Allergan Moving Ahead With DARPin Program
Company plans a phase 3 trial in wet AMD.
BY JERRY HELZNER, SENIOR EDITOR
■ Allergan (Irvine, CA) has reported encouraging progress on its lead DARPin (designed ankyrin repeat proteins) program, the anti-VEGF drug abicipar pegol, licensed from Molecular Partners (Zurich, Switzerland) in 2011. The company also announced plans to move the anti-VEGF program into a pivotal phase 3 trial.
The drug previously demonstrated significant efficacy as well as a potential three-month dosing interval in treating wet AMD as monotherapy in a phase 2 study. The company said the priority now is to advance abicipar pegol into phase 3 next year.
In its most recent update, Allergan said it has now completed the topline analysis of data from the stage 3, phase 2, 64-patient study of abicipar pegol in wet AMD. The analysis showed that after 16 weeks, mean visual acuity improvement from baseline was 8.2 letters for abicipar pegol 2 mg, 6.3 letters for abicipar pegol 1 mg, and 5.3 letters for ranibizumab (Lucentis, Genentech). After 20 weeks, (12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection) mean visual acuity improvement from baseline was 9.0 letters for abicipar pegol 2 mg, 7.1 letters for abicipar pegol 1 mg, and 4.7 letters for ranibizumab. No serious adverse events were reported in any of the three groups.
FDA APPROVES PHASE 3 PLAN
These data, along with data from earlier studies, were reviewed with the FDA at an end of a phase 2 meeting where the FDA was in accord with Allergan’s decision to advance abicipar pegol to phase 3 clinical trials and agreed with the proposed phase 3 study design.
“An unmet need clearly exists in patients with wet AMD, both in terms of a desire for better visual outcomes and for less frequent injections,” said Scott M. Whitcup, MD, Allergan’s chief scientific officer. “We are encouraged by the results of the phase 2 studies and look forward to initiating phase 3 of the abicipar pegol program next year.”
In the phase 3 program, Allergan will compare abicipar 2 mg dosed every 8 weeks, abicipar 2 mg dosed every 12 weeks and ranibizumab dosed every 4 weeks.
Christian Zahnd, CEO of Molecular Partners, said the company is pleased to see its previous findings confirmed and that “this DARPin has the potential to bring substantial patient value by potentially providing equal or better efficacy with a more patient-friendly dosing regimen as compared to standard of care.”
■ Novartis/Alcon anti-VEGF drug “ideally suited” for sustained release. A small-molecule anti-VEGF drug being developed by Novartis (Basel, Switzerland) and Alcon (Fort Worth, TX) has demonstrated safety and promising efficacy in a phase 2 study for wet AMD and could be the first anti-VEGF drug to be delivered in a sustained-release format, says Pravin Dugel, MD, of Retina Consultants of Arizona, who presented the phase 2 data at the recent ASRS meeting.
The drug, ESBA 1008, was administered by intravitreal injection in the phase 2 study, but longer-range plans call for it to be ultimately delivered via an implant or reservoir type of device. Dr. Dugel said the data indicated excellent efficacy, increased durability, and the potential for low systemic exposure.
“There are a number of excellent sustained-release concepts now being developed for delivery of eye drugs,” says Dr. Dugel. “ESBA 1008 is ideally suited for a drug-delivery device.”
■ Ozurdex approved for certain DME patients. . The FDA has approved Allergan's Ozurdex dexamethasone intravitreal implant for the treatment of diabetic macular edema (DME) in adult patients who have an artificial lens implant (pseudophakic) or who are scheduled for cataract surgery (phakic). The implant demonstrated long-term efficacy without the need for monthly injections and is the first corticosteroid approved for use in certain DME patients.
The approval is based on the MEAD, study, which included two multicenter three-year sham-controlled, masked, randomized studies assessing the proportion of patients with 15 or more letters improvement in BCVA.
The most common adverse events in the studies included cataracts and elevated IOP, which generally returned to baseline between treatment cycles.
