Welcome to Glaukos Corporation's Fourth Quarter and Full Year 2020 Financial Results Conference Call. A copy of the company's press release issued after the market close today is available at www.glaukos.com. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one on your telephone. This call is being recorded, and archive replay will be available online in the Investor Relations section at www.glaukos.com. I will now turn the call over to Chris Lewis, Director of Investor Relations and Corporate Strategy and Development.
Thank you, and good afternoon. Joining me today are Glaukos President and CEO, Tom Burns, CFO, Joe Gilliam, and COO, Chris Calcaterra. Following our prepared remarks, we'll open the call to questions. To ensure ample time and opportunity to address everyone's questions, we request that you limit yourself to one question and one follow-up. If you still have additional questions, you may get back into the queue. Please note that all statements other than statements of historical facts made on this call that address activities, events or developments we expect, believe, or anticipate will or may occur in the future are forward-looking statements.
These include statements about our plans, objectives, strategies, and prospects regarding, among other things, our sales, our products, our pipeline technologies, our U.S. and international commercialization, integration, and market development efforts, the efficacy of our current and future products, our competitive market position, financial condition, and results of operations, as well as the expected impact of the COVID-19 pandemic on our business and operations. These statements are based on current expectations about future events affecting us and are subject to risks, uncertainties, and factors relating to our operations and business environment, all of which are difficult to predict and many of which are beyond our control. Therefore, they may cause our actual results to differ materially from those expressed or implied by forward-looking statements. Read today's press release and our recent SEC filings for more information about these risk factors.
You'll find these documents in the investor section of our website at www.glaukos.com. Finally, please note that during today's call, we will also discuss certain non-GAAP financial measures, including results on an adjusted basis. We believe these financial measures can facilitate a more complete analysis and greater transparency into Glaukos' ongoing results of operations, particularly when comparing underlying results from period to period. Please refer to these tables in our earnings press release that is available in the investor section of our website for a reconciliation of these measures to their most directly comparable GAAP financial measure. With that, I will turn the call over to Glaukos President and CEO, Tom Burns.
Thank you, Chris. Good afternoon, everyone, and thank you for joining us today. Before we discuss our fourth quarter results, I want to spend a few minutes reflecting on the year 2020. By all accounts, the COVID-19 global pandemic created an unprecedented past year and challenged the conventional ways our companies, employees, and customers operate both personally and professionally. The response plans we prioritized and implemented in 2020, including protecting the health and safety of our employees and their families, supporting our customers, preserving jobs globally, protecting core research and development projects, and maintaining our strong financial and operating position following the pandemic, have allowed us to stay focused and advance our key strategic priorities during uncertain times. As a result, I believe we exited 2020 a more efficient and more capable company with fundamental prospects that have never been stronger.
As the corporate pioneer of MIGS and corneal cross-linking, we have been honored to partner with our customers and clinical investigators to help them navigate a rapidly changing environment through the implementation and expansion of various virtual and digital programs including customer support, training, case proctoring, and educational initiatives. I'm confident that these efforts have helped deepen our customer relationships and prepare us for the future well beyond COVID-19. Finally, I want to thank these very customers for everything they are doing to serve the needs of patients worldwide during the pandemic. Overall, I'm proud of our performance this past year and of our team's resiliency and steadfast dedication to advancing our mission to create novel platforms that disrupt conventional treatment paradigms, advance the existing standard of care, and enrich the lives and treatment alternatives for patients worldwide.
In doing so, we strive to create a world-class global vision care leader uniquely positioned to drive innovation across glaucoma, corneal health, and retinal disease. Within each of these areas, we are moving full speed ahead with the same pioneering discipline, pipeline development expertise, and skilled commercial execution that has made us the worldwide leader of the MIGS marketplace today. Our ability to execute our plans over the past year not only illustrates our effective ongoing response to the current market environment, but is also a reflection of the progress we continue to make towards our broader strategic vision. Consider our key 2020 accomplishments. One, we executed on our corneal health franchise integration, expansion, and market development plans, evidenced by record new starts and Photrexa sales.
