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US-12624098-B2 - Treatment of age-related macular degeneration and diabetic macular edema by administration of a bispecific antibody to VEGF and ANG-2

US12624098B2US 12624098 B2US12624098 B2US 12624098B2US-12624098-B2

Abstract

The current invention relates to the use of bispecific antibodies that bind to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2) for the treatment of ophthalmologic diseases, such as age-related macular degeneration and diabetic macular edema, where the bispecific antibodies are administered intravitreally every 8 weeks or less frequently.

Inventors

  • Aaron Osborne
  • Jayashree Sahni
  • Robert James Weikert

Assignees

  • HOFFMANN-LA ROCHE INC.
  • GENENTECH, INC.

Dates

Publication Date
20260512
Application Date
20230209

Claims (19)

  1. 1 . A method of treating a patient suffering from an ocular vascular disease, the method comprising: administering to the patient an effective amount of a bispecific antibody which binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2), and comprises the amino acid sequences of SEQ ID NO: 17, of SEQ ID NO: 18, of SEQ ID NO: 19, and of SEQ ID NO: 20, wherein the bispecific antibody is administered intravitreally every 8 weeks or less frequently following a treatment initiation comprising 3 to 7 monthly administrations, in a dose of about 5 to 7 mg, wherein the ocular vascular disease is Age-Related Macular Degeneration (AMD).
  2. 2 . The method according to claim 1 , wherein AMD is neovascular (wet) AMD (nAMD).
  3. 3 . The method according to claim 1 , wherein the bispecific antibody is administered every 10 to 12 weeks.
  4. 4 . The method according to claim 1 , wherein the bispecific antibody is administered every 11 to 13 weeks.
  5. 5 . The method according to claim 1 , wherein the bispecific antibody is administered every 12 to 14 weeks.
  6. 6 . The method according to claim 1 , wherein the bispecific antibody is administered every 13 to 15 weeks.
  7. 7 . The method according to claim 1 , wherein the bispecific antibody is administered every 14 to 16 weeks.
  8. 8 . The method according to claim 1 , wherein the bispecific antibody is administered in a dose of about 6 mg.
  9. 9 . The method according to claim 8 , wherein the bispecific antibody is administered at a concentration of about 120 mg/ml.
  10. 10 . The method according to claim 1 , wherein the patient has not been previously treated with an anti-VEGF treatment.
  11. 11 . The method according to claim 1 , wherein the patient has been previously treated with an anti-VEGF treatment.
  12. 12 . The method according to claim 1 , wherein the treatment initiation comprises 4 to 6 monthly administrations.
  13. 13 . The method according to claim 12 , wherein administration following the treatment initiation comprises a dosing schedule that extends the administration interval in stable absence of disease, or shortens the interval if there is disease activity.
  14. 14 . The method according to claim 13 wherein such dosing schedule includes that the patient receives Q8W or Q12W or Q16W dosing.
  15. 15 . The method according to claim 13 , wherein the stable absence of disease is determined as: Central Subfield Thickness (CST) increased by <50 μm; and/or Best Corrected Visual Acuity (BCVA/ETDRS) decreased by <5 letters and the disease activity is determined as Central Subfield Thickness (CST) increased by ≥50 μm; and/or Best Corrected Visual Acuity (BCVA/ETDRS) decreased by ≥5 letters.
  16. 16 . The method according to claim 13 wherein such dosing schedule includes that the patient receives Q8W dosing.
  17. 17 . The method according to claim 13 wherein such dosing schedule includes that the patient receives Q12W dosing.
  18. 18 . The method according to claim 13 wherein such dosing schedule includes that the patient receives Q16W dosing.
