WO2019040397A1 - Procédé de traitement ou de prévention de la dégénérescence maculaire liée à l'âge néovasculaire - Google Patents

Procédé de traitement ou de prévention de la dégénérescence maculaire liée à l'âge néovasculaire Download PDF

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WO2019040397A1
WO2019040397A1 PCT/US2018/047169 US2018047169W WO2019040397A1 WO 2019040397 A1 WO2019040397 A1 WO 2019040397A1 US 2018047169 W US2018047169 W US 2018047169W WO 2019040397 A1 WO2019040397 A1 WO 2019040397A1
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administration
agent
vegf antagonist
administered
vegf
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Kourous REZAEI
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Ophthotech Corporation
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    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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Definitions

  • This invention relates to methods and compositions useful for the treatment or prevention of an ophthalmological disease or disorder, namely neovascular age-related macular degeneration, comprising administration of an effective amount of an anti-C5 agent in combination with a VEGF antagonist.
  • Age-related macular degeneration is a disease
  • Age-related macular degeneration is classified into one of two general subgroups: the non-neovascular (non-exudative or dry) form of the disease and the neovascular (exudative or wet) form of the disease (NVAMD).
  • NVAMD neovascular (exudative or wet) form of the disease
  • NVAMD although less prevalent, commonly causes sudden, often substantial, loss of central vision and is responsible for most cases of severe loss of visual acuity in this disease (Vingerling, 1995).
  • This type of AMD results when abnormal blood vessels (neovascularization) proliferate under and/or within the retina. These blood vessels leak blood and fluid into and under the retina, which results in rapid vision loss.
  • the end stage of the disease features scarring with irreversible destruction of the central retina.
  • VEGF Vascular Endothelial Growth Factor
  • VEGF is an endothelial cell survival factor and a mitogen. Endothelial cells are a key component of neovascular tissue. All approved anti-VEGF agents for NVAMD are administered by the intravitreal route of administration. These include Lucentis ® (ranibizumab) and Eylea ® (aflibercept) (Brown et al., 2006; Heier et al, 2012; osenfeld et al, 2006).
  • Avastin ® (bevacizumab) is currently used to treat -50% of the eyes with NVAMD in the United States.
  • Avastin ® (bevacizumab)
  • Avastin ® , Lucentis ® , and Eylea ® on average, all improve the visual outcome in eyes with NVAMD.
  • the primary functional impact of these anti- VEGF agents is to decrease intraretinal and subretinal fluid associated with abnormal blood vessels.
  • maximal therapy with intravitreal monotherapy anti-VEGF agents the majority of patients do not achieve significant visual gain (> 15 letters of vision), and approximately 20% to 30% lose additional vision from baseline.
  • the complement pathway is part of the innate immune system and is a complex system of serum proteins that interact in a cascade. This
  • complement cascade is activated via the classical (antibody-dependent), the alternative (antibody-independent) and the lectin pathways. Activation of the complement cascade has been implicated in drusen formation (Klein, 2004, Bora, 2005). Additionally, complement components may induce up-regulation of VEGF, a well-known mediator of choroidal neovascularization (CNV) (Nozaki et al., 2006). Preclinical laser-induced CNV models have also implicated complement activation.
  • CNV choroidal neovascularization
  • the choroid may serve as a nidus for the deposition of membrane attack complex (MAC) when compared to other tissues in the body (Chirco et al., 2015).
  • MAC accumulation leads to mitochondrial damage and cellular dysfunction in RPE cells (Georgiannakis et al. 2015).
  • MAC membrane attack complex
  • MAC is also responsible for causing pores in the affected cells that eventually leads to cell death.
  • Avastin ® , Lucentis ® , and Eylea ® on average, all improve the visual outcomes in eyes with NVAMD. Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, a majority of patients do not achieve
  • ARC 1905 (avacincaptad pegol sodium), a PEGylated RNA aptamer, is a potent and specific inhibitor of complement activation. It inhibits C5, a central component of the complement cascade, which plays multiple roles in innate immunity and inflammatory diseases. Inhibition of this key step in the complement cascade at the level of C5 prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced their generation.