Two, w e successfully launched the next generation iStent inject W device in the U.S. and select international markets. Three, reported strong international glaucoma sales and secured new market-expanding regulatory approvals in key markets such as Australia, Japan, and India. Four, we advanced key market access and reimbursement initiatives, including the creation of new Category III CPT codes for iDose and standalone MIGS. Five, w e implemented a global systems upgrade transformation designed to support long-term growth. Six, w e executed financially during unprecedented times, not only through encouraging sales recovery trends but also with strong gross margins, disciplined operating spending, and continued preservation of our strong balance sheet, bolstered by a $288 million convertible debt financing to further strengthen our ability to aggressively invest in our pipeline and future growth opportunities.
Last but certainly not least, we advanced our industry-leading proprietary pipeline that we believe has the ability to significantly expand our addressable market opportunities beginning this year. As most of you know, our goal is to leverage our development expertise and commercial infrastructure to provide a portfolio of novel solutions that meet the full algorithm of customer needs. A key pillar in delivering on this strategy is the continued progression of our deep pipeline. I'd like to spend a few minutes highlighting exciting new clinical data shared earlier this year for two of our key glaucoma pipeline programs, iDose TR and iStent infinite.
Starting on iDose TR, our travoprost drug delivery implant, we were delighted to announce what we believe is powerful and compelling data that further underscores the potential for this technology to safely provide multiple years of sustained glaucoma pharmaceutical therapy and 24/7 compliance to tackle the significant problem of patient non-adherence to topical glaucoma medication regimens. The recently announced 24-month interim analysis of our ongoing 36-month phase IIb trial showed compelling results with both iDose arms continuing to demonstrate robust IOP lowering over 24 months to the magnitude of approximately 7 to 8 millimeters of mercury o r nearly 30% reductions from baseline over the first 24 months. Interestingly, a subset analysis showed at least 20% of iDose subjects achieved robust average IOP reductions from baseline of at least 40%.
These results were achieved with a single iDose implant compared to the timolol control arm that received twice-daily drops over the 24-month evaluation period, or nearly 1,500 eye drops per eye. As a reminder, iDose TR is implanted into the trabecular meshwork to avoid migration through a very facile procedure, and the most recent phase II data readout demonstrated a favorable safety profile with no clinically significant corneal endothelial cell loss, no serious corneal adverse events, and no adverse events of conjunctival hyperemia reported to date in either high-dose solution arm. We believe there is an important unmet clinical need and strong appetite within the ophthalmic community for safe, effective, and durable sustained-release pharmaceutical alternatives to traditional topical medications. This powerful 24-month interim data reaffirms our excitement about the potential commercial prospects of iDose.
We continue to progress towards enrollment completion in our ongoing iDose TR phase III clinical program, which will mark another critical step in bringing this technology to the market. We are targeting FDA approval for this promising technology in 2023. The 12-month phase III trial results are expected to support our anticipated NDA submission for iDose TR in 2022. The powerful iDose data available thus far underscores our confidence in the potential of this Novel Drug Delivery platform to produce future generations of sustained therapies for glaucoma and potentially other ocular diseases. As such, we continue to invest resources to expand our pharmaceutical development capabilities and to develop future iDose solutions.
With that in mind, we are in late-stage development with finalized designs for next generation iDose TR extended release implants, also known as iDose TREX, which is in a similar size and form factor to the original iDose TR. It's designed to provide nearly twice the drug capacity to extend efficacy durations even longer. We will be engaging with the FDA in the near future to determine the most appropriate and expeditious regulatory pathway for this novel product. We are also seeking additional drug classes that may be synergistically used in conjunction with the iDose platform. Through our research and development agreement with D. Western, we are currently assessing multiple ROCK compounds which are showing positive results in animal models, and we're establishing prototype implants for lead candidates in these same models.
