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1. WO2020194244 - CLINICALLY PROVEN SUBCUTANEOUS PHARMACEUTICAL COMPOSITIONS COMPRISING ANTI-CD38 ANTIBODIES AND THEIR USES IN COMBINATION WITH BORTEZOMIB AND DEXAMETHASONE

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[ EN ]

We claim:

1) A method of treating a subject with multiple myeloma, comprising:

a) providing a healthcare professional a pharmaceutical composition comprising an antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and recombinant human hyaluronidase (rHuPH20), wherein the pharmaceutical composition is clinically proven for subcutaneous administration;

b) providing the healthcare professional information that the pharmaceutical

composition is clinically proven for subcutaneous administration;

c) providing the healthcare professional information that the pharmaceutical

composition can be administered in combination with bortezomib and dexamethasone; wherein performing the steps a), b) and c) results in the medical professional to administer subcutaneously the pharmaceutical composition, bortezomib and dexamethasone to the subject having multiple myeloma, thereby treating the subject having multiple myeloma.

2) A method of treating a subject with multiple myeloma, comprising subcutaneously administering to the subject a pharmaceutical composition comprising an antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and rHuPH20 in combination with bortezomib and dexamethasone, wherein the pharmaceutical composition is clinically proven for subcutaneous administration.

3) The method of claim 1 or 2, wherein the method results in reduced occurrence or severity of infusion related reactions (IRR) in a subject when compared to an intravenous administration of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6.

4) The method of any one of claims 1-3, wherein the pharmaceutical composition

comprises about 1,800 mg of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 30,000 U of rHuPH20.

5) The method of any one of claims 1-4, wherein the pharmaceutical composition comprises about 120 mg/mL of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 2,000 U/mL of rHuPH20.

6) The method of any one of claims 1-5, wherein the pharmaceutical composition

comprises one or more excipients.

7) The method of claim 6, wherein the one or more excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

8) The method of any one of claims 1-7, wherein the pharmaceutical composition

comprises

a) between about 5 mM and about 15 mM histidine;

b) between about 100 mM and about 300 mM sorbitol;

c) between about 0.01% w/v and about 0.04 % w/v PS-20; and

d) between about 1 mg/mL and about 2 mg/mL methionine, at a pH of about 5.5-5.6.

9) The method of claim 8, wherein the pharmaceutical composition comprises about 10 mM histidine.

10) The method of claim 8 or 9, wherein the pharmaceutical composition comprises about 300 mM sorbitol.

11) The method of any one of claims 8-10, wherein the pharmaceutical composition comprises about 0.04% (w/v) PS-20.

12) The method of any one of claims 8-11, wherein the pharmaceutical composition comprises about mg/mL methionine.

13) The method of any one of claims 1-12, wherein the pharmaceutical composition comprises

a) about 1,800 mg of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6;

b) about 30,000 U of rHuPH20;

c) about 10 mM histidine;

d) about 300 mM sorbitol;

e) about 0.04 % (w/v) PS-20; and

f) about 1 mg/mL methionine, at a pH of about 5.6.

14) The method of any one of claims 1-13, wherein the pharmaceutical composition comprises

a) about 120 mg/mL of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6;

b) about 2,000 U/mL of rHuPH20;

c) about 10 mM histidine;

d) about 300 mM sorbitol;

e) about 0.04 % (w/v) PS-20; and

f) about 1 mg/mL methionine, at a pH of about 5.6.

15) The method of any one of claims 1-14, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8.

16) The method of any one of claims 1-15, wherein the antibody that specifically binds CD38 is an IgGl isotype.

17) The method of any one of claims 1-16, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10.

18) The method of any one of claims 1-17, wherein the antibody that specifically binds CD38 is a biosimilar of DARZALEX® brand of daratumumab.

19) The method of any one of claims 1-18, wherein the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of the antibody that specifically binds CD38 and about 30,000 U of rHuPH20 once a week, once in two weeks, once in three weeks or once in four weeks.

20) The method of any one of claims 1-19, wherein bortezomib is administered at a dose of about 1.3 mg/m2twice a week.

21) The method of any one of claims 1-20, wherein dexamethasone is administered at a dose of between about 20 mg and about 80 mg weekly.

22) The method of any one of claims 1-21, comprising administering the pharmaceutical composition, bortezomib and dexamethasone for one or more 3 -week cycles.

23) The method of claim 22, wherein the pharmaceutical composition is administered once a week in the first, the second and the third 3 -week cycle, once in three weeks in the fourth, the fifth, the sixth, the seventh and the eighth 3 -week cycle, and thereafter once in four weeks.

24) The method of claim 23, wherein bortezomib is administered at a dose of about 1.3 mg/m2 twice a week on week 1 and week 2 in cycles 1-8.

25) The method of claim 24, wherein dexamethasone is administered at a dose of 20 mg as a pre-infusion medication on the same day when the pharmaceutical composition is administered and optionally at a dose of 20 mg the day after the pharmaceutical composition is administered.

26) The method of any one of claims 1-25, wherein bortezomib is administered

subcutaneously or intravenously.

27) The method of any one of claims 1-26, wherein dexamethasone is administered orally.

28) The method of any one of claims 1-27, wherein dexamethasone is self-administered.

29) The method of any one of claims 1-28, wherein multiple myeloma is relapsed,

refractory, or both relapsed and refractory.

30) The method of any one of claims 1-28, wherein multiple myeloma is newly diagnosed multiple myeloma.

31) The method of any one of claims 1-29 wherein the subject is eligible for high dose chemotherapy (HDC) and stem cell transplant (SCT).

32) The method of claim 30, wherein SCT is autologous SCT (ASCT), allogenic SCT or syngeneic SCT.

33) The method of claim 31, wherein SCT is ASCT.

34) The method of claim 32, wherein HDC is melphalan.