Lucentis (ranibizumab) is a humanized anti-VEGF antibody fragment that inhibits VEGF activity by competitively binding with VEGF. Lucentis (ranibizumab) is derived from Avastin (bevacizumab), a full-length humanized monoclonal antibody against VEGF. Genentech has developed Lucentis with a marketing tie-up with Novartis Ophthalmics.

Lucentis is injected inside the eye (intravitreous injection) as an office procedure that is best performed by Ophthalmologists with specialty training in Retina and Vitreous surgery.

Wet macular degeneration is less common but more severe than the dry form. It accounts for approximately 10% of all AMD but 90% of all blindness from the disease. This form is characterized by choroidal neovasculariztion (CNV), the development of abnormal blood vessels beneath the retinal pigment epithelium (RPE) layer of the retina. These vessels can bleed and eventually cause macular scarring which can result in profound loss of central vision (disciform scar).

FDA has approved Lucentis for Wet Macular Degeneration treatment

Benefits of Lucentis treatment:

• About 95% patients with wet macular degeneration maintain their baseline vision whilst on treatment with Lucentis. The vision loss, if any, is less than 15 letters of visual acuity. This level of vision loss is considered to be not clinically significant. This is an important treatment effect because to date all other available macular degeneration treatments (vitamins, PDT or Macugen) at best delay the inevitable vision loss but importantly, do not prevent ongoing vision loss. The results from Lucentis clinical trials support its use to prevent further vision loss from wet macular degeneration.

• About one-third patients (34%-40%) GAIN vision and the effect is sustained over the course of Lucentis treatment (1 to 2 years). Most of the vision gain occurs rapidly within the first month of treatment. This vision gain is clinically significant - defined as gaining more than 15 letters of visual acuity. This is perhaps the most significant reason for initiating Lucentis treatment in wet macular degeneration. The vision gain after Lucentis treatment makes it possible for patients to look forwards to doing things like reading again, however not everyone will get such a positive outcome. There is no other macular degeneration treatment that has been shown to improve vision in the settings of a FDA controlled clinical trial.

The Figures below show the Lucentis Clinical Trial Results

 




 

 


 

 

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Aging Eye Times Comments:

The clinical trials have shown a remarkable vision benefit once Lucentis treatment is initiated and continued without break for 1 to 2 years however, it is not known for how many years the treatment should continue and what happens if the treatment is discontinued. The drug has to be injected inside the eye (intravitreous injections) and up to one-third patients (37%) have reported eye pain. Several other side effects (eye pressure rise, vitreous floaters, retinal bleed and eye inflammation) have been reported but these side effects should be largely manageable. The required repeated injections and long-term treatment duration certainly necessitates considerable patient motivation and commitment. Keep in mind that the best vision gain occurs with every month injections. Less frequent injections do not cause comparable vision gain although further vision loss is prevented. Therefore, as remarkable as the vision benefit with Lucentis appears, we recommend an engaged discussion with your Ophthalmologist in order to get the most accurate vision outcome and risk-benefit perspective given your specific circumstances.

An important issue is whether Lucentis causes regression of the Choroidal Neovascularization (CNV) lesion as we believe CNV regression without causing scarring would be akin to curing wet macular degeneration. Scarless CNV regression will be the sine qua non of curing or reversing AMD. The published data (Heier JS et al. Ophthalmology. 2006;113:642e1-642.e4) suggests that although the total area of leakage from CNV is significantly lessened by Lucentis treatment, the total physical size of CNV lesion does not show much reduction. The size of CNV area remains at about 95% of its baseline size even after 7 months of Lucentis (0.5mg once monthly) injections. Therefore it seems that vision improves after Lucentis treatment because leakage of blood and fluid from abnormal CNV vessels is lessened and the effect is sustained because CNV growth is halted. However Lucentis does not considerably regress the CNV lesion and in that sense does not cure macular degeneration.



"Lucentis clears the smoke (reduces leakage from CNV) and prevents the fire from spreading (halts progression of CNV), but leaves the fire still burning (underlying disease process driving CNV is still active)".

We caution against the "irrational exuberance" being exhibited by some experts in comparing Lucentis to the "discovery of Penicillin" or "reversed aging".

Cost of Treatment:
One Lucentis injection is expected to cost US $ 1950/-. In the clinical trials that reported a gain in vision, Lucentis was used every month i.e. 12 injections per year costing US $ 23,500/- at currently proposed selling price.

