Author

share

This article as been read 149 times
Share this content

Points de Vue, International Review of Ophthalmic Optics, N68, Spring, 2013

Future treatments of exudative AMD

Date of publication :
05/2013

Content

SUMMARY

Previous treatments of exudative AMD were physical or mechanical. Presently, treatment concepts are based on the biological processes of new vessel formation believed to be relevant to exudative AMD pathogenesis. Current pharmacotherapeutic agents target fluid leakage in order either to reduce its accumulation within the retina or to decrease its release. The available agents block the hyperpermeability by preventing the action of VEGF, i.e. the binding to the circulating growth factor or to the endothelial cell surface receptors. The approved drugs are estimated to improve vision in about 1/3 of the treated eyes. However, one out of six exudative cases still progress to legal blindness.

ANTI VGEF TARGETING

Antibodies 

The three anti-VEGF compounds in use (Sodium Pegaptanib-Pfizer; Bevacizumab-Genentech/Roche; Ranibizumab-Genentech/Novartis) have demonstrated their efficacy. Their different physical and biochemical properties are in part responsible for their pharmacodynamic turnover. They all bind to all VEGF isoforms and one specifically to isoform 165.

ESBA (Alcon) is a very small molecule as it is a single chain monoclonal antibody. It binds to Placenta Growth Factor (PlGF) in addition to all VEGF isoforms. The phase IIa trial is ongoing.

AGN 153998 (Allergan) is synthesized with DARP in technology. This novel class of protein combines the properties of antibodies with the characteristics of small molecules. The protein has completed two separated studies applied as eye-drops and a phase IIa trial is ongoing in exudative AMD.

Extracellular

VEGF receptors A fully human fusion protein containing key domains of extra cellular VEGF receptor R1 and R2 have been synthetized. It binds to all relevant subtypes of VEGF-A with very high potency (IC50 of < 10 pM) and with a very long half-life in the eye (> 6 days). VEGF trap (Aflibercept, EYLA, Regeneron/Bayer) contains all human amino acid sequences, and also binds PlGF receptors tightly. VEGF trap has been specially formulated for intravitreal injection and penetrates into all layers of the retina (MW 110,000). This drug has been recently approved in the US after completion of two phase III trials. KH902 (Chengdu Kanghong), also a fusion protein, is presently recruiting in phase III trials in 10 Chinese clinical centres.

Intra cellular VEGF receptors

The intra cellular inhibitors target the downstream signaling cascade of growth factors. PKC inhibitors prevent the phosphorylation of the intracellular portion of the receptor after penetrating necessarily into the cell which might explain their current limited efficacy. Pazopanib (Glaxo Smith Kline) blocks completely the progression of experimental CNV.

Pazopanib has been administered orally in cancerology, by the conjunctival, scleral or topical route in ophthalmology. In the phase IIa study terminated in August 2012, eye drops were administered 3 times a day for subfoveal minimally classic or sub epithelial CNV with a visual acuity of more than 23 letters and a Central Macular Thickness(CMT) of more than 300µm. A phase II trial is ongoing with a possibility of rescue treatment with ranibizumab.

Vatalanib (Novartis) was orally administrated in a phase II trial terminated in 2008.

TG100801 (TargeGen) has been shown to reduce the amount of fluid in the retina following 30 days of eye drops in experimentation. The phase II trial in exudative AMD was terminated in 2010 .

AL-39324 (Alcon) completed a phase II trial with intravitreal administration in 2011(results not available). AG-013958 (Pfizer) study was terminated in 2011 due to the lack of efficacy in phase I/II studies.

SiRNA (Bevasiranib- ACU 301-Opko Health) is a small Interfering Ribonucleic Acid (RNA) designed to silence VEGF-A mRNA. The intravitreal administration in a phase II study did not show a robust effect possibly because the RNA acts on the synthesis of VEGF but does not neutralize the cellular and the already circulating growth factor. The phase III study (CARBON) in exudative AMD was thus withdrawn. However, this pathway may be used again.

rAAV-sFLT-1 or adeno-associated virus (AAV)-mediated expression of a soluble form of the Flt-1 VEGF receptor, showed the regression of experimentally induced new vessels in 85% and prevention of their development in all treated eyes. These results lead to a phase I/II trial (AVALANCHE) for AMD choroidal neovascularisation. The duration of effect is thought to be long-term (years) following a single administration. .

