Post-Approval Studies Are Improving Outcomes
Good news for Jetrea and Iluvien.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ It’s accepted that results of pivotal phase 3 clinical trials will largely determine the success or failure of a specific investigational drug. However, recent examples are demonstrating that data from “real world” post-approval studies can drive greater use of a drug, first by showing how increased efficacy rates can be achieved through more focused patient selection, and second by providing new clinical information that makes physicians more comfortable in using the drug.
Perhaps the most dramatic example of a productive post-approval study is ORBIT, which enrolled a total of 539 patients with symptomatic VMA/VMT at 90 US retinal centers for treatment with ocriplasmin (Jetrea; ThromboGenics). For this study, patient assessment and selection — as determined by the individual treating physicians — was largely based on factors that had predicted success in previous ocriplasmin trials, such as younger age, absence of epiretinal membrane, phakic eyes, and smaller full-thickness macular holes.
Researchers led by Brian C. Joondeph, MD, of Denver, found that overall pharmacologic VMA/VMT resolution at month 1 was 45.8% (220/480). Pharmacologic VMA/VMT resolution improved over time to a rate of 59.0% (283/480) at month 12. The full-thickness macular hole closure rate was 30.5% (36/118) at month 1 and 32.2% (38/118) at month 12. The researchers, who presented their findings at ARVO 2017, concluded that overall VMA/VMT resolution at 1 month was significantly higher than the pivotal phase 3 MIVI-TRUST results (45.8% in ORBIT compared to 26.5% in MIVI-TRUST), demonstrating the importance of patient selection. No new safety signals were identified.
For the Iluvien sustained-release implant for DME (Alimera Sciences), post-approval studies such as the European Registry Safety Study have shown real-world experience to be positive and that side effects have been manageable. This more recent study, which now includes patients who had been unsuccessfully treated with anti-VEGF, indicates that Iluvien is a suitable option for patients who have failed anti-VEGF.
“The early adoption is usually on a limited number of patients until the doctor gets comfortable with the paradigm change that Iluvien brings,” says Dan Myers, Alimera CEO. “As more patients benefit from an efficacy and treatment burden perspective and the doctor realizes the side effect profile if very manageable, real-world data begin to be generated. The confidence that the data generate leads to greater Iluvien uptake.”
Letter to the Editor
■ When will Retinal Physician provide coverage for ignored topics like cystoid macular edema (CME) that is not associated with diabetes, RVO, or post-cataract surgery? Is there not a branch/group that covers “orphan” patients with CME initially arising post epiretinal membrane surgery/retinal detachments and the like? Why not become advocates for such patients who are also in need of precision eye care? A paucity of innovative care is not acceptable. Such patients are virtually ignored in the climate of revolutionary knowledge, research, and clinical trials. Why not provide presentations on advancement of retinal regeneration via GABA1 and MANF,2 for example? Health care and research entities must lead the way to encourage scientists/clinicians to explore such unmet patient needs.
— Marcia A. Miller, PhD, D(ABMM), Professor Emerita-Microbiology, University of Illinois College of Medicine-at Peoria.
- Rao, MB, Didiano D, Patton JG. Neurotransmitter-regulated regeneration in the zebrafish retina. Stem Cell Reports. 2017;8(4):831-842.
- Neves J, Zhu J, Sousa-Victor P, et al. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science. 2016;353(6294):aaf3646.
From the editor: Thank you for your feedback, Dr. Miller. We plan to cover this important topic in an upcoming issue.
Novartis AMD Drug Achieves 12-Week Durability
The majority of patients met that standard.
■ The possibility of every-12-week dosing for wet AMD is closer to becoming a reality as several drug companies continue to take aim at that standard for retreatment. Most recently, 2 large, pivotal phase 3 studies for the Novartis wet AMD drug RTH258 (brolucizumab) have confirmed earlier clinical data indicating the drug was capable of providing a 12-week response in a significant percentage of patients. Recently released 48-week data from the HAWK and HARRIER studies show that 57% of the HAWK participants and 52% of the HARRIER participants could be maintained exclusively on a 12-week retreatment regimen of 6 mg RTH258 (after initial loading) while maintaining vision gains noninferior to aflibercept (Regeneron; Eylea). The studies encompassed a total of more than 1,800 participants.
RTH258 is a small-molecule, humanized single-chain antibody fragment that can be delivered in high concentrations, providing superior tissue penetration and rapid clearance from the circulation. It has a high affinity to all types of VEGF-A isoforms. Novartis said it expects to complete final manufacturing studies and file a New Drug Application with the FDA in 2018.
“These results clearly and convincingly demonstrate RTH258 has the potential to reduce injection burden while providing excellent visual outcomes,” said Vasant Narasimhan, MD, global head of drug development at Novartis, in a statement. “Based on these robust data, we are looking forward to working with regulatory agencies to bring this pioneering treatment to patients.”