  • the C5a fragment is an important inflammatory activator inducing vascular permeability, recruitment and activation of phagocytes.
  • C5b is involved in the formation of MAC: C5b-9, which initiates cell lysis. By inhibiting these C5-mediated inflammatory and MAC activities, therapeutic benefit may be achieved in NVAMD.
  • VA assessments were primarily safety assessments to detect any decrease in vision associated with the intravitreal injections. There were no safety issues identified through measurement of VA. Assessment of VA was focused on the treatment-naive (TN) patient subgroup of 43 patients who had received 6 injections at doses of 0.3 mg, 1 mg or 2 mg. There was a trend towards a mean increase in VA (number of ETDRS letters) from Baseline at all time points for patients in the 0.3, 1 and 2 mg dose groups in the TN subgroup who received 6 injections. At Week 24, there was an improvement in mean VA from Baseline of 13.6 ETDRS letters for the 0.3 mg dose group, 11.7 ETDRS letters for the 1 mg dose group and 15.3 ETDRS letters for the 2 mg dose group.
  • ARC 1905 intravitreal injection in combination with VEGF therapy in subjects with idiopathic polypoidal choroidal vasculopathy (IPCV).
  • Subjects included in the study were treatment experienced (prior treatment with anti-VEGF monotherapy of > 8 injections in the previous 12 months) of either gender aged 50 years or above with diagnosis of IPCV.
  • Subjects received 3 monthly intravitreal injections of ARC1905 (1 mg/eye) in combination with intravitreal injection of anti-VEGF agent (Avastin ® 1.25 mg/eye or Lucentis ® 0.5 mg/eye or Eylea ® 2 mg/eye).
  • the present invention relates to methods and compositions useful for the treatment or prevention of an ophthalmological disease or disorder, particularly NVAMD.
  • the present invention provides methods for treating or preventing NVAMD, comprising administering to a subject in need thereof: (a) ARC1905 and (b) a VEGF antagonist, wherein ARC1905 and the VEGF antagonist are administered in an amount that is effective for treating or preventing NVAMD.
  • the present invention provides new and improved methods and compositions for treating and preventing NVAMD, including, e.g., combination therapies, and treatment and dosing regimens.
  • the invention provides coformulations that comprise an anti-C5 agent and a VEGF antagonist.
  • the coformulations are pharmaceutically acceptable compositions comprising an effective amount of an anti-C5 agent and VEGF antagonist, and a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides new and improved methods and compositions for treating and preventing NVAMD, including new dosing regimens.
  • ARC 1905 or another pharmaceutically acceptable salt thereof is administered in combination with a VEGF antagonist.
  • ARC 1905 or another pharmaceutically acceptable salt thereof is administered in combination with ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, tivozanib, abicipar pegol or ESBA1008.
  • the invention provides treatment regimens, including treatment and dosing regimens, related to the coadministration of ARC 1905 (or another pharmaceutically acceptable salt thereof) and a VEGF antagonist.
  • VEGF refers to a vascular endothelial growth factor that induces angiogenesis or an angiogenic process.
  • VEGF includes the various subtypes of VEGF (also known as vascular permeability factor (VPF) and VEGF-A) that arise by, e.g., alternative splicing of the VEGF-A/VPF gene including VEGF 121, VEGF 165 and VEGF 189.
  • VPF vascular permeability factor
  • VEGF-A vascular permeability factor
  • VEGF includes VEGF-related angiogenic factors such as PIGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, which act through a cognate VEFG receptor (i.e., VEGFR) to induce angiogenesis or an angiogenic process.
  • VEGF includes any member of the class of growth factors that binds to a VEGF receptor such as VEGF -1 (Flt-1), VEGFR-2 (KDR/Flk-1), or VEGFR-3 (FLT-4).
  • VEGF can be used to refer to a "VEGF” polypeptide or a "VEGF” encoding gene or nucleic acid.
