Ranibizumab

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Ranibizumab ?
Monoclonal antibody
Type Fab fragment
Source Humanized (from mouse)
Target VEGF-A
Clinical data
Trade names Lucentis
AHFS/Drugs.com monograph
MedlinePlus a607044
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status POM (UK) -only (US)
Routes Intravitreal injection
Pharmacokinetic data
Half-life Approx. 9 days[1]
Identifiers
CAS number 347396-82-1 YesY
ATC code S01LA04
DrugBank DB01270
UNII ZL1R02VT79 YesY
KEGG D05697 N
ChEMBL CHEMBL1201825 N
Chemical data
Formula C2158H3282N562O681S12 
Mol. mass 48,350 g/mol
 N (what is this?)  (verify)

Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment (Fab) derived from the same parent mouse antibody as bevacizumab (Avastin). It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A. It is an anti-angiogenic that has been approved to treat the "wet" type of age-related macular degeneration (AMD, also ARMD), a common form of age-related vision loss.

Ranibizumab sells for a significantly higher price when compared to bevacizumab.[2] Clinical trials have shown both to be equally effective; however, data suggests use of bevacizumab, which is not approved by the FDA for use in the eye, may be associated with increased risk for serious adverse events.[3] There are also reports of infection after dividing bevacizumab into smaller doses in attempts to make it suitable for use in the eye.[4][5]

Ranibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis,[6] under the brand name Lucentis.

By blocking VEGF-A in the eye, ranibizumab may prevent and reverse vision loss caused by wet macular degeneration.

Administration[edit]

The drug is injected intravitreally (into the vitreous humour of the eye) once a month. If monthly injections are not feasible, the regimen may be reduced to 1 injection every 3 months after the first 4 months.[1]

Dosing every 3 months is linked to a loss of approximately 5 letters (1 line) in visual acuity for the following 9 months as compared with dosing on a monthly basis. Large phase 3 clinical trials (MARINA and ANCHOR) which randomized patients with wet macular degeneration showed that 95% of ranibizumab-treated patients maintained visual acuity compared with 62% of those administered placebo (P < .01) at 1 year; moreover, up to 40% demonstrated an improvement in vision of at least 3 lines. Vision maintenance and loss were defined as a loss of less than 15 letters and a gain of 15 or more letters in visual acuity, respectively, as measured using the Early Treatment of Diabetic Retinopathy eye chart.[7]

Similar results were found in a randomized controlled trial of patients suffering from macular edema caused by central retinal vein occlusion. Participants injected once a month for 6 months showed a gain of approximately 13 to 15 letters in visual acuity, measured using the Early Treatment of Diabetic Retinopathy eye chart.[8][9]

Side effects[edit]

The most common side effects in clinical trials were conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation.

Although there is a theoretical risk for arterial thromboembolic events in patients receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen in patients randomized to placebo.

Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis, retinal detachment, and traumatic cataracts. Other serious ocular adverse events observed among ranibizumab-treated patients (incidence rate < 1%) included intraocular inflammation and blindness.[10]

Interactions[edit]

No significant interactions are known.[11]

Comparison to Bevacizumab and Marketing Issues[edit]

On November 3, 2010, The New York Times reported that Genentech began offering secret rebates to about 300 ophthalmologists in an apparent inducement to get them to use more ranibizumab rather than their less expensive bevacizumab. This may have been in anticipation of the results of the CATT clinical trial,[12] which was sponsored by the National Eye Institute, and compared the relative safety and efficacy of ranibizumab and bevacizumab in treating AMD. In 2008, bevacizumab cost Medicare only $20 million for about 480,000 injections, while ranibizumab cost Medicare $537 million for only 337,000 injections.[13] A small study showed no superior effect of ranibizumab versus bevacizumab in direct comparison.[14] The initial results of the larger Comparison of Age-related Macular Degeneration Treatments Trials (CATT) trial were published in the New England Journal of Medicine in May 2011.[12] The trial showed that the two drugs "had equivalent effects on visual acuity when administered according to the same schedule;" however, serious adverse events were more common in the bevacizumab arm of the trial.

