2023-06-10 01:06:36 ET
Summary
- OTLK is developing an ophthalmic formulation of bevacizumab.
- There is a logic behind this, and there's also positive data.
- However, certain developments stop me from being overly enthusiastic.
Outlook Therapeutics ( OTLK ) is developing the first ophthalmic formulation of anti-VEGF monoclonal antibody bevacizumab. This has been a long way in the making. The BLA is supported by three phase 3 trials, NORSE 1, NORSE 2 and NORSE 3. NORSE 1 produced positive data way back in August 2020. NORSE 2 produced positive data exactly one year later, although the trial used a slightly nonstandard dosing regimen for the ranibizumab comparator arm. NORSE 3 was a short, 3-month supportive study, also producing positive data.
Outlook went with this data to the FDA in March 2022. However, 2 months later, the FDA asked for more data, and Outlook pulled its BLA. It regrouped, resubmitted its BLA with the additional data in September, and the FDA accepted it in October, giving a PDUFA date for August 29, 2023.
Bevacizumab, branded Avastin in cancer, is an anti-VEGF mAb widely used off-label in wet AMD and other retinal diseases. Wet AMD is a disease where abnormal blood vessels form in the retina. These blood vessels leak blood and other fluid into the retina, whence the term “wet” AMD (advanced macular degeneration). Left untreated, this fluid buildup may cause permanent damage to the retina, causing loss of central vision. For over a decade, it has been known that vascular endothelial growth factor (VEGF) is responsible for abnormal blood vessel formation, not only in the tumor microenvironment, but also in the retina. Just like with cancer, anti-VEGF molecules can bind to and inhibit VEGF, stopping the formation of these blood vessels.
Now, bevacizumab is a major anti-VEGF treatment widely used in cancer. Interestingly, it has never been FDA-approved for ophthalmic use despite ophthalmologists using Avastin off label for over a decade. In fact, 50% of all wet AMD injections - approximately 3.5 million injections in the US - use off-label bevacizumab. It is widely used because it is cheap, costing about $50 per injection versus nearly $2000 for branded Eylea/Lucentis, and it is safe and very effective. Studies have shown that ophthalmologists will generally start off a patient with off-label bevacizumab - more so if the patient has inadequate coverage - and only move on to another drug as required.
In a large, 1200+ patient trial sponsored by National Institutes of Health (NIH) and coordinated by the University of Pennsylvania, called the “CATT” trial, bevacizumab was compared with ranibizumab in wet AMD patients. Data showed that the two treatment options produced almost equivalent outcomes in patients, with minor points in favor of ranibizumab. The data was this:
Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 ?m) than in the other groups (152 to 168 ?m, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
This was the trial that was replicated in NORSE 2 with some modifications. NORSE 2 data , which slightly favored bevacizumab, was as follows:
The NORSE TWO pivotal data met both primary and secondary endpoints with statistically significant and clinically relevant results:
41.7% (p = 0.0052) ONS-5010 subjects gained ? 15 letters of vision
56.5% (p = 0.0016) ONS-5010 subjects gained ? 10 letters of vision
68.5% (p = 0.0116) ONS-5010 subjects gained ? 5 letters of vision
ONS-5010 subjects gained 11.2 letters (p = 0.0043) in BCVA
Results from NORSE TWO also demonstrated that ONS-5010 ophthalmic bevacizumab has a strong safety profile. In findings that are consistent with historical bevacizumab data reported in prior research, in all three ONS-5010 registration trials there was only one ocular inflammatory adverse event, which was treated topically and resolved without sequelae. The safety findings continue to support minimal ocular inflammation and safety signals consistent with what was previously reported in the 2011 CATT trial (National Eye Institute) and other large bevacizumab-controlled ophthalmic studies.
Here, the Lucentis arm used the regimen used in the PIER trial, which was:
Patients received Lucentis 0.3 mg or 0.5 mg intravitreal injections … once a month for 3 consecutive doses, followed by a dose administered once every 3 months.
