Allergan Sees Delay in DARPin Program
Wet AMD drug remains in phase 2.
BY JERRY HELZNER, SENIOR EDITOR
■ Allergan recently reported that its DARPin (designed ankyrin repeat proteins) program for the treatment of wet AMD will be delayed by one to two years, as more phase 2 testing is needed before the program can advance to phase 3. Allergan’s DARPin therapy is part of a partnership with Molecular Partners planned to result in a form of combination therapy using both anti-VEGF and anti-PDGF (platelet-derived growth factor) drugs.
The DARPin anti-VEGF drug had successfully completed phase 2a development and was shown to be safe and well tolerated, with no dose-limiting toxicity, after a single administration. Moreover, preliminary efficacy results from this study suggested a dosing interval of up to three months. Based on these results, Allergan had initiated a double-masked phase 2b study comparing two high doses of DARPin with ranibizumab (Lucentis, Genentech, South San Francisco, CA), the current standard of care.
Regarding the continued progress of DARPin through clinical trials, Allergan has now completed the initial analysis for the second stage of the randomized controlled phase 2 trial comparing two different doses of the anti-VEGF DARPin with ranibizumab. The company says the data, which it received recently from Molecular Partners, suggest some product differentiation between the DARPin and Lucentis but do not support directly moving to phase 3.
“Instead, we plan to perform additional phase 2 work to more completely access safety and efficacy and to guide the phase 3 study design,” said Scott Whitcup, MD, executive vice president and chief scientific officer. “This will likely delay eventual approval by approximately one to two years compared to starting a phase 3 program by the end of 2013.”
“This phase 2 trial was designed so that we could have multiple stages,” noted Dr. Whitcup. “The current plan, because it will save us a fair bit of time, is to have a third stage of the existing phase 2 study. It allows us to enroll patients more quickly. So the plan is to get that next phase of the phase 2 amended and for patients to start probably as early as Q3 of this year. We’re still meeting on the study design. Some of the analyses are still coming in. So those will guide exactly what the next stage of the phase 2 looks like.”
Data from the phase 2 trial will be presented at the AAO Retina Subspecialty Day in November.
■ Strong US launch of Jetrea. Thrombogenics, the developer of recently approved Jetrea (ocriplasmin), the first pharmaceutical treatment for symptomatic vitreomacular adhesion (VMA), reported that it recorded US sales of $10.2 million in the January 14 through April 30 launch period. Thrombogenics said that 40% of targeted US retina practices have purchased the product and that 50% of those practices have already reordered Jetrea.
Thrombogenics also reported encouraging results from a phase 2a study using Jetrea to treat VMA in patients with wet AMD. At day 28, 24% of the Jetrea-treated patients achieved resolution compared to 12% who received sham injections. The company plans to conduct a larger study to confirm these results.
■ QLT focuses on synthetic retinoids. Having sold its interest in Visudyne photodynamic therapy (PDT) for the treatment of wet AMD to Valeant Pharmaceuticals and its punctal plug drug delivery system to Mati Therapeutics, QLT is now solely focused on its development program for synthetic oral retinoids to treat retinal disease. This program is currently in a phase 2 trial.
The QLT synthetic retinoids are designed to counteract the genetic defects that lead to deficiencies in the key visual component 11-cis-retinal in such diseases as Lebers congenital amaurosis and retinitis pigmentosa.
In addition, QLT has announced it plans to distribute $200 million to shareholders in the form of a special dividend of approximately $3.95 a share. The exact amount of the distribution per share will be finalized in late June.
■ One drawback to combination AMD therapy. With growing interest in combination therapy for the treatment of retinal disease, clinical trials of various combinations are requiring that the patients receive two intravitreal injections at the same visit, usually 30 minutes apart.
Regeneron Plans New Clinical Trials
Company sees future in combination therapy.