ROCK inhibitors, when used in conjunction with prostaglandins, have been shown as a powerful treatment in reducing intraocular pressure in U.S. pivotal studies. Moving on to iStent infinite, our three-stent system designed for use in a standalone procedure for late-stage glaucoma patients. We are excited to have recently announced strong 12-month IDE pivotal data that shows 76% of subjects achieved 20% or greater reduction in month 12 mean IOP on the same or lower medication burden, with more than 50% of subjects achieving month 12 IOP reductions of at least 30%. Subjects also achieved a 13% mean reduction in medication burden at 12 months. The safety profile in the study was highly favorable, with no explants, infections, or device-related interventions or hypotony reported through 12 months.
When pairing these strong pivotal results with the advanced disease progression profile of the enrolled subjects that were on an average of three medications with two failed prior surgeries, we believe ophthalmic surgeons will view iStent infinite's risk-benefit profile very favorably and as a compelling new treatment option. We continue to target FDA approval of iStent infinite in late 2021. Beyond these important glaucoma pipeline programs, we also remain in early preparations for the potential U.S. commercial launch of Santen Pharmaceutical's PRESERFLO MicroShunt, an elegant ab externo surgical implant for late-stage glaucoma management. We continue to ramp up our commercial preparations for this promising opportunity ahead of an anticipated FDA approval and commercial launch. We also recently announced that we are in late-stage development of iPRIME, a highly complementary new viscodelivery device designed to be a truly minimally invasive system to further support the needs of physicians and patients.
Within corneal health, we issued a separate press release this afternoon announcing positive phase III results for our next-generation corneal cross-linking iLink Epioxa investigational therapy. We're excited to announce results from a multi-center randomized controlled phase III pivotal study that met the primary efficacy endpoint with statistically significant improvement in maximum corneal curvature or Kmax. Kmax is an objective measurement of the steepest corneal curvature based on corneal topography, where an increase in Kmax denotes corneal steepening and keratoconus disease progression. At six months, the Epioxa treatment arm showed a Kmax mean improvement of 0.2 diopters from baseline compared to a Kmax mean worsening of 0.8 diopters from baseline in the placebo control arm, resulting in the statistically significant mean treatment effect of one diopter meeting the study's primary efficacy endpoint.
Most importantly was that the Epioxa therapy demonstrated the ability to halt or reduce the progression of keratoconus while disease progression was observed in the study's placebo control arm. The treatment was generally well-tolerated and the majority of adverse events reported were mild and transient in nature. These positive results underscore our view that Epioxa may provide the ophthalmic community and keratoconus patients with the first non-invasive bio-activated drug treatment alternative designed to reduce procedure times, improve patient comfort, and shorten recovery times. The positive phase III results are expected to support a U.S. NDA submission in 2022, and we are targeting FDA approval for Epioxa in 2023. Beyond these near to medium-term opportunities, we also continue to invest in and advance our key earlier-stage R&D programs, including in dry eye and retina.
While these opportunities remain in pre-clinical developmental stages, we are excited with the initial progress we're demonstrating within these programs. Our pipeline has the ability to fundamentally transform Glaukos by significantly expanding our addressable markets over time. To enable this, we have built a strong balance sheet to provide us with the financial flexibility to remain on offense as the COVID-related dynamics play out by expanding our global infrastructure, strengthening our pharmaceutical expertise, upgrading our enterprise systems, advancing our core R&D programs, and supporting our clinical programs as they progress towards becoming commercial realities. Speaking of commercial realities, we've been pleased with the strong recovery trends in our business since the peak of the pandemic that continued through the fourth quarter.
While procedure recovery trends remain somewhat volatile, I've been encouraged by how physician offices, ASCs, and hospitals are navigating this new normal, and I'm pleased to report fourth quarter net sales of $73.2 million that exceeded our expectations across our glaucoma and corneal health franchise globally. During the fourth quarter, we commenced an official full-scale launch of the iStent inject W in the U.S. The iStent inject W builds upon the proven foundation of our iStent inject platform and is designed to offer ophthalmic surgeons the same established safety and efficacy of iStent inject with the added benefits designed to optimize stent visualization, streamline implantation, and deliver procedural predictability. The early feedback and real-world results for iStent inject W remain very positive and reaffirms our confidence in the commercial prospects for this important technology.
