Item
8.01. Other Events
On
June 9, 2019, the Company announced results from a Phase 2 clinical trial in patients with Stage 2 T1D (Teplizumab for Prevention
of Type 1 Diabetes In Relatives “At-Risk”) conducted at TrialNet sites and sponsored by the NIDDK, part of the National
Institutes of Health, or NIH that were reported at the American Diabetes Association meeting in June 2019 and published in the
New England Journal of Medicine. A total of 76 subjects were enrolled, 44 randomized to teplizumab and 32 to placebo. The data
show that teplizumab significantly delayed the median onset of clinical diabetes from 24.4 months (placebo) to 48.4 months (teplizumab)
(p=0.006). The safety profile in At-Risk subjects who received a single course of teplizumab was consistent with those from subjects
with recent-onset clinical T1D who received two courses of the drug. Teplizumab is the first immune modulator therapy that has
demonstrated an unequivocal delay the onset of clinical disease in T1D.
Stage
2: At-Risk Study
The At-Risk study was
developed and conducted by Type 1 Diabetes TrialNet, funded by the National Institutes of Health, the American Diabetes Association,
or the ADA, and the JDRF. The objective of the study was to determine whether treatment of at-risk subjects with teplizumab
results in a delay or prevention of T1D. The primary endpoint was completed in 2018. The study was conducted in 18 sites in the
United States, Canada and Germany.
Individuals
over eight years of age with Stage 2 T1D (presence of at least two T1D autoantibodies and dysglycemia, who were non-diabetic relatives
of T1D individuals) were randomized 1:1 to receive teplizumab or placebo. Dysglycemia was defined on oral glucose tolerance test
(OGTT) as: (a) Fasting plasma glucose ≥ 110mg/dL, and <126mgdL, or (b) 2-hour plasma glucose ≥140mg/dL, and <200mg/dL,
or (c) 30, 60, or 90-minute value on OGTT ≥200mg/dL.
The
primary endpoint was the time from randomization to the clinical diagnosis of diabetes, using ADA criteria. Criteria for T1D onset
are, based on glucose testing, or the presence of unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis).
One of the following criteria must be met on two occasions as soon as possible but no less than one day apart for diabetes to
be defined:
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Symptoms
of diabetes plus casual plasma glucose concentration > 200 mg/dL (11.1 mmol/l). Casual is defined as any time of day without
regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
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Fasting
plasma glucose ≥ 126 mg/dL (7 mmol/l). Fasting is defined as no caloric intake for at least 8 hours.
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2-hour
plasma glucose ≥ 200 mg/dL (11.1 mmol/l). The test should be performed using a glucose load containing the equivalent of
1.75g/kg body weight to a maximum of 75 g anhydrous glucose dissolved in water.
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Teplizumab
was administered over a 14-day course: 51 μg/m2, 103 μg/m2, 207 μg/m2, and 413 μg/m2 on study days 0–3, respectively,
and 826 μg/m2 on each of study days four through 13. A total of 112 participants were screened and 76 were randomized, 44 to
teplizumab and 32 to placebo. The baseline characteristics were balanced for age (median ~13-14 years of age), relationship to
the relative with T1D, type of T1D autoantibodies and HbA1c.
Treatment
with a single course of teplizumab delayed the time to T1D (see figure below): 19 of the 44 (43%) teplizumab-treated and 23 of
the 32 (72%) placebo-treated participants were diagnosed with T1D. The annualized rates of T1D development were 14.9% and 35.9%
per year, for the teplizumab and placebo groups, respectively. The median time to T1D was 24.4 months in the placebo and 48.4
months in the teplizumab groups (hazard ratio = 0.412 (95% CI: 0.216, 0.783) p=0.006 (2-sided)).
Time
to T1D
In
pre-specified analyses, the effects of teplizumab on the primary outcome based on baseline characteristics were evaluated. Participants
without anti-ZnT8 antibodies showed a greater response to teplizumab compared to those with those who did not have the antibody.
The presence of HLA-DR4 and absence of HLA-DR3 were associated with more robust responses to teplizumab, and the response to teplizumab
was greater in participants whose C-peptide responses to the OGTT at baseline were below the median (1.75 nmol/L).
Teplizumab
treatment was associated with few adverse events, described in the table below. Similar to previous studies with teplizumab in
recent onset T1D patients, the lymphocyte count declined to a nadir on day 5 by 72.3% (IQR 82.1, 68.4%)(p<0.0001)(Fig. 2A).
Fifteen (34.1%) of the grade 3 events in the teplizumab group involved lymphopenia during the first 30 days after study drug administration.
The lymphocyte counts recovered quickly: Lymphopenia resolved in all participants by day 45 except in one, whose counts returned
on day 105. A spontaneously resolving rash, as previously noted, occurred in 36% of drug treated participants. The rates of infection
were similar in the two treatment arms.
Adverse
Events Possibly, Probably or Definitely Related to Study Drug
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Adverse
Effect Category
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Teplizumab
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Placebo
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No.
of Events
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No.
of Subjects (%)
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No.
of Events
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No.
of Subjects (%)
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Blood/Bone
Marrow***
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45
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33
(75)
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2
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2
(6.2)
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Dermatology/Skin***
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17
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16
(36.4)
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1
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1
(3.1)
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Pain
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11
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5
(11.4)
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5
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3
(9.4)
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Infection
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8
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5
(11.4)
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5
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3
(9.4)
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Gastrointestinal
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5
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4
(9.1)
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3
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3
(9.4)
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Metabolic/Laboratory
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7
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4
(9.1)
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2
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2
(6.2)
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Pulmonary/Upper
Respiratory
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6
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4
(9.1
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0
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0
(0)
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Constitutional
Symptoms
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3
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2
(4.5)
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0
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0
(0)
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Allergy/Immunology
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2
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2
(4.5)
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0
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0
(0)
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Cardiac
General
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1
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1
(2.3)
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1
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1
(3.1)
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Endocrine
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0
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0
(0)
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2
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2
(6.2)
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Vascular
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1
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1
(2.3)
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1
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1
(3.1)
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Neurology
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1
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1
(2.3)
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0
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0
(0)
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Ocular/Visual
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1
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1
(2.3)
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0
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0
(0)
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Musculoskeletal/Soft
Tissue
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2
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1
(2.3)
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0
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0
(0)
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Hepatobiliary/Pancreas
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0
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0
(0)
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1
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1
(3.1)
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Syndromes
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1
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1
(2.3)
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0
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0
(0)
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Hemorrhage/Bleeding
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1
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1
(2.3)
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0
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0
(0)
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Total
Events and Subjects
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112
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44
(100)
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23
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32
(100)
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***
p < 0.001 Teplizumab vs placebo
Anti-CD3
mAb treatment has been associated with Epstein Barr virus, or EBV, reactivation. At entry, 30 participants (39%) (16 teplizumab
and 14 placebo) had antibodies against EBV. At weeks 3-6 after study drug treatment, there was quantifiable EBV DNA in whole blood
in eight of the seropositive participants – all in the teplizumab group, one of whom had symptoms of pharyngitis, rhinorrhea,
and cough on day 38. In these participants, the EBV DNA levels were below the level of quantification between day 43 and 134 (average
77 days). At entry, 17 participants (ten teplizumab and seven placebo) had antibodies against cytomegalovirus, or CMV. One teplizumab
participant, who was CMV seropositive, had detectable levels of CMV DNA at day 20 that was undetectable by day 42.
These
results demonstrate that a single course of teplizumab significantly delayed the progression to clinical T1D in high risk Stage
2 non-diabetic relatives who had at least two autoantibodies and dysglycemia. The median delay in the diagnosis of diabetes was
approximately two years, and at the conclusion of the trial, the frequency of diabetes-free individuals was double in the drug
(57%) vs placebo-treated subjects (28%). The relatively rapid rate of progression to clinical diabetes in the placebo group reflects
the very high risk of these individuals and reflects the inevitability of progression from Stage 2 to Stage 3 disease, when two
or more autoantibodies and dysglycemia are found, consistent with observations of high rates of beta cell killing in these individuals.
The rapid development of clinical T1D may reflect the enrichment of pediatric participants (72.4%) in whom the rate of progression
is rapid.