EXTRA CELLULAR MATRIX CONTROL

Anti integrins

Integrins are receptors that mediate the attachment between a cell and the surrounding tissues (or another cell or the extra cellular matrix). The molecules of integrin are made of 2 sub units embedded in the cell membrane. The receptors α5β3 and α5β1 of the endothelial cells are implicated by interacting with fibronectin in the anchorage and migration of these cells. A cascade of subsequent intra cellular signaling results in a cell proliferation through a pathway independent of VEGF. 
Targeting integrin α5β1 effectively inhibits endothelial cell proliferation in culture. Integrin α5β1 and αvβ3 are expressed in ocular neovascularization.


Fig. 1

Volociximab (Ophthotech) is a chimerical monoclonal antibody specifically blocking the binding of fibronectin to the α5β1 integrin. Three volociximab injections at 3 concentrations together with ranibizumab resulted at 8 weeks in a VA improvement of +9,5 letters in 37 naive AMD patients.

ALG-1001 (Allegro) is a synthetic oligopeptide that mediates α5β1, αvβ3, and αvβ5 integrins. Its efficacy lasted for 90 days following one intravitreal injection in diabetic macula oedema. A phase IIa study is currently in progress on 30 patients with subfoveal CNV.

MEC modulators 

Combretastatin A4 (OxiGen, Johns Hopkins) is a prodrug (CA4P) derived from the root bark of the Combretum caffrum tree, commonly known as South African Bush Willow. It inhibits the polymerization of tubulin, thus preventing the production of microtubules that are essential to cytoskeleton formation, cell shape, cell movement, and cellular division. The endothelial cells rapidly balloon, stopping blood flow through the capillaries, causing cell necrosis. The phase II completed in 2012 used intravenous administration.

iSONEP (Sonepcizumab/Lpath Inc./Pfizer) is a humanized monoclonal antibody against bioactive lipid S1P that could contribute to vascular remodelling associated with exudative AMD. S1P has a pronounced non-VEGF-dependent angiogenic effect. In addition, S1P stimulates migration, proliferation and survival of fibroblasts, endothelial cells, pericytes and inflammatory cells. iSONEP lowers selectively the effective concentration of S1P in the extracellular fluid. In the ongoing phase II, iSONEP is administered intravitreally.

Studies with Mecalamine (ATG003, CoMentis), an antagonist of nicotinic acetylcholine receptors, and Squalamine (Genaera Corp), a powerful antiangiogenic compound derived from shark livers, were terminated for various reasons.

ANTI ANGIOGENIC COMPOUNDS 

Anti PDGF

Platelet-Derived Growth Factor (PDGF) acts as a mitogen for vascular pericytes and other cells (smooth muscle cells, fibroblasts, and mesenchymal cells). In normal conditions, pericytes transmit survival signals to the endothelial cells. During experimental new vessel growth, an increased expression of PDGF occurs in the endothelial cells that leads to an induction of recruitment and maturation of the pericytes. Thus, blocking PDGF appears to result in loss of pericytes and possible reduction of maturation of new vessels. There is evidence that, in newly formed vessels, there is a period during which endothelial cells are dependent on VEGF and are responsive to the withdrawal of PDGF. Blockade of both factors is more effective at suppressing neovascularization than blockade of each factor alone. 
E10030 (Ophthotech) an anti-PDGF pegylated aptamer showed in preclinical models a neovascular regression when administered intravitreally in combination with ranibizumab. In a phase II study of 449 patients treated every four weeks for 24 weeks, the combined regimen achieved a better visual result than ranibizumab alone (10.6 letters vision gain compared to 6.5 letters). A phase III trial is planned.

PEDF

PEDF or –Pigment Epithelium Derived growth Factor is one of the most potent angiogenic inhibitors in both the retina and vitreous, counterbalancing the pro-angiogenic factor VEGF and displays antivascular permeability, anti-inflammatory, antifibrotic activities.

AdGVPEDF (GenVec) using a modified adenoviral vector as delivery system, allows expression of large amount of PEDF in the target tissue, A clinical study suggested the possibility that antiangiogenic activity may last for several months (up to 6 months) after a single intravitreous injection as half of the treated lesions did not change in size from baseline. Adenoviral vector-mediated ocular gene transfer showed to be a viable approach..

