Lucentis Wins FDA Approval
Monthly Dosing Favored over Quarterly.
The FDA has approved Lucentis, Genentech's much-awaited treatment for wet AMD. Approval came on June 30, the final day of the 6-month Priority Review period, and carried no major restrictions.
"In my opinion, the Lucentis approval stands out as one of the most important medical developments in ophthalmology during my 25 years in the field because it has the potential to reverse vision loss associated with wet AMD," said Eugene de Juan, MD, president of the American Society of Retina Specialists.
In 2 pivotal phase 3 clinical studies, approximately 95% of patients who received monthly intravitreal injections of Lucentis maintained or improved their vision. The label for Lucentis will recommend a monthly dosing regimen if that is feasible.
Earlier, Genentech had said that 1-year results from its phase 3b PIER study of a quarterly dosing regimen of Lucentis indicate that a monthly or individualized retreatment schedule is probably preferable in achieving sustainable improvement in visual acuity (see PrONTO study results, page 18).
The PIER study met its primary efficacy endpoint by preventing vision loss as measured by mean change in visual acuity from baseline to month 12. In the study, patients receive Lucentis (0.3 mg or 0.5 mg respectively) or sham injections once per month for the first 3 months, followed thereafter by doses once every 3 months for a total of 24 months. One-year data from this study were presented at the Retinal Physician Symposium in the Bahamas in June.
The previous pivotal phase 3 studies of Lucentis (MARINA and ANCHOR) evaluated a monthly Lucentis treatment schedule and resulted in gains in visual acuity averaging 15 letters after 1 year.
In the PIER study, patients treated with Lucentis, on average, demonstrated an initial increase in mean visual acuity compared to baseline after 3 monthly injections. At month 3, patients treated with Lucentis, on average, gained 2.9 letters and 4.3 letters (0.3 mg and 0.5 mg dose groups, respectively) compared to a loss of 8.7 letters among patients in the sham group. After month 3, patients treated with Lucentis received additional doses at months 6, 9, and 12. On average, patients treated with Lucentis returned to baseline visual acuity by month 12, while patients in the sham group experienced significant vision loss. At month 12, patients treated with Lucentis lost 1.6 letters and 0.2 letters (0.3 mg and 0.5 mg) compared to an average loss of 16.3 letters in the sham group.
"Data from ongoing phase 3b studies and Investigator Sponsored Trials should help us learn more about the optimal dosing regimen," said Hal Barron, MD, Genentech senior vice president, development, and chief medical officer.
Supports Individualized Lucentis Dosing
OCT Used to Determine Retreatment Schedule.
Monthly injections of Lucentis for wet AMD may not be needed if optical coherence tomography (OCT) measurements are used to decide when retreatment is needed. In fact, most patients should be able to achieve maximum benefits from Lucentis with 5-6 injections per year.
So says The University of Miami's Bascom Palmer Eye Institute in announcing 1-year results of the PrONTO Study, a clinical study of 40 patients with wet AMD who received intravitreal injections of Lucentis.
The PrONTO Study (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with Intra-Ocular Lucentis) is a prospective, open-label, uncontrolled study designed to evaluate the use of OCT as a way to determine when patients needed an injection of Lucentis.
The average patient in the PrONTO Study received 5 or 6 injections over a 1-year period, with all patients receiving a monthly injection for the first 3 months. OCT was used to follow the patients and determine when retreatment was necessary. Overall, average vision improved in the treated eye almost 2 lines after 1 year. Additionally, 82% of patients had the same or better vision after 1 year and 35% of patients experienced a twofold improvement in vision as defined by gaining 3 lines of vision on a standardized eye chart.
"By using OCT in this uncontrolled study, we were able to give fewer injections into the eye and observed vision improvement for most of our 40 patients," said Philip J. Rosenfeld, MD, PhD, associate professor of ophthalmology at the Bascom Palmer Eye Institute and the principal investigator of the PrONTO study. "In addition to the improved vision, Lucentis appears to have caused a reduction in leakage from the abnormal blood vessels, and we observed a restoration of normal macular anatomy in this study."
