Phase 3 Failures Stunning But Not Uncommon

Why phase 2 promise is no harbinger of success.


Editor’s note: Paul A. Yates, MD, PhD, is associate professor of ophthalmology and bioengineering and director of retina services at the University of Virginia; CEO of RetiVue LLC; and principal investigator in a phase IIb/III clinical trial evaluating Oracea for the treatment of GA.

In recent months, 2 retina drugs that showed great promise in phase 2 studies disappointed in large-scale pivotal phase 3 clinical trials. Both Ophthotech’s PDGF inhibitor Fovista for wet AMD in combination with anti-VEGF, and Genentech’s complement factor D inhibitor lampalizumab for GA, had stirred high hopes in the retina community. Did something go wrong?

Fovista and lampalizumab are just the most recent retina drugs to disappoint in phase 3 trials. About a decade ago, Opko’s revolutionary RNA-interference drug bevasiranib failed in a phase 3 trial for wet AMD, and Alcon’s anecortave acetate (Retaane) did the same.

History tells us that investigational ophthalmic drugs perform significantly above industry average at a 17% likelihood of going from phase 1 to FDA approval vs 9.6% for all other disease indications.1 But it is in phases 1 and 2 where ophthalmic drugs gain most of their advantage, performing significantly above the mean, advancing from phase 1 to phase 2 84.8% of the time vs 63.2% for all indications and from phase 2 to phase 3 44.6% of the time vs 30.7% for all indications. In phase 3 studies, ophthalmic therapies actually revert to the mean, with phase 3 results leading to FDA approval 45.2% of the time vs 49.6% for all indications.

Why is the success rate so high in phases 1 and 2? In part, toxicities are likely lower for ophthalmic drugs, due to dosing and local application. Preclinical animal studies also likely weed out drug candidates that cause toxicity. Nevertheless, unanticipated ocular toxicities, such as intraocular inflammation or corneal deposits, have caused some trials to be suspended in phase 1. Also, intravitreal anti-VEGF injections have been demonstrated to affect plasma levels of VEGF, so these generalizations are not absolute.2

In critical phase 3 studies, ophthalmics revert to the mean. This can in part be attributed to a preponderance of novel, first-in-class therapeutics for ophthalmology. While this makes ophthalmic therapeutics an exciting field, it also means greater likelihood of failure. Additionally, phase 2 trials for any indication have a well-known set of confounding variables that complicate predicting successful phase 3 outcomes. These issues include the following:

  1. Smaller sample sizes in phase 2 leading to nonuniformity in treated vs control populations even after attempts to assure uniformity.
  2. Generalization, by which pivotal phase 3 trials necessarily include a broader population that may not have been fully represented by the phase 2 study group.
  3. Proceeding into phase 3 when statistical significance is not achieved in phase 2, leading to high false positive rates, with perhaps fewer than half of positive phase 2 results representing true positives.3
  4. Proceeding into phase 3 studies based on post-hoc subgroup analysis of the phase 2 data to parse out a treatment effect. Subgroup analysis to search for a significant P value (P<.05) is commonly referred to as P-hacking.
  5. Use of secondary outcome measures to drive phase 3 trials even when primary outcome measures are not met.
  6. Primary outcome measures are met but expected secondary outcomes measures are not in phase 2. This should serve as a red flag that the underlying hypothesis is not correct.

This all means that, in this context, phase 3 failures are to be expected — and even expected often. All pharmaceutical companies will certainly perform exacting risk–benefit analyses before spending hundreds of millions of dollars on pivotal trials for their new drug candidate. But there is financial incentive to move drug candidates forward where they deem doing so to be a reasonable risk.

Risk of phase 3 failure can be mitigated by increasing patient population in phase 2 and honing the optics through which positive phase 2 results are viewed before proceeding into phase 3. Thus far, development costs and risk–benefit analyses have supported the current, more limited phase 2 trial models, leading to greater phase 3 failures.

