PRISE (Personalized Response and Immunologic Surveillance of Endogenous C-Peptide Preservation in New, Recent, and Established Onset Type 1 Diabetes Treated With Human Anti-Thymocyte Globulin [h-ATG]) Study

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of SAB-142 for Delaying the Progression of Type 1 Diabetes (T1D) in Patients With Stage 3 New Onset T1D, Recent Onset T1D, and Established T1D

This Phase 3, multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy, safety, and tolerability of SAB-142, a fully human anti-thymocyte globulin (h-ATG), in participants aged 5 to 40 years with Stage 3 type 1 diabetes (T1D). The study will enroll participants with recent-onset T1D (>100 days to <1 year from diagnosis) and established-onset T1D (≥1 year to ≤2 years from diagnosis) who retain residual beta-cell function as demonstrated by stimulated C-peptide levels >0.2 nmol/L. Participants will be randomized in a 2:1 ratio to receive SAB-142 or placebo in addition to standard diabetes care. The primary objective is to determine whether SAB-142 preserves beta-cell function over 12 months as measured by stimulated C-peptide response during a mixed meal tolerance test (MMTT). External data from the SAB-142-201 SAFEGUARD study will be incorporated to include participants with new-onset T1D (<100 days from diagnosis) in the primary efficacy analysis.

Type 1 diabetes is an autoimmune disease characterized by progressive destruction of pancreatic beta cells. SAB-142 is a purified fully human multi-specific anti-thymocyte globulin designed to modulate autoimmune responses while potentially avoiding some of the immunogenicity and adverse effects associated with rabbit-derived anti-thymocyte globulin preparations. This study will evaluate whether SAB-142 preserves endogenous insulin production and improves clinical outcomes in participants with Stage 3 T1D who have residual beta-cell function.

The study consists of three disease-duration cohorts:

Cohort 1: New-onset T1D (<100 days from diagnosis; external data from SAB-142-201 SAFEGUARD) Cohort 2: Recent-onset T1D (>100 days to <365 days from diagnosis) Cohort 3: Established-onset T1D (365 to 730 days from diagnosis)

Approximately 72 participants will be enrolled into Cohorts 2 and 3 and randomized 2:1 to SAB-142 or placebo. An additional 36 age-matched participants from SAB-142-201 SAFEGUARD will comprise Cohort 1, resulting in a combined efficacy dataset of approximately 108 participants. Participants will receive an induction treatment period at baseline and a maintenance treatment period at Month 6. Follow-up continues through Month 12.

Inclusion Criteria:

1. Participant and/or appropriate legal guardian for participants below the legal age of consent must have given written informed consent and/or assent according to local, regional and/or country specific guidance before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects. Participants and legal guardians must be capable of providing informed consent and not be incapacitated.

2. Males and females 5-40 years old*, inclusive, at the time of randomisation.

   * Note: Age step-down rules apply, as described in protocol Section 6.1.

3. Weight ≥16.0 kg at time of randomisation. Participants age 18-40 will have a body mass index (BMI) between 16 to 32 (inclusive).

4. Participant has received a diagnosis of T1D according to American Diabetes Association criteria (refer Section 22.1) as following:

   • For Cohort 2: within >100 days but <1 year (365 days) of randomisation;
   • For Cohort 3: within ≥1 year (365 days) but <2 years (730 days) of randomisation. For participants who were initially misdiagnosed with Type 2 diabetes (T2D), time from misdiagnosis with T2D to randomisation is up to 1 and 2 years.

   Note: Unless previously diagnosed with preclinical (Stage 1 or Stage 2 T1D), participant must have initiated insulin therapy the time of randomisation.

5. Participant has random C-peptide levels of >0.2 nmol/L, measured during Screening. One random C-peptide retest during screening period is allowed.