INFLAMMATION

Background for the implication of inflammation

Aberrant activation of the complement system is implicated in neovascular and atrophic AMD. Human pathologic studies of AMD eyes demonstrated the presence of inflammatory cells in the RPE-Bruch’s membrane-choriocapillaris. Drusen contain many bioactive components of the complement cascade as C3 (C3a) and C5 (C5a) that induce VEGF expression in RPE. The presence of pro-inflammatory molecules in drusen creates a stimulus for chronic inflammation in the RPE-Bruch’s membrane-choriocapillaris complex that may result in some features of late AMD.

Plasma levels of systemic biomarkers are elevated in AMD patients. The complement activation products (C3d, Ba, C3a, C5a, SC5b-9) have been shown to be elevated in AMD patients vs. controls, particularly the markers of chronic complement activation. The levels are correlated with CFH genotype.

Anti inflammatory drugs 

Steroids add to their anti-inflammatory property a potent anti angiogenic effect and antifibrotic effect. They may thus be of interest in adjunct rather than alone.

Dexamethasone has been inserted in an implant and injected intravitreally after a ranibizumab loading dose. The phase II trial showed a decrease in the need for anti VEGF injections.

Fluocinolone implants are unavailable at this stage in the European market.

Inhibition of C5 

These compounds block the terminal complement activity, but the proximal complement functions remains intact

Eculizumab (Soliris,Alexion Pharmaceuticals) is a monoclonal antibody preventing the cleavage of C5 and subsequently the formation of the cytolytic membrane attack complex (MAC). A phase 2 study is in progress with intravenous administration for GA and high-risk drusen.

ARC-1905 (Ophthotech) is an aptamer administered intravitreally. A phase I/II study is in progress for exudative AMD (with ranibizumab) and for dry AMD (drusen/GA).

Inhibition of C3 

Inhibition of C3 effectively shuts down all downstream complement activation such as local inflammation, tissue damage and upregulation of angiogenic factors (i.e VEGF).

POT-4/AL-78898A (Potentia/Alcon) a synthetic peptide of 13aa blocks the proteolysis by the C3 convertase. The product is “gel-like” when injected into the vitreous. The effect is long-lasting (3 to 6 months). A phase II trial for exudative AMD and GA has included 27 patients, with a 52 week follow-up. No toxicity was observed in the dose escalation study until 450µg.

Others compounds are in preclinical evaluation. Anti -C5 JPE1375 (Jerini Ophtalmics) and Neutrazimab (G2 Therapies) C5a receptor antagonist, LFG316 (Novartis) anti-C5 agent. Anti-C3: C3bBb degradation: sCR1, anti-properdin antibody and TT30 (Alexion) recombinant fusion protein against C3 convertase, Anti-factor B antibody: TA106 (Taligen) Anti factor H analogues: TT30 and Ophterion. Anti factor D: BCX1470 (Alcon). FCFD4514S (Genentech/Roche).

CONCLUSION

The multiplicity of emerging therapies evidence the complexity of the pathophysiology of exudative Age related Macular Degeneration. Exploration of new agents with different mechanisms of action may be considered for each step of angiogenesis, for each metabolic pathway, and for each cellular dysfunction. Treatments might act on either pathway that lead either to the ingrowth of choroidal new vessels (CNV), or from initial to active CNV or those that induce CNV maturation (from active to involution CNV). Exclusive inhibition of one mechanism may not address the complex processes and multiple steps that ultimately lead to visual loss. Different drugs may be required addressing multiple targets or acting in synergy. A personalized treatment for each patient would finally result based on a number of possible criteria i.e. clinical features, environmental risk factors, genetic background, etc. However, these approaches will not cure AMD. The only desired and efficient treatment will be prevention that will only be possible when the pathophysiology of the disease has been elucidated.


Fig. 2


Fig. 3: B-M Potentia study eye--Previously treated with Macugen X3, Avastin X5, Lucentis X4--Last injection 18 months prior to enrollment—Follow up after 1 injection of 1050 µg POT


Fig. 4: Effect of the different compounds on experimentally laser-induced CNV

References

 