Although disappointing, failure should be reassuring. Drug development provides an almost impossibly large hill to climb. If drugs reach the top of that hill and are proven to work in phase 3, they work because the biology is correct, not because of how much money was spent on development or clinical trials.


  1. Thomas DW, Burns J, Audette J, Carroll A, Dow-Hygelund C, Hay M. Clinical development success rates 2006-2015. Biotechnology Innovation Organization. Available at,%20Biomedtracker,%20Amplion%202016.pdf .
  2. Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Acta Ophthalmol. 2012;90(1):e25-e30.
  3. Liu PY, LeBlanc M, Desai M. False positive rates of randomized phase II designs. Control Clin Trials. 1999;20(4):343-352.

Allergan Builds Strong Retina Pipeline

A mix of late- and early-stage initiatives.


■ Through a combination of internal research, partnerships, and acquisitions, Allergan has been expanding its presence in developing medical therapies for retinal disease, and today has one of the strongest retina-related pipelines in ophthalmology. In addition to its FDA-approved sustained-release implant, Ozurdex, the company now has late- and early-stage investigational initiatives for both the most prevalent retinal diseases and for less common inherited retinal dystrophies.

“Our core focus in retina is on unmet medical needs,” says Jag Dosanjh, Allergan senior vice president of Eye Care. “Currently, we have a phase 3 trial ongoing for a more durable therapy for wet AMD, a phase 2 trial for the unmet need of GA, and longer-range early phase programs in gene editing through our recent collaboration with Editas, and via optogenetics — providing light perception to damaged or naïve photoreceptor cells through our 2016 acquisition of RetroSense.”

The gene-editing collaboration with Editas provides Allergan with an entry into the revolutionary CRISPR-Cas9 technology that appears to have wide-ranging applications. The companies have selected Leber congenital amaurosis as their first therapeutic target.

Dosanjh estimates that the Allergan pipeline today encompasses the majority of the medical management of retinal diseases for the key patient types.

“We don’t have any ‘me-too’ therapies in the pipeline,” notes Dosanjh. “Through our open science model, we are committed to pursuing the best concepts, whether they are developed internally, through acquisition, or by collaborating with outside partners.”

One productive partnership is with Switzerland-based Molecular Partners, which developed the science for the designed ankyrin repeat protein (DARPin) abicipar pegol, a small molecule that binds to soluble isoforms of VEGF-A. Currently the DARPin is in 2 large-scale, phase 3 clinical trials for wet AMD (CEDAR and SEQUOIA).

A novel internally developed initiative is the study of brimonidine, which has neuroprotective qualities that might slow the progression of GA in a sustained-release format. After promising phase 1 and phase 2a studies, the concept is currently fully recruited in the phase 2b BEACON study utilizing a sustained-release delivery system similar to Ozurdex.

Early AMD Diagnosis From Blood Samples

Metabolites can be a biomarker of the disease.

■ Patients with any stage of AMD carry signs of the disease in their blood that may be found through special laboratory tests, according to a new study led by AMD researchers at Massachusetts Eye and Ear in Boston. The study, published in Ophthalmology, describes a new technique known as metabolomics.

“With metabolomics, we can identify blood profiles associated with AMD and its severity through laboratory testing,” said co-senior author Joan W. Miller, MD, chief of ophthalmology at Mass. Eye and Ear and Massachusetts General Hospital. “Because the signs and symptoms of early stage AMD are very subtle, with visual symptoms only becoming apparent at more advanced stages of the disease, identification of biomarkers in human blood plasma may allow us to better understand the early to intermediate stages of AMD so we may intervene sooner, and ultimately provide better care.”

The researchers’ approach revealed 87 metabolites, or small molecules in the blood, that were significantly different between subjects with AMD and those without. Furthermore, the team noted varying characteristics between the blood profiles of each stage of disease.

Six of the 7 most significant metabolites identified in the study were lipids. Previous research has suggested that lipids may be involved in the development of AMD, although the exact role of lipids in the disease process remains unclear. The results from this study support this suggestion, as well as indicate that metabolomics profiling may provide novel insights into relationship between lipids and AMD.