Of the 2 currently approved drugs for wet AMD, Eylea is indicated for every-8-week dosing, and ranibizumab (Lucentis; Genentech) is indicated for monthly dosing, or less frequently with regular assessment.
■ Study: 12-week dosing for Eylea. As further confirmation that the response of individual patients to anti-VEGF therapy can vary widely, analysis of the second year of the phase 3 VIEW trials for Eylea (aflibercept; Regeneron) shows more than 50% of patients in the 2 mg dose cohort were able to do well on an every-12-week dosing regimen. In the first year of the VIEW study, patients received 2 mg aflibercept either monthly or every 8 weeks (after 3 monthly injections). In the second year, that dose was maintained. However, the patients were seen monthly but treated on a prespecified PRN schedule. Treatment was mandated at 3 months after the last injection.
A total of 529 eyes with wet AMD required 12-week Eylea dosing in the second year of the trial vs 509 eyes that required more frequent injections. The 12-week cohort completed the second year while maintaining their first-year visual and OCT gains and without need of rescue therapy. The average number of Eylea injections in the second year for this group was 3.
The findings are based on research reported at the recent Macula Society annual meeting by David Boyer, MD, of Los Angeles.
“This study confirms the variability of response by patients receiving anti-VEGF treatment. Some patients may still require every 4 week injections and some may require injections at 12 weeks or greater,” concluded Dr. Boyer.
■ Persistent DME after anti-VEGF. Researchers led by Scott M. Whitcup, MD, of Mission Viejo, California, conducted a post-hoc analysis of the Protocol I study to determine the association between anatomic response (duration of edema) after 24 and 52 weeks and average vision improvement at 156 weeks.
Of the 367 eyes reviewed, the researchers found that patients with persistent edema after 6 months (central retinal thickness of more than 250 microns) had worse visual outcomes at 156 weeks than patients whose edema had cleared quickly. The average difference between the two groups was 3.8 letters.
The researchers, who presented their findings at ARVO 2017, suggested that practitioners consider additional or alternative therapies for patients with persistent edema.
■ FDA: systemic fluoroquinolones do not cause RD. As part of its continuing review of the safety of antibiotics, the FDA has concluded that systemic fluoroquinolones taken by injection or by mouth do not appear to cause retinal detachment. Earlier research had suggested a potential link, but “patient cases identified by the FDA and findings from published studies currently do not support” an association, the FDA said.
Six Years of Endophthalmitis Cases Reviewed
Corneal ulcer and post-cataract infection lead causes.
■ Medical student Louise Lu and Ron A. Adelman, MD, of the Yale University Medical Center, reviewed the medical records for 6 years of the culture-proven endophthalmitis cases (n=94) at a tertiary referral center. Their comprehensive findings included clinical etiologies, microbial spectrum, antibiotic resistance, and VA outcomes.
The etiologies of endophthalmitis were exogenous in 68.8% of cases and endogenous in 31.2%. The most common inciting factors for exogenous endopthalmitis were progression of corneal ulcer (22%) and postoperative infection after cataract extraction (17%). The microbial spectrum of causative organisms was dominated by coagulase-negative Staphylococcus (30.9%), followed by Staphylococcus aureus (23.4%) and Pseudomonas aeruginosa (10.6%). The most frequent fungal isolates were Candida species (4.3% of total samples).
Antibiotic susceptibilities of gram-positive bacteria were: vancomycin, 96.7%; cefazolin, 79.3%; clindamycin, 69.0%; doxycycline, 96.6%; erythromycin, 55.9%; gentamicin, 96.6%; oxacillin, 69.0%; penicillin G, 28.8%; and TMP+SMX, 84.4%. Antibiotic susceptibilities of gram-negative bacteria were overall very high, with greater than 90% susceptibility among isolated culture samples.
Final VA outcomes of 20/400 or better were reported in 62.5% of patients; counting fingers, hand motion, or light perception were reported in 10.0% of patients; and no light perception was reported in 27.5% of patients for whom VA data were available.
The researchers, who reported their findings at ARVO 2017, concluded that VA was improved in the majority of patients after treatment for endophthalmitis; nevertheless, a significant percentage of patients had a final VA of no light perception.
■ Progression to surgery of ERMs. Researchers at Ophthalmic Consultants of Boston conducted a retrospective study to determine the time to progression to surgery of patients who presented with idiopathic epiretinal membranes (ERMs) and initial good vision of 20/40 or better.
A total of 72 eyes from 60 patients were identified. Average age was 68 ± 6.3 years. Average presenting Snellen VA was 20/29 (range 20/20 to 20/40). Average follow-up duration was 3.72 ± 1.83 years (range 1.02 to 7.03). On presentation, 36 eyes were asymptomatic; and metamorphopsia was present in 16 eyes, generalized blurry vision in 13 eyes, and other symptoms in 7 eyes. Seventeen patients were pseudophakic. The Kaplan-Meier survival curve for progression to surgical intervention for all eyes at 6.5 years was 22%. VA at time of surgery averaged 20/75.
The researchers, who presented their findings at ARVO 2017, concluded that patients with ERMs who are not considered initial candidates for surgical intervention often inquire about their risk of progression. This study shows progression to surgical membrane peeling at 6.5 years is 22%. Further research is needed to weigh the rate of progression against any irreparable vision loss that may occur from long-standing ERMs.
■ Oral therapy shows promise in wet AMD. Tyrogenex (Rockville, MD) said a phase 1, dose-escalation trial of its X-82 oral therapy for wet AMD showed encouraging signs of biological activity, including the fact that 60% of the 25 trial participants who completed the study did not need anti-VEGF rescue during the entire 24 weeks of the study. The company said it would now move the tyrosine kinase inhibitor ahead into the phase 2 APEX study, also for wet AMD and now fully enrolled. The data were reported in the journal JAMA Ophthalmology.
■ Clearside reports positive extension study. Clearside Biomedical reported that new, 6-month extension data from its phase 2 TANZANITE clinical trial continued to show that a combination of its proprietary triamcinolone acetonide suspension (CLS-TA) delivered through suprachoroidal administration and Eylea provided a significantly more durable response than Eylea alone in combating RVO.
The company said 17 of 23 patients in the combination arm did not require retreatment after 9 months, while only 4 of 23 patients in the Eylea control arm reached the 9-month mark without needing retreatment.
CLS-TA is currently in the phase 3 Sapphire study.
Oklahoma ODs Do Very Few Injections
Researchers conduct scope-of-practice study.
■ Researchers at Kellogg Eye Center at the University of Michigan set out to determine whether the expanded scope of practice granted to optometrists in Oklahoma was translating to ODs performing the more complex procedures that in almost all other states are the province of ophthalmologists.
In reviewing the 2008-2012 Medicare claims of 621 ODs and 183 ophthalmologists practicing in Oklahoma, the researchers found that the ODs performed only a total of 51 intraocular/periocular injections compared to 21,427 by ophthalmologists. For other procedures permitted for ODs under the state’s expanded scope of practice, ophthalmologists performed punctal procedures, chalazion removals, and argon and selective laser trabeculoplasties at a far greater rate than ODs.
Optometrists performed more eyelash epilations (1,673 vs 1,089) and superficial foreign body removals (551 vs 256) than ophthalmologists did, but still at a lower individual rate (rate ratios = 0.76 and 0.87). The researchers plan to report the complex procedure numbers for 2 other expanded-practice states, Kentucky and New Mexico, at a future date.
The researchers, who reported their findings at ARVO 2017, also raised the question of whether ODs could “maintain the necessary skills for more complex procedures if they are performing these procedures so infrequently.”
■ Allergan seeks durable response in phase 3 DARPin trial. Competition continues to heat up in the race for more durable therapies for wet AMD as Allergan has completed enrollment for 2 pivotal phase 3 clinical trials for its DARPin drug, abicipar pegol. Abicipar pegol belongs to a new class of genetically engineered antibody mimetic proteins called DARPins, which exhibit highly specific and high-affinity target protein binding. Molecular Partners, a Swiss company that is partnering with Allergan in the development of abicipar pegol, is pioneering this new class of drugs.
The trials, CEDAR and SEQUOIA, are each enrolling 900 patients and will compare abicipar pegol to ranibizumab (Lucentis; Genentech) for wet AMD regarding safety, efficacy, and the potential to dose abicipar pegol every 8 to 12 weeks vs Lucentis every 4 weeks.
The potential for every 12-week abicipar pegol dosing was demonstrated in the phase 2b PALM trial, which studied the drug for DME. Results from Allergan’s 151-patient study showed that abicipar pegol injected every 8 or 12 weeks for DME offered comparable functional and anatomical effects as Lucentis injected monthly. Patients receiving 2 mg abicipar pegol required fewer injections than patients receiving ranibizumab over a 28-week period, according to a news release from Molecular Partners.
Top-line data for CEDAR and SEQUOIA are expected in 2018.
■ Spark seeks landmark gene-therapy approval. Gene therapy pioneer Spark Therapeutics has announced the completion of the rolling submission of a Biologics License Application (BLA) with the FDA for voretigene neparvovec, an investigational, single-treatment gene therapy for patients with vision loss due to confirmed biallelic RPE65 mutation-associated inherited retinal disease (IRD). The BLA submission includes data from 3 clinical trials that enrolled 41 participants with RPE65-mediated IRD, including the first randomized, controlled phase 3 trial for a gene therapy for a genetic disease.
The FDA will have 60 days to review the submission to determine if it is complete. If so, the application will be considered filed and the review period will begin.
“Completion of the rolling BLA is another step forward in our goal to bring this investigational gene therapy to people living with RPE65-mediated IRD who currently have no approved pharmacologic treatment options,” said Jeffrey D. Marrazzo, Spark CEO, in a press release. “We look forward to working closely with the FDA, with the hope of bringing voretigene neparvovec, the first potential gene therapy for a genetic disease in the United States, to patients as quickly as possible.”