Ranibizumab

• CAS Number: 347396-82-1

Ranibizumab ( Lucentis ® trade name, manufacturer, Novartis ) is a drug used for the treatment of wet ( neovascular ) age-related macular degeneration ( AMD), as well as impaired visual acuity associated with a diabetic macular edema is displayed.

Ranibizumab is a humanized recombinant monoclonal antibody fragment (Fab ) and inhibits the " Vascular Endothelial Growth Factor " (VEGF - A), a protein involved in the formation of small blood vessels ( angiogenesis) is important.

• 3.1 Chemical and pharmaceutical information
• 3.2 history
• 3.3 ranibizumab versus bevacizumab
• 3.4 Comparative Studies
• 3.5 studies

Clinical information

Ranibizumab is administered by intravitreal injection of local anesthetic into the vitreous of the eye. The recommended dose is from 0.5 mg ( 0.05 ml). In the first three months of treatment the medicament is injected at monthly intervals. In the subsequent maintenance phase of the ophthalmologist monthly reviews of the vision of the patient with a standardized letter chart. If the vision loss more than five letters, the drug is given again. The AMD is the leading cause of blindness in old age in industrialized countries.

Limited due to a diabetic macular vision is continued by monthly injections of 0.05 ml to the maximum visual acuity has been reached.

The use of this product must only be performed by a qualified ophthalmologist who has the necessary infrastructure to practice aseptic application.

Adverse effects (side effects)

The most common adverse effects of therapy with ranibizumab are eye problems with pain, bleeding, foreign body sensation, increased intraocular pressure ( glaucoma) or floaters ( small black dots, spots or thread-like structures in the visual field ) as well as headache and arterial hypertension. Severe, rarely, infections inside the eye, damage to the retina or cataracts (cataract ). To reduce the risk of infection, the patient can dropwise antibiotic eye drops.

Pharmacological properties

Ranibizumab is a humanized, recombinant monoclonal antibody fragment, which was developed specifically for the treatment of exudative age-related macular degeneration. The drug is used against the human vascular endothelial growth factor A (VEGF -A). Ranibizumab binds with high affinity all isoforms of VEGF -A. This is considered a key molecule in the pathogenesis of exudative AMD.

The binding of VEGF-A by the activation of the receptors prevents ranibizumab VEGFR -1 and VEGFR-2 on the surface of endothelial cells. Due to its small size it can penetrate all layers of the retina and leads directly to the choroidal neovascularization (CNV ), which are prone to bleeding. The properties of antibody fragment ranibizumab as reduce the risk of inflammation. Because ranibizumab has a low plasma half-life after intravitreal injection, the risk of systemic side effects is small.

Other Information

Chemical and pharmaceutical information

Ranibizumab is the Fab fragment of the humanized monoclonal antibody bevacizumab which is produced by recombinant DNA technology in Escherichia coli. It differs from the latter in 6 amino acids, of which four are located in the VEGF - binding site and is not glycosylated.

History

Lucentis was developed by Genentech, a subsidiary of the Swiss company Hoffmann -La Roche, and Novartis. Novartis owns the worldwide distribution rights for ranibizumab with the exception of North America ( U.S., Canada and Mexico). For these countries, Genentech has the distribution rights. The production for all sales areas is carried out by Hoffmann -La Roche. Lucentis ® was approved by the European Commission for all countries of the European Union in January 2007. The approval in the U.S. was done in June 2006 and for Switzerland in September 2006.

2011, the National Health Service spoke of health economic reasons against a payment for the therapy of type 2 diabetic patients. Availability for this group of patients is consequently in the United Kingdom in question.

Ranibizumab versus bevacizumab

Ranibizumab was primarily indicated for the treatment of AMD based on the results of the MARINA and ANCHOR studies. The price of U.S. $ 1,950 per injection was already felt in the introduction in the U.S. in June 2006 by many ophthalmologists as outrageously high. Extrapolations could cost amounting to several billion U.S. $ or € per year solely on the basis of this one drug for the health system seem possible. Many eye doctors differed so in the context of medical therapy on the freedom considerably cheaper, biochemically very similar bevacizumab (Avastin ®), which was not approved for this indication (so-called off-label use ).