References

Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29:95-112 Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J, DiBartolomeo R, Wei LL. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase 1 clinical trial. Hum Gene Ther. 2006;17:167-76 Doukas J, Mahesh S, Umeda N, Kachi S, Akiyama H, Yokoi K, Cao J, Chen Z, Dellamary L, Tam B, Racanelli-Layton A, Hood J, Martin M, Noronha G, Soll R, Campochiaro PA. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008 ;216:29-37 Gehrs KM, Jackson JR, Brown EN, Allikmets R, Hageman GS. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010;128:349-58. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705-32. .Imai D, Yoneya S, Gehlbach PL, Wei LL, Mori K. Intraocular gene transfer of pigment epithelium-derived factor rescues photoreceptors from light-induced cell death. J Cell Physiol. 2005; 202:570-8 JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552-77. Lai CM, Estcourt MJ, Wikstrom M, Himbeck RP, Barnett NL, Brankov M, Tee LB, Dunlop SA, Degli-Esposti MA, Rakoczy EP. rAAV.sFlt-1 gene therapy achieves lasting reversal of retinal neovascularization in the absence of a strong immune response to the viral vector. Invest Ophthalmol Vis Sci 2009; 50: 4279-87 Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2002 ;43:2428-34. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835–46. Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103:2328-33. Park K, Jin J, Hu Y, Zhou K, Ma JX. Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization. Am J Pathol. 2011;178:688-98. Patel M, Chan CC. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008 ;30:97-110 Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci 2009;50:5818-27. Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. Systemic complement activation in age-related macular degeneration. PLoS One. 2008 Jul 2;3:e2593 Shen JK, Dong A, Hackett SF, Bell WR, Green WR, Campochiaro PA. Oxidative damage in age-related macular degeneration. Histol Histopathol 2007;22:1301-8. Skeie JM, Fingert JH, Russell SR, Stone EM, Mullins RF. Complement component C5a activates ICAM-1 expression on human choroidal endothelial cells. Invest Ophthalmol Vis Sci. 2010;51:5336-42. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT; Genetic Factors in AMD Study Group.Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-61. Zahn G, Vossmeyer D, Stragies R, Wills M, Wong CG, Löffler KU, Adamis AP, Knolle J. Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch Ophthalmol. 2009 ;127:1329-35 Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614. Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem 2009;284:9529-39.

Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29:95-112

Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J, DiBartolomeo R, Wei LL. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase 1 clinical trial. Hum Gene Ther. 2006;17:167-76

Doukas J, Mahesh S, Umeda N, Kachi S, Akiyama H, Yokoi K, Cao J, Chen Z, Dellamary L, Tam B, Racanelli-Layton A, Hood J, Martin M, Noronha G, Soll R, Campochiaro PA. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008 ;216:29-37

Gehrs KM, Jackson JR, Brown EN, Allikmets R, Hageman GS. Complement, age-related macular degeneration and a vision of the future. 
Arch Ophthalmol. 2010;128:349-58.

Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. 
Prog Retin Eye Res. 2001;20:705-32.

.Imai D, Yoneya S, Gehlbach PL, Wei LL, Mori K. Intraocular gene transfer of pigment epithelium-derived factor rescues photoreceptors from light-induced cell death.  J Cell Physiol. 2005; 202:570-8

JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552-77.

Lai CM, Estcourt MJ, Wikstrom M, Himbeck RP, Barnett NL, Brankov M, Tee LB, Dunlop SA, Degli-Esposti MA, Rakoczy EP. 
rAAV.sFlt-1 gene therapy achieves lasting reversal of retinal neovascularization in the absence of a strong immune response to the viral vector. Invest Ophthalmol Vis Sci 2009; 50: 4279-87

Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2002 ;43:2428-34.

Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835–46.

Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103:2328-33.

Park K, Jin J, Hu Y, Zhou K, Ma JX. Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization. Am J Pathol. 2011;178:688-98.

Patel M, Chan CC. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008 ;30:97-110

Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci 2009;50:5818-27.

Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. Systemic complement activation in age-related macular degeneration. PLoS One. 2008 Jul 2;3:e2593

Shen JK, Dong A, Hackett SF, Bell WR, Green WR, Campochiaro PA. Oxidative damage in age-related macular degeneration. Histol Histopathol 2007;22:1301-8.

Skeie JM, Fingert JH, Russell SR, Stone EM, Mullins RF. Complement component C5a activates ICAM-1 expression on human choroidal endothelial cells. Invest Ophthalmol Vis Sci. 2010;51:5336-42.

Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT; Genetic Factors in AMD Study Group.Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-61.

Zahn G, Vossmeyer D, Stragies R, Wills M, Wong CG, Löffler KU, Adamis AP, Knolle J. Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch Ophthalmol. 2009 ;127:1329-35

Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614.

Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem 2009;284:9529-39.

Keywords
Author

share

This article as been read 149 times
Share this content

Points de Vue, International Review of Ophthalmic Optics, N68, Spring, 2013

Continue reading