Another aspect of the PrONTO study was to determine how quickly Lucentis stopped the leakage of fluid and the growth of abnormal blood vessels in these wet AMD patients. Using OCT as a diagnostic tool, Dr. Rosenfeld found an improvement in the macular anatomy within 1 day following the injection, resulting in vision improvement within 2 weeks and continued improvement in most patients over the first 3 months of the study.
Aside from the typical complaints of mild discomfort after an injection into the eye, Dr. Rosenfeld said there were no treatment-related or drug-related serious ocular or systemic adverse events reported during the first year of the study. Overall, the drug appeared to be safe and the injection process was very well tolerated by patients. To date, no one left the study or refused an injection, and the study is ongoing through 2 years.
After 3 months, the improvement appeared to be maintained in most patients with intermittent injections every 3 to 4 months as determined using OCT. However, Dr. Rosenfeld said some patients may need more frequent injections and some patients may never need another injection. After 1 year, 17.5% of patients did not need another injection and 20% only needed 1 additional injection, indicating highly variable individual responses that are easily monitored using OCT.
"It's not surprising that everyone is a little different. OCT allows us to tailor our therapy to the individual patient," said Carmen A. Puliafito, MD, MBA, professor of ophthalmology and chairman of Bascom Palmer Eye Institute.
A Pill for Diabetic
Eli Lilly Receives Priority Review for Arxxant.
BY LESLIE GOLDBERG, ASSISTANT EDITOR
Since 1923, Eli Lilly and Company based in Indianapolis, Ind, has been a pioneer in improving the lives of diabetics through innovative research and drug therapies. This effort has continued with the recent development of the oral medication ruboxistaurin mesylate (Arxxant). Originally targeted at the devastating complications of diabetes, including blindness, kidney damage, and nerve damage, Arxxant has shown the most promise in helping diabetics by slowing vision loss caused by diabetic retinopathy (DR). The FDA has informed Lilly that it will conduct a priority 6-month review of Lilly's NDA submission for Arxxant.
Arxxant is a specific protein kinase C beta (PKC) inhibitor and is the first of a new class of compounds being investigated for the treatment of DR, diabetic peripheral neuropathy, and diabetic nephropathy. PKC is a signaling enzyme in the body and overactivation has been linked to the underlying process of microvascular damage caused by diabetes. While tight blood sugar control lowers the risk of diabetic microvascular damage, there are currently no oral medications approved in the United States to treat DR. According to the World Health Organization and the American Diabetes Association, DR is the leading cause of vision loss in adults 20 to 74 years old in industrialized countries.
Lilly has announced that its first foray into the ophthalmology market has produced encouraging results from an analysis of pooled data from 2 3-year phase 3 trials involving 813 patients. The data showed 32 mg of Arxxant daily reduced the risk of sustained moderate vision loss by 41% when compared to placebo in patients with moderate to severe, nonproliferative DR. Vision loss occurred in only 6.1% of patients treated with Arxxant compared to 10.2% of patients treated with placebo. Vision loss was defined as a 3-line loss on the eye chart that was sustained for at least 6 months.
Investigators found that Arxxant was generally well tolerated and had an overall adverse event profile, as well as a serious adverse event profile, similar to placebo.
"These data are exciting because they show that ruboxistaurin has the potential to be the first oral therapy to specifically reduce the risk of vision loss caused by diabetic retinopathy," says Lloyd Paul Aiello, MD, PhD, lead investigator of the study and associate professor of ophthalmology, Harvard Medical School, director, Beetham Eye Institute, Section on Eye Research, Joslin Diabetes Center, in Boston.
The findings were presented in an oral session at the American Diabetes Association's (ADA) 66th Annual Scientific Sessions in Washington, DC, and are included in Lilly's New Drug Application submitted to the FDA in February 2006.
Trap Shows Promise for AMD
Regeneron Initiates a Phase 2 Study.
Regeneron Pharmaceuticals, Inc., has announced positive short-term preliminary results from a relatively small phase 1 trial of the Vascular Endothelial Growth Factor (VEGF) Trap in 21 patients with wet AMD.
In addition to meeting its primary endpoints of safety and tolerability at all dose levels, the VEGF Trap demonstrated positive preliminary efficacy results over 6 weeks. Based on these data, the company announced the start of a phase 2 trial in wet AMD.
"We are very encouraged, both by the promising safety and tolerability data from this trial and by the observed improvements in both retinal swelling and visual acuity in patients following a single dose of this very high-affinity VEGF-blocking agent," said George Yancopoulos, MD, PhD, Regeneron's chief scientific officer. "With the start of the phase 2 trial, we hope to validate these early preliminary findings in a more comprehensive study, determine an optimal dosing regimen, and progress rapidly to registration studies for the VEGF Trap in wet AMD. In addition, we have initiated a small pilot study in patients with diabetic macular edema (DME)."
In the phase 1 study, a total of 21 patients with wet AMD received a single intravitreal injection of 0.05, 0.15, 0.5, 1.0, 2.0, or 4.0 mg of VEGF Trap. The patients were followed for 6 weeks, at which time they were permitted, according to the study protocol, to receive other available treatments. The data released covers the initial 6-week evaluation phase of the trial, for which data is now available for all 21 patients. Preliminary results were as follows:
►Single doses of the VEGF Trap were generally well tolerated at all dose levels tested (0.05 to 4.0 mg), with no systemic or serious adverse events reported. Dose escalation to the highest planned dose was achieved without reaching a maximum tolerated dose.
►Of the 20 patients evaluable for efficacy, 95% demonstrated stabilization or improvement in visual acuity, defined as less than or equal to a 15-letter loss on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart.
►BCVA for all patients in the study increased by a mean of 4.8 letters at 6 weeks. In the two highest dose groups (2 mg and 4 mg), the mean improvement in BCVA was 13.5 letters, with 3 of 6 patients gaining 15 or more letters.
►There was a large, rapid and sustained decrease in retinal thickness as measured by ocular coherence tomography.
Based on the preliminary phase 1 results, the company announced the start of a 150-patient, 12-week, phase 2 trial of the VEGF Trap in wet AMD. The trial is designed to evaluate treatment with multiple doses of the VEGF Trap using different doses and different dosing regimens, as well as safety and efficacy.
►Avastin reimbursement. Spurred by the requests of the American Academy of Ophthalmology and other ophthalmology-related organizations, several states have initiated Medicare coverage for Avastin injections for wet AMD.
Noridian Administrative Services recently announced it will provide payment for these intravitreal injections and for periodic OCT testing to determine the need for retreatment. Noridian is the Medicare administrator for Arkansas, Arizona, Colorado, Hawaii, Iowa, North Dakota, Nevada, Oregon, South Dakota, Utah, Washington, and Wyoming.
Noridan joins CIGNA Medicare, which administers the program for Idaho, North Carolina, and Tennessee.
NHIC, which covers California, Massachusetts, New Hampshire, and Vermont will also reimburse Avastin.
Pinnacle Medicare Services has announced coverage for Avastin in the following areas: Arkansas, New Mexico, Oklahoma, Eastern Missouri, Rhode Island, and Louisiana.
WPS, which administers the program for Illinois, Michigan, Minnesota, and Wisconsin will now bill for the treatment.
Note: Practices will need to check for specific billing policies as these policies vary from state to state.
►New approach to AMD. In a study conducted by OSI Pharmaceuticals, researchers explored the effects of inhibiting both VEGF-A and PDGF-B (platelet-derived growth factor B) on unwanted blood vessels characteristic of wet AMD. OSI says results indicate that inhibition of both factors is more effective than blocking VEGF-A alone and suggest that a combination treatment strategy using both an anti-VEGF therapy such as Macugen and a PDGF inhibitor may provide enhanced treatment for neovascular AMD. OSI says further exploration of this treatment approach is warranted. OSI plans to initiate clinical trials in humans later this year.
►Macugen sales decline. OSI Pharmaceuticals reported that U.S. sales of its Macugen treatment for wet AMD fell from approximately $59 million in the fourth quarter of 2005 to just under $51 million in the first 3 months of 2006.
