ZT-01 for Type 1 Diabetes

(ZONE Trial)

Recruiting at 24 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Zucara Therapeutics Inc.

Disqualifiers: Type 2 diabetes, Kidney disease, others

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

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

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

Compensation: Varies

Number of Visits: 8

Duration: 8 weeks

186 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a drug called ZT-01 to help adults with type 1 diabetes who have low blood sugar at night. ZT-01 increases a hormone that raises blood sugar levels. The study will see if ZT-01 reduces nighttime low blood sugar episodes and check its safety.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you will continue using your usual methods of measuring blood sugar and giving insulin during the study.

Is ZT-01 safe for humans?

The safety data for ZT-01 is not directly available, but similar treatments like GLP-1 receptor agonists have shown mild and temporary gastrointestinal side effects in Type 1 Diabetes patients. Additionally, α-1 antitrypsin therapy, another treatment for Type 1 Diabetes, was found to be safe and well-tolerated in children and adolescents over a long-term study. ^{1 2 3 4 5}

How is the drug ZT-01 different from other treatments for type 1 diabetes?

ZT-01 is unique because it targets zinc transporter 8 (ZnT8), a protein involved in insulin production and release, which is also a major target in type 1 diabetes. This approach may help improve beta cell function and potentially offer a new way to manage the disease. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment ZT-01 for Type 1 Diabetes?

Research suggests that targeting zinc transporter-8 (ZnT8) could be beneficial in treating Type 1 Diabetes, as ZnT8 is involved in the autoimmune response that damages insulin-producing cells. This makes ZnT8 a promising target for therapies aimed at improving beta cell function and managing the disease. ^{6 7 11 12 13}

Eligibility Criteria

Adults with type 1 diabetes who have had the condition for at least 5 years and experience low blood sugar at night. They must have an HbA1c level of 10% or less, a BMI between 18.5 to <33 kg/m^2, and no severe hypoglycemia or hospitalizations for diabetic ketoacidosis recently. People with abnormal liver function, significant kidney disease, other specific health conditions, or using automated insulin delivery systems cannot participate.

Inclusion Criteria

I have had type 1 diabetes for 5 years or more.

You have experienced low blood sugar episodes at night in the recent past.

Your body mass index (BMI) at screening needs to be between 18.5 and 33 kg/m2.

Exclusion Criteria

I have a serious kidney condition.

I have been hospitalized for diabetic ketoacidosis more than once in the last 6 months.

You are currently using an automated insulin delivery system, like a closed loop or artificial pancreas.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ZT-01 or placebo by subcutaneous injection daily for 28 days in two crossover periods

8 weeks

6 visits (in-person), 2 phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• ZT-01

Trial Overview The trial is testing ZT-01's ability to prevent nighttime low blood sugar in people with type 1 diabetes by increasing glucagon levels. Participants will self-inject either ZT-01 at varying doses or a placebo before bed while wearing a glucose monitor over two separate periods without knowing which they're receiving.

Participant Groups

Group I: ZT-01 7 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 7 mg each by subcutaneous injection daily for 28 days, randomized to order

Group II: ZT-01 22 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 22 mg by subcutaneous injection daily for 28 days, randomized to order

Group III: ZT-01 15 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 15 mg by subcutaneous injection daily for 28 days, randomized to order

ZT-01 is already approved in United States, Canada for the following indications:

Approved in United States as ZT-01 for:

• Prevention of nocturnal hypoglycemia in type 1 diabetes

Approved in Canada as ZT-01 for:

• Prevention of nocturnal hypoglycemia in type 1 diabetes

Who Is Running the Clinical Trial?

Zucara Therapeutics Inc.

Lead Sponsor

Trials

2

Recruited

210+

Findings from Research

ZnT8 is a crucial biomarker for diagnosing and characterizing type 1 diabetes mellitus (T1DM), as it helps identify autoantibodies and specific T cells related to the disease.

Research indicates that ZnT8 could serve as a potential therapeutic target for T1DM, with studies suggesting that ZnT8-specific immunotherapy may offer a new treatment approach, although further research is needed before widespread clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus. Yi, B., Huang, G., Zhou, ZG.[2022]

Insulin replacement therapy has made type 1 diabetes manageable, but it does not fully replicate the body's natural insulin response, leading to potential long-term complications.

Monoclonal antibodies (mAbs) are promising tools for treating type 1 diabetes due to their high specificity, and engineering these antibodies can enhance their effectiveness in immunomodulatory therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered antibodies for type 1 diabetes. Hampe, CS.[2021]

Research indicates that using pancreatic islet auto-antigens, like the ZnT8 protein, for immune regulation may provide a safe and specific treatment for Type 1 diabetes (T1DM) by identifying high-risk individuals and potentially preventing the disease.

ZnT8-specific CD8+ T cells are prevalent in T1DM patients and targeting them through antigen-based immunotherapy could help restore beta cell function and slow the progression of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-specific immunotherapies in type 1 diabetes. Zhang, X., Dong, Y., Liu, D., et al.[2022]

Complete loss of the zinc transporter ZnT8 accelerated the onset of type 1 diabetes (T1D) in NOD mice, indicating that ZnT8 plays a significant role in autoimmunity related to T1D.

Heterozygous mice with partial loss of ZnT8 showed increased mitochondrial fitness in beta cells, suggesting that maintaining zinc homeostasis could be a potential strategy for modulating T1D progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zinc transporter 8 haploinsufficiency protects against beta cell dysfunction in type 1 diabetes by increasing mitochondrial respiration. Kim, YK., Walters, JA., Moss, ND., et al.[2023]

Despite the discovery of insulin 100 years ago, managing type 1 diabetes (T1D) remains difficult due to the need for constant adjustments in insulin dosages and carbohydrate intake, highlighting the limitations of current treatments.