6. Participant completed all scheduled samples for C-peptide collected during the MMTT test during Screening.

7. Participant has a positive result on testing for at least one of the following T1D-related autoantibodies during screening:

   • Glutamic acid decarboxylase 65 (GAD65)
   • Islet antigen 2 (IA-2)
   • Zinc transporter 8 (ZnT8)
   • Insulin autoantibodies (if testing within the first 14 days of insulin treatment)

8. Female participants:

   1. Must be of nonchildbearing potential, i.e., pre-pubertal*, surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening, or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle -stimulating hormone [FSH] level consistent with postmenopausal status, per local laboratory guidelines), or
   2. If of childbearing potential, must:

   i.Have a negative result on a serum (beta human chorionic gonadotropin [β-hCG]) at screening and a negative urine β-hCG pregnancy test prior to study drug administration on Day 1 of both treatment periods.

   ii.Agree not to become pregnant or donate ova from the time of signing the consent form until the end of the study visit.

   iii.If not exclusively in a same-sex relationship or abstinent as a committed lifestyle, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception [Section 11.3.1]) from the time of signing the consent and for the duration of the study.

   * Note: Female participants will be considered to be pre-pubertal (and of nonchildbearing potential) if they have not yet started menstruation. This should also be verified by the parent(s)/guardian(s). If a female participant reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forwards, and contraceptive requirements will apply.

9. Male participants, if not biologically or surgically sterilised, must:

   1. Agree not to donate sperm from the time of signing the consent form until End of Study (EOS).
   2. If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception [refer to Section 11.3.1]) from the time of signing the consent form until EOS.
   3. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, agree to use a condom from the time of signing the consent form until EOS.

10. Prior to receiving study drug, participant must agree to receive locally, regionally and/or country-specific required age-appropriate immunisations. Participants are advised but not required to comply with the guidelines for immunosuppressed individuals and those with chronic disease (diabetes mellitus) according to current local, regional and/or country-specific guidelines. Note: Vaccines are permitted within the timeframes specified in exclusion criterion #17.

11. Participant agrees not to receive other forms of experimental treatment from the time of signing informed consent and for the duration of the study, particularly agents that may be immune modulatory in nature and/or stimulate pancreatic β cell regeneration or insulin secretion.

12. Participant has suitable venous access for blood sampling.

13. Participant is willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion Criteria:

1. Participant has known allergy, hypersensitivity or moderate to severe allergic reaction including anaphylaxis to natural or recombinant antibodies, biologic treatments, passive vaccines, pork, or any other component of the study drug formulation (including biologic medications). This includes participants with Hereditary Fructose Intolerance.

2. Participant has a known allergy or hypersensitivity to any of the protocol-required concomitant medications.

3. Participant has been an active participant in a therapeutic drug, invasive medical device, or vaccine clinical trial within 12 weeks before Screening Visit (SV)2.

4. Participant has received teplizumab or any investigational immunomodulatory anti-CD3 treatment within any timeframe prior to screening.

5. Participant has a significant uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, neurologic, haematologic, rheumatologic, oncologic, psychiatric, or immune deficiency that may interfere with the participant's safely participating in the study or with interpretation of the safety and/or efficacy profile of investigational medicinal product (IMP). For any disorders, a participant with a stable, well-controlled condition that is not felt to interfere with study participation may be enrolled.

6. Participant has any autoimmune disease other than T1D (e.g., latent autoimmune diabetes in adults, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythaematosis) that is currently managed with systemic immunotherapy, with the exception of clinically stable thyroid or celiac disease.

7. Participant is prone to infections, or has chronic, recurrent or opportunistic infectious disease, including but not limited to renal, respiratory or skin infections, Pneumocystis carinii, aspergillosis, latent or active granulomatous infection, histoplasmosis, or coccidioidomycosis.

8. Participant has a history of or serologic evidence at screening of current or past infection with human immunodeficiency virus (HIV)-1 or 2, hepatitis B virus (HBV), or hepatitis C virus (HCV) antibodies.

9. Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-rays (posterior anterior and lateral), and/or TB testing. Note: Blood testing (e.g., QuantiFERON® TB Gold test) is strongly preferred; if not available, any local approved TB test is allowed.

