Miebo
A Deeper Look at the Phase 3 “GOBI” Clinical Trial
Part 1
Recently, the FDA approved the eye drop Miebo, developed by Novaliq GmbH and marketed by Bausch & Lomb, for the treatment of evaporative dry eye disease. The results of the phase 3 clinical trial (called GOBI) were published in the May 2023 issue of the journal Ophthalmology.
Miebo contains 100% perfluorohexyloctane with no inactive ingredients. Perfluorohexyloctane belongs to a class of chemicals known as fluorinated alkanes, or hydrofluorocarbons. For patients concerned about how “natural” their eyes drops are, Miebo would qualify as very unnatural, because fluorinated alkanes do not exist in nature.
Perfluorohexyloctane, when mixed with a water-containing liquid, spreads on the surface of the liquid to create a monolayer (a single continuous interconnected layer of individual molecules of the drug). This monolayer slows evaporation of water. Therefore, perfluorohexyloctane potentially functions similar to Meibomian gland oil secretions to slow the evaporation of the aqueous layer of tears. However, the FDA label states that “The exact mechanism of action for Miebo in dry eye disease is not known.”
Perfluorohexyloctane has an interesting history in ophthalmology. It was originally used in complex retinal detachment surgery without undergoing clinical trials (not unusual in surgical innovation). The first article I can find related to its use in dry eye disease was published in 2015. Novaliq GmbH filed a patent on the molecule for ophthalmic administration in September, 2016. It has been marketed over-the-counter in the EU as EvoTears for several years (EvoTears costs about $15 for 3 mL).
Because it does not contain water, Miebo does not require anti-bacterial preservatives.
The Miebo GOBI trial was double-blind and “saline controlled.” Double-blind means that neither the patients nor the investigators knew which eye drop the patient received – Miebo or saline. The saline control was hypotonic saline 0.6% preserved with benzalkonium chloride 0.01% (normal saline is 0.9%). Both drops were used four times a day. Patient symptoms were scored using a visual analog scale (VAS) from 0 (no discomfort) to 100 (maximal discomfort). Patients were asked to separately rate the symptom of “dryness” and the combined symptoms of “burning or stinging.” The results of treatment with Miebo vs treatment with saline were compared to identify whether Miebo had any clinical benefit.
To be eligible for the trial, patients had to score at least 25 on the Ocular Surface Disease Index (OSDI) symptom questionnaire.
At week 8, the average VAS “dryness” score had decreased by about 27 points in the Miebo treatment group (indicating less symptoms) and by about 20 points in the saline treatment group. Due to the large number of patients in the trial, this difference was considered highly statistically significant (P < 0.001, smaller number means more statistically significant).
There are three questions the shrewd reader asks at this point. First, was the saline control an appropriate control? Second, is the ~ 7 point difference in the average VAS improvement meaningful to patients? Third, why weren’t the results of the OSDI symptom survey reported post-treatment?
In Part 2, we will deep-ish dive into these issues.
Part 2
There are three questions the shrewd reader asks at this point. First, was the saline control an appropriate control? Second, is the ~ 7 point difference in the average VAS meaningful to patients? Third, why weren’t the results of the OSDI symptom survey reported post-treatment?
Let’s talk first about the saline control. Hypotonic saline is the most “do nothing” control eye drop available. It has no lubricating properties. It will dilute hypertonic (excessively concentrated) tears. Using saline as a control will boost Miebo’s treatment benefit. It’s like having a thoroughbred (Miebo) and a pony (saline) in a symptom race. What if Miebo was compared against a well-formulated preservative free hypotonic artificial tear that contained lubricants? Now you have two thoroughbreds in the race.
Of course, Big Pharma remembers what happened with Restasis and they aren’t going to make that mistake again. Restasis was originally not approved by the FDA because there was insufficient evidence that the active ingredient – cyclosporine – added any value. Allergan had accidentally created a terrific OTC dry eye drop that worked just as well without cyclosporine as with it. Allergan had to wheedle and plead and torture their clinical data to finally get FDA approval for Restasis (based on Schirmer test scores rather than symptom reduction).
Amazingly, the GOBI saline control eye drop was preserved with benzalkonium chloride (BAK). BAK is well known to cause ocular surface irritation, which may have partially counteracted the benefit caused by the hypotonic saline itself, or may actually have made some saline-treated patients worse.