“Our work gives us a novel biomarker for early diagnosis, and it gives us clues to differentiate the progressors from nonprogressors,” said co-senior author Deeba Husain, MD, a retina specialist at Mass. Eye and Ear and associate professor of ophthalmology at Harvard Medical School.

Advisory Panel Backs Spark Gene Therapy

On track for landmark FDA approval.


■ Spark Therapeutics cleared a major hurdle October 12 when an FDA advisory panel voted 16-0 to recommend FDA approval of the company’s gene therapy procedure for treating progressively blinding inherited retinal dystrophies (IRDs), initially Leber congenital amaurosis. If the FDA accepts the recommendation, which usually carries significant weight, the Spark procedure would be the first-ever gene therapy for a genetic disease to be approved in the United States.

The vote came several months after Spark’s submission of a biologics license application (BLA) with the FDA for voretigene neparvovec (Luxturna). Voretigene neparvovec is an investigational, single-treatment gene therapy using an adeno-associated virus (AAV) as a delivery platform for patients with vision loss from confirmed biallelic RPE65 mutation-associated IRD. The BLA included data from 3 clinical trials that enrolled participants with RPE65-mediated IRD, including the first randomized, controlled phase 3 trial for a gene therapy for a genetic disease.

Key to the advisory panel’s favorable recommendation was the pivotal phase 3 trial that met its primary endpoint of improvement of functional vision in a 20-patient intervention group compared to a 9-patient control group, as measured by the change in bilateral mobility testing between baseline and 1 year. All patients in the control group then opted for intervention and 8 of those individuals also responded positively to treatment. Patients who received the therapy were successful in navigating a marked path in dim light, something they could not do at baseline testing. There were no serious adverse events reported.

Subjects who received gene therapy outperformed control subjects in full-field light sensitivity threshold testing and the mobility test change score for the first injected eye. Visual acuity did not show statistically significant evidence of benefit.

“This is the first of hopefully many gene therapy approaches to treat both IRDs and other retinal diseases. We look forward to helping our patients with these previously untreatable conditions.” said Peter Kaiser, MD, Chaney Family Endowed Chair for Ophthalmology Research with the Cole Eye Institute at Cleveland Clinic.

Letter to the editor: The Winning Save

■ It is amazing to me that the government’s plan for health care reform has not involved more input from providers. It’s like politicians designing a high-speed underground train from New York to San Francisco without the input of architects, engineers, and builders. The 2017 ASRS meeting debuted a brilliant eye-care contest entitled “The Winning Pitch,” which followed a similar model to the entrepreneur contest TV show “Shark Tank.” I propose the same be done to stimulate improvement in quality and cost of retinal care: “The Winning Save” contest.

The requirements for entries to “The Winning Save” would be (1) no outside interference between physician and patient, and patient welfare is the ultimate goal; (2) decision making controlled by physician and patient; (3) minimal oversight by third parties/regulations; (4) minimal, if any, paperwork, utilization review, explanation of benefits, and so on.

This could be done for each of our subspecialties and can apply broadly to other medical fields. The government should ask us how we could make things better!

Paul E. Tornambe, MD • Poway, California

Editor’s note: This letter represents an excerpt of the full letter to the editor. Read it in its entirety at "Letter to the Editor: The Winning Save."

Ophthotech Will Study Zimura in Wet AMD

Phase 2a trial in combination with Lucentis.


■ As part of its refocused research effort following the failure of Fovista in wet AMD, Ophthotech Corporation has initiated an open-label phase 2a clinical trial of Zimura (avacincaptad pegol), the company’s complement factor C5 inhibitor, in patients with wet AMD. Zimura will be administered in combination with Lucentis (ranibizumab) in patients with wet AMD who have not been previously treated with anti-VEGF drugs. A range of Zimura dosing regimens will be assessed.