10. Serious systemic viral, bacterial, or fungal infection (e.g., pneumonia, pyelonephritis), infection requiring hospitalisation or IV anti-infective treatments or significant acute or chronic viral (including history of recurrent or active herpes zoster, acute or active CMV, EBV as determined at screening), bacterial, or fungal infection (e.g., osteomyelitis) 30 days before and during screening. Note: Participants with confirmed active EBV or CMV infection based on polymerase chain reaction (PCR) test can be retested; asymptomatic participants with the most recent PCR-negative (defined as PCR <1000 copies/mL or its equivalent in plasma or serum based on the site-specific PCR assay) test are eligible for participation. Participants with an active mild infection at Screening may be enrolled once the symptoms have resolved and all I/E are met. Participants who have an active infection and/or fever ≥38.0°C (100.4°F) within the 48 hours prior to dose administration should not be dosed.

11. Participant has a diagnosis of significant liver disease or at screening ALT and/or AST >2× or total bilirubin of >1.5× of the age- and sex-specific upper limit of normal (ULN) according to the site laboratory and confirmed by repeated tests. Liver function tests can be repeated during screening and if normalised, participant may be eligible for randomisation. Note: Participants with Gilbert's syndrome are allowed to enrol if only total and/or indirect bilirubin are elevated above ULN while ALT, AST, and alkaline phosphatase (ALP) are within the normal laboratory ranges.

12. An individual has any of the following haematologic parameters, confirmed by repeat tests, during Screening:

    • Lymphocyte count: <1000/μL
    • Neutrophil count: <1500/μL
    • Platelet count: <100 000 platelets/μL
    • Haemoglobin: <10 g/dL

    Note: Specific haematologic, oncologic or other systemic conditions that might otherwise result in exclusion and/or is heretofore unrecognised should be considered in individuals who have one or more blood cell counts below or above the references ranges.

13. Current or prior (within 5× half-lives before SV2) treatment that is known to cause a significant, ongoing change in the course of T1D or immunologic status, including systemic glucocorticoids, verapamil, baricitinib, and others. Note: Inhaled and topical corticosteroids are allowed. Short courses, i.e., approximately 2 weeks or less, of systemic corticosteroids for transient conditions are allowed.

14. Current or prior (within 5× half-lives before SV2) use of drugs other than insulin to treat hyperglycaemia (e.g., metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, glucagon-like peptide 1 agonists [glucagon-like peptide-1], dipeptidyl peptidase-4 [DPP-IV] inhibitors, or amylin).

15. Current or prior (within 5× half-lives before SV2) use of any medication known to significantly influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, niacin).

16. Current or planned highly restrictive dietary regimen(s) that would interfere with participant well-being or impact on the investigational drug.

17. Recent or planned vaccinations as follows:

    Countries within the EU member states only:

    • Live vaccines (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, and smallpox): from 30 days before dosing through 6 months following administration of SAB-142 for each TP;
    • Recombinant, inactivated or otherwise "non-live" vaccines: from 30 days before dosing or within 60 days following dosing; or planned/required within 30 days prior to or 60 days following Day 1 of TP2.
    • Live vaccines (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, and smallpox): Within the 30 days before dosing or within 30 days following dosing; or planned/required within 30 days prior to or 30 days following Day 1 of each TP.
    • Recombinant, inactivated or otherwise "non-live" vaccines: Within the 30 days before dosing or within 30 days following dosing; or planned/required within 30 days prior to or 30 days following Day 1 of each TP.

18. Female is lactating and/or plans to lactate with the intent to provide her own breast milk to a baby at any point during the study.

19. An individual who has a history of alcohol, drug, or chemical abuse within 12 months prior to study screening (positive tetrahydrocannabinol is allowed) Note: Abuse is defined according to local, regional and/or country specific guidance. Participants who are tested positive for illicit substances but have a prescription medication to manage their concomitant conditions such as attention-deficit/hyperactivity disorder (ADHD) or others are allowed to participate in the study.

20. An individual who has a medical, psychological or social condition that, in the opinion of the Investigator, would interfere with safe and proper completion of the trial.

21. An individual who is an employee of the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site. Note: Investigators should ensure that all study inclusion criteria and no study exclusion criteria have been met at screening. If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.

22. An individual who is considered failing to thrive or extremely obese may be excluded based on assessment by the PI or if participation in the study may place the participant at risk.

23. An individual who has been placed in an institution by official or court order.