Age-related macular degeneration (AMD) and RANIBIZUMAB (Lucentis)

Transcription

1 Aggiornamento biotecnologico: MoAb anti VEGF Age-related macular degeneration (AMD) and RANIBIZUMAB (Lucentis) Giulia Germena

2 AMD DRY (non-neovascular) Atrophic cell death in the macula No leakage WET (neovascular) Abnormal neovascularization under the macula Leakage of blood or serum Althought neovascular AMD affects only ~10% of patients with AMD,it is responsible of ~ 80% of cases among patiens with severe vision loss. [4]

3 Overview Normal vision AMD vision Strong risk factor: Aging Smoking Family history of macular degeneration Macular Degeneration Gene (Complement Factor H) Other factor: Sunlight exposure Hypertension Hight fat intake

4 Why the vision loss? Neovascular AMD involves the growth of abnormal new blood vessels into the subretinal space and retinal pigment epithelium. These weak vessels leak blood or serum, causing damage to the macula, which is crucial for fine vision. Narayanan et al. Nature Reviews Drug Discovery 5, (October 2006) [4]

5 VEGF pathway and angiogenesis Adapted from BioCarta Pathway [10]

6 Treatment of macular degeneration sirna VEGF Gene therapy PEDF=anti-angiogenic aptamer sirna VEGFR-1 anti VEGF MoAb anti VEGF Inhibits integrin expression Inhibits angiogenesis downstream pathway [8]

7 Treatment of macular degeneration Laser: Thermal photocoagulation Photodynamic therapy (PDT): intravenously injection of verteporfin (Visudyne) and laser activation. Slows retinal damage NO stop of the vision loss NO restore of the vision Injected inside the the eye (intravitreous injection): Macugen (Pegaptanib) Treatment Lucentis (Ranibizumab) Treatment

8 Recommended dose: 0.3 mg for i.i. administered once every 6 weeks. Macugen (Pegaptanib) Treatment Macugen is a selective PEG-conjugated aptamer that blocks VEGF actions and prevents the growth of abnormal new vessels and prevents leakage of fluid and blood in the retina. Approved by the FDA in December [8]

9 Ranibizumab (Lucentis) Ranibizumab is a fragment of a recombinant monoclonal antibody that binds to and inhibits all the biologically active forms of the VEGF-A. Is produced in E.coli and is designed for intraocular use. Bevacizumab is produced in CHO and is designed for intravenous infusion. Both the antibody are derived from the same mouse monoclonal antibody. However, ranibizumab has been genetically engineered to increase its affinity for binding and inhibiting the growth factor. Steinbrook, R. (2006). "The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration." N Engl J Med 355(14): [1].

10 Trials for ranibizumab: The FDA approval of Lucentis (June 2006) is based on data from two large Phase III clinical trials (MARINA and ANCHOR). In these studies: Nearly all patients (approximately 95 percent) treated with Lucentis (0.5 mg) maintained (defined as the loss of less than 15 letters in visual acuity) and up to 40 percent improved (defined as the gain of 15 letters or more in visual acuity) vision at one year, as measured on the Early Treatment of Diabetic Retinopathy (ETDRS) eye chart. On average, patients treated with Lucentis in the MARINA [2] study experienced an improvement from baseline of 6.6 letters at two years compared to a loss of 14.9 letters in the sham group. In the ANCHOR [7] study, patients treated with Lucentis, on average, experienced an 11.3 letter gain from baseline at one year compared to a loss of 9.5 letters in the (PDT) control group.

11 MARINA Trial Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular AMD Adapted from [8]

12 Too expensive and so.. One Lucentis injection cost $ 1950; in the clinical trials that reported a gain in vision, Lucentis was used every month. 12 injection per year will cost $ 23,400. [8] Chance: NO vision gain Use something less expensive

13 The off-label use of Avastin February 2004, the FDA approved bevacizumab for the treatment of metastatic cancer of the colon or rectum; a 4ml vial (100mg of MoAb) cost $ 550. On the molar basis a dose of 0.05ml (1.25mg of MoAb) is similar to the approved dose of ranibizumab. In 2005, Rosenfeld s group published two case reports showing that the use of bevacizumab in AMD patients gave benefits.[3] PROS and CONS: Bevacizumab is 3 times large than ranibizumab and may remain in the eye longer frequency of injection decrease. Moreover have longer halflife compared to ranibizumab. Ranibizumab have greater affinity for VEGF and is formulated for intraocular use so, more drugs may penetrate all the layer of the retina; moreover have an half-life of hours that could theoretically be associated with less systemic toxicity; the lacking of the Fc portion could induce less inflammation.

14 Market for therapies The worldwide pharmaceutical market for the treatment of neovascular AMD is currently defined by only 2 products: verteporfirin(visudyne, Novartis) and pegaptanib(macugen, OSI Pharmaceuticals/Pfizer). Ranibizumab is the first treatment that stabilize vision in more than 90% of wet AMD patiens and improve vision in a significant proportion of patients. Althought bevacizumab and ranibizumab are related, Genentech engineered ranibizumab specifical for penetrate the retina and there are no plans to develop bevacizumab for AMD. The National Eye Institute has received an outside proposal to conduct a comparative study, and results from such an investigation would have a significant impact on the commercial potential of ranibizumab. [4]

15 References: [1] Steinbrook, R. (2006). "The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration." N Engl J Med 355(14): [2] Rosenfeld, P. J., D. M. Brown, et al. (2006). "Ranibizumab for neovascular agerelated macular degeneration." N Engl J Med 355(14): [3] Rosenfeld, P. J. (2006). "Intravitreal avastin: the low cost alternative to lucentis?" Am J Ophthalmol 142(1): [4] Narayanan, R., B. D. Kuppermann, et al. (2006). "Ranibizumab." Nat Rev Drug Discov 5(10): [5] Ferrara, N. (2002). "VEGF and the quest for tumour angiogenesis factors." Nat Rev Cancer 2(10): [6] Dass, C. R., T. M. Tran, et al. (2007). "Angiogenesis inhibitors and the need for antiangiogenic therapeutics." J Dent Res 86(10): [7] Brown, D. M., P. K. Kaiser, et al. (2006). "Ranibizumab versus verteporfin for neovascular age-related macular degeneration." N Engl J Med 355(14): [8] [9] [10]