Drug Trials Snapshots: TZIELD

HOW TO USE THIS SNAPSHOT

The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:

Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the TZIELD Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

TZIELD (teplizumab-mzwv)
TEE-zeeld
Provention Bio, Inc.
Original Approval date: November 17, 2022

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

TZIELD is a drug that is used to delay the onset of type 1 diabetes in children and adults who are at high risk for type 1 diabetes.

How is this drug used?

TZIELD is an injection given by a healthcare professional directly into a vein (intravenous infusion) once per day for 14 days.

Who participated in the clinical trials?

The FDA approved TZIELD based on evidence from one clinical trial (Study TN-10) of 76 patients at high risk of developing type 1 diabetes. Study TN-10 was conducted at 30 sites in 5 countries including the United States, Canada, Australia, the United Kingdom, and Germany.

How were the trials designed?

The effectiveness of TZIELD was investigated in a randomized, double-blind, event-driven, placebo-controlled study (Study TN-10, NCT01030861) in 76 patients, 8 to 49 years of age with stage 2 type 1 diabetes. Stage 2 type 1 diabetes was defined as having both of the following:

1. Two or more of the following pancreatic islet autoantibodies:

• Glutamic acid decarboxylase 65 (GAD) autoantibodies
• Insulin autoantibody (IAA)
• Insulinoma-associated antigen 2 autoantibody (IA-2A)
• Zinc transporter 8 autoantibody (ZnT8A)
• Islet cell autoantibody (ICA)

2. Dysglycemia on oral glucose tolerance testing

In this trial, patients were randomized to receive TZIELD or placebo once daily by intravenous infusion for 14 days. The primary endpoint in this trial was the time from randomization to development of stage 3 type 1 diabetes diagnosis.

How were the trials designed?

In addition to TN-10, the safety of TZIELD was also evaluated in a larger pool of adult and pediatric patients who participated in four controlled clinical trials (three placebo-controlled and one open-label standard-of-care controlled) in an unapproved population. In total, the clinical trials evaluated for safety included 773 subjects who received TZIELD and 245 who received placebo or control. In these studies, 436 patients received a 14-day dosing regimen of TZIELD with a total drug exposure that was comparable to the total drug exposure achieved with the recommended dosage, 168 patients received a 14-day course of TZIELD with a lower total TZIELD drug exposure, and 169 patients received a 6-day course of TZIELD with a lower total TZIELD drug exposure.

DEMOGRAPHICS SNAPSHOT

Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of TZIELD.

Figure 1. Baseline Demographics by Sex, Efficacy Population

_{Source: Adapted from FDA Review}

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy of TZIELD.

Figure 2. Baseline Demographics by Race, Efficacy Population

_{Source: Adapted from FDA Review}

Figure 3 summarizes the percentage of patients by age enrolled in the clinical trial used to evaluate the efficacy of TZIELD.

Figure 3. Baseline Demographics by Age, Efficacy Population

_{Source: Adapted from FDA Review}

Figure 4 summarizes the percentage of patients by ethnicity enrolled in the clinical trial used to evaluate the efficacy of TZIELD.

Figure 4. Baseline Demographics by Ethnicity, Efficacy Population

_{Source: Adapted from FDA Review}

Who participated in the trials?

Table 1. Baseline Demographics, Efficacy Population, Study TN-10

Demographic	TZIELD N=44 n (%)	Placebo N=32 n (%)
Sex
Female	19 (43)	15 (47)
Male	25 (57)	17 (53)
Age group, years
<18	29 (66)	26 (81)
≥18	15 (34)	6 (19)
Pediatric age groups, years
8 to <11	10 (23)	8 (25)
11 to <14	10 (23)	9 (31)
14 to <18	9 (20)	9 (28)
Race
White	44 (100)	30 (94)
Asian	0 (0)	1 (3)
Multiple	0 (0)	1 (3)
Ethnicity
Hispanic or Latino	1 (2)	1 (3)
Not Hispanic or Latino	43 (98)	29 (91)
Unknown	0 (0)	2 (6)

_{Adapted from FDA Review and TZIELD Prescribing Information}

What are the benefits of this drug? 

