CATT Results Released: Avastin and Lucentis Equivalent for AMD

29 04 2011

Well, it’s the big news today. The one-year results of the NIH sponsored CATT trial, comparing Avastin (bevacizumab) and Lucentis (ranibizumab) in a head-to-head comparison for the treatment of AMD were released early. The results at one year show equal efficacy in terms of visual acuity. Interestingly, the study also show that prn dosing results in equal visual acuities when compared to monthly dosing.

Here are the key paragraphs from the NIH press release. The full article is available online at the NEJM site, if you have access to that site.

“NEI launched CATT in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported results for 1,185 patients treated at 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or PRN, or Avastin monthly or PRN. Enrollment criteria required that study participants had active disease.

“Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the PRN groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. PRN groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care did not know which study drug a patient was getting, to make sure that the data was not affected by how anyone felt about the treatment.

“Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on a PRN schedule, there also was no difference (within one letter) between drugs. PRN dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with PRN than with monthly treatment but overall visual results were still excellent.

“‘In addition to the primary finding of equivalence between Lucentis and Avastin for visual acuity, CATT also demonstrates that PRN dosing is a viable treatment option for either of these drugs,’ said Daniel F. Martin M.D., study chair for CATT and chairman of the Cole Eye Institute at the Cleveland Clinic. ‘Substantial visual acuity gains may be accomplished with a lower treatment burden.’

“Adverse events indicate development or worsening of a medical condition. They may or may not be causally associated with the clinical trial treatment, but they are always monitored and reported in any clinical trial. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

“Serious adverse events (primarily hospitalizations) occurred at a 24 percent rate for patients receiving Avastin and a 19 percent rate for patients receiving Lucentis. These events were distributed across many different conditions, most of which were not associated with Avastin in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. Differences in serious adverse event rates require further study.

“Investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety.

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Lucentis vs Avastin: Who will win the race?

9 08 2010

As we await the results of the NIH sponsored CATT trial, a head-to-head comparison of ranibizumab (Lucentis) and bevacizumab (Avastin), other smaller studies are trickling in, pointing to what many of us suspect from clinical experience — their efficacy is pretty much the same. Fong et al. published a study in the February issue of Ophthalmology (Intravitreal bevacizumab and renibizumab for age-related macular degeneration) which compared the results from 342 pateints treated with bevacizumab and 128 with ranibiumab. It was a non-randomized trial and the bevacizumab patients were younger. The study showed that both groups had fairly equal results at 12 months. About 23% of bevacizumab patients and 25% of ranibizumab patients had visual acuity of 20/40 or better. More patients with bevacizumab (27%) had improved vision compared to ranibizumab (20%). So, I think we can call it close to even, and remember that about 25% will have improvement of vision and the same percentage with get to 20/40 or better.

The one point that stood out was that in a year, the bevacizumab patients needed about 4 injections, whereas the ranibizumab patients needed 6 injections. This is in keeping with the thought that bevacizumab, being a larger molecule, stays around longer and has a longer duration of action.

Which brings us to the road ahead. The fact that the CATT study has not been stopped, points to the fact that bevacizumab is likely not either significantly less effective or more dangerous than its $2000 per dose cousin, ranibizumab. Both drugs are made by Genentech, bevacizumab being the off-label one. It’s tough for a company to have two of its drugs competing against one another, especially if the off-label one wins or comes close to being even. I believe that Genentech’s approach in the coming years will be to make ranibizumab easier to use. The concern with both these drugs is the ongoing burden of repeat injections. We have a history of the development of sustained-release intraocular drugs in ophthalmology, and the next step is to get one of these drugs into a sustained release form to decrease the number of injections required. Genentech will develop ranibizumab in a sustained release form, leaving bevacizumab to be injected repeatedly. So the issue of equal efficacy will become moot.





Bilateral same-day intravitreal injections? Yes!

8 01 2010

One of the growing issues in treating age-related macular degeneration (AMD) is to reduce the burden of treatment for the patients, many of whom are elderly, and may require injections of VEGF inhibitors every 4-8 weeks. A long-standing tradition in ophthalmology has been to avoid bilateral same-day surgical intervention. The rationale has been that if you operate on two eyes on the same day, any infection that develops in one eye may spread to the other eye, and that if there is any contamination of instruments or compounds used during the surgery, operating on both eyes on the same day increases the likelihood that both eyes will be adversely affected.

Intravitreal injections, which have become standard of care for treatment of AMD are fairly innocuous in terms of surgical insult. The “wound” is a 31 gauge needle entry site. Nevertheless, endophthalmitis may develop. For example, in the VISION study of intravitreal pegaptanib, the incidence of endophthalmitis was 0.16%. In the MARINA study of intravitreal ranibizumab, it was 0.05%. And in the ANCHOR study of ranibizumab, it was 0.05% (3 cases our of 5,921 injections). A study by Pilli et all reported an incidence of 0.029% (3 cases in 10,254 injections). These incidences were for unilateral injections.

So, is there an increased risk for bilateral same-day injections? Lima et al (Yannuzzi’s group) out of New York published their retrospective analysis of bilateral same-day intravitreal injections of VEGF inhibitors in the October 2009 issue of Retina. They report that of 1,534 bilateral injections (3,068 injections total), the incidence of culture-proven endophthalmitis was 0.065%, and the incidence of acute intraocular inflmaation was 0.033%. None of those cases were bilateral. There were no cases of retinal breaks. They conclude that it appears that there is no increased risk for same-day bilateral injections of VEGF inhibitors, as the complication rates are similar.

It’s noteworthy that all patients in their study were done in the office, and received surface disinfection with 5% providone-iodine solution, followed by 2 days of either polytrim or ofloxacin qid.

The study is very useful and gives comfort to those of us considering bilateral same-day injections. In any disease process where the incidence of an occurence is very low, large numbers of patients are needed to determine whether or not there is a difference in incidence between groups, and so, it is fair to say that there is no obvious increase in the risk of complications from bilateral VEGF inhibitor injections, while recognizing the limitation of the comparison.





ANCHOR Study: Lucentis is better than Photodynamic Therapy for Classic ARMD

29 10 2009

Here’s the abstract for the two-year study results.  There are a few key points:  Ranibizumab patients maintained vision better (90%) vs. PDT patients (65%).  More ranibizumab patients gained vision (about 35-40%) than PDT patients (6%).  Injections were monthly.

Ophthalmology. 2009 Jan;116(1):57-65.e5.
Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.
Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group.

Collaborators (87)
Vitreoretinal Consultants, Methodist Hospital, Houston, Texas 77030, USA. dmbmd@houstonretina.com
Comment in:

Ophthalmology. 2009 Aug;116(8):1593.
OBJECTIVE: The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. DESIGN: Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. PARTICIPANTS: Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs.

INTERVENTION: Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). MAIN OUTCOME MEASURES: The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored.

RESULTS: Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]).

CONCLUSIONS: In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.