Genentech estimates that the average (mean) number of Lucentis injections are expected to range between 5 and 7 per year. Some patients may need as few as 5 to 6 injections per year and some may need 12 injections per year. The actual number of injections needed will be physician directed and driven by individual patient's disease status and response to treatment. Even so, it is important to remember that the clinical trails showed that vision is not gained with lesser number of injections per year. Genentech has reported the results of a study using Lucentis injection once every month for the first 3 months and then every 3 months for the rest of the year (i.e. total 6 injections a year). This dose did not result in vision gain after 12 months of treatment. Therefore it is likely that the total number of injections needed per year for vision gain will be closer to 12. This important point may not be readily evident by a casual read of the FDA approved Lucentis label reproduced below (prescribing information):

"Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months."

While accurate in context, the above statement may be misleading out of context. It does not indicate that the total vision gain at the commencement of the every 3 month injections was approximately 5-letters (1-line) and all of the gained vision is lost over the following 9 months (whilst the patient are on every 3 months injections) so that there is no net gain of vision after 1 year.
 

Lucentis and Avastin:
Lucentis (Ranibizumab) is a fragment derived from Avastin (Bevacizumab). Avastin has been approved by FDA for treatment of colon cancer. There are some physicians who have used Avastin injections in the eye for treating wet macular degeneration (just like Lucentis injections) and reported good results. This off-label use of Avastin considerably reduces the cost of treatment. Genentech does not support this off label use and has no plans to conduct clinical trials to study Avastin use in the eye. Unless controlled clinical trials confirm Avastin efficacy in the eye, its use for macular degeneration treatment will be based on anecdotal evidence and will be driven primarily by cost issues. While a single Lucentis injection will cost $ 1950/-, a single dose of Avastin costs $ 17/-, i.e. Lucentis is more than 100 times more expensive than Avastin. CNN reports that The National Eye Institute, part of the National Institutes of Health, has received an outside proposal to conduct a study comparing Avastin and Lucentis in treating AMD.

Side Effects:
The most commonly reported adverse events included conjunctival hemorrhage, eye pain, floaters, increased eye pressure and inflammation of the eye. Serious adverse events were rare and often related to the injection procedure including endophthalmitis (severe inflammation of the interior of the eye), intraocular inflammation, retinal detachment, retinal tear, increased eye pressure and traumatic cataract.

January 2007 Lucentis Safety Update
Based on the results of an ongoing study (SAILOR), Genentech has uncovered an important safety concern regarding Lucentis. There is a high incidence of strokes in patients receiving 0.5-mg dose of Lucentis (1.2% patients had stroke with this dose). Patients with a history of prior stroke appeared to be at higher risk for a subsequent stroke. Note that 0.5 mg dose is the recommended usual dose of Lucentis. The risk of stroke is lessened by reducing the dose of Lucentis to 0.3 mg (0.3% patients had stroke with this dose). We do not know whether reducing the dose of Lucentis to 0.3 mg from the recommended dose of 0.5 mg in order to lessen the risk of stroke will also reduce the beneficial effect of Lucentis on macular degeneration. Perhaps the reduced Lucentis dose will have to be combined with other treatments (PDT or Macugen) or the dosing frequency will have to be modified.

Lucentis mechanism of action:
Lucentis binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). It binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. The binding of Lucentis to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Patient Information Sheet (source: FDA)

Lucentis Prescribing Information (source: FDA)

As an FDA-approved therapy, Lucentis is covered by Medicare. The Genentech Access to Care Foundation (GATCF) helps patients who are uninsured or rendered uninsured by payer denial. GATF Phone: (800) 232-0592.
Genentech has established a Single Point of Contact (SPOC) to assist patients and health care providers with the reimbursement process. SPOC Phone: (866) 724-9394 Email: spoconlineluc-d@gene.com.

Lucentis Clinical Trials

FOCUS: (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) trial is a Phase I/II randomized, single-masked study evaluating the safety, tolerability and efficacy of Lucentis in combination with PDT in 162 patients with predominantly classic subfoveal wet AMD. In this study, patients were randomized 2:1 to receive PDT followed by either 0.5 mg injections of Lucentis or sham injections for 23 months.
 

MARINA: Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab (formerly, RhuFab) In the treatment of Neovascular AMD is a Phase III study of 716 patients in the United States with minimally classic or occult wet AMD.

ANCHOR: (ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD) is a randomized, multi-center, double-masked, active-treatment-controlled Phase III study comparing two different doses of Lucentis to PDT in 423 patients.

PIER: A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in 187 Subjects with Subfoveal Choroidal Neovasularization with or without Classic CNV Secondary to Age-Related Macular Degeneration. In this trial, Lucentis is administered once per month for the first three doses followed thereafter by doses once every three months for two years.