BY JERRY HELZNER, SENIOR EDITOR
■ In a move strongly indicating that Regeneron sees combination therapy as the next big potential advance in the treatment of retinal diseases, the company has purchased full rights to two novel antibodies it developed in-house as part of its partnership with Sanofi.
The company says it plans to study the two antibodies — one an anti-PDGF (platelet-derived growth factor) and one an anti-VEGF agent called ANG2 — in early-stage clinical trials planned to begin in the near future. The anti-PDGF drug will be tested in combination with the company’s blockbuster anti-VEGF drug Eylea for the treatment of wet AMD.
Regeneron is moving quickly in its development of combinations as that arena is becoming increasing competitive. Other companies pursuing combination therapies for retinal disease are Ophthotech (anti-PDGF and anti-VEGF), Allegro (Integrin Peptide and anti-VEGF) and Allergan (DARPins).
Regeneron now owns exclusive rights to the antibody targeting the PDGF family of receptors and ligands in ophthalmology and all other indications. The new anti-VEGF Regeneron has acquired is under study for oncologic indications but targets the ANG2 (angiopoietin2) receptor and ligand in ophthalmology.
Regeneron will pay Sanofi $10 million up front for the anti-PDGF antibody, and up to $40 million in development milestone payments, and royalties on sales. With respect to the ANG2 antibody in ophthalmology, Regeneron will pay Sanofi $10 million up front, a potential $5 million development milestone payment, and royalties on sales.
In addition, Regeneron continued to report sharp growth in sales of Eylea for the treatment of wet AMD and macular edema associated with CRVO. The company has slightly raised its estimate for full-year US sales of Eylea to $1.25 billion–$1.325 billion from $1.2 billion–$1.25 billion, while also reporting first quarter US Eylea sales of $314 million and profits of $1.78 a share. The profit number sharply exceeded the consensus analyst estimate of 95 cents a share for the quarter.
Pravin Dugel, MD, who served as a key investigator in Ophthotech’s successful large-scale phase 2b trial combining the anti-pdgf Fovista with ranibizumab, says the greater efficacy and potentially longer duration of effective combination treatments should offset the burden of the double-injection requirement.
■ GenSight funded for RP and Leber’s research. GenSight Biologics, a Paris-based developer of gene therapies for ocular diseases, will receive $41.3 million in venture capital funding for the development of two ocular gene therapies. One is an optogenetic treatment for RP, the other a gene-correction therapy for Leber hereditary optic neuropathy (LHON), a condition that causes central vision loss from degeneration of the optic nerve.
Both treatments are slated to move into clinical trials, with the LHON therapy study expected to start in 2013. GenSight has not yet announced a start date for the optogenetic therapy trial.
■ Study: delayed onset of fungal endophthalmitis. After retrospectively studying a 2012 outbreak of fungal endophthalmitis (Bipolaris hawaiiensis) linked to contaminated triamcinolone syringes sold by a Florida compounding pharmacy, Kent W. Small, MD, of the Molecular Insight Research Foundation in Los Angeles, found that 10 of the 16 eyes injected eventually developed fungal endophthalmitis.
In a study presented at the recent ARVO meeting, Dr. Small noted that the time to onset of signs and symptoms ranged from two weeks to seven months, with a median time of three months. The typical presenting signs were painless loss of vision in an eye that was white and quiet-appearing except for cells in the interior chamber of the vitreous. Vitreous biopsy obtained by pars plana vitrectomy was more sensitive in making the diagnosis of fungal endophthalmitis than was vitreous culture or in-office vitreous taps.
Dr. Small, whose study only dealt with the onset phase of the disease, noted that fungal endophthalmitis, due to an airborne black plant mold, is rare and that its delayed onset can make diagnosis difficult without a documented “outbreak.”
Small KW. Fungal endophthalmitis onset due to intravitreal triamcinilone contaminated by a compounding pharmacy. Invest Ophthalmol Vis Sci. 2013;54:ARVO E-Abstract 1123.
Same-day, Next-day RD Surgery
Study finds no difference in outcomes.
■ Though a fovea-threatening retinal detachment (RD) is considered an emergency situation calling for immediate treatment, researchers at the University of California San Francisco sought to compare the outcomes of same-day RD surgery vs next-day RD surgery.
The researchers, headed by Ian Gorovoy, MD, and presenting at the recent ARVO meeting, looked at 88 consecutive RD cases, 43 of which had same-day surgery and 45 of which underwent next-day repair. The patients were examined at three and six months postoperatively and at final follow-up. The researchers found that 83% of all patients had 20/40 or better visual acuity (VA) at three months postoperatively, with postoperative VA strongly correlating to preoperative VA. They found no significant differences between patients who had same-day RD surgery and next-day RD repair.
The researchers concluded that same-day and next-day RD surgery produced equivalent outcomes. However, they noted that same-day surgery tended to be more expensive, often required rescheduling of existing cases, and limited the time for performing preoperative examinations.
Gorovoy I, Porco T, Stewart JM. Same day versus next day repair of fovea threatening primary rhegmatogenous retinal detachments. Invest Ophthalmol Vis Sci. 2013;54:ARVO E-Abstract 2877
■ Stanford to participate in stem cell trial. StemCells, Inc., announced the addition of the Byers Eye Institute at Stanford, Palo Alto, CA, as a second site for the company’s phase 1/2 clinical trial of its proprietary HuCNS-SC product candidate (purified human neural stem cells) in dry AMD. The first site to announce its participation in the study is the Retina Foundation of the Southweat in Dallas.
Theodore Leng, MD, FACS, clinical assistant professor in ophthalmology at the Stanford University School of Medicine, is the lead investigator at the site.
“The company’s preclinical data indicates that transplanting neural stem cells to protect photoreceptors may prove to be a viable approach to this debilitating disease. The (preclinical) data provides a very strong rationale for this innovative cell therapy trial,” said Dr. Leng.
“The clinical strategy with our neural stem cells is to preserve visual function before it is lost,” said Stephen Huhn, MD, FACS, FAAP, vice president and head of the human neural stem cells program at StemCells, Inc. “Our published preclinical data supports this approach in dry AMD and we will hope to replicate those results in this clinical trial.”
■ Regeneron to expand NY facilities. Regeneron Pharmaceuticals, developer of Eylea for the treatment of wet AMD and macular edema associated with CRVO, will expand its corporate headquarters and laboratories in Westchester County, NY, and create more than 400 new high-skill jobs.
The project will add two new buildings with 300,000 square feet of laboratory and office space to the Regeneron complex in the town of Mount Pleasant. Currently, Regeneron occupies approximately 590,000 square feet of space at the site and will occupy another 85,000 square feet of additional space there later this year. Construction of the new buildings is anticipated to begin in late 2013 and to be completed in late 2015.
■ Surgical masks no factor in endophthalmitis prevention. A study conducted by Erin Lessner, MD, of the University of South Carolina Department of Ophthalmology, set out to determine whether intravitreal injections would be safer if given with the physician wearing a surgical mask. One set of 25 patients was injected while the doctor was wearing a mask and another set of 25 patients was injected with the same doctor not wearing a mask. Other factors were the same for both groups, with the same antibiotics given to both groups pre- and post-injection. When not wearing a mask, the physician did not talk during the procedure.
No incidents of endophthalmitis were reported in either group. The researcher believes that larger studies are needed to see if wearing a mask can serve as an infection preventative, especially if the physician has a respiratory infection while performing intravitreal injections.
■ Alimera gets PDUFA date for Iluvien. Alimera Sciences said its recent resubmission of the New Drug Application for its Iluvien sustained-release implant for DME has been acknowledged by the FDA as a complete class 2 response and that a new Prescription Drug User Fee Act (PDUFA) goal date of October 17, 2013 has been established. RP