The results of several subsequent head-to-head trials of the two anti-VEGF treatments were later published, and the overall results reinforced CATT's findings. The two therapies performed equally at restoring visual acuity according to a 2012 meta-analysis,[15] and also in the IVAN trial, alone and in the investigators' meta-analysis pooling its own results with CATT's.[16] A 2012 meta-analysis focused specifically on safety issues concluded that the rates of several adverse events were higher with bevacizumab, although the absolute rates of ocular serious adverse events were low with both therapies: ocular adverse events were about 2.8 times as frequent with bevacizumab than with ranibizumab, and "The proportion of patients with serious infections and gastrointestinal disorders was also higher." The authors concluded that " clinicians and patients should continue to carefully weight up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals detected in this systematic review"[3]

References[edit]

  1. ^ a b Lucentis Prescribing Information. Genentech. June 2010.
  2. ^ Peter Whoriskey and Dan Keating (December 7, 2013). "An effective eye drug is available for $50. But many doctors choose a $2,000 alternative.". The Washington Post. 
  3. ^ a b Schmucker C, Ehlken C, Agostini HT, et al. (2012). "A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard". PLoS ONE 7 (8): e42701. doi:10.1371/journal.pone.0042701. PMC 3411814. PMID 22880086. 
  4. ^ Alicia Mundy (June 17, 2010). "Medicare Eye Study Finds Untapped Savings". The Wall Street Journal. 
  5. ^ Tufail, A.; Patel, P. J.; Egan, C.; Hykin, P.; Da Cruz, L.; Gregor, Z.; Dowler, J.; Majid, M. A.; Bailey, C.; Mohamed, Q.; Johnston, R.; Bunce, C.; Xing, W. (2010). "Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study". BMJ 340: c2459–c2459. doi:10.1136/bmj.c2459. 
  6. ^ Lucentis Fact Sheet. Genentech.
  7. ^ Lai, T. Y. Y.; Lai, T. Y. (2013). "Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema". Clinical Interventions in Aging 8: 467–483. doi:10.2147/CIA.S36811. PMC 3677930. PMID 23766636.  edit
  8. ^ Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY, CRUISE Investigators (2010). "Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study.". Ophthalmology 117 (6): 1124–1133. doi:10.1016/j.ophtha.2010.02.022. PMID 20381871. 
  9. ^ Braithwaite T, Nanji AA, Greenberg PB (2010). "Anti-vascular endothelial growth factor for macular edema secondary to central retinal vein occlusion". Cochrane Database Syst Rev 10: CD007325. doi:10.1002/14651858.CD007325.pub2. PMID 20927757. 
  10. ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. [page needed]
  11. ^ Ranibizumab, Lexi-Drugs. Ranibizumab. Lexi-Comp, Inc; 2007.
  12. ^ a b Catt Research, Group; Martin, DF; Maguire, MG; Ying, GS; Grunwald, JE; Fine, SL; Jaffe, GJ (2011). "Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration". New England Journal of Medicine 364 (20): 1897–1908. doi:10.1056/NEJMoa1102673. PMC 3157322. PMID 21526923. 
  13. ^ Andrew Pollack (November 3, 2010). "Genentech Offers Secret Rebates for Eye Drug". The New York Times. 
  14. ^ Subramanian, M L; Abedi, G; Ness, S; Ahmed, E; Fenberg, M; Daly, M K; Houranieh, A; Feinberg, E B (2010). "Bevacizumab vs ranibizumab for age-related macular degeneration: 1-year outcomes of a prospective, double-masked randomised clinical trial". Eye 24 (11): 1708–1715. doi:10.1038/eye.2010.147. PMID 20885427. 
  15. ^ Jiang S; Park C; Barner JC (Jun 2014). "Ranibizumab for age-related macular degeneration: a meta-analysis of dose effects and comparison with no anti-VEGF treatment and bevacizumab". J Clin Pharm Ther 39 (3): 234–9. doi:10.1111/jcpt.12146. PMID 24635444. Retrieved 4 May 2014. 
  16. ^ Chakravarthy U; Harding SP; Rogers CA; Downes SM; Lotery AJ; Culliford LA; Reeves BC; IVAN study investigators (Oct 12, 2013). "Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial". Lancet 382 (9900): 1258–67. doi:10.1016/S0140-6736(13)61501-9. PMID 23870813. 

External links[edit]