL within 6 weeks of the transplant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for exams and tests

Conditioning

Participants undergo conditioning with JSP191, alemtuzumab, and total body irradiation to prepare for the transplant

1 week

Inpatient hospital stay

Transplant and Recovery

Participants receive a high-dose donor graft infusion followed by post-transplant cyclophosphamide

40-50 days

Inpatient hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including engraftment and GvHD assessment

104 weeks

2 visits per week for 100 days, then periodic visits up to 5 years

Treatment Details

Interventions

• JSP191

Trial Overview The study tests JSP191 in patients with CGD undergoing stem cell transplants from unrelated donors. It aims to improve success rates by including a conditioning phase where JSP191 is administered intravenously before the actual transplant procedure.

Participant Groups

Group I: Single arm study Experimental Treatment 1 Intervention

Eligible CGD patients will receive one time infusion of study product along with Alemtuzumab and TBI as part of HSCT conditioning regimen

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

In a study of 85 patients with chronic granulomatous disease (CGD), 8% were identified as having the variant type X91+, with a median age of onset at just 4 months, highlighting the early impact of this condition.

Patients with X91+ CGD showed a wide range of neutrophil function, as indicated by the stimulation index (SI), which suggests that clinical manifestations can vary significantly, and underscores the need for awareness to avoid missed diagnoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variant Type X91+ Chronic Granulomatous Disease: Clinical and Molecular Characterization in a Chinese Cohort. Sun, B., Zhu, Z., Hui, X., et al.[2022]

In a study of 15 patients with p22(phox)-deficient chronic granulomatous disease (CGD), the survival rate after 2 years of age was notably high at 93%, indicating a prolonged survival plateau beyond this age.

Prophylactic treatment with interferon-gamma (IFN-γ) did not significantly reduce the rate of severe infections in these patients, suggesting that its efficacy in preventing infections may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of patients with p22 (phox) -deficient chronic granulomatous disease on Jeju Island, Korea. Kang, HS., Hwang, G., Shin, KS.[2020]

Chronic granulomatous disease (CGD) is primarily caused by defects in the NADPH oxidase complex, leading to impaired immune function, but newer forms like NCF4/p40phox deficiency are milder and do not typically result in severe infections.

Hematopoietic stem cell transplantation (HSCT) has shown a significant improvement in survival rates for CGD patients, exceeding 84-90%, and ongoing research into gene therapy and immunomodulators offers promising future treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Granulomatous Disease: a Comprehensive Review. Yu, HH., Yang, YH., Chiang, BL.[2021]

Long-term antibiotic prophylaxis in patients with chronic granulomatous disease (CGD) significantly reduced severe bacterial infections from 4.8 to 1.6 severe infections per 100 patient months, highlighting its efficacy in managing bacterial complications.

However, the use of antibiotics was associated with an increase in fungal infections, particularly from Aspergillus species, which have become the leading cause of complications and mortality in CGD patients, indicating a need for balanced prophylactic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up and outcome of 39 patients with chronic granulomatous disease. Liese, J., Kloos, S., Jendrossek, V., et al.[2015]

In a study of 26 boys with X-linked chronic granulomatous disease (X-CGD), haploid hematopoietic stem cell (haplo-HSC) transplantation combined with third-party umbilical cord blood (tpCB) transplantation showed promising results, with a 5-year event-free survival rate of 81% and an overall survival rate of 89%.

The treatment led to normal NADPH oxidase activity within one month post-transplantation, indicating effective restoration of immune function, and no primary implant failures were reported, highlighting the safety and efficacy of this combined transplantation approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease]. Tang, XF., Lu, W., Jing, YF., et al.[2020]

A study of 75 carriers of X-linked chronic granulomatous disease (XL-CGD) revealed that they experience significantly reduced quality of life (QoL) compared to both adult CGD patients and age-matched female controls, highlighting the impact of this condition even in carriers.

Over 40% of XL-CGD carriers reported moderate to severe anxiety, which was linked to higher depression scores and lower self-esteem, indicating a need for proactive psychological assessment and management for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom. Battersby, AC., Braggins, H., Pearce, MS., et al.[2021]

In a study of 12 female carriers of X-linked Granulomatous Disease (XL-CGD), it was found that 50% had skewed X-chromosome inactivation (XCI) and 65% showed misrepresentation of the wild-type gene, indicating potential immune dysfunction despite having some functional immune cells.

The research revealed that many carriers experienced immune dysregulation, characterized by changes in various immune cell populations and a correlation between residual reactive oxygen species (ROS) levels and the presence of INFγ-expressing T cells, suggesting that even carriers with some functional immune response can suffer from significant health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers. Chiriaco, M., Salfa, I., Ursu, GM., et al.[2021]

A 14-month-old boy with X-linked chronic granulomatous disease successfully underwent HLA-haploidentical stem cell transplantation, leading to normalized immune function and disease-free status for over three years without antibiotic prophylaxis.

The use of donor lymphocyte infusions helped maintain the transplant's effectiveness, suggesting that HLA-haploidentical HSCT is a viable treatment option for patients lacking matched donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: HLA-haploidentical HSCT rescued with donor lymphocytes infusions in a patient with X-linked chronic granulomatous disease. Scheiermann, J., Künkele, A., von Stackelberg, A., et al.[2023]

A case study of a boy with chronic sterile multifocal osteomyelitis and autoimmune conditions revealed that he had homozygous RAG1 mutations, indicating a genetic basis for his symptoms.

This finding expands the understanding of RAG deficiency, showing that it can lead to a combination of immunodeficiency, autoimmunity, and granulomatous disease, highlighting the complexity of immune system disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease. Reiff, A., Bassuk, AG., Church, JA., et al.[2021]

The study identified the peptide pR89-101 from the C-terminal region of myelin basic protein (MBP) as a major encephalitogenic determinant in SJL/J mice, which can induce experimental allergic encephalomyelitis (EAE).

The peptide pR89-101 was shown to be highly immunogenic and equally encephalitogenic as intact MBP, indicating its potential role in triggering autoimmune responses in this mouse model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. Sakai, K., Zamvil, SS., Mitchell, DJ., et al.[2019]

Immunization with myelin basic protein (MBP) can induce experimental allergic encephalomyelitis (EAE) in mice, serving as a model for multiple sclerosis, with specific MBP peptides like Ac1-11 and p35-47 being particularly effective.

NZW and (NZB x NZW)F1 mouse strains are susceptible to EAE induced by MBP and its peptides, demonstrating that their antigen-presenting cells can effectively present MBP to T-cells, despite genetic differences in T-cell receptor gene segments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis. Zamvil, SS., al-Sabbagh, A., Nelson, PA., et al.[2018]

In a study using F1 (SJL/J×C57BL/6) mice with MOG35-55-induced EAE, treatment with Ig-MOG led to recovery from the disease, while Ig-PLP1 treatment worsened the condition by reducing protective anti-MOG antibodies.

The exacerbation of EAE by Ig-PLP1 was linked to a specific reduction in protective IgG2a/b antibodies produced by marginal zone B cells, suggesting a regulatory mechanism that could be targeted for therapeutic strategies in autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses. Cascio, JA., Khairallah, MT., Wan, X., et al.[2021]

MOG antibodies (MOG-abs) are increasingly recognized as important biomarkers in demyelinating diseases of the central nervous system, particularly in pediatric patients, where they are associated with a variety of clinical syndromes such as acute disseminated encephalomyelitis (ADEM) and optic neuritis (ON).

The review emphasizes the need for serologic testing for MOG-abs in children, as their presence can influence long-term monitoring, treatment decisions, and patient counseling, highlighting the importance of a proposed clinical classification system for pediatric MOG antibody-associated disorders (MOGAD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. Bruijstens, AL., Lechner, C., Flet-Berliac, L., et al.[2022]

In a study of 123 patients with MOG-antibody-associated disease (MOGAD), researchers identified two main immune response patterns, with one being linked to active disease characterized by strong interactions with immune receptors.

The findings suggest that targeting Fcγ receptors (FcγRs) could be a promising therapeutic strategy for MOGAD, as these receptors play a key role in the disease's pathogenicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Humoral signatures of MOG-antibody-associated disease track with age and disease activity. Spatola, M., Chuquisana, O., Jung, W., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Variant Type X91+ Chronic Granulomatous Disease: Clinical and Molecular Characterization in a Chinese Cohort. [2022]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Long-term outcome of patients with p22 (phox) -deficient chronic granulomatous disease on Jeju Island, Korea. [2020]

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

Chronic Granulomatous Disease: a Comprehensive Review. [2021]

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

Long-term follow-up and outcome of 39 patients with chronic granulomatous disease. [2015]

5. China pubmed.ncbi.nlm.nih.gov

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease]. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: HLA-haploidentical HSCT rescued with donor lymphocytes infusions in a patient with X-linked chronic granulomatous disease. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. [2019]

11. Switzerland pubmed.ncbi.nlm.nih.gov

'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis. [2018]

12. Netherlands pubmed.ncbi.nlm.nih.gov

In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses. [2021]

13. England pubmed.ncbi.nlm.nih.gov

E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. [2022]

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

Humoral signatures of MOG-antibody-associated disease track with age and disease activity. [2023]