There is something uniquely exciting about being the first company to bring a much-needed product to market.
Outlook Therapeutics Inc (NASDAQ:OTLK) is hoping to become the first and only company to commercialize a US Food & Drug Administration (FDA) approved ophthalmic formulation of bevacizumab, otherwise known as the cancer drug Avastin, for use in a damaging retinal condition known as wet age-related macular degeneration, or wet AMD.
The chronic eye disorder leaks fluid into the retina and causes blurred vision or blind spots, which can eventually lead to loss of sight. For the nearly 700,000 people who suffer from the disease in the US alone, treatment options include expensive anti-vascular endothelial growth factor (anti-VEGF) drugs that can cost up to $2,000 a sitting and cause painful side effects like intraocular inflammation.
That’s what makes bevacizumab an attractive option – at around $100 per shot, there is a serious cost advantage. The problem, as with any off-label drug, is that there are risks to using unapproved bevacizumab across the value chain: potencies can vary, no physician standards in how to administer the drug, or a syringe malfunction, adding an extra layer of stress to an already unpleasant procedure.
Outlook Therapeutics is in the envied position of being the first and only company to develop what is essentially a known quantity with an established market in its lead drug candidate ONS-5010. If approved, ONS-5010, which will be marketed as LYTENAVA, will be the first on-label ophthalmic formulation of bevacizumab.
“Physicians already know how to use it, the FDA is comfortable with it and patients are already being treated with it, so it’s a huge market potential for us,” Outlook Therapeutics’ CEO Lawrence Kenyon told Proactive.
The market potential is significant: an estimated US$13.1 billion value from anti-VEGF drugs alone, not including unapproved bevacizumab, which represents around 50% of the wet AMD treatment market in the US. What’s more, wet AMD is a disease that primarily affects the steadily increasing elderly population.
The FDA is very familiar with the use of bevacizumab for wet AMD, but Outlook Therapeutics still needed trial data to prove that ONS-5010 was safe and effective as a treatment. So the group designed an initial proof-of-concept study called NORSE ONE that would provide more data on a small number of patients that showed bevacizumab was behaving as expected.
The study, which was run in Australia, only included 60 patients and would not achieve statistical significance by design. A control arm for the main anti-VEGF drug Lucentis was also included. As an endpoint, patients were expected to achieve a three-line (15-letter) gain in vision. Patients were either treatment-naïve or had a long-term history with wet AMD treatments, meaning they were not as likely to achieve the primary endpoint.
When the data from NORSE ONE was released last year, the results were “exactly what we expected to see,” according to Kenyon. The company saw that treatment naïve patients would have the best chance to see gains, with a third of the ONS-5010 patients achieving a three-line gain. The study also confirmed that ONS-5010 provided the benefit for patients losing their vision without any intraocular inflammation that is common with other anti-VEGF drugs.
But it is the pivotal NORSE TWO safety and efficacy study that investors are watching closely as it will achieve statistical significance.
The firm used the lessons learned from NORSE 1 to help design NORSE TWO, increasing its assurance in the process. What’s more, a Comparison of Age-related Macular Degeneration Treatments Trials (CATT) trial ran in 2011 by the National Eye Institute demonstrated bevacizumab to be equivalent to Lucentis – further adding to Outlook Therapeutics’ confidence.
NORSE TWO involves US patients. It is a randomized, masked, controlled trial of ONS-5010 versus Lucentis, both study arms include predominantly treatment-naïve patients with baseline visual acuity of less than 20/50 at the start of the study. The safety and efficacy data is expected in 3Q 2021 and will support a planned new US Biologics License Application (BLA) filing – essentially, an FDA submission for approval.
Outlook Therapeutics designed a superiority clinical trial, allowing it to enroll far fewer patients instead of doing a much larger non-inferiority study to Lucentis. The study compares monthly-dosed ONS-5010 to quarterly dosed Lucentis with the same endpoint as NORSE ONE. Based on data from the CATT study, that number should be about one-half of the monthly-dosed ONS-5010 patients.
“What we're hoping to see, quite frankly, is a difference of 10 points between those two arms, based on the historical data,” Kenyon said. “We can't use historical data to get approved, but if those numbers are proven out in the NORSE TWO study, we think we easily meet the endpoint.”
Because NORSE ONE and TWO were so streamlined and efficient, Outlook Therapeutics did not have enough patients in the safety database, which requires a minimum of 300 patients on the drug for approval. It recently ran a NORSE THREE open-label safety trial to bring it up to the required number of patients.
Topline results from NORSE THREE released in March 2021 demonstrated that ONS-5010 showed no unexpected safety trends and had a safety profile consistent with that of prior published data on the use of bevacizumab for ophthalmic conditions – results which Kenyon terms “excitingly boring.”
Initial response to the trial from the medical community is promising. NORSE THREE enrolled 197 patients in four weeks – a fact that CEO Kenyon called “pretty exciting.”
“It tells us doctors must feel comfortable that ONS-5010 is providing the same benefits that they would expect from any anti-VEGF treatment for wet AMD,” he noted.
Assuming NORSE TWO goes according to plan, Outlook Therapeutics expects to receive BLA approval from the FDA by mid-2022, giving it the first and only approved bevacizumab for use in retinal indications. And it has the cash runway to get it through the process, having recently closed a $35 million bought deal offering.
'Right product at right time'
Kenyon, who has been involved in multiple C-level roles at biotech firms for the last 20 years, says NORSE TWO is the lowest risk pivotal trial he’s ever seen. “It's not a slam dunk by any means, but quite frankly, we know in our minds that our bevacizumab is the same as Avastin. We haven't proven it, but we're confident that's the case.”
If the company can get ONS-5010 approved as the first ophthalmic formulation of bevacizumab, it is looking at a 12-year exclusivity period. Avastin will go off patent right around the time and Outlook Therapeutics would likely be approved to use the formulation. “It’s the right product at the right time,” Kenyon said.
Eventually, Outlook Therapeutics will look at using ONS-5010 to treat other retinal conditions, but for now, the firm’s sights remain firmly set on tackling wet AMD. Its executive team is well-versed in bringing new drugs to market – in fact, chief commercial officer Jeff Evanson previously served as the franchise head of the Lucentis program at Alcon/Novartis [AC3]. The firm has a solid base with which to build the infrastructure needed to bring ONS-5010 to market.
Kenyon is confident that the coming months will prove what Outlook Therapeutics’ team firmly believes – that ONS-5010 is the safe answer to treat debilitating retinal diseases.
“We’ve spent the last couple of years focusing on ONS-5010,” Kenyon said. “Long term, we think ONS-5010 would be a great building block. We have the potential to build an ophthalmic company around ONS-5010 once we get this asset across the finish line.”
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