However, according to the labeling, the standard regimen is this:
The recommended dose for Lucentis in adults is 0.5 mg (0.05 mL) or 0.3mg (0.03mL) given monthly as a single intravitreal injection.
Thus, the PIER regimen falls midway between the once-monthly regimen, which doctors may not always use but Novartis recommends as more effective, and the as-needed regimen with monthly evaluation, which was already used in the CATT trial, but which may cause neglect . There is no “official” dosing regimen for bevacizumab, although, anecdotally, it is also used monthly, at 1.25mg in adults. So, while using the PIER regimen is a small worry, I do not think it is an off-the-chart concern. It is moot, though, whether the different regiment produced slightly different data in CATT and NORSE 2.
So, given the wide off-label use of bevacizumab, what is the necessity of an approved formulation besides helping the company ramp up prices? Well, the drug comes in bulk from unapproved repackaged IV bevacizumab from compounding pharmacies. Because these compounding pharmacies are not FDA-regulated, differences in drug concentration (hence potency) and contaminants may appear in the repackaged syringe. A study from last year discusses some of the problems with compounded bevacizumab:
Typically, 70 to 80 separate aliquots are taken from one bevacizumab vial and repacked for intraocular use. This repetitive process opens the door to contamination; one of the most serious risks from contamination is bacterial endophthalmitis. Unfortunately, cases of endophthalmitis caused by repackaging of bevacizumab have been reported.
The repackaging process relies on human judgment as to the quantity of drug aliquoted into each syringe, and given that only a tiny amount is needed, even a small variation due to human error can significantly affect the actual dosage that a retina patient eventually receives. Studies3 have shown that prefilled syringes vary in terms of how much bevacizumab is provided, with underdosing being common; the impact of underdosing, of course, is that patients may appear not to be responding appropriately to treatment, when in fact they simply may be receiving a subtherapeutic dose of the anti-VEGF medication.
Other risks derive from lack of FDA-reviewed analytical methods, specifications, drug stability data, unknown quantities of particulates or bacterial endotoxins, unverified FDA-approved pH levels, or even the temperatures at which the syringes are filled, stored, and shipped. Faulty performance along any of these dimensions can damage the molecule and compromise its safety and efficacy.
The company also cites several issues:
As reported in a study published in JAMA, 81% of all tested syringes of repackaged bevacizumab received from compounding pharmacies contained suboptimal protein concentrations, which could result in lower clinical efficacy.
Non-standard materials used to transfer and hold repackaged bevacizumab can potentially add particulates to non-ophthalmic-designed bevacizumab, which in turn may fail to meet the standards FDA requires for ophthalmic compounds.
Risks
More importantly, Lucentis' patent expired in 2020 and the drug is already available in a generic form. Eylea patent will expire this year, and multiple ANDAs are in line. Thus, the cost differential between these proven ophthalmic anti-VEGF inhibitors and bevacizumab is going to reduce significantly over the next few years. The need for an on-label bevacizumab ophthalmic formulation (note, ONS5010 is NOT a biosimilar because it is not for the same approved indication), therefore, reduces significantly.
Outlook’s other problem is cash. It has a cash balance of just $43mn. Last quarter, the company spent some half a million in R&D and a bit above $6mn in G&A. The company states that the current cash is “ expected to be sufficient to fund its operations through the anticipated approval of the BLA for ONS-5010 in the third calendar quarter of 2023, and potentially through the fourth calendar quarter of 2023.”
Bottomline
OTLK stock is up over 50% since early May, when it presented earnings. There is a logic to the company’s development of ONS5010, and their trial data has been very positive. On the flipside, like I discussed, they have low cash, not enough to produce a solid marketing team, and the availability of Lucentis and Eylea generics will curtail their market. If I am in a gambling mood, I will buy some shares and wait for the August PDUFA, but I will not be holding beyond that date.
For further details see:
Outlook Therapeutics: August PDUFA May Be A Buy With Some Caveats