The FDA has already approved the Ozurdex implant for the treatment of macular edema following branch or central RVO and noninfectious posterior uveitis.
Long-term Study Favors Monthly Anti-VEGF
After seven years, 43% of patients maintain driving vision.
■ Given that wet AMD is a chronic disease that requires lifetime treatment, Marc C. Peden, MD, of Retina Associates of Florida in Tampa, wanted to determine what anti-VEGF dosing regimen would best serve patients over the longer term. To that end, he and colleagues retrospectively studied the outcomes of 109 patients who had been on regular fixed-interval anti-VEGF dosing regimens of four to eight weeks (but usually monthly) for five, six, or seven years. All the patients in the study were treated at Dr. Peden’s practice, and 97% of them received regular injections of Lucentis (ranibizumab).
“Our goal was to find a dosing regimen that consistently results in overall better vision gains,” he wrote as an introduction to his FIDO (Fixed-Interval Dosing) study that he recently presented at the ASRS annual meeting.
The FIDO study found that giving patients an average of 10.6 regular anti-VEGF injections per year produced superior results than PRN dosing. Patients in the FIDO study maintained an average 12.1 letter vision gain at seven years, and more of these patients had 20/40 or better vision (43.2%) when compared to patients in the Seven-Up study treated with anti-VEGF on a PRN schedule (23%). The FIDO dosing schedule allowed 43% of patients to maintain driving vision after seven years of anti-VEGF treatment, reported Dr. Peden, while 93.2% of eyes in FIDO were able to improve or stabilize vision at seven years. Only three of 44 patients in the study lost vision at the seven-year mark, Dr. Peden reported.
“Based on data from the ANCHOR and MARINA studies of Lucentis, we chose to treat our patients aggressively,” said Dr. Peden. “If you opt for PRN dosing and wait for signs of active disease to return, I believe you are undertreating your patients.”
The FIDO study did not make a direct assessment of geographic atrophy, but Dr. Peden said geographic atrophy “did not appear to have an impact” on visual acuity outcomes.
“The study is the longest follow-up of continuous fixed-interval dosing to date,” Dr. Peden concluded. “We have never had seven-year data on this dosing regimen before.”
■ FDA and EU Approve Eylea for DME. The FDA has approved Eylea (aflibercept, Regeneron, Tarrytown, NY) intravitreal injection to treat DME. The recommended dosage is 2 mg every 8 weeks after five initial monthly injections. Although Regeneron says it may be dosed as frequently as 2 mg every 4 weeks, additional efficacy was not demonstrated with more frequent dosing.
In addition, the European Union has also approved Eylea (Bayer HealthCare, Leverkusen, Germany) for the same indication. Bayer holds the rights to market Eylea internationally.
The approval of Eylea in DME in the United States was based on the one-year data from the phase 3 VISTA-DME and VIVID-DME studies of 862 patients, which compared Eylea 2 mg given monthly, Eylea 2 mg given every two months (after five initial monthly injections), or macular laser photocoagulation at baseline and then as needed. In the DME studies, after one year, the mean changes in BCVA, as measured by the ETDRS chart for the monthly and every two month Eylea groups, were statistically significantly improved compared to the laser photocoagulation control group and were similar to each other. Across both trials, patients in both Eylea dosing groups gained, on average, the ability to read approximately two additional lines on an eye chart compared with almost no change in the control group.
Regeneron says the reason five monthly loading doses are needed for DME, as opposed to the three monthly loading doses recommended for treating wet AMD, is because DME is more of a “VEGF-driven” disease and requires additional administration of Eylea to successfully attack the disease. Regeneron estimates that 570,000 Americans have been diagnosed with DME, of whom 40% are being treated with anti-VEGF drugs.
■ Genentech seeks Lucentis approval for DR. Genentech, a member of the Roche Group, has submitted a supplemental Biologics License Application for Lucentis (ranibizumab) to the FDA for the treatment of diabetic retinopathy (DR). The submission is based on results of the RISE and RIDE phase 3 clinical trials, which demonstrated the benefits of Lucentis treatment for DR over a three-year study period. Currently, no ocular medications are approved for the treatment of diabetic retinopathy.