OSI CEO Colin Goddard, PhD, attributed the decline to increased use of off-label Avastin. He added that Macugen sales had stabilized in April.
In response to a question during OSI's first-quarter conference call about OSI's long-term commitment to Macugen, Dr. Goddard said the company was watching the marketplace and "if we got it wrong (on Macugen), we will not allow this to be dragged out."
►Acuity reports trial data. Acuity Pharmaceuticals said its lead clinical compound bevasiranib sodium, formerly known as Cand5, appeared safe and showed clinical evidence of efficacy in the first results from the phase 2 CARE trial for the treatment of wet AMD.
Bevasiranib is a first-in-class small interfering RNA (siRNA) therapeutic designed to turn off or silence the gene that produces VEGF, the growth factor believed largely responsible for wet AMD.
"I am encouraged by these initial results, which show a trend toward dose-dependent efficacy without discernable adverse effects in these AMD patients with serious progressive disease," said Lawrence Singerman MD, clinical professor of ophthalmology at Case University and a principle investigator for the study at its Cleveland site. "Bevasiranib and its unique mechanism has the strong potential to be useful as a maintenance therapy, first using a VEGF antagonist to 'mop-up' existing VEGF and then using bevasiranib to stop further production in the eye, and it may also be an effective new therapy for wet AMD on its own."
Acuity said preliminary top-line phase 2 results show bevasiranib to be safe and well tolerated, with a dose-related effect evident across multiple endpoints including near vision, lesion size, and time to rescue.
►Rosenfeld to advise iCO. iCo Therapeutics Inc., which has a treatment for AMD in development, said that Philip Rosenfeld, MD, has joined iCo's strategic advisory team. Dr. Rosenfeld is professor of Ophthalmology at the Bascom Palmer Eye Institute at the University of Miami, Miller School of Medicine.
"Dr. Rosenfeld has been involved in the clinical testing of virtually every medical treatment for age-related macular degeneration and was the first to demonstrate the usefulness of Avastin in treating the disease," said Andrew Rae, iCo president and CEO. "Dr. Rosenfeld's vision and pioneering efforts with Avastin have led to a paradigm shift in the way AMD is treated today."
►Macugen study for maintenance. (OSI) Eyetech and Pfizer, Inc., have initiated the phase 4 LEVEL study (EvaLuation of Efficacy and safety in maintaining Visual acuity with sEquential treatment of neovascuLar AMD) that will explore the safety and efficacy of Macugen as a maintenance therapy for patients who have received prior wet AMD treatment and experienced improvement. The 54-week trial comprises up to 1000 patients at 100 sites across the country.
"Clinical data suggest that a non-selective anti-VEGF-A therapy can improve vision in a significant portion of patients and that this improvement may stabilize after a few injections. It makes sense to study whether these gains can also be maintained using a selective anti-VEGF therapy," said Thomas R. Friberg, MS, MD, professor of Ophthalmology and Bioengineering, U. of Pittsburgh Medical Center.
►Macugen data for CRVO, PDR. Recently released interim phase 2 study results showed that Macugen resulted in better visual acuity outcomes in patients with macular edema due to central retinal vein occlusion (CRVO), compared with those receiving a sham injection.
More than 90% of the 98 patients in the study maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) at 30 weeks when treated with Macugen injections (0.3 mg or 1.0 mg) compared to approximately 69% of those treated in the control arm.
Patients treated with Macugen for 30 weeks had, on average, an improvement in visual acuity while the control group demonstrated a mean decrease in visual acuity from baseline to week 30.
In another study conducted by the Valley Retina Institute, McAllen, Texas, and presented at ARVO, 0.3 mg of Macugen was administered intravitrealy every 6 weeks to 10 eyes of 10 patients with proliferative diabetic retinopathy (PDR). Assessment was performed with slit lamp biomicroscopy, fundus exam, fluorescein angiography, and optical coherence tomography (OCT).
Researchers found that the study's endpoints were met, as all 10 eyes demonstrated a marked regression of neovascularization, improved visual acuity, as well as a decrease in central retinal thickness within the first month following treatment, without recognizable adverse effects.