There was no statement in the article that the saline control drop was pH adjusted and buffered. If it was, leaving this information out was a mistake. Most likely there was water, sodium chloride and BAK in those bottles and nothing else. The problem is that unbuffered saline is usually acidic (has a pH lower than natural tears) and gets more acidic as time goes by. Acidic eye drops are not friendly to the ocular surface.
Now you have a thoroughbred (Miebo) running forward, in a race against a pony (unbuffered saline preserved with BAK) who is sometimes running forward, and sometimes stopping and backing up.
This will certainly make it easier for Miebo to win the race, and by a larger margin.
Nothing prevented the study investigators from packaging both eye drops in bottles with preservative-free multi-dose droppers, except the increased hassle and expense. Ditto utilizing a well-designed hypotonic saline control eye drop with a less irritating preservative, a neutral pH and a buffer system.
So my first objection to the GOBI trial is that the choice of control eye drop could be predicted to maximize the difference in outcomes between Miebo and the control. This is just good business for Novaliq GmbH and B+L, but does not fairly represent the benefit of Miebo to patients who may be paying a great deal of money out of pocket for it.
In Part 3, we will wander into the confusing land of statistics and outcome measures.
Part 3
There are three questions the shrewd reader asks at this point. First, was the saline control an appropriate control? Second, is the ~ 7 point difference in the average VAS meaningful to patients? Third, why weren’t the results of the OSDI symptom survey reported post-treatment?
My second objection to the GOBI report is that I dislike highly distilled statistics, because it is difficult to apply them in a predictive fashion to an individual patient. Statistical results reported in text format – as opposed to a graph or a table – are rarely read in detail (I read them). This makes the Results section a good place to stash less favorable data.
For example, buried deep in the fine print is an important statistic related to how many patients reported a 30% or greater reduction in their VAS dryness score after 8 weeks of treatment. This was 57.5% for the Miebo group and 46.6% for the saline group, which was much less statistically significant (P = 0.010) than the difference in average VAS dryness improvement (which had a P < 0.001). We can call this result “a little more than half” for Miebo and “a little less than half” for saline. Would you spend $200 a month out of pocket for this eye drop? For how long?
The VAS score is primitive – it is a single number. It is therefore straightforward to create a two-color bar graph comparing the results of Miebo vs saline, using categorical data such as “+10%, -10%, -20%, -30%, etc.” change in VAS dryness score (with positive numbers indicating worsening). Each percentage change category on the X axis would show the corresponding percent of patients in the two treatment groups whose VAS changed by that percentage, on the Y axis.
This type of graph is very easy for clinicians to interpret, and gives a comprehensive picture of the response of the entire trial population to the study drug vs the control drug. Investigators avoid publishing comprehensive trial data in this form when it would undercut the reader’s impression of the drug’s overall statistical effectiveness, which can also be conveyed by a blingy graph that only has two bars and will appear in all the sponsored symposia lectures (hint, see Figure 3).
My third objection is the failure to use the OSDI as an outcome measure. Patients were required to have an OSDI score of 25 or higher to be eligible for the study. If you’re going to collect OSDI data during enrollment, why not collect it at 8 weeks? I bet they did.
Diligent blog reader, stay with me now…
Patients were randomized between the Miebo and saline groups, with care taken to ensure an even distribution of severity through separately randomizing patients by VAS score (either less than 70, or 70 and greater). Because one person’s “80” symptom level might be another person’s “40,” the VAS is best used to assess the overall treatment effect in a patient population, not to predict the benefit to an individual patient based on that patient’s VAS for dryness. In other words, the VAS outcome measure can tell the FDA that a drug decreases dryness symptoms. It cannot tell you, the patient, how likely it is that the drug will work for you based on your current VAS score for dryness.
In contrast, the OSDI allows you to compare yourself to patients in the clinical trial. Although there is still a personal, subjective element to the OSDI, your own total score will decently stratify you against the range of OSDI scores of trial participants. The OSDI also allows for subgroup analysis based on symptom severity.
However, the GOBI trial avoided reporting any sub-group outcomes based on severity – even outcomes based on the VAS, which was considered an adequate proxy for severity since it was used for randomization. They didn’t report post-treatment OSDI data at all.