  • the term "effective amount,” when used in connection with an ophthalmological disease of NVAMD, refers to an amount of the compositions of the invention comprising ARC 1905 or another pharmaceutically acceptable salt thereof and a VEGF antagonist or a pharmaceutically acceptable salt thereof that is useful to treat or prevent NVAMD.
  • the "effective amount” can vary depending upon the mode of administration, specific locus of the
  • ophthalmological disease the age, body weight, and general health of the mammal.
  • an anti-C5 agent and the VEGF antagonist are administered within 24 hours of each other. In some embodiments, an anti- C5 agent and the VEGF antagonist are administered on the same day. In some embodiments, an anti-C5 agent and the VEGF antagonist are administered concurrently or sequentially. In some embodiments, an anti-C5 agent is administered within about 1 min, about 2 min, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours or about 48 hours of administration of the VEGF antagonist. In some embodiments, the VEGF antagonist is
  • the anti-C5 agent is administered prior to administration of the VEGF antagonist.
  • an anti-C5 agent is administered at least about 1 min, about 2 min, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours or about 48 hours before or after administration of the VEGF antagonist.
  • an anti-C5 agent and a VEGF antagonist are present in the same pharmaceutical composition and administered as a co-formulation.
  • a method for treating or preventing NVAMD comprising administering to a subject in need thereof (a) a
  • an anti-C5 agent wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5 complement and has the sequence of SEQ ID NO: 1 or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing NVAMD, and wherein the administration comprises administering the VEGF antagonist followed by administration of about 4.0 mg of said anti-C5 agent approximately 48 hours after administration of the VEGF antagonist.
  • a method for treating or preventing NVAMD comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5
  • a VEGF antagonist a pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing NVAMD, and wherein the administration comprises:
  • a first administration period which occurs once every month, ⁇ about seven days, wherein throughout said first administration period a first dose of the anti-C5 agent is administered on the same day following
  • administration of the VEGF antagonist and a second dose of the anti-C5 agent is administered about 14 days after administration of the VEGF antagonist;
  • a second administration period commencing after the first administration period and which occurs once every month, ⁇ about seven days, wherein a single dose of the anti-C5 agent is administered on the same day following administration of the VEGF antagonist.
  • a method for treating or preventing NVAMD comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5
  • a VEGF antagonist a pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing NVAMD, and wherein the administration comprises:
  • a first administration period which occurs once every month, ⁇ about seven days, wherein throughout said first administration period a first dose of the anti-C5 agent is administered on the same day following
  • administration of the VEGF antagonist and a second dose of the anti-C5 agent is administered about 14 days after administration of the VEGF antagonist;
  • a second administration period commencing after the first administration period and which occurs once every month, ⁇ about seven days, wherein the anti-C5 agent is administered as a monotherapy and is followed about 48 hours later by administration of a combination of the VEGF antagonist followed by administration of the anti-C5 agent on the same day.
  • the first administration period is at least about 3 months.
  • the VEGF antagonist is the antibody
  • ranibizumab or a pharmaceutically acceptable salt thereof (see US Patent No. 7,060,269 ( Figure 1) for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety).
  • Ranibizumab is commercially available under the trademark Lucentis®.
  • the VEGF antagonist is the antibody bevacizumab or a pharmaceutically acceptable salt thereof (see US Patent No. 6,054,29 for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety).
  • Bevacizumab is commercially available under the trademark Avastin®.
  • the VEGF antagonist is aflibercept or a pharmaceutically acceptable salt thereof (Do et al. (2009) Br J Ophthalmol. 93: 144-9, which is hereby incorporated by reference in its entirety).
  • Aflibercept is commercially available under the trademark Eylea®.
  • the VEGF antagonist is tivozanib or a pharmaceutically acceptable salt thereof (US Patent No. 6,821,987, which is hereby incorporated by reference in its entirety).
  • the VEGF antagonist is pegaptanib or a pharmaceutically acceptable salt thereof (US Patent No. 6,051,698 ( Figure 1), which is hereby incorporated by reference in its entirety).
