Methods for treating type 1 diabetes
Provided herein are a method of treating type 1 diabetes (T1D). In some embodiments, such method can include administering to a subject in need thereof a 12-day course of teplizumab at a total dose of more than about 9000 μg/m 2 .
1 . A method of delaying progression of Stage 3 type 1 diabetes (T1D) in a patient diagnosed with Stage 3 T1D, comprising administering to the patient two 12-day courses of teplizumab, wherein each 12-day course comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12.
2 . The method of claim 1 , wherein the two courses of teplizumab are administered at an interval of about 6 months to about 12 months.
3 . The method of claim 2 , further comprising administering to the patient one or more additional 12-day courses of teplizumab.
4 . The method of claim 3 , wherein each of the one or more additional 12-day courses of teplizumab comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12.
5 . The method of claim 3 , wherein each of the additional 12-day courses of teplizumab is administered at about 6 months to about 24 months after the preceding course.
6 . The method of claim 2 , wherein the second of said two courses of teplizumab is administered to the patient 6-12 months after the first of said two courses of teplizumab.
7 . The method of claim 1 , comprising
determining, before and after administration of each 12-day course, a baseline of a level of TIGIT+KLRG1+CD8+ T-cells with respect to all CD3+ T-cells,
monitoring the level of the TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells, and
administering an additional 12-day course when the level of the TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells returns to the baseline level.
8 . The method of claim 7 , wherein the level of TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells is measured by flow cytometry.
9 . The method of claim 7 , comprising determining the level of TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells about 1-6 months, 2-5 months, or 3 months after the administration of each 12-day course.
10 . The method of claim 7 , wherein if the patient has more than 10% TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells, subsequent monitoring is annual.
11 . The method of claim 7 , wherein if the patient has less than 10% TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells, subsequent monitoring is about every 3-6 months.
12 . The method of claim 1 , wherein the patient has been diagnosed with Stage 3 T1D within 6 weeks prior to the administering step.
13 . The method of claim 12 , wherein the patient in need thereof is 8 years of age or older.
14 . The method of claim 1 , wherein the administering step results in reduction of insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof by at least 10% as compared to pre-treatment levels.
15 . The method of claim 1 , wherein each dose is administered parenterally.
16 . The method of claim 1 , wherein each dose is administered by intravenous infusion.
17 . The method of claim 16 , wherein each dose of teplizumab is administered by intravenous infusion over a period of at least 30 minutes.
18 . The method of claim 1 , wherein the patient in need thereof is 8 years of age or older.
19 . The method of claim 1 , wherein the patient in need thereof has a peak C-peptide level of ≥0.2 pmol/mL during a mixed meal tolerance test (MMTT).
20 . The method of claim 1 , wherein the patient receiving teplizumab has a higher mean C-peptide value compared with a control receiving placebo.
21 . The method of claim 1 , comprising assessing the area under the time-concentration curve (AUC) of C-peptide following a mixed meal tolerance test (MMTT) at 78 weeks.
22 . The method of claim 1 , wherein the patient has at least 20% of beta-cell function prior to the administering step.
23 . The method of claim 1 , wherein the patient in need thereof is or has tested positive for at least one T1D-related autoantibody selected from glutamic acid decarboxylase 65 autoantibodies, islet antigen 2 autoantibodies, zinc transporter 8 autoantibodies, islet cell cytoplasmic autoantibodies, and insulin autoantibodies.
24 . The method of claim 23 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
25 . The method of claim 24 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dL (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT);
(iii) a hemoglobin A1C (HbA1c) level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
26 . The method of claim 1 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
27 . The method of claim 26 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dl (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT);
(iii) a hemoglobin A1C (HbA1c) level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
28 . The method of claim 1 , wherein the patient has been diagnosed with Stage 3 T1D within 12 weeks prior to the administering step.
29 . The method of claim 1 , wherein the two courses of teplizumab are administered at an interval of 6 months.
30 . The method of claim 1 , wherein the patient has been diagnosed with Stage 3 T1D within 4 months prior to the administering step.
31 . The method of claim 1 , wherein the patient has been diagnosed with Stage 3 T1D within 12 months prior to the administering step.
32 . The method of claim 31 , wherein the patient has a non-fasting C-peptide level of ≥0.2 pmol/mL.
33 . A method of delaying progression of Stage 3 type 1 diabetes (T1D) in a patient in need thereof, comprising parenterally administering to the patient in need thereof two 12-day courses of teplizumab at an interval of about 6 months to about 12 months, wherein each 12-day course comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12,
wherein the patient has been diagnosed with Stage 3 T1D within 12 weeks prior to the administering step.
34 . The method of claim 33 , further comprising administering to the patient one or more additional 12-day courses of teplizumab.
35 . The method of claim 34 , wherein each of the additional 12-day courses comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12.
36 . The method of claim 35 , wherein each of the additional 12-day courses is administered at about 6 months to about 24 months after the preceding course.