ICo DME Drug Disappoints in Trial
But some patients benefit from treatment.
■ Eight-month data from a one-year study of the antisense inhibitor iCo-007 (ICo Therapeutics, Vancouver, Canada) for the treatment of DME indicates a lack of overall efficacy in achieving the primary endpoint of improvement in visual acuity, with patients in all four study arms showing loss of vision. However, a minority of individuals in the 185-patient phase 2 IDEAL trial did appear to benefit from the treatment, with some patients gaining five or more letters of vision at eight months.
The company released only interim data relating to the primary endpoint of visual acuity. Data relating to secondary endpoints, such as changes in central retinal thickness and duration of response, will be made available late this year.
“Quite simply, we don’t yet know enough about our patient groups and the subgroup populations to determine what exactly this data means. To this end, further data analysis at 12 months, including secondary endpoints will be necessary to better understand the viability of iCo-007 in DME” said Andrew Rae, president & CEO of iCo Therapeutics. “There were patients that responded to treatment and others that didn’t respond. Central retinal thickness and subgroup analyses represent just a few examples of outstanding data sets that are required to give clarity to the VA data we have generated at eight months.”
The IDEAL study consists of four patient cohorts: 350 µg iCo-007 monotherapy; 700 µg iCo-007 monotherapy; iCo plus laser treatment, and iCo-007 plus Lucentis (ranibizumab, Genentech). The iCo-007 was administered by intravitreal injection at baseline, month 4 and, if necessary, at month 8.
Mean changes in visual acuity measures in all four groups at both month four and month eight were negative. Using the last observation carry forward (LOCF) method, mean change in VA at eight months was approximately minus 11 letters (350 µg monotherapy), minus 21 letters (700 µg monotherapy), minus 14 letters (350 µg + laser arm) and minus 14 letters (350 µg + Lucentis).
Some patients in each cohort did show improvements in mean change in VA. At eight months, using the LOCF analysis, roughly 20% of patients in the 350 µg monotherapy arm gained five letters or greater of vision vs 13% in the 700 µg monotherapy arm, 12% in the 350 µg + laser arm and 11% in the 350 µg + Lucentis arm. At four months, patients gaining fiv=e letters or more for the 350 µg, 700 µg, 350 µg + laser and 350 µg + Lucentis arms were approximately 24%, 18%, 21% and 30%, respectively.
The IDEAL trial is a multicenter study chaired by Quan Dong Nguyen, MD, MSc, professor and chair of Ophthalmology and director of the Stanley M. Truhlsen Eye Institute at the University of Nebraska Medical Center. RP
■ Squalamine/Lucentis combo RVO trial. A combination of squalamine and Lucentis produced significant gains in visual acuity and resolution of foveal edema in 95% of patients with macular edema secondary to RVO after 10 weeks, according to John Wroblewski, MD, of Cumberland Valley Retina Specialists, Hagerstown, MD, lead investigator of the ongoing 38-week, 20-patient trial.
Dr. Wroblewski, who presented his data at ASRS meeting in San Diego, reported that patients demonstrated a mean 20.3 letter gain in visual acuity at 10 weeks. He said overall early results regarding visual acuity, resolution of edema, and percentage of early responders “appear to be better than those seen in historical monthly Lucentis (monotherapy) RVO trials.” Patients in the trial self-administered squalamine eyedrops twice daily for 10 weeks and received Lucentis injections at weeks 2 and 6.
Dr. Wroblewski said he will report final trial data in the first quarter of next year.
■ In the July/August issue, an item in Subspecialty News relating to the Italian Medicines Agency and its recent decision to reimburse off-label use of Avastin for wet AMD incorrectly stated that two companies participated in the development of Avastin. The drug was developed solely by the Genentech division of Roche. In addition, the article incorrectly stated that two drug companies were advocating the safety monitoring of all Italian patients who receive Avastin off-label for wet AMD. Only Novartis has advocated such monitoring. Retinal Physician regrets the errors.