Hmmm, why is this? Taking a page out of Allergan’s book, the patent holders presumably did not want the FDA to narrow the indicated patient population by pointing out to the agency – or anyone reading the journal Ophthalmology – that certain groups of dry eye patients saw little or no benefit from Miebo relative to hypotonic saline. This might be less severe dry eye patients with lower OSDIs, it might be more severe dry eye patients with higher OSDIs, who knows. Probably the study investigators know, but they aren’t sharing that information. The very lack of sharing makes me suspect that Miebo is not only not super-effective for the majority of patients, but that it is not at all effective (relative to hypotonic saline) for identifiable sub-groups of the patients enrolled in the trial.
Stay tuned for Part 4, where I try to make all this have meaning for you, the actual patient.
Part 4
So what does my statistical monologue mean to you?
In my career I have seen vulnerable dry eye patients sucked into the spiral of ‘just one more month, just one more month’ of a particular costly treatment. I don’t want this to be you, when it comes to Miebo.
Please keep these points in mind….
Based on the GOBI trial, slightly more than half (57.4%) of patients who use Miebo will have a decrease in their dry eye symptoms – as measured by the Visual Analog Scale – of 30% or greater. That’s it. That’s what we know about the likelihood of benefit as it applies to you, the individual patient.
In slightly less than half (46.6%) of the control patients, hypotonic saline was also effective at reducing the VAS score by 30% or more. Even with BAK in it.
The investigators defined these patients as “eye dryness responders,” which suggests that they considered a VAS change less than 30% to be noise. This is not due to the investigators discounting the importance of a small decline in symptoms, but rather due to the inherent fluctuation in a patient’s self-assigned VAS score relative to the true severity of their dryness symptoms. Like I said earlier, small absolute changes in VAS – such as from 45 to 40 – are probably just noise.
Let’s flip the language around while we’re here: 42.6% of patients using Miebo were classified as eye dryness symptoms non-responders.
Are you underwhelmed? I’m underwhelmed.
Miebo probably works by creating an artificial lipid layer that slows evaporation of your own tears from the surface of your eye, thereby ensuring that the tonicity of your tears is closer to normal. If your dry eye symptoms are unrelated to your tear tonicity, Miebo may be less likely to work any better than an artificial tear would work.
Meibomian gland disease affects your tear film in a variety of ways not directly related to tear tonicity or an inadequate lipid layer. You could have a thick lipid layer made up of degraded lipids which affect the pH of your tears. Just having Meibomian gland disease does not automatically mean that Miebo is your wonder drop.
There is very limited animal data that suggests that Miebo penetrates Meibomian glands. This leads to the notion that somehow Miebo could decrease the viscosity of oils in those glands. Do not get sucked into the ‘just one more month’ mindset that you will unclog and revitalize your Meibomian glands through the use of Miebo eye drops.
If you want to try Miebo, do it systematically. Do an OSDI on yourself. Use Miebo 4 times a day diligently for 8 weeks. Don’t change anything else about your treatment regimen during this time. Don’t have in-office treatments like LipiFlow or IPL. Repeat the OSDI at the end of the 8 weeks (not sooner). Be honest on the OSDI. Don’t make mental excuses for an OSDI that isn’t better. Understand how the Placebo Effect might affect your OSDI (watch this video to learn more about the Placebo Effect).
If your OSDI total score is lower and there is no other reason for this to happen – for example, you didn’t go on a humid Caribbean vacation and leave your laptop at home – Miebo may be helping you.
What if your OSDI isn’t lower? Are you a bad patient?
No. If Miebo doesn’t help you, you are in good company and lots of it.
Remember that about 40% of the time, study patients using Miebo had a decrease in VAS score of less than 30%, which the investigators did not consider sufficient to classify those patients as “eye dryness responders.” So you’re part of the 40%.
Only you can decide what a meaningful decrease in your OSDI score is. It is completely fair to make this decision based on how much Miebo is costing you. The more it costs, the more you have a right to expect a substantial and sustained improvement in your dry eye symptoms, and a reduction in the need for other treatments.
More information
Publication of the GOBI trial:
Tauber J, Berdy GJ, Wirta DL, et al. NOV03 for dry eye disease associated with meibomian gland dysfunction: Results of the Randomized Phase 3 GOBI Study. Ophthalmology. 2023;130(5):516-524. doi:10.1016/j.ophtha.2022.12.021
Good geek links:
https://go.drugbank.com/drugs/DB17823
https://en.wikipedia.org/wiki/Fluorocarbon
https://pubchem.ncbi.nlm.nih.gov/compound/1-_Perfluorohexyl_octane#section=Consolidated-References
Patent filing:
