IL-2 + Abatacept for Frontotemporal Dementia

Overseen By Maria B Pascual

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: The Methodist Hospital Research Institute

Disqualifiers: Infections, Cardiac dysfunction, Cancer, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Neuroinflammation is a significant component of Frontotemporal Disorder (FTD). Our preliminary unpublished data demonstrated that regulatory T cells (Tregs) have a compromised phenotype and reduced suppressive function in FTD patients, skewing the immune system toward a proinflammatory status and potentially contributing to disease progression. Low dose interleukin-2 (IL-2) is now viewed as a very promising immunoregulatory drug with the capacity to selectively expand and restore functional Tregs. Our preclinical data also demonstrated synergistic effect of interleukin-2 and abatacept (CTLA4-IgG) in remodeling immunologic pathways. Abatacept is an FDA approved medication that has been indicated as a monotherapy or concomitantly with other anti-inflammatory drugs to modulate inflammation in autoimmune disorders. This study is a phase I, open-label study to assess safety and tolerability of low dose IL-2 plus abatacept immunotherapy in FTD individuals. In the first part of this study, 5 FTD patients will be recruited. These five individuals will receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks for a total of 21 weeks (part-1 of the study). If the treatment strategy is safe and well-tolerated, up to 5 additional FTD subjects will be recruited to receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks for a total of 21 weeks (part 2 of the study).

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications, but you must be on a stable dosage for at least 4 weeks before starting the study and remain on a stable dosage during the study.

What data supports the effectiveness of the drug IL-2 Plus Abatacept for Frontotemporal Dementia?

Abatacept has been shown to be effective in treating rheumatoid arthritis by improving disease activity and quality of life, and it has also helped in cases of immune system disorders like CTLA4-haploinsufficiency. This suggests that abatacept can modulate immune responses, which might be beneficial in treating conditions like Frontotemporal Dementia that involve immune system components. ^{1 2 3 4 5}

Is the combination of IL-2 and Abatacept safe for humans?

Abatacept, also known as Orencia or CTLA4-Ig, has been used safely in humans for conditions like rheumatoid arthritis and immune-related disorders, with a safety profile comparable to other similar treatments. While severe infections are more common than with placebo, opportunistic infections and malignancies are not increased. In pediatric cases of immune disorders, abatacept showed no side effects over 7-15 months of use. ^{1 6 7 8 9}

How is the drug IL-2 Plus Abatacept different from other treatments for frontotemporal dementia?

IL-2 Plus Abatacept is unique because it combines IL-2, which can help regulate immune responses, with Abatacept, a drug that blocks specific signals needed for T-cell activation, potentially reducing inflammation. This combination targets immune pathways differently than other treatments, which may not focus on immune modulation for frontotemporal dementia. ^{1 4 10 11 12}

Eligibility Criteria

This trial is for individuals with Frontotemporal Dementia (FTD). Participants should have a compromised immune system, specifically with regulatory T cells that are not functioning properly. The study aims to recruit FTD patients who can undergo treatment with immunotherapy drugs.

Inclusion Criteria

English language speaking

I have been diagnosed with frontotemporal dementia.

Formal education of eight or more years

Exclusion Criteria

I have had issues with my bowels like blockages, tears, or serious bleeding needing surgery.

I have been diagnosed with a form of dementia such as Alzheimer's or Parkinson's.

I have a seizure disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

5 FTD patients receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks for a total of 21 weeks

21 weeks

Treatment Part 2

Up to 5 additional FTD subjects receive subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks for a total of 21 weeks

21 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• IL-2 Plus Abatacept

Trial Overview The trial is testing the combination of two drugs: Abatacept and Aldesleukin (IL-2), which may help regulate the immune system in FTD. It's an open-label phase I study, starting with five patients receiving these drugs over 21 weeks to check safety and tolerability before possibly expanding to more participants.

Participant Groups

Group I: Abatacept plus Aldesleukin every 4 weeks Active Control 1 Intervention

Subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every four weeks will be administered for a total of 21 weeks

Group II: Abatacept plus Aldesleukin every 2 weeks Active Control 1 Intervention

Subcutaneous abatacept (125 mg) followed by five-day-courses of IL-2 (1MUI/day) every two weeks will be administered for a total of 21 weeks

IL-2 Plus Abatacept is already approved in United States, European Union for the following indications:

Approved in United States as Orencia for:

• Moderate to severe adult rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Active psoriatic arthritis

Approved in European Union as Orencia for:

• Moderate to severe adult rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Active psoriatic arthritis

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Findings from Research

Two pediatric cases of severe CTLA4-haploinsufficiency, which did not respond to standard immunosuppressive treatments, showed rapid improvement when treated with abatacept, a CTLA4-Fc fusion protein.

Abatacept was well-tolerated with no side effects reported during a follow-up period of 7 to 15 months, indicating its safety for medium-term use in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency. Lanz, AL., Riester, M., Peters, P., et al.[2021]

Abatacept is a novel immunotherapy that targets T-cell costimulation, providing an alternative treatment option for rheumatoid arthritis (RA) patients who do not respond to traditional TNF-alpha antagonists, which affect about 20% of patients.

Clinical trials have demonstrated that abatacept effectively improves disease activity, enhances quality of life, and slows the progression of RA, marking it as a significant advancement in biological therapies for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept in the treatment of rheumatoid arthritis. Todd, DJ., Costenbader, KH., Weinblatt, ME.[2015]

In a study of 528 rheumatoid arthritis patients who switched from TNF inhibitors to either abatacept (ABA) or tocilizumab (TCZ), both treatments showed significant improvements in disease activity after 6 months, with similar mean changes in the Clinical Disease Activity Index (CDAI).

The likelihood of achieving low disease activity or remission was comparable between the two groups, indicating that both ABA and TCZ are effective options for patients with moderate to high disease activity after prior TNF inhibitor treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry. Harrold, LR., Reed, GW., Solomon, DH., et al.[2018]

Abatacept is a human fusion protein that works by binding to CD80/CD86 on antigen-presenting cells, which blocks the signals that activate naïve T cells, a key factor in the inflammation process of rheumatoid arthritis.

By interfering with this co-stimulatory signal, abatacept targets a central pathway involved in rheumatoid arthritis, potentially leading to reduced inflammation and improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Abatacept in the treatment of active rheumatoid arthritis]. Nielsen, H., Hansen, A.[2015]

In a 12-month study involving 339 patients with rheumatoid arthritis (RA) who were not responding to methotrexate, those treated with 10 mg/kg abatacept showed significant improvements in disease activity, with 62.6% achieving a 20% improvement in symptoms compared to 36.1% in the placebo group.

Abatacept was well tolerated, with a similar incidence of adverse events compared to placebo, and no significant formation of neutralizing antibodies, suggesting it is a safe option for patients with RA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Kremer, JM., Dougados, M., Emery, P., et al.[2022]

Mutant forms of CTLA-4-Ig can effectively treat immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) without compromising the efficacy of cancer immunotherapy, unlike the conventional abatacept.

The study suggests that the clinically available drug belatacept, which binds to B7-1 and B7-2 but not to anti-CTLA-4 antibodies, could be a promising option for managing irAEs while maintaining the therapeutic effects of anti-CTLA-4 and anti-PD-1 treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4- and PD-1-targeted immunotherapy. Liu, M., Wang, X., Du, X., et al.[2023]

Abatacept is an effective treatment for rheumatoid arthritis (RA), particularly in patients who do not respond to TNF-alpha blockers, showing similar efficacy in those who have failed both TNF-alpha and DMARD therapies.

The safety profile of abatacept is reassuring, with malignancy rates consistent with those in similar RA populations and no increased risk of opportunistic infections reported in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Selective co-stimulation blockade. CTLA4-Ig (Abatacept)]. Alten, R., Märker-Hermann, E.[2021]

Abatacept is an effective treatment for rheumatoid arthritis (RA), showing positive results in various clinical trials when used alone or in combination with methotrexate and other therapies.

The safety profile of abatacept is generally favorable, with adverse events similar to other biologics, although there is a higher incidence of severe infections compared to placebo, necessitating further research on long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A novel treatment option in rheumatoid arthritis: abatacept, a selective modulator of T-cell co-stimulation]. Dejaco, C., Duftner, C., Wipfler, E., et al.[2021]

Abatacept effectively targets T-cell activation, which is crucial in the development of rheumatoid arthritis, showing significant efficacy in phase III trials for patients who did not respond to other treatments.

The safety profile of abatacept is favorable when used in combination with disease-modifying antirheumatic drugs (DMARDs), making it a promising option for managing rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept in the treatment of rheumatoid arthritis. Vital, EM., Emery, P.[2021]

Abatacept (CTLA4-Ig) is effective in improving symptoms and physical function in rheumatoid arthritis patients who did not respond adequately to methotrexate or TNF antagonists.

In addition to symptom relief, abatacept also slows down the radiological progression of joint damage in patients resistant to methotrexate, highlighting its potential as a long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of CTLA4-Ig on radiographic outcome of patients with rheumatoid arthritis]. Harigai, M.[2016]

Abatacept is a novel fusion protein that works by modulating T cell activation through the CD28-CD80/86 pathway, which is crucial in the immune response related to rheumatoid arthritis.

Clinical trials have shown preliminary evidence supporting the efficacy of abatacept in treating rheumatoid arthritis, along with a review of its safety and effectiveness based on current data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Ruderman, EM., Pope, RM.[2018]

In a study involving 40 mice, abatacept (Aba) significantly improved symptoms of allergic rhinitis (AR) by reducing sneezing and nose rubbing, similar to the effects of dexamethasone, a known anti-inflammatory drug.

Aba treatment led to a notable decrease in key inflammatory markers, including T helper 2 cytokines and immunoglobulin levels, indicating its potential as an effective therapy for allergic rhinitis by suppressing allergic inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept (Cytotoxic T Lymphocyte Antigen 4-Fragment Crystallizable) Reduces Allergic Inflammation of Ovalbumin-Sensitized Mice. Chung, J., Choi, MR., Kim, MG., et al.[2023]

References

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

Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency. [2021]

2. India pubmed.ncbi.nlm.nih.gov

Abatacept in the treatment of rheumatoid arthritis. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry. [2018]

4. Denmark pubmed.ncbi.nlm.nih.gov

[Abatacept in the treatment of active rheumatoid arthritis]. [2015]

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

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. [2022]

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

Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4- and PD-1-targeted immunotherapy. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

[Selective co-stimulation blockade. CTLA4-Ig (Abatacept)]. [2021]

8. Austria pubmed.ncbi.nlm.nih.gov

[A novel treatment option in rheumatoid arthritis: abatacept, a selective modulator of T-cell co-stimulation]. [2021]

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

Abatacept in the treatment of rheumatoid arthritis. [2021]

10. Japan pubmed.ncbi.nlm.nih.gov

[Effect of CTLA4-Ig on radiographic outcome of patients with rheumatoid arthritis]. [2016]

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

The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. [2018]

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

Abatacept (Cytotoxic T Lymphocyte Antigen 4-Fragment Crystallizable) Reduces Allergic Inflammation of Ovalbumin-Sensitized Mice. [2023]