Although repackaged intravenous (IV) Avastin^® (bevacizumab) is widely prescribed off-label to treat retinal diseases through intravitreal injection, bevacizumab has never been approved for these indications. There can be risks associated with the use of unapproved bevacizumab products from compounding pharmacies. Outlook Therapeutics is in late-stage clinical development with a version of bevacizumab formulated specifically for ophthalmic use in such retinal diseases as wet age-related macular degeneration (AMD). Outlook’s compound, if approved, will provide a true on-label, cGMP-produced, responsibly priced ophthalmic bevacizumab, not only offering another safe and efficacious, on-label therapeutic option aross the spectrum of retinal care, but potentially expanding access to therapy to patients in markets where unapproved bevacizumab is not available and access to anti-VEGF treatments is limited.

From Biosimilars to Ophthalmology

Outlook Therapeutics has an unusual history for a company focused on retinal diseases. We founded Oncobiologics in 2010 as a unique biosimilar company with in-house development and manufacturing. On our journey to develop an oncology biosimilar of bevacizumab for the branded oncology drug Avastin^® (Genentech), we realized we could pursue a unique opportunity. Rather than compete with six or seven other potential biosimilar bevacizumab products in the oncology market, we could develop a novel ophthalmic bevacizumab formulated specifically for the treatment of retinal diseases. 

In 2018, we pivoted to become an ophthalmology company and changed our name to Outlook Therapeutics. From that point forward, we have focused completely on our retinal strategy. Our lead asset, ONS-5010, is a version of bevacizumab we expect to call LYTENAVA™, if approved, and we hope it will become a widely accepted, new approved option for the treatment of wet AMD and other retinal diseases.

Three Indications for Anti-VEGF Drugs

Within the ophthalmology space, anti-VEGF drugs like bevacizumab are used to treat diabetic macular edema (DME) and branch retinal vein occlusion (BRVO) in addition to wet AMD. This class of drugs has been considered the standard of care for retinal disease for nearly 15 years. There currently are three approved anti-VEGF drugs for treatment of these indications, all of which, like cancer, have leaky blood vessels as a major contributor of disease. 

Anti-VEGF drugs, including Avastin^®, target leaky blood vessels, which, in the case of retinal disease, proliferate behind the retina to cause vision loss and potentially blindness. Anti-VEGF drugs cause these abnormal blood vessels to dry up, thereby allowing vision to be improved if not restored. Anti-VEGF drugs for ophthalmic use are injected into the vitreous of the eye, on a dosing schedule that varies roughly from monthly to quarterly, depending on the patient’s situation. In general they are probably dosed approximately six times per year. 

Bevacizumab Most Prescribed, But Not Approved for Retinal Diseases

More than 34 million patients globally have retinal diseases that can be treated with anti-VEGF therapies, and the value of the global market for anti-VEGF treatments for these indications is estimated to be in excess of $13 billion in 2020. That figure does not include sales of unapproved repackaged IV Avastin^®, which is used to treat up to 50% and 30% of wet AMD patients in the United States and Europe, respectively. 

The driver behind the use of unapproved repackaged IV Avastin^® is the cost. The currently approved therapies run nearly $2,000 per dose, compared with approximately $100 per treatment for unapproved Avastin^®. We expect to market LYTENANA™, if approved, under a responsible pricing policy that provides a win–win scenario for clinicians, patients, and payors. 

Meeting a Key Unmet Need

There are some risks with the ophthalmic use of unapproved repackaged IV Avastin^®. First, it was formulated for oncology indications, not for retinal diseases. Second, Avastin^® is repackaged into syringes at a compounding pharmacy, where a single vial of IV Avastin^® is repackaged into 70–80 doses in syringes, with 70–80 different needles dipped into that vial. There is no way to ensure complete sterility during the process, which is not performed in a cGMP environment. There also are no standards regarding the needles used for ophthalmic drugs, and generally the syringes into which the Avastin^® is repackaged are not designed for use in the eye. Furthermore, there is no testing of the Avastin^® in those syringes of any kind, including with respect to how long the syringe can be stored. 

There is consequently a risk of syringe malfunction or contamination, as well as drug contamination or subpotency, all of which can potentially lead to severe complications, including infection of the eye (endophthalmitis) and even blindness or loss of an eye. 

Bringing to market an FDA-approved, cGMP-produced, responsibly priced ophthalmic formulation of bevacizumab designed specifically for retinal diseases will eliminate the problems that can occur when using unapproved repackaged IV Avastin^® from a compounding pharmacy. We believe that there is tremendous opportunity to greatly reduce the cost of care for patients while increasing patient safety. 

Furthermore, in many parts of the world, even unapproved repackaged IV Avastin^® is not available, and patient access to treatment is limited by the cost of the approved drugs. Our hope is therefore also to expand access to care on a global basis.

Going for a BLA

Outlook intends to file a Biologic License Application (BLA) for our ophthalmic formulation of bevacizumab (ONS-5010/LYTENAVA™) as a new drug for the treatment of retinal diseases. We are able to pursue this path because Avastin^® has never been approved for use in these indications. If approved, LYTENAVA™ will have 12 years of regulatory exclusivity.

Very Late-Stage Clinical Development

Our development of ONS-5010 for wet AMD is in the late clinical stages. We fully enrolled a pivotal study in early July and are expecting topline phase III data to be reported in early Q3 next year. We already have data from one completed clinical experience trial, and a third ongoing supplemental safety study will also be included in our BLA package. We intend to file our BLA with the FDA in late Q3 2021, with approval anticipated as early as mid-2022. 

One of the reasons we have been able to accelerate the development of ONS-5010 is access to a wealth of clinical use data, since unapproved bevacizumab has been so widely used for many years. Additionally, there are strong data demonstrating bevacizumab’s value in treating retinal disease from the National Eye Institute’s CATT study, which found that bevacizumab was not inferior to LUCENTIS^® (Novartis).¹

In our phase III program, ONS-5010 is dosed monthly. The LUCENTIS^® control arm involves three monthly loading doses of LUCENTIS^® followed by quarterly doses thereafter. By using these two different arms, we are confident that monthly dosing of LYTENAVA™ will be shown to be superior to quarterly dosing of LUCENTIS^®, which would result in a positive outcome for the study. 

We also expect to pursue approvals for ONS-5010 in DME and BRVO. If all goes as planned, we will start those studies in mid-2021 and aim to get FDA approval on those indications a year or two after the first approval for wet AMD.

Building a Midsized Ophthalmic Company

We believe that partnering with a life sciences company with commercial infrastructure would support our goals.. For the Asian market, we formed a joint venture with China-based Syntone Technologies to develop and manufacture LYTENAVA™ for Greater China. 

We have been successfully raising funds as we move through the development process for LYTENAVA™, with plans to generate a next round with our future partners, allowing us to keep our infrastructure lean and focused as we look to develop a pipeline around ONS-5010 and build out the company into a successful, mid-size ophthalmic company.

Reference

1. NIH study finds Avastin and Lucentis are equally effective in treating age-related macular degeneration. National Institutes of Health. 28 Apr. 2011. Web.