Integrin Peptides: a New Type of Anti-VEGF
First human trial is highly promising.
Jerry Helzner, Senior Editor
■ Researchers have reported encouraging results from the first human study of a new type of antiangiogenic drug being developed by Allegro Ophthalmics, said lead investigator David S. Boyer, MD, of Los Angeles.
The drug, which currently goes by the designation ALG-1001, is a synthetic anti-integrin oligopeptide. In the initial human study, the objective was to evaluate the safety of intravitreal ALG-1001 in humans with end-stage DME, with a primary endpoint of observing dose-limiting toxicity.
Fifteen patients with end-stage DME completed this open-label, company-sponsored study. Baseline BCVA was ≥ 20/100 and patients had not undergone anti-VEGF treatment or focal laser within 90 days — many patients were refractory to bevacizumab and previous photocoagulation.
Three monthly intravitreal injections of 2.5-mg ALG-1001 were given, with subjects followed for an additional three months. Safety measurements included BCVA, slit-lamp evaluation, fundus exam, IOP measurements, OCT, FA, fundus photos, B-scan and ERG.
Dr. Boyer reported no serious adverse events, with no inflammatory reactions or sustained elevations in IOP. He found a clinically significant effect demonstrated, with eight of 15 subjects reporting a three-line or more increase in BCVA after receiving three injections with up to a corresponding 83% reduction in central macular thickness on OCT.
The clinical benefit lasted at least 90 days after the last treatment, or until the end of the study. The nonresponders did not experience any loss in BCVA from baseline or an increase in OCT central macular thickness over five months.
This was the first human exposure to ALG-1001. The lack of toxicity across all study metrics was consistent. Overall, the study found ALG-1001 was very well tolerated. Despite the small study size, a clinically significant indicator of efficacy was apparent, with improvements in BCVA accompanying anatomic improvements in OCT central macular thickness. Improvement was seen at the end of the study, or 90 days past the last treatment, in nearly all the study subjects who showed a positive response.
|■ Same-day bilateral intravitreal injections. Brazilian researchers led by Gian Pierozzi, MD, and presenting at ARVO 2012. sought to determine the safety of same-day bilateral intravitreal injections.|
In a retrospective study, patients receiving bilateral intraocular injections on the same day were identified. Main outcome was to identify the following complications: retinal detachment, intraocular inflammation, cataract, injection-related issues, retinal tear and endophthalmitis.
All patients underwent intravitreal injection in the operating room and received either bevacizumab or triamcinolone acetonide. Preparation for the injections included the use of two drops of 5% betadine on the eye and 10% povidone-iodine on the eyelid five minutes before injection. All the surgical gloves and sterile drapes were exchanged between the injections. Topical fourth-generation quinolone was used QID for seven days after the injections. Patients were instructed to not rub their eyes and avoid swimming for seven days.
Overall, 128 injections were performed in 44 patients. Twenty-five patients were male. The average age was 63.5 years. The main diagnoses were wet AMD and macular edema.
No cases of endophthalmitis, intraocular inflammation, cataract, injection issue, retinal tear or retinal detachment were detected.
The researchers concluded that bilateral same-day intravitreal injection appears to be a secure method of treatment in their general practice, with no additional risks when the suggested protocol is followed.
In the article by Jonathan M. Smith, MD, and David H. W. Steel, MD, titled “Rebleeding after diabetic vitrectomy” in the September 2012 issue of Retinal Physician, Figures 1 and 3 were mislabeled. The figure labeled as Figure 3 on page 59 should be labeled as Figure 1 and appear on page 58. The figure labeled as Figure 1 on page 58 should be labeled as Figure 3 and appear on page 59. Retinal Physician regrets the error.
Patients Benefit from Remote DR Screening.
Imaging done at the primary care provider.
■ Researchers led by Cory VanAlstine of the Devers Eye Institute sought to determine what, if any, benefits patients derived from having the screening for diabetic retinopathy (DR) performed at their primary care provider's office instead of at a separate visit to an ophthalmologist.
The researchers noted that previous studies have demonstrated that using telemedicine to provide DR screening exams is cost-saving from the perspective of the provider. They then sought to evaluate the cost-benefit of this method from the perspective of the patient, using time as the metric for cost.
They first developed a cost-effectiveness survey, which was administered to participants enrolled in a clinical trial. In this trial, DR screening was performed using either a non-mydriatic camera placed at the primary care clinic, or by the participant's eyecare provider. At the primary care facility, retinal images were taken by a technician and forwarded electronically to an ophthalmologist for evaluation.
Imaged participants found to have moderate diabetic retinopathy or worse were referred to an eyecare provider for follow-up care. The researchers modeled this care process and compared the time reported by patients using the telemedicine model to the time to obtain screening from their eyecare provider. From this, the researchers estimated the breakeven pre-test probability of DR that would make screening by the primary care clinic cost-saving from the patient's perspective.
The 127 participants in the study had a mean age of 56 years. Sixty-one percent of participants drove themselves and 28% had someone else drive them to their appointments (the balance walked or used public transportation). The median time to travel to the primary care clinic and obtain a DR screening image was 40 minutes; the median travel time to and length of an eyecare provider visit was 60 minutes. The model showed a cost-savings from the patient perspective, so long as the pretest probability of moderate or worse DR was less than 33%. Data from the clinical trial showed that 7.7% of participants were diagnosed as having moderate or worse diabetic retinopathy.
The researchers found that preliminary results demonstrated that in this population, the use of telemedicine to provide DR screening exams is time-saving from a patient perspective. Future work will examine financial impact, long-term time savings, the impact of incidental ocular findings and the importance of patient-specific pretest vision status.
The research was presented at ARVO 2012.
VanAlstine C et al. Cost-Effectiveness of Telemedicine Screening for Diabetic Retinopathy. ARVO 2012 (abstract).
|■ Eylea approved by FDA for CRVO. Regeneron Pharmaceuticals said the FDA has approved Eylea (aflibercept) for treatment of macular edema following CRVO. The recommended dose is 2 mg monthly.|
“This second US approval for Eylea provides a new treatment option for the treatment of macular edema following CRVO,” said George D. Yancopoulos, MD, PhD, the company's chief scientific officer and president of Regeneron Laboratories. “Based upon the pivotal phase 3 study results, Eylea has been shown to significantly improve visual outcomes in a disease characterized by high VEGF levels.”
This new approval of Eylea was based on data from the phase 3 COPERNICUS and GALILEO studies. In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters of BCVA at 24 weeks compared to baseline as measured by ETDRS.
■ Study design for wet AMD eyedrop. Ohr Pharmaceuticals has announced its study design for the 120-patient phase 2 clinical trial for its squalamine eyedrop in the treatment of wet AMD.
Beginning soon, retina specialists at 21 US sites will initially administer a ranibizumab injection. Patients will then begin to self-administer the squalamine eyedrop twice a day. No further ranibizumab injections will be given unless specific rescue criteria are met during monthly examinations over the nine-month treatment period.
Ohr acquired the rights to the antiangiogenic squalamine from Genaera, which ended its trial after the successful launch of ranibizumab.
Triesence Effective for Macular Edema
Off-label usage is increasing.
■ Though primarily used for visualization during vitrectomy, sympathetic ophthalmia and temporal arteritis, Triesence (triamcinolone acetonide injectable suspension) has been gradually gathering a following of retina specialists who are using Alcon's preservative-free drug off label as a treatment for macular edema.
Researchers from Sydney, Australia, presenting at ARVO 2012, conducted a 143-patient (168 eyes) study that confirmed the usefulness of Triesence in treating this condition.
Each eye received at least one injection of intravitreal Triesence. BCVA, central subfield retinal thickness and IOP were examined at baseline, week 1, month 1, month 2 and month 3 after the injection.
The researchers found that most of the eyes had improved VA during follow-up when compared to baseline. BCVA at month 1 had the largest increase (7.4 letter gain), and followed by week 1 (2.3 letter gain) and month 3 (2.2 letter gain). Only a minor loss of 1.4 letters in BCVA was observed at month 2.
Central subfield thickness reduced correspondingly after the intravitreal Triescence injection and the greatest reduction was found at week 1. IOP higher than 25 mm Hg was found in five cases and higher than 30 mm Hg in three cases. No case of endoph-thalmitis was reported.
The researchers concluded that intravitreal Triescence injection was safe and efficacious in improving VA and reducing central macular thickness in eyes with macular edema. The study results suggested intravitreal Triescence injection is a promising alternative for treatment of macular edema.
Lil H, Raffles A, Chang A, of the Sydney Retina Clinic & Day Surgery, Sydney, Australia. Intravitreal Triesence for Macular Edema Treatment; ARVO 2012 (abstract).
Allergan Commits to DARPin Research
Major collaboration with Molecular Partners.
■ Allergan, Inc., and Molecular Partners AG announced that they have significantly expanded their existing relationship by entering into two separate agreements to discover, develop and commercialize proprietary therapeutic DARPin products for the treatment of serious ophthalmic diseases.
The agreement comes following a highly encouraging phase 2a study of a DARPin in the treatment of wet AMD in which the drug demonstrated both safety and efficacy with no dose-limiting adverse events at the highest doses. The companies have already initiated a phase 2b study with the same drug.
Molecular Partners will receive combined up-front payments of $62.5 million under the two agreements and is eligible to receive additional success-based payments, including up to $1.4 billion in aggregate development, regulatory and sales milestones, and tiered royalties up into the low double-digits for future product sales.
The first agreement is an exclusive license agreement for the design, development and commercialization of a potent dual anti-VEGF-A/PDGF-B DARPin (“MP0260”) and its corresponding backups for the treatment of wet AMD and related conditions. Under the license agreement, Allergan and Molecular Partners will work together to develop MP0260 through human proof of concept, at which point Molecular Partners has the option to co-fund Allergan's development costs in exchange for a significant increase in royalties.
The second agreement is an exclusive discovery alliance agreement under which the parties will collaborate to design and develop DARPins against selected targets implicated in causing serious diseases of the eye. During the research phase, Allergan has the right to exercise three options to exclusively license collaboration compounds for ophthalmology. Upon execution of each option, Allergan will pay Molecular Partners an option exercise fee and be solely responsible for all downstream development, manufacturing and commercialization activities.