“We believe that supplementing anti-VEGF therapy with a complement inhibitor such as Zimura may have the potential to further enhance the efficacy of anti-VEGF monotherapy in wet AMD,” stated Kourous A. Rezaei, MD, senior vice president of Medical Strategy. “Our earlier phase 1/2a clinical trial assessing Zimura in combination with Lucentis, while small and uncontrolled, showed intriguing results.” Dr. Rezaei added that another recent study further supported that anti-VEGF therapy upregulates complement activation and therefore complement inhibition during anti-VEGF therapy may have therapeutic merit.

The company also announced it is on track to initiate 2 additional Zimura clinical trials before year end. The company’s strategy in orphan indications will be led by a randomized, controlled clinical trial to assess Zimura monotherapy in Stargardt disease. The other trial will be an open-label phase 2a clinical trial evaluating Zimura in combination with anti-VEGF therapy for idiopathic polypoidal choroidal vasculopathy, an age-related eye disease. Ophthotech is also planning a phase 2a clinical trial of Zimura monotherapy for intermediate/posterior noninfectious uveitis beginning next year.

Also, after the recent announcements of conflicting topline results of clinical trials from Genentech and Apellis Pharmaceuticals, assessing the role of 2 different types of complement inhibitors to treat GA, Ophthotech has decided to modify its ongoing phase 2/3 clinical trial of Zimura monotherapy in GA. The trial will be modified to accelerate the anticipated timeline to obtain topline data by reducing the number of patients, shortening the time point for attaining the primary efficacy endpoint and thereby reducing the cost to complete the study. The modified study design will incorporate patients already enrolled in the study.

Retina Scans May Help Identify Alzheimer Proteins

Imaging detects beta-amyloid deposits.

■ A 16-patient study led by researchers at Cedars-Sinai and NeuroVision Imaging offers a scientific basis for using noninvasive eye imaging to detect the pathologic hallmarks of Alzheimer disease. The experimental technology, developed by Cedars-Sinai and NeuroVision, scans the retina using techniques that can identify beta-amyloid protein deposits that replicate those in the brain.

The researchers report the feasibility of identifying beta-amyloid in the eye using autofluorescence imaging. They also provide detailed analyses and several new findings on Alzheimer pathology in the retina, results of additional research with donated eyes and brains of 37 deceased patients, 23 with confirmed Alzheimer disease and 14 controls.

Among key findings, the researchers report a 4.7-fold increase in retinal plaque burden in patients with Alzheimer’s, compared to controls, and observations regarding geometric distribution and layer location of amyloid pathology in the retina. With the imaging technology’s ability to detect autofluorescence signals related to retinal beta-amyloid, these findings may lead to a practical approach for large-scale identification of the at-risk population and monitoring of Alzheimer’s, the researchers say.

“This clinical trial is reinforced by an in-depth exploration of the accumulation of beta-amyloid in the retina of Alzheimer’s patients vs matched controls, and a comparison analysis between retina and brain pathologies. Findings from this study strongly suggest that retinal imaging can serve as a surrogate biomarker to investigate and monitor Alzheimer’s disease,” stated Maya Koronyo-Hamsoui, PhD, associate professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai, and a cofounder, inventor and scientist at NeuroVision, in a news release. She is the senior leading author of an article in JCI Insight recently published online.


Research and industry news in retina.


Promising Data in Neurotech MacTel Trial

■ Neurotech Pharmaceuticals, in collaboration with the Lowy Medical Research Institute (LMRI), announced 24-month results demonstrating that NT-501 delivering ciliary neurotrophic factor (CNTF) has a beneficial effect in patients with the rare neurodegenerative disease macular telangiectasia (MacTel) type 2. NT-501 utilizes the company’s proprietary Encapsulated Cell Therapy (ECT) platform that can be customized to deliver specific therapeutic molecules to the back of the eye for retinal disease.

The phase 2 study enrolled 67 patients (99 eyes) at 8 sites in the United States and 3 in Australia. Eligible eyes were randomized to receive the implant or a sham procedure. At 24 months, there was significantly less photoreceptor loss in eyes treated with NT-501 vs sham. The area of ellipsoid zone break increased by 0.213 mm2 in sham eyes compared to 0.148 mm2 in treated eyes.

SciFluor Eye Drop Promising for DME

■ SciFluor Life Sciences said its eye drop therapy demonstrated safety and biological activity in a 40-patient phase 1/2 clinical trial for DME and will be advanced into a phase 2 trial. The drug, known as SF0166, is also currently in a phase 1/2 study for wet AMD. It is a small-molecule integrin antagonist.

The drug was self-administered in 2 dose strengths (2.5% and 5%) twice a day for 28 days, with 28-day follow up. Reductions in central retinal thickness and improvement in VA was observed in a significant number of patients.

“The safety and biological activity, clearly demonstrated in this first-in-patient study, support continued clinical development of SF0166,” said David Boyer, MD, Retina-Vitreous Associates Medical Group of Los Angeles.

PanOptica has Funding for Eye Drop Trial

■ PanOptica has obtained $11 million in Series B financing to advance its next-generation, small molecule, anti-VEGF eye drop therapy for wet AMD (PAN-90806) into a phase 1/2 clinical trial as monotherapy. The company expects that the trial will begin in early 2018 with initial data available in the first half of 2019.

Ohr Provides Update on Squalamine Trial

■ During its recent quarterly conference call, Ohr Pharmaceutical said it was on track to release clinical trial data from the phase 3 MAKO study early next year. The trial for the aminosterol eye drop for the treatment of wet AMD has been scaled back in size to move up the timetable for results to be released.

“Our near-term priority is completing the MAKO study investigating squalamine combination therapy in the treatment of wet AMD,” stated Jason Slakter, MD, Ohr CEO, in a news release. “Over 200 patients are enrolled and, following our decision to amend the trial, we expect topline data in early calendar 2018. Our confidence in squalamine remains high and we believe that, as part of combination therapy, it has the potential to provide improved and sustained vision gains, and set a new standard of care in wet-AMD.” Dr. Slakter added that, during the quarter, the company received net proceeds of approximately $12.7 million from a public offering, which fully funds the company through data readout from the MAKO study and into 2018.

ThromboGenics Reacquires Global Rights to Jetrea

■ ThromboGenics, the Netherlands-based developer of Jetrea (ocriplasmin), the only FDA-approved pharmacolgic treatment for symptomatic vitreomacular adhesion/traction (VMA/VMT), said it will regain full global rights to the drug from Alcon based on a mutual agreement that the unique characteristics of Jetrea make ThromboGenics a better fit for building a sustainable long-term niche business. ThromboGenics had retained the US rights to Jetrea.

Jetrea was first introduced in 2013 and has been approved in 54 countries worldwide, with nearly 30,000 patients being treated in about 20 countries.

“We are pleased to have reached this agreement with Alcon and Novartis in relation to the non-US rights to Jetrea. We intend to take time to evaluate how best to capitalize on the global opportunity that we now have with Jetrea,” Patrik De Haes, MD, CEO of ThromboGenics, said in a news release. “In the near term, it is our key priority to secure the continuity of care by ensuring that patients and physicians have timely access to this unique pharmacological treatment for symptomatic VMA/VMT.”

Graybug Begins Phase 1 Trial for Wet AMD

■ Graybug Vision said it has begun dosing patients with wet AMD in its first clinical trial of GB-102, its lead drug candidate. GB-102 is a novel intravitreal injectable depot formulation of sunitinib malate, a tyrosine kinase inhibitor that blocks multiple angiogenesis pathways VEGFR 1, 2, and 3. Based on preclinical studies, the company believes GB-102 has the potential for twice-per-year treatment. The multicenter clinical trial, which is being conducted in the United States, is designed to evaluate the safety, tolerability, and efficacy of GB-102.

The two-part ADAGIO study will evaluate wet AMD patients currently being treated with available IVT anti-VEGF agents who are then switched over to treatment with GB-102 alone. Part 1 is a multicenter, open-label, single IVT injection study of up to 4 dose levels of GB-102 administered in ascending dosing cohorts. 

Following the single IVT injection of GB-102, patients will undergo monthly evaluation for 8 months to assess safety, tolerability, and functional/pharmacodynamic parameters, including VA and OCT of the retina. Part 2 is a multicenter, double-masked, randomized (1:1:1), parallel-group, safety, and efficacy evaluation of repeated IVT injections of 2 dose levels of GB-102 compared to a standard IVT regimen of aflibercept (Eylea).

Maryland Team Wins “Retina-in-a-Dish” Contest

■ A team led by Erin Lavik, ScD, and representing the University of Maryland Baltimore County has won the NEI 3-D Retina Organoid Challenge and a prize of $90,000 by submitting a model that would be used to create an artificial retina.

Lavik’s team proposed building a retina by screen printing adult neural progenitor-derived retinal neurons in layers that mimic the structure of the human retina. The system is designed to be scalable, efficient, and reproducible, enabling high-throughput screening for drug testing.

The winning team prevailed over 12 other proposals.

Phosphorus Launches New Genetic Tests

■ Phosphorus, which develops and markets genetic tests, has introduced a new battery of diagnostic tests for individuals designed to identify mutated genes associated with inherited retinal dystrophies. The tests encompass a range of 146 genes whose mutations are responsible for such diseases as Leber congenital amaurosis, RP, achromatopsia, Usher syndrome, and others.

Phosphorus offers the tests in cooperation with ophthalmologists and uses its CLIA-certified laboratory to evaluate test results, says Gregory Kellogg, MS, CGC, clinical product manager.

Practitioners who want to recommend genetic testing for inherited retinal dystrophies may want to also look into the “Identify Your IRD” program now being offered by Spark Therapeutics to determine if their patients meet eligibility requirements for this free initiative.

Oculus, Aerie, and Guardion Acquisitions

■ Oculus announced that is has acquired Insight Instruments, including all of that company’s manufacturing capabilities. The acquisition expands the company’s range of surgical products used in retina procedures, led by Oculus’ BIOM product line.

Also, Aerie Pharmaceuticals has acquired Envisia’s proprietary PRINT technology for sustained-release drug delivery and intends to develop it in conjunction with Aerie’s retinal disease program that currently has preclinical initiatives in wet AMD, DME, and DR. Envisia will receive an initial payment of $25 million in cash and Aerie stock.

In other merger news, Guardion Health Sciences has completed its acquisition of Vector Vision, which was announced earlier this year. Vector Vision is a leader in standardized vision testing, including contrast sensitivity, glare disability, and EDTRS VA testing.

Eylea US Sales Rose 11% in Quarter

■ Regeneron said second-quarter US sales of Eylea (aflibercept) increased 11% to $919 million from the $831 million recorded in the comparable quarter of 2016. The company said full-year US sales of Eylea are now estimated to grow by approximately 10% on a year-over-year basis. Worldwide Eylea sales also increased by 11% in the second quarter to $1.46 billion on a similar year-over-year basis.

Navilas Updates Its 577 Laser

■ OD-OS, a leader in navigated retinal laser systems, has announced the release of the latest major update for Navilas 577s. The update, provided free to all Navilas 577s users, accelerates the speed at which laser spots are delivered. As a result, treatment times for both the newly introduced preplanned peripheral treatment option and navigated microsecond pulsed treatments are reduced. In addition to making treatments faster, the update also improves laser uptake evaluation and the overall user experience.


■ In the supplement that mailed with the October issue, entitled, “The Tie2 Pathway: What Retina Specialists Need to Know,” the sponsoring company, Aerpio Pharmaceuticals, was not identified in the document as the sponsor. Retinal Physician apologizes for this omission, and this has been corrected in the digital version.