We've also launched iStent inject W more broadly in many of our key international markets, including various European countries, Japan, and Australia. This adds to a number of 2020 accomplishments in our international glaucoma franchise that positions us well for long-term growth, including Standalone Indication Approval in Australia, iStent inject W regulatory approval in Japan, iStent and iStent inject regulatory approval in India, and continued progress across many of our key market access initiatives. Finally, over the course of 2020, we made significant strides to firmly establish corneal health as a new franchise and future growth engine for our organization. Not only are we ahead of plan on the cost savings targets we announced at the time of the deal, but more importantly, we continue to execute on our commercial strategies and market development initiatives.
Which include driving increased awareness of keratoconus broadly across the optometric and ophthalmic community, advancing the diagnosis of this important debilitating condition, streamlining the referral pattern from initial diagnosis to treatment, implementing customer-friendly programs to drive new account starts, optimizing reimbursement, investing in health economics to further solidify the value of corneal cross-linking to patients and healthcare systems and finally, training corneal health professionals on our iLink procedure. To support this progress, we continue to opportunistically expand our U.S. corneal health commercial team. We are pleased to see another new record for U.S. TREX sales established in the fourth quarter, an encouraging sign that our strategies and programs we've introduced are resonating. While we remain in the early stages of unlocking the combined organization's full potential, we're encouraged with this performance and excited about the opportunity ahead.
In summary, we're creating a unique vision care leader prepared to drive a robust cadence of innovation that can significantly expand our market opportunities and drive sustainable growth and profitability over the next decade. While we of course remain cautious on the near-term uncertainties associated with COVID-19, the strong foundation and team rebuilt leaves me confident in our ability to execute on our plan and advance our mission to transform the treatment of chronic eye diseases for the benefit of patients worldwide. With that, I'm going to turn the call over to Joe to discuss our fourth quarter 2020 financial results. Joe.
Thanks, Tom. As a reminder, I will be discussing our financial performance on a non-GAAP or pro forma basis, and will summarize our GAAP performance later in my prepared remarks. I encourage each of you to review our GAAP to non-GAAP reconciliation, which can be found in today's press release as well as the investor relations section of our website. Glaukos net sales for the fourth quarter of 2020 were $73.2 million, representing sequential growth of 13%. Net sales grew 11% versus fourth quarter 2019 reported sales of $65.8 million, and increased approximately 1% on a pro forma year-over-year basis, adjusting for a full fourth quarter 2019 contribution of Avedro, given that transaction closed in November 2019. These results exceeded our expectations and reflect the continued recovery despite ongoing COVID-19 related headwinds and associated volatility.
With respect to the pandemic impact, it is worth noting that performance in the quarter was strong across each of our franchises, but we did experience more intra-quarter volatility than normal, including a more pronounced softness around the holidays in November and exiting the year than we might typically experience. Now, turning to our U.S. glaucoma franchise specifically. Our fourth quarter U.S. glaucoma sales were approximately $43.7 million, representing sequential growth of 12%, which we believe reflects a combination of COVID-related dynamics, a more stable competitive landscape, and continued stable pricing. It is also worth noting that we began to see an uptick in new doctor training during the quarter, an encouraging sign, even if we are not fully back to normal yet. Internationally, our glaucoma franchise delivered fourth quarter sales of approximately $14.6 million, representing sequential growth of 15%.
The COVID-19 impact to our international glaucoma business has varied by market, but our overall recovery in the quarter was led by Japan, Australia, and the other major European markets, while the situation in Brazil and Latin America generally remains challenging. In corneal health, fourth quarter net sales were $14.9 million, representing sequential growth of 15%. The fourth quarter performance was driven by record U.S. Photrexa sales of $12.5 million and the continued trend of strong new U.S. Photrexa starts as our commercial integration and strategies continue to deliver despite the pandemic. Shifting gears for the remainder of our P&L, our non-GAAP gross margin in the fourth quarter was approximately 83.4% versus 84.7% in the same quarter in 2019, and 84.9% in the third quarter of 2020.