37 . The method of claim 33 , wherein the patient in need thereof is 8 years of age or older.
38 . The method of claim 33 , wherein each dose is administered by intravenous infusion.
39 . The method of claim 38 , wherein each dose of teplizumab is administered by intravenous infusion over a period of at least 30 minutes.
40 . The method of claim 33 , wherein the patient has been diagnosed with Stage 3 T1D within 6 weeks prior to the administering step.
41 . The method of claim 33 , wherein the second of said two courses of teplizumab is administered to the patient 6-12 months after the first of said two courses of teplizumab.
42 . The method of claim 33 , wherein the patient in need thereof is or has tested positive for at least one T1D-related autoantibody selected from glutamic acid decarboxylase 65 autoantibodies, islet antigen 2 autoantibodies, zinc transporter 8 autoantibodies, islet cell cytoplasmic autoantibodies, and insulin autoantibodies.
43 . The method of claim 42 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
44 . The method of claim 43 , wherein the patient in need thereof is 8 years of age or older.
45 . The method of claim 44 , wherein each dose of teplizumab is administered by intravenous infusion over a period of at least 30 minutes.
46 . The method of claim 43 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dl (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an OGTT;
(iii) an HbA1c level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
47 . The method of claim 33 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
48 . The method of claim 47 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dl (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an OGTT;
(iii) an HbA1c level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
49 . The method of claim 33 , wherein the two courses of teplizumab are administered at an interval of 6 months.
50 . The method of claim 33 , wherein the patient in need thereof has a peak C-peptide level of ≥0.2 pmol/mL during a mixed meal tolerance test (MMTT).
51 . A method of delaying progression of Stage 3 type 1 diabetes (T1D) in a patient in need thereof, comprising administering, by intravenous infusion, to the patient in need thereof, two 12-day courses of teplizumab at an interval of 6 months to 12 months, wherein each 12-day course comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12,
wherein the patient has been diagnosed with Stage 3 T1D within 8 weeks prior to the administering step.
52 . The method of claim 51 , wherein the patient in need thereof is 8 years of age or older.
53 . The method of claim 51 , wherein the patient in need thereof is or has tested positive for at least one T1D-related autoantibody selected from glutamic acid decarboxylase 65 autoantibodies, islet antigen 2 autoantibodies, zinc transporter 8 autoantibodies, islet cell cytoplasmic autoantibodies, and insulin autoantibodies.
54 . The method of claim 53 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
55 . The method of claim 54 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dl (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an OGTT;
(iii) an HbA1c level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
56 . The method of claim 51 , wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
57 . The method of claim 56 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dL (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an OGTT;
(iii) an HbA1c level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).
58 . The method of claim 51 , wherein each dose of teplizumab is administered by intravenous infusion over a period of at least 30 minutes.
59 . The method of claim 51 , wherein the patient has been diagnosed with Stage 3 T1D within 6 weeks prior to the administering step.
60 . The method of claim 51 , wherein the two courses of teplizumab are administered at an interval of 6 months.
61 . The method of claim 51 , wherein the patient in need thereof has a peak C-peptide level of ≥0.2 pmol/mL during a mixed meal tolerance test (MMTT).
62 . A method of delaying progression of Stage 3 type 1 diabetes (T1D) in a patient in need thereof, comprising
administering, by intravenous infusion, to the patient in need thereof, two 12-day courses of teplizumab at an interval of 6 months, wherein each 12-day course comprises a first dose of 106 μg/m 2 teplizumab on day 1, a second dose of 425 μg/m 2 teplizumab on day 2, and one dose of 850 μg/m 2 teplizumab on each of days 3-12,
wherein the patient in need thereof has been diagnosed with Stage 3 T1D within 12 weeks prior to the administering step,
wherein the patient in need thereof is or has tested positive for at least one T1D-related autoantibody selected from glutamic acid decarboxylase 65 autoantibodies, islet antigen 2 autoantibodies, zinc transporter 8 autoantibodies, islet cell cytoplasmic autoantibodies, and insulin autoantibodies, and
wherein the patient in need thereof has or has tested positive for hyperglycemia or overt hyperglycemia.
63 . The method of claim 62 , wherein the patient in need thereof is 8 years of age or older.
64 . The method of claim 62 , wherein the patient has been diagnosed with Stage 3 T1D within 6 weeks prior to the administering step.
65 . The method of claim 64 , wherein the patient in need thereof is 8 years of age or older.
66 . The method of claim 62 , wherein the patient in need thereof has or has tested positive for at least one of the following:
(i) a fasting plasma glucose level of ≥126 mg/dL (7.0 mmol/L);
(ii) a 2-hour plasma glucose level of ≥200 mg/dL (11.1 mmol/L) during an OGTT;
(iii) an HbA1c level of ≥6.5% (48 mmol/mol); and
(iv) a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L).