  • a composition comprising pegaptanib is commercially available under the trademark
  • the VEGF antagonist is sorafenib or a pharmaceutically acceptable salt thereof (Kernt et al. (2008) Acta Ophthalmol. 86:456-8, which is hereby incorporated by reference in its entirety).
  • composition comprising sorafenib is commercially available under the trademark Nexavar®.
  • the anti-C5 agent is ARC 1905.
  • ARC 1905 is a PEGylated RNA aptamer consisting of a 13 kDa modified RNA aptamer that is conjugated at the 5' terminus to a -43 kDa branched polyethylene glycol (PEG) moiety.
  • PEG polyethylene glycol
  • the aptamer portion of ARC1905 is 39 nucleotides in length and modified with a primary amine at the 5' terminus to provide a reactive site for subsequent site specific conjugation ("PEGylation").
  • composition consists of 2' hydroxyl purines and modified 2' fluoro pyrimi dines and 2' methoxy purines.
  • the modified nucleotides minimize endonuclease digestion and contribute to activity.
  • the 3 ' terminus is capped with an
  • ARC1905 has the structure set forth below:
  • each 20 kDa mPEG of the above structure has a molecular weight of about 20 kDa.
  • ARC 1905 drug product is formulated at a concentration of 20 mg/mL (oligonucleotide mass) in phosphate buffered saline at pH 6.8-7.8 as a sterile aqueous solution. Sodium hydroxide or hydrochloric acid may be added for pH adjustment.
  • ARC 1905 drug product is presented in a USP Type I high recovery glass vial that contains a 0.5 mL v-shaped well sealed with fluorotec coated, halobutyl rubber stoppers and aluminum crimp seals. The product is supplied in single use vials and is preservative-free and intended for intravitreal injection only. The product should not be used if cloudy or if particles are present. Injection volume for each administration of ARC1905 is 0.1 mL (100 ⁇ .) providing a 2 mg/eye dose.
  • the anti-C5 agent is Soliris® (ecluzimab, US Patent No. 6,355,245 which is hereby incorporated by reference in its entirety) or LFG-316 (Novartis; US Patent Application No. 2010/0034809 which is hereby incorporated by reference in its entirety), or A217 (Quidel Corp., San Diego, CA).
  • ARC 1905 is administered to treatment-naive patients (patients having any prior treatment for AMD or any intravitreal treatment for any indication in the study eye prior to baseline visit, except oral supplements of vitamins and minerals, are excluded) with active subfoveal NVAMD (as documented by fluorescein angiography) in combination with Lucentis
  • ARC 1905 is formulated as
  • Lucentis ® is a recombinant humanized IgGl kappa isotype monoclonal antibody fragment designed for intraocular use. Lucentis ® has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.
  • ARC1905 and Lucentis ® are injected without dilution.
  • ARC1905 is supplied in a single-use glass vial as noted above.
  • Lucentis ® injection is a preservative-free colorless to pale yellow sterile solution, presented in a single-use glass vial or as a pre-filled syringe designed to deliver 0.05 mL of 10 mg/mL ranibizumab injection aqueous solution with 10 mM histidine HC1, 10% a, a-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
  • a vial is used, aseptic technique, all (0.2 mL) of the Lucentis ® injection vial contents are withdrawn through a 5-micron 19- gauge filter needle attached to a 1-cc tuberculin syringe.
  • the filter needle should be discarded after withdrawal of the vial contents and should not be used for intravitreal injection. Where a vial is used the filter needle should be replaced with a sterile 30-gauge ⁇ 1/2-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.