This reflects the modest headwinds associated with iStent inject to iStent inject W transition and the sale of inventory that had been produced less efficiently during the height of the pandemic. It is worth noting that our non-GAAP adjustments to COGS include substantial adjustments related to Avedro acquisition accounting. Our overall non-GAAP operating expenses were approximately $61.5 million in the fourth quarter of 2020, remaining below pre-COVID levels but up 7% sequentially compared to the third quarter, as we continue to reverse temporary cost saving initiatives and restore expansionary spending as the recovery warranted, a trend that we would expect to continue in 2021. Our non-GAAP SG&A expenses in the fourth quarter were approximately $40.2 million, up 7% sequentially compared to the third quarter, reflecting increased commercial activity.
Our non-GAAP R&D expenses in the fourth quarter were approximately $21.3 million, up 6% sequentially compared to the third quarter as we continue to restore earlier stage pipeline programs and human capital investments across the organization. We finished the fourth quarter with a non-GAAP operating loss of $0.4 million and a non-GAAP net loss of $0.8 million, or $0.02 per diluted share. Our GAAP net loss was $10.6 million, or $0.24 per diluted share for the fourth quarter of 2020. We invested in approximately $2.1 million of capital expenditures in the fourth quarter. Looking ahead, we expect our capital expenditures to increase substantially over the next two to three quarters as we enhance and expand our facilities in Southern California and Boston to meet our expanding development and operational needs.
As of December 31st, 2020, we had cash equivalents, short-term investments, and restricted cash of approximately $414 million, an increase of $16 million compared to $398 million at the end of the third quarter of 2020. Finally, let me make a few comments on the state of our markets and opportunity today and how we believe things are unfolding for 2021. We believe the competitive landscape and pricing dynamics remain stable across each of our major business areas. As Tom mentioned earlier, our integration efforts and strategies are driving increasing penetration in corneal health alongside a successful launch of iStent inject W globally in glaucoma. Not surprisingly, the overall ophthalmic market still faced COVID-related headwinds in terms of new patient consultation visits, practice closures due to personnel testing positive, and the ability of surgical practices to work fully staffed and at full capacity given enhanced safety protocols.
Having said that, we've been encouraged by improving trends on each of these fronts through the fourth quarter and thus far in 2021. We've also been encouraged by our improving new surgeon training trends and our increasing access to practices, albeit with restrictions that make typical day-to-day commercial activities challenging still. We do recognize, though, that the dynamics associated with COVID-19 and its variants remain fluid. For example, as the global vaccination efforts ramped in late January and February, it appears that some patients may be predictably electing to defer procedures until after they've been fully vaccinated. This is a short-term but relevant trend. To put this in context, our performance thus far in 2021 has exceeded our plan as we experienced year-over-year growth trends across each of our franchises in January.
The vaccine dynamics and several lost selling days throughout much of the U.S. due to the recent severe winter weather led to a softening of those trends in February. As we put all this together in the context of our expectations going forward, we expect first quarter 2021 net sales to increase approximately 15% to 20% compared to first quarter 2020, which reflects our typical seasonality patterns and the first quarter trends I disclosed earlier. It is worth noting that we believe the range of potential outcomes for the full year 2021 remain more sensitive to COVID-19 and the dynamics associated with the rollout globally of vaccines than the increasingly solid underlying fundamentals for which we have a degree of control. Having said that, assuming the pandemic-related trends continue to gradually improve from here, we would expect our second quarter sales to increase sequentially versus the first.
With that, I'll now turn things back to Tom for a few closing remarks.
All right. Thank you, Joe. I would like to conclude by acknowledging how proud I am of the actions our organization has taken throughout the COVID-19 pandemic while advancing our key strategic priorities in a rapidly changing environment. We are focused on near-term execution and excited about our long-term future, where in just the next three years, we expect to have five major new product introductions. Beyond that, we have a fulsome portfolio of pipeline opportunities as we seek to build and expand upon our core microsurgical and sustained release pharmaceutical platforms. While the ongoing pandemic may well persist through 2021, the strong foundation and team we have built leaves me confident in our ability to execute on our plan as we strive to create a strategic vision care leader with disruptive franchises across glaucoma, corneal health, and retinal disease. With that, I'll open the call to questions. Operator?