  19. 19 . The method according to claim 1 , wherein the effective amount of the bispecific antibody prolongs the time to retreatment and/or prolongs the time to loss of visual acuity and, wherein the retreatment with the bispecific antibody is administered in presence of a disease activity which is determined as: Central Subfield Thickness (CST) increase by ≥50 μm; and/or Best Corrected Visual Acuity (BCVA/ETDRS) decrease by ≥5 letters.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 16/985,477, filed Aug. 5, 2020, which is a continuation of International Application No. PCT/EP2019/052704, filed Feb. 5, 2019, claiming priority to provisional Application No. 62/627,103 filed Feb. 6, 2018 and provisional Application No. 62/729,333, filed Sep. 10, 2018, which are incorporated herein by reference in their entireties. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 16, 2023, is named P34648-US-3_Corrected_SeqListing.xml and is 37,522 bytes in size. The current invention relates to the use of antibodies which bind to VEGF and ANG2 for the treatment of ophthalmologic diseases. BACKGROUND OF THE INVENTION Angiogenesis is implicated in the pathogenesis of a variety of disorders which include solid tumors, intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis (Folkman, J., et al., J. Biol. Chem. 267 (1992) 10931-10934; Klagsbrun, M., et al., Annu. Rev. Physiol. 53 (1991) 217-239; and Gamer, A., Vascular diseases, in: Pathobiology of ocular disease, A dynamic approach, Garner, A., and Klintworth, G. K. (eds.), 2nd edition, Marcel Dekker, New York (1994), pp. 1625-1710). Ranibizumab (trade name Lucentis®) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin®). However, it has been affinity matured to provide stronger binding to VEGF-A (WO 98/45331). It is known that systemic blockade of VEGF-A is associated with an increased risk of certain adverse events, therefore ranibizumab is missing an Fc part in order to reduce systemic exposure and the risk of systemic toxicities. It is an anti-angiogenic agent that has been approved to treat the “wet” type of age-related macular degeneration (neovascular AMD), a common form of age-related vision loss. Corneal angiogenesis assays have shown that both ANG-1 and ANG-2 had similar effects, acting synergistically with VEGF to promote growth of new blood vessels. Asahara, T., et al., Circ. Res. 83 (1998) 233-40. The possibility that there was a dose-dependent endothelial response was raised by the observation that in vitro at high concentration, ANG-2 can also be pro-angiogenic (Kim, I., et al., Oncogene 19 (2000) 4549-52). At high concentration, ANG-2 acts as an apoptosis survival factor for endothelial cells during serum deprivation apoptosis through activation of Tie2 via PI-3 Kinase and Akt pathway (Kim, I., et al., Oncogene 19 (2000) 4549-52). Ocular vascular diseases such as “wet” age related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR), are due to abnormal choroidal or retinal neovascularization respectively. Bleeding and leakage from these vessels can cause retinal dysfunction and loss of vision Other retinal vascular disease, such as diabetic macular edema (DME) and macular edema secondary to retinal vein occlusion (RVO) are due to abnormal retinal leakage leading to retinal swelling and impairing visual function. These conditions are leading causes of visual loss in industrialized nations. Since the retina consists of well-defined layers of neuronal, glial, and vascular elements, relatively small disturbances such as those seen in vascular proliferation or edema can lead to significant loss of visual function. Inherited retinal degenerations, such as Retinitis Pigmentosa (RP), are also associated with vascular abnormalities, such as arteriolar narrowing and vascular atrophy. They affect as many as 1 in 3500 individuals and are characterized by progressive night blindness, visual field loss, optic nerve atrophy, arteriolar attenuation, and central loss of vision often progressing to complete blindness. Ischemic retinopathies are characterized by loss or dysfunction of the retinal vasculature which results in a reduction of blood flow and hypoxia. The retina responds to hypoxia by generating signals to grow new blood vessels, but these new vessels are usually fragile and disorganized. It is the growth of these abnormal new vessels that creates most of the threat to vision since they can leak, hemorrhage or lead to scarring that may end in retinal detachment. Current treatments for ischemic retinopathies seek to halt the growth of the pathological vessels but do not address the underlying ischemia that drives their growth. Furthermore, standard treatment for diabetic retinopathy, an ischemic retinopathy that affects millions, involves destruction of a portion of the retina with a laser in an attempt destroy ischemic tissue in order to stop new vessel growth and preserve central vision. Strategies have been employed to block the function of vascular endothelial growth factor (VEGF), a major promoter of abnormal vessel growth and leak