Are Bevacizumab to date before only smaller open trials in AMD. It is therefore not known whether bevacizumab as good, worse or possibly better than ranibizumab in AMD acts. The manufacturer of bevacizumab, Hoffmann -La Roche, Novartis is one of 33%, but made ​​no effort to seek an authorization of this drug for the treatment of AMD. Then were initiated on the initiative of ophthalmologists therapy studies to determine the comparative efficacy of ranibizumab versus bevacizumab. In a first direct, but small comparative study, there was no evidence of superiority over the much cheaper bevacizumab. As scandalous attempt Genentech was felt in the United States by many observers, the sale of bevacizumab to ophthalmologists to prevent (Genentech also sells bevacizumab in the U.S.). In a compromise was reached in December 2007 that bevacizumab can be used under certain conditions again by ophthalmologists. The possible liability risks for Genentech were minimized.

The largest scientific society of German Ophthalmologists, the German Ophthalmological Society, stressed in a statement of 20 September 2007 that had to be based " treatment for the benefit of patients on the principles of evidence-based medicine," why " should be the therapy with a drug whose efficacy and safety has been tested in clinical trials for this indication. " and advocated the implementation of an appropriate study to come up with that to compare the efficacy and safety of Avastin for Lucentis directly.

Comparative studies

A number of clinical studies examining comparative efficacy of ranibizumab and bevacizumab for wet macular degeneration. In May 2011, the results of the CATT study were published in the New England Journal of Medicine. As a result of the study showed that after one year of treatment, the effect of the two drugs was virtually the same. Concerning adverse events, the authors recommended further research. On May 6, 2012, a preliminary result of the British IVAN study was made public that showed an effect equivalence of two substances after 12 months of treatment. The results of the German and the Austrian VIBERA Manta comparative study were the end of 2012 yet.

The dispute over bevacizumab for AMD and the above-mentioned Studies followed in the public with great interest, because here come important questions of principle of off- label use of drugs for the language. However, it is in the German health care system can not be an approved drug against the will of the authorization holder ( the manufacturer ) to make for a different indication for admission, which is met with criticism from the medical profession.

Studies

• Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V: Preclinical pharmacokinetics of ranibizumab ( rhuFabV2 ) after a single intravitreal administration. In: Invest. Ophthalmol. Vis. Sci .. 46, No. 2, February 2005, pp. 726-33. doi: 10.1167/iovs.04-0601. PMID 15,671,306th
• Kim IK, Husain D, Michaud N, et al.: Effect of intravitreal injection of ranibizumab in combination with verteporfin PDT on normal primate retina and choroid. In: Invest. Ophthalmol. Vis. Sci .. 47, No. 1, January 2006, pp. 357-63. doi: 10.1167/iovs.04-0087. PMID 16,384,985th
• Coscas G, Coscas F, G Soubrane: Traitement par injection intra- Vitréenne de ranibizumab ( Lucentis ®) pour the néovaisseaux choroïdiens occultes prédominants liés à la DMLA. In: Journal Français d' Ophthalmology Vol 29 - N ° 7 - Septembre 2006 p. 731-737
• Guymer RH: Managing neovascular age-related macular degeneration: a step into the light. In: Med J. Aust .. 186, No. 6, March 2007, pp. 276-7. PMID 17,371,204th
• Epstein P: Trials that matter: two faces of progress in the treatment of age-related macular degeneration. In: Ann. Intern. Med. 146, No. 7, April 2007, pp. 532-4. PMID 17,404,357th
• Smith TC, Lee L: Age related macular degeneration - new Developments in treatment. In: Aust Fam Physician. 36, No. 5, May 2007, pp. 359-61. PMID 17,492,074th
• Landa G, amde W, Doshi V, et al.: Comparative study of intravitreal bevacizumab (Avastin ) versus ranibizumab ( Lucentis ) in the treatment of neovascular age-related macular degeneration. In: Ophthalmologica. 223, No. 6, 2009, pp. 370-5. doi: 10.1159/000227783. PMID 19,590,252th
• Fong DS, Custis P, Howes J, Hsu JW: Intravitreal bevacizumab and ranibizumab for age -related macular degeneration a multicenter, retrospective study. In: Ophthalmology. 117, No. 2, February 2010, pp. 298-302. doi: 10.1016/j.ophtha.2009.07.023. PMID 19,969,368th
• Ranibizumab and bevacizumab for neovascular Age-Related Macular Degeneration. In: N Engl J Med April 2011 doi:. 10.1056/NEJMoa1102673. PMID 21,526,923th
• Philip J. Rosenfeld: Bevacizumab versus ranibizumab for AMD. In: New England Journal of Medicine. 364, 2011, pp. 1966-1967, doi: 10.1056/NEJMe1103334.