Yeah. First question, line of Andrew Brackmann from William Blair.
Hey, guys. Good afternoon. Thanks for taking the questions. Tom, maybe start on your iDose commentary from earlier in this year. When you released that 24-month data you showed, obviously this was in a sort of trial which was kind of in a vacuum because it ensured compliance. Maybe two questions here. First, how are you thinking about those results in sort of a more apples-to-apples or real-world comparison? Secondly, as we think about future reimbursement efforts here and commercialization efforts, how well do you think that dynamic is understood by payers and then ultimately users of this product?
Well, thanks, Andrew. Happy to answer your question. Well, first of all, I think when we look at the data, I think the people have been following my comments in this area for many years. We initially said that we needed to have a product that provided consistent IOP reductions in pressure for at least six months to have a commercially viable program or product. If we reached 12 months, we thought we had the ideal. What I'm so excited about when I look at this data is that we're now looking out at two years with average mean IOP reductions of 7 to 8 millimeters, nearly 30% reductions in pressure from pre-treatment baselines. This is pretty extraordinary. This is an intracameral implant that is done with a facets out procedure. It's not subject to migratory change like you'll see with erodible implants.
It has a superlative safety profile. We saw minimal corneal endothelial cell loss with the iDose versus placebo. We didn't see conjunctival hyperemia or hyperchromia. The data is superlative. We're going to continue to track the data out for three years and see if we can get some additional hang time by following these patients out. I am extraordinarily pleased with the data we've been able to present, and I think that gives us powerful prospects when we do seek reimbursement going forward when we commercialize. We clearly already have a Category III CPT code established for the professional fee payment side well in advance of commercial approval.
Then we'll seek and generate a J-code, which will allow us then to carve out and receive a fair value proposition for the iDose when we commercialize. We're doing all of the extensive pharmacoeconomic work that you would expect behind the scenes. Importantly, as investors, when you look, for instance, at Durysta, a rollable implant that lasts typically in the range of four to six months, we're seeing that the J-code established for that product is around $2,000. I'm not going to suggest any proportionality based on sustained-release delivery, but I will tell you that that's an excellent precedent and predicate for us as we establish the basis for our J-code when we do commercialize. I can't tell you how excited we are about the data, the appetite, and the pulse that exists, the resonating feedback we're receiving from surgeons since we've introduced this data.
I think it becomes a powerful platform for us to enter the next stage of our development and growth.
Great. Thanks for that, Tom. Joe, maybe one for you, a little bit more granularity on the trends that you're seeing here so far in 2021. Anything specific that you'd point to in terms of prevalence of COVID or reopening in certain states that gives you more or less confidence here as it relates to how you think the U.S. market looks sort of on the other side of post-vaccination or more uniform declines in cases? Thanks for taking questions.
Yeah. Thanks, Andrew. Yeah, as we tried to say in the prepared remarks, obviously, the U.S. dynamics remain fluid. I think first and foremost, as it relates to the COVID trends themselves, we see the same data, obviously, that all of you are seeing as it plays out here in terms of improving underlying trends of the disease transmission. We saw that really through the fourth quarter and thus far into the first. What we're seeing now is a little bit of, I think, transitory or transient impact from the vaccine rollout. Probably to be expected that as patients are in the category that can get vaccinated, they tend to hold off a bit more on their procedures until after they've been fully vaccinated.
That's what we were trying to talk about in the context of a really strong January for us that softened a little bit in February as the vaccine rollout started to happen. As you think about that beyond, and obviously, I commented on this, we would expect sequential improvement from here, all else being equal with respect to COVID, its variants, and the global rollout of those vaccines. Sitting here, we're increasingly encouraged with the trend line that is emerging for the year.
Great. Thanks, guys.
Your next question will go to Matthew O'Brien with Piper Sandler. Sandler?
