There’s a question the CEO of Outlook Therapeutics Inc (NASDAQ:OTLK) likes to pose about why having US Food and Drug Administration (FDA)-approval will propel the company’s upcoming treatment for retinal eye diseases to the top of the market.
“Say I’m an eye care doctor. I’m considering an off-label product that has no labelling for the treatment I’m about to perform, and then, I have available to me a new biologic complete with FDA-approved packaging, labelling, instructions, and certainty that it meets specifications required for ophthalmic use. Which one would I be more likely to choose?”
The answer is the reason for the late clinical-stage biopharmaceutical company and CEO Russ Trenary’s quest to get proprietary drug Lytenava into the hands of healthcare professionals.
READ: Outlook Therapeutics encouraged by FDA acceptance of application for drug to treat retinal eye disease wet AMD
Achieving FDA approval – something that Outlook Therapeutics hopes will happen by the end of summer 2023 – will mark the launch of the first standardized and regulated bevacizumab in the ophthalmology arena, which currently uses a drug normally prescribed for treating cancer that is re-handled and re-packaged for use in ophthalmology.
‘Off-label’ is when an FDA-approved medication is used for a different purpose than previously approved.
The protein behind retinal diseases
In humans, vascular endothelial growth factor (VEGF) causes several types of retinal diseases including wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), and branch retinal vein occlusion (BRVO).
A signal protein produced by cells to stimulate the formation of blood vessels, VEGF can also cause abnormal blood vessels to grow in the wrong place in the back of your eye. Anti-VEGF drugs stop the abnormal blood vessels leaking, growing and bleeding under the retina.
“Initially the leakage from new vessels stimulated by VEGF impairs your vision, but ultimately, it can cause a vast level of blindness,” Trenary said.
How a cancer drug came to be used for eye disease
Biotechnology company Genentech first developed an anti-VEGF drug called bevacizumab under the brand name Avastin. It’s administered in large volumes via a drip IV line to patients who have various types of cancer.
A similar drug called ranibizumab was an early option to treat patients with wet AMD and other vision problems. However, the price per injection came in around US$2,000 per shot, which, when a patient needs monthly injections, adds up quickly.
In May of 2005, a retina specialist from Bason Palmer provided the first eye injection of bevacizumab to treat a wet AMD patient.
Based on this success, “Some doctors got together with the National Eye Institute in the US, and conducted a study,” Trenary said. “The repackaged clinical supplies under an IND and GMP conditions took Avastin and put it into a small volume vials and injected it into patients’ eyes.”
That would drop the price of the injections significantly, he said, assuming quality, safety and efficacy could be maintained at the highest level. Although quality issues became numerous over time, off-label Avastin use grew to be approximately 50% of the injection volume in the US, according to market research.
Outlook Therapeutics’ ophthalmic formulation
Iselin, New Jersey-based Outlook Therapeutics has been studying an ophthalmic formulation of bevacizumab – identified as ONS-5010 – and the company plans to market it under the brand name Lytenava.
Three clinical trials – Norse One, Two and Three – were conducted with patients in the US and Australia who have wet AMD, DME, or BRVO.
The results were impressive. In patients with 20:50 or worse vision, the treatments allowed many to read three additional lines on an eye test chart.
Trenary said the Norse Two pivotal trial, which included wet AMD patients only, showed that almost 42% of the 228 eyes in that study were three-line gainers, while 56% gained two lines, and 68.5% gained one line of extra vision.
“According to our study data, almost 70% of those patients gained at least a line of vision, which is five letters on the eye chart,” Trenary said. “So, we're really happy with the data that we put together and we submitted our biologics license application (BLA) to FDA in the last week of August 2022.”
The FDA filed Outlook Therapeutics’ application on October 28, and the administration is expected to render a final decision by the end of August 2023, Trenary said.
Why choose an FDA-approved treatment over off-label?
Eye disease specialists like to do ‘loading doses’ when treating their patients, which means the doctors inject the drug into their patients’ eyes once a month for approximately three months, Trenary said.
After the loading doses are complete, those doctors often wait to see the degree of improvement. Depending on the outcomes they may add additional injections during the course of a year.
It sounds good, but if the doctor is using off-label bevacizumab there may be a problem with what’s actually in those injections, according to Trenary. Or more precisely, what’s not.
A study published in the Journal of the American Medical Association in 2015 evaluated pharmacy-compounded bevacizumab. Led by Dr Nicolas Yannuzzi, a group of doctors found these intravitreal injections contained statistically significant variations in protein concentration among samples.
“They did a random sample of compounded bevacizumab, and studied the amount of drug protein concentration and found that 81% of the samples had insufficient drug protein concentration,” said Trenary.
“It brings up a question in a doctor’s mind: ‘I can see the volume that's going in, but I can't see how much drug is in there’.”
That’s the pharmacological bulls-eye Outlook Therapeutics is aiming to hit.
“We have to validate processes regarding the amount of drug that goes into each one of our vials and syringes. So, we think there are a whole host of reasons, just by virtue of meeting FDA requirements in ophthalmology, that a doctor would logically choose our bevacizumab over the off-label bevacizumab they've used in the past,” he said, adding the FDA ophthalmic standards are different than what’s required for a biologic that’s administered via drip IV.
Trenary said the FDA requires Outlook Therapeutics to hit targets in drug protein concentration, particulates, osmolarity, how the drug is suspended in solution, in pH levels and endotox levels, stability and shelf life, and even the way it’s packaged.
“We have to show the same amount of drug protein concentration, vial by vial, syringe by syringe,” he said.
Market size means there’s a lot riding on FDA approval
In the US alone, the sales value for this particular treatment for retinal diseases is about US$7 billion. Trenary said the vast majority of that goes to companies with biologics with a high price point, although those are only around 50% of the injections.
“The other 50% of injections that are off-label and have no FDA approved ophthalmic labelling are priced far less than the products approved for ophthalmic indications. So those really add only several hundred million dollars of sales value to the total market size,” he said.
The American Society of Retinal Specialists conducted a survey of ophthalmology surgeons that showed about 66% of patients are started on off-label Avastin. However, the study also showed the doctors would often switch to using Lucentis or Eylea, according to Trenary.
It could be for scientific and medical reasons, he said, and in the US, that’s enough to get an ophthalmologist to tell the payer – health plan providers, Medicare, and Medicaid – they need to try a different drug.
“If we can deliver something that has the right amount of drug, it's been temperature controlled, it's got the right pH level, a lack of particulates, and has FDA-approved packaging, the endotox levels are correct, everything meets FDA standards, then maybe if you start two-thirds of your patients on it, you'll be able to keep using it. You may not have to switch,” he said.
And the launch isn’t coming as a surprise to American eye doctors. A recent flash market survey by Spherix asked the retinal community if they knew Outlook Therapeutics is trying to get FDA approval for Lytenava.
“Half of the doctors said they knew, which surprised me because we don’t have any reps yet,” said Trenary, adding Spherix also asked if the new drug would be an improvement.
“Eighty per cent of the doctors said it was advancement. So, they get the fact we're going to meet FDA requirements,” he said. “We’re really happy to see those results.”
Planning for the commercial launch
With those statistics in mind, Outlook Therapeutics has entered into a strategic relationship with healthcare company AmerisourceBergen in preparation for the commercial launch of Lytenava in the US and Canada.
“We're going to be able to launch this product in 2023 in a way that you couldn't do 10 years ago, because there was no distribution company that had this level of service they could offer to a drug or biologic company,” Trenary said, noting it puts Outlook Therapeutics on an even footing with the big pharmaceutical companies.
“It adds a lot of muscle to our efforts to get an ophthalmic FDA-approved bevacizumab into the hands of doctors treating retinal disorders and working to improve vision for the people who need an anti-VEGF drug.”
Contact the author at susie@proactiveinvestors.com