Type 1 diabetes is a lifelong condition where your body cannot make enough insulin on its own to keep blood sugar levels normal, and you need daily insulin injections or an insulin pump. TZIELD is a prescription medicine that delays the onset of type 1 diabetes in patients who are at high risk for having the disease. A high-risk person has two or more type 1 diabetes-related autoantibodies and abnormal blood sugar levels that are not yet high enough for a diagnosis of diabetes. During the clinical trial that followed each participant for about 51 months those taking TZIELD had a 59% lower risk of developing type 1 diabetes compared to those taking placebo. Participants taking TZIELD developed type 1 diabetes generally 50 months after receiving the medication, compared to 25 months among those taking placebo.

What are the benefits of this drug (results of trials used to assess efficacy)?

Table 2. Primary Efficacy Endpoint Analysis Results, Efficacy Population, Study TN-10

Parameter	TZIELD N=44	Placebo N=32	Total N=76
Event numbers, n (%)
Number of patients diagnosed with T1D	20 (45)	23 (72)	43 (57)
Number of censored patients	24 (55)	9 (28)	33 (43)
Censored due to reaching trial end: follow-up still ongoing at cutoff date	22 (50)	8 (25)	30 (39)
Censored due to discontinuation from study for reasons other than diagnosis	2 (5)	1 (3)	3 (4)
Follow-up time
Median follow-up time (month)	50.6	49.9	50.6
Time to event summary statistics
Median time to T1D diagnosis (month) (95% CI)	49.5 (32.1, NE)	24.9 (9.5, 48.6)	42.6 (25.9, 55.2)
Primary analysis: Cox proportional hazard model
Hazard ratio (95% CI)	0.41 (0.22, 0.78)
p-value	0.0066

_{Adapted from FDA Review}

Figure 5. Kaplan-Meier Curve of Time to Diagnosis of Stage 3 Type 1 Diabetes in Adult and Pediatric Patients Aged 8 Years and Older With Stage 2 Type 1 Diabetes by Treatment Group, Efficacy Population, Study TN-10

_{TZIELD Prescribing Information}

Were there any differences in how well the drug worked in clinical trials among sex, race, and age?

• Sex: TZIELD worked similarly in males and females.
• Race: The number of participants of races other than White was small; therefore, differences in how TZIELD worked among races could not be determined.
• Age: TZIELD worked similarly in all age groups.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 3. Primary Efficacy Endpoint Analysis Results by Sex and Age, Efficacy Population, Study TN-10

Subgroup	Hazard Ratio (95% Credible Interval)a
Sex
Female (N=34)	0.22 (0.07, 0.68)
Male (N=42)	0.58 (0.25, 1.31)
Age group, years
8 to <11 (N=18)	0.37 (0.09, 1.46)
11 to <14 (N=19)	0.34 (0.12, 0.97)
14 to <18 (N=18)	0.62 (0.21, 1.82)
≥18 (N=21)	0.41 (0.14, 1.15)

_{Source: Adapted from FDA Review
^a Estimates and credible intervals for treatment effect include relevance of outcomes from other subgroups.}

What are the possible side effects?

TZIELD may cause serious side effects including:

• Cytokine release syndrome with signs and symptoms including fever, headache, fatigue, muscle and joint pain, and increased liver enzymes in your blood
• Decrease in white blood cells that can affect your body’s ability to fight infections
• Serious allergic reactions (hypersensitivity)

The most common side effects of TZIELD are lymphopenia (decrease in a certain type of white blood cells called lymphocytes), rash, leukopenia (decrease in the total number of white blood cells), and headache.

What are the possible side effects (results of trials used to assess safety)?

Table 4. Common Adverse Reactions in Adult and Pediatric Patients Aged 8 Years and Older With Stage 2 Type 1 Diabetes, Safety Population, Study TN-10b

Adverse Reaction	TZIELD N=44 %	Placebo N=32 %
Lymphopenia	73	6
Rashc	36	0
Leukopenia	21	0
Headache	11	6
Neutropenia	5	3
Increased alanine aminotransferase	5	3
Nausea	5	3
Diarrhea	5	0
Nasopharyngitis	5	0

_{Source: TZIELD Prescribing Information
^a That occurred during treatment and through 28 days after the last study drug administration
^b Adverse reactions that occurred in 2 or more TZIELD-treated subjects
^c Composite of rash-related terms including rash erythematous, rash macular, rash papular, rash maculo-papular, and rash pruritic}

Were there any differences in side effects among sex, race, and age?

• Sex: The occurrence of side effects was similar in males and females.
• Race: There were no differences in side effects by race, although the safety data among patients of races other than White and Asian was limited.
• Age: People who are at high risk for type 1 diabetes are generally children and younger adults. There were no differences in side effects by age. Studies to assess side effects generally did not include those 65 years of age and older.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table 5. Adverse Events by Sex, 14-Day Treatment Period, Safety Population, Pooled Analysis¹

Event	TZIELD, N=773		Control, N=245
	Female n/Ns (%)	Male n/Ns (%)	Female n/Ns (%)	Male n/Ns (%)
Any TEAE	276/278 (99.3)	481/495 (97.2)	71/93 (76.3)	116/152 (76.3)
SAE	1/278 (0.4)	9/495 (1.8)	1/93 (1.1)	0/152 (0.0)

_{Source: Adapted from FDA Review
¹ Pooled analysis taken from full Integrated Summary of Safety (ISS), limited to adverse events reported during the 14-day course one treatment period
Abbreviations: N, number of patients in treatment arm; n, number of patients with adverse event; Ns, total number of patients for each specific subgroup and were assigned to that specific arm; SAE, serious adverse event; TEAE, treatment-emergent adverse event}

Table 6. Adverse Events by Race, 14-Day Treatment Period, Safety Population, Pooled Analysis¹

Event	TZIELD, N=773			Control, N=245
	White n/Ns (%)	Asian n/Ns (%)	All Others n/Ns (%)	White n/Ns (%)	Asian n/Ns (%)	All Others n/Ns (%)
Any TEAE	546/554 (98.6)	193/200 (96.5)	18/19 (94.7)	139/188 (73.9)	44/51 (86.3)	4/6 (66.7)
SAE	9/554 (1.6)	1/200 (0.5)	0/19 (0.0)	1/188 (0.5)	0/51 (0.0)	0/6 (0.0)

_{Source: Adapted from FDA Review
¹ Pooled analysis taken from full Integrated Summary of Safety (ISS), limited to adverse events reported during the 14-day course one treatment period
Abbreviations: N, number of patients in treatment arm; n, number of patients with adverse event; Ns, total number of patients for each specific subgroup and were assigned to that specific arm; SAE, serious adverse event; TEAE, treatment-emergent adverse event}

Table 7. Adverse Events by Age, 14-Day Treatment Period, Safety Population, Pooled Analysis¹

Event	TZIELD, N=773		Control, N=245
	<18 Years n/Ns (%)	≥18 Years n/Ns (%)	<18 Years n/Ns (%)	≥18 Years n/Ns (%)
Any TEAE	468/477 (98.1)	289/296 (97.6)	121/165 (73.3)	66/80 (82.5)
SAE	7/477 (1.5)	3/296 (1.0)	0/165 (0.0)	1/80 (1.3)

_{Source: Adapted from FDA Review
¹ Pooled analysis taken from full Integrated Summary of Safety (ISS), limited to adverse events reported during the 14-day course one treatment period
Abbreviations: N, number of patients in treatment arm; n, number of patients with adverse event; Ns, total number of patients for each specific subgroup and were assigned to that specific arm; SAE, serious adverse event; TEAE, treatment-emergent adverse event}

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GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.

COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.

EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.

PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

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