There is a pressing need for disease-modifying therapies (DMTs) that can preserve or restore insulin-producing β-cells, and the paper suggests that combination therapies and innovative trial designs could accelerate the development and evaluation of these potential treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. Anderson, RL., DiMeglio, LA., Mander, AP., et al.[2023]

GLP-1 receptor agonists (like exenatide and liraglutide) can significantly lower hemoglobin A1C levels, plasma glucose, and body weight in patients with type 1 diabetes who are already on insulin, without increasing the risk of hypoglycemia.

The most common side effects of GLP-1 RAs are mild and transient gastrointestinal issues, making them a safe option for patients struggling with insulin side effects or those needing to lose weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. Harris, KB., Boland, CL.[2022]

Current treatments for Type 1 diabetes (T1D), like cyclosporin, show that it is possible to prevent the disease, but they come with significant long-term safety risks.

The concept of antigen-specific tolerization is proposed as a safer strategy to achieve long-term protection against T1D, emphasizing the need for careful trial design to balance safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials in type 1 diabetes: Antigen-specific therapies. Coppieters, KT., Harrison, LC., von Herrath, MG.[2021]

A Phase I/II study involving pediatric patients with recent-onset Type 1 diabetes showed that multiple infusions of α-1 antitrypsin (AAT) are safe and well-tolerated, with no serious adverse events reported over a long-term follow-up of up to 5 years.

Participants demonstrated normal growth and pubertal development, suggesting that AAT could be a promising immunotherapy for preserving β-cell function in Type 1 diabetes without compromising overall health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of α-1 antitrypsin therapy in children and adolescents with Type 1 diabetes. Brener, A., Lebenthal, Y., Interator, H., et al.[2019]

The review highlights a growing need for effective therapies for type 1 diabetes (T1D), as currently, insulin is the only approved treatment, and many new drugs are in clinical development, including those with established and novel mechanisms of action.

New drug classes under investigation include SGLT inhibitors, GLP-1 agonists, and immunomodulatory drugs, with many compounds currently in Phase 1 and 2 trials, indicating a promising future for combination therapies that could enhance treatment options for T1D.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addressing Unmet Medical Needs in Type 1 Diabetes: A Review of Drugs Under Development. Mittermayer, F., Caveney, E., De Oliveira, C., et al.[2018]

A small phase 1 trial has shown that a peptide-based antigen-specific immunotherapy is safe for recently diagnosed adults with type 1 diabetes.

This treatment approach is considered promising for potentially preventing or reversing type 1 diabetes, highlighting its role as a disease-modifying strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy. Coppieters, K., von Herrath, M.[2018]

In a study of 213 pediatric patients with Type 1 diabetes, anti-ZnT8 antibodies (ZnT8A) were found in 49.8% of patients, enhancing the diagnostic sensitivity for T1D from 85.9% to 90.6%.

ZnT8A demonstrated similar sensitivity to GADA at disease onset (61.1%) and identified 4.7% of patients who were previously classified as autoantibody negative, highlighting its potential as a crucial addition to current diagnostic methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-zinc transporter protein 8 autoantibodies significantly improve the diagnostic approach to type 1 diabetes: an Italian multicentre study on paediatric patients. Fabris, M., Zago, S., Liguori, M., et al.[2020]

Zinc transporter 8 (ZnT8) is linked to both type 1 and type 2 diabetes, with its expression and zinc content in beta cells decreasing in diabetic mice, suggesting it plays a role in insulin production and beta cell function.

The prevalence of ZnT8 autoantibodies (ZnT8A) increases with the severity of diabetes, indicating that ZnT8 may have different implications in the pathogenesis of type 1 and type 2 diabetes, as well as varying responses to ZnT8 treatment in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus. Yi, B., Huang, G., Zhou, Z.[2022]

The study reveals that the ZnT8 protein, found on the surface of pancreatic β-cells, can trigger a strong immune response, indicating its role as a self-antigen in type 1 diabetes.

In patients with type 1 diabetes, antibodies against ZnT8 were shown to bind to live insulin-producing cells, suggesting that these antibodies may contribute to β-cell dysfunction and damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A subclass of serum anti-ZnT8 antibodies directed to the surface of live pancreatic β-cells. Merriman, C., Huang, Q., Gu, W., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus. [2022]

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

Engineered antibodies for type 1 diabetes. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Antigen-specific immunotherapies in type 1 diabetes. [2022]

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

Zinc transporter 8 haploinsufficiency protects against beta cell dysfunction in type 1 diabetes by increasing mitochondrial respiration. [2023]

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

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. [2023]

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

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. [2022]

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

Trials in type 1 diabetes: Antigen-specific therapies. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Long-term safety of α-1 antitrypsin therapy in children and adolescents with Type 1 diabetes. [2019]

9. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Addressing Unmet Medical Needs in Type 1 Diabetes: A Review of Drugs Under Development. [2018]

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

Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy. [2018]

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

Anti-zinc transporter protein 8 autoantibodies significantly improve the diagnostic approach to type 1 diabetes: an Italian multicentre study on paediatric patients. [2020]

12. Japan pubmed.ncbi.nlm.nih.gov

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus. [2022]

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

A subclass of serum anti-ZnT8 antibodies directed to the surface of live pancreatic β-cells. [2021]