  • Intravitreal injections are administered according to the following regimens:
  • ARC1905 and Lucentis are administered monthly for a total of 6 times, in the following sequence, 2 days apart:
  • ARC 1905 and Lucentis are administered monthly for a total of 6 times, in the following sequence:
  • ARC 1905 and Lucentis are administered monthly for a total of 3 times, in the following sequence, 14 days apart:
  • Maintenance Phase ARC1905 and Lucentis are administered monthly for a total of 3 times (Month 3 - Month 5), in the following sequence:
  • Maintenance Phase ARC1905 and Lucentis are administered monthly for a total of 3 times (Month 3 - Month 5), in the following sequence, 2 days apart:

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Abstract

La présente invention concerne un procédé de traitement ou de prévention de la dégénérescence maculaire liée à l'âge néovasculaire, comprenant des injections intravitréennes d'un agent anti-C5 et d'un antagoniste de VEGF.
PCT/US2018/047169 2017-08-21 2018-08-21 Procédé de traitement ou de prévention de la dégénérescence maculaire liée à l'âge néovasculaire WO2019040397A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021091718A1 (fr) * 2019-10-27 2021-05-14 Iveric Bio, Inc. Agent anti-c5 pour le traitement de la dégénérescence maculaire liée à l'âge (dmla) sèche ou d'une atrophie géographique secondaire à la dmla sèche
US11066465B2 (en) 2015-12-30 2021-07-20 Kodiak Sciences Inc. Antibodies and conjugates thereof
US11155610B2 (en) 2014-06-28 2021-10-26 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
WO2024006902A3 (fr) * 2022-06-30 2024-02-01 Iveric Bio, Inc. Composites d'hydrogel de silice à libération prolongée pour le traitement de troubles ophtalmologiques et leurs méthodes d'utilisation
US11912784B2 (en) 2019-10-10 2024-02-27 Kodiak Sciences Inc. Methods of treating an eye disorder
US12016875B2 (en) 2013-07-12 2024-06-25 Iveric Bio, Inc. Methods for treating or preventing ophthalmological conditions

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WO2007103549A2 (fr) * 2006-03-08 2007-09-13 Archemix Corp. Aptamères de liaison du complément et agents anti-c5 utiles dans le traitement de troubles oculaires
WO2016025313A1 (fr) * 2014-08-11 2016-02-18 Samir Patel Méthodes de traitement ou de prévention d'affections ophtalmologiques
US20160296550A1 (en) * 2013-07-12 2016-10-13 Ophthotech Corporation Methods for Treating or Preventing Ophthalmological Conditions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007103549A2 (fr) * 2006-03-08 2007-09-13 Archemix Corp. Aptamères de liaison du complément et agents anti-c5 utiles dans le traitement de troubles oculaires
US20160296550A1 (en) * 2013-07-12 2016-10-13 Ophthotech Corporation Methods for Treating or Preventing Ophthalmological Conditions
WO2016025313A1 (fr) * 2014-08-11 2016-02-18 Samir Patel Méthodes de traitement ou de prévention d'affections ophtalmologiques

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12016875B2 (en) 2013-07-12 2024-06-25 Iveric Bio, Inc. Methods for treating or preventing ophthalmological conditions
US11155610B2 (en) 2014-06-28 2021-10-26 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
US11066465B2 (en) 2015-12-30 2021-07-20 Kodiak Sciences Inc. Antibodies and conjugates thereof
US11912784B2 (en) 2019-10-10 2024-02-27 Kodiak Sciences Inc. Methods of treating an eye disorder
WO2021091718A1 (fr) * 2019-10-27 2021-05-14 Iveric Bio, Inc. Agent anti-c5 pour le traitement de la dégénérescence maculaire liée à l'âge (dmla) sèche ou d'une atrophie géographique secondaire à la dmla sèche
EP4048288A4 (fr) * 2019-10-27 2023-11-29 IVERIC bio, Inc. Agent anti-c5 pour le traitement de la dégénérescence maculaire liée à l'âge (dmla) sèche ou d'une atrophie géographique secondaire à la dmla sèche
WO2024006902A3 (fr) * 2022-06-30 2024-02-01 Iveric Bio, Inc. Composites d'hydrogel de silice à libération prolongée pour le traitement de troubles ophtalmologiques et leurs méthodes d'utilisation

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