Hi, guys. Good afternoon. This is Drew on for Matt, and thank you for taking the questions. I appreciate the color on the first couple of quarters here, and I know you don't want to provide guidance for the first year or for the full year but maybe you could help us a little bit directionally as we think about 2021. I guess, in 2019, your glaucoma business was about a $230 million business. Is there any reason to think that 2021 can't post a little bit of growth off that 2019 figure?
Thanks, Drew. Well, obviously, we're not giving that full-year guidance directly or indirectly, and I think it has a lot more to do with the pace and how the vaccine rollout happens globally, some of the dynamics that we're seeing in the U.S., how they do or don't emerge in the ex-U.S. markets, especially as vaccines pick up there as well, and the timing of all that. What I'll say is kind of what I said in the first question here. I think we're increasingly encouraged by the trend lines that are underlying what's happening. If the world, including the United States, continues to progress the way we're seeing it, both in terms of COVID-19 and the vaccines, I think we're set up for hopefully incremental growth as we progress throughout the quarters of 2021.
Great. Understood. Obviously, I just want to touch on the Epi-on data. Congrats. It looks like very good data. I just wanted to drill down a little bit more into it. I apologize, I'm going off memory a little bit here, so correct me if I'm wrong, but I believe in your Epi-off FDA studies, you were getting a little bit closer to that two diopter mark between the treatment and the sham at six months, and then a little bit of improvement out to a year. Obviously, Epi-on comes with a much improved safety profile. I guess, one, is that an appropriate comparison, and how clinically significant is that delta? Two, what role do you see for the combination of these therapies once you have both available? Thank you.
No, great questions. This is Tom. As we look at the data, it's hard to draw comparisons between the data that we see that we just disclosed versus the earlier data with Epi-off. Even though the patients have similar inclusion criteria, clearly in the Epi-on study, we had patients where we recruited more earlier intervention patients who were slower progressors. It's hard to do an apples-to-apples comparison. I will tell you that we're excited about the data. The fact that we can perfuse oxygen on the surface of the eye, use a surfactant to be able to drill through the corneal epithelium, and use a higher UVA radiation protocol, we were able to achieve this one diopter difference versus placebo and be able to shut off progression and halt progression in the patients.
What I do think is I do think by removing the corneal epithelium, you will see a greater reduction in Kmax. To answer your question, I see an excellent opportunity to bifurcate and segment the market.
To use Epi-on in earlier stage, earlier intervention, perhaps in patients on a little more modest to moderate disease progression, and then be able to reserve Epi-Off for patients who are in more advanced stages, who need to have not only a halt to the progression but need to have a nice reduction in Kmax moving forward. To me, it offers us a great opportunity to bifurcate, segment, and be able to serve the market algorithmically, much like we do on the glaucoma side, where we have different technologies for different disease stage management.
Wonderful. Thank you.
You're welcome.
Next question comes from Robbie Marcus with JP Morgan.
Hi, this is actually Alan, not Robbie. I had a quick question on kind of the market dynamics that you saw entering the year. You highlighted that competitive trends have stabilized but just kind of diving a little bit deeper into that, when we look back to the last we saw of quote unquote normalized trends, it did look like there was a little bit of going on, even though you said the market was still growing kind of healthy double-digit. When you say that's stabilized, how should we really think about that with respect to that double-digit growth number and also whether or not you're still seeing any amount of competitive erosion from both similar MIGS devices and also more invasive surgical alternatives?
Thanks, Alan. It's Joe. Maybe I'll start, and Chris, if you want to add some color, you can. I think the way to think about the competitive landscape, and obviously there's an awful lot of other things going on in the marketplace from COVID, so I probably will resist from commenting on the specific percentages and numbers that you were referencing. I'll say this. Obviously, if you go back a year, as we were entering into 2020, we talked on this very call about some of the emerging competitive landscape dynamics and what we thought that would mean for the business as it unfolded in 2020. Obviously, a lot happened over the course of 2020. We feel good about the way we've navigated that.
We feel good about our product introduction in the form of iStent inject W and generally our access to accounts and the relationships that we have there and what that's meant for our business. What we're saying is, I think if you look back versus a year ago at how things have transpired, we feel like that competitive landscape noise, if you will, has settled a bit and is much more stable relative to sitting here 12 months ago.
Yeah. I'll add a little color as well, Alan. This is Chris. I would say, going back a year ago, there was a lot of trying and trialing going on. Since then, there's less of that. Speaking of Ivantis, it's been out there. The Hydrus has been out there for two years. We've had a very good recapture rate of those accounts that had been trying that product. Additionally, in July of last year, you had the NCCI edit on the OMNI device. That too has had an impact. Finally, as Joe mentioned, the iStent inject W has done very well for us and has been well received by the ophthalmic community. I think all of those factors have led us to say that the competitive environment is stable to improving.
Got you. Just a quick follow-up. You're slated to still launch your kind of first forays into the more moderate to severe environment with MicroShunt and Infinite. It's a market where there's already competitive devices out there already. How should we think about your ability to really drive uptake with those products and whether we should expect any kind of revenue benefit in 2021, or if that's more of a 2022 story? Thank you, guys.
Sure. I'm going to talk about the product itself in the first part of your question. Joe will follow up with the financials and so forth. As we talk to key opinion leaders and do our channel checks on this product with those who have been in the investigational stage and by the way, it's also in Europe at this stage. It's a less invasive procedure. The material itself is more biocompatible. There really hasn't been a lot of new products in end-stage therapy glaucoma. We're excited about this product because it serves as a capstone to our overall product portfolio and our algorithm. There's a place for this product. We think that while the market is not as big as the combo cataract market, it's still significant.
This product has the potential to really have an impact on the marketplace. We're excited to have it. We see it as an important product within our portfolio.
Yeah. In terms of the numbers, Alan, I think obviously based upon the commentary from our partner, Santen, we continue to expect that we should be able to see PRESERFLO MicroShunt in 2021. As a result, we would hope that that has some contribution this year. We're certainly preparing organizationally for a commercial launch around that product as soon as they're able to hopefully gain an approval. Whether it comes to that product or iStent infinite or any others, clearly there'll be a more pronounced impact to 2022 as we turn the corner there and get hopefully a full-year benefit of sales for both iStent infinite as well as PRESERFLO MicroShunt.
Your next question, Chris Cooley with Stephens.
Good afternoon. Thanks for taking the questions, and hope everyone is well. Maybe just two from me. If we could start with record sales of Photrexa. Could you give us some additional color there, whether you're seeing that as a result of an expanded install base? I know there were some metrics that you provided at the time of the Avedro acquisition announcement. Just kind of curious how you've tracked relative to that or if you're just seeing greater utilization within some select practices now that better understand the therapy and have good protocols for diagnosis and pulling those patients through the channel. I've got a quick follow-up.
Hey, Chris. It's Chris. I'll address your question. I would say it's a combination of several factors. I think the fact that we've expanded the sales organization, both by adding corneal health sales managers as well as integrating our existing glaucoma sales reps into the process. I would say it's a stabilization of reimbursement. Our market access team, which is clearly the best in the industry has done a fantastic job of stabilizing reimbursement. I think it has a lot to do with our marketing programs, where we've reached out to the optometric community to identify early diagnosis, then referral patterns into those practices who do the iLink procedure. I think it's also the flexibility that we've had around the capital equipment placement by providing different programs to ensure that the equipment wasn't an impediment to the sale.
A lot of direct-to-consumer campaigns and digital campaigns and webinars. All of these things have combined to increase placements as well as utilization within existing accounts.
Yeah, I would just add one quick thing to that, Chris, which is numerically 2020, when you look at despite the pandemic, as you've heard us say, I think on multiple occasions over the course of the year, we had record new starts or installations of systems in the U.S. The numbers back up what Chris is talking about in terms of expanding access to Photrexa, and then within those accounts, driving incremental utilization through all the referral networks and the things that Chris is talking about. I really think it's been a combination of both when you're thinking about building your models.
Lastly from me, I'll throw out a treble hook here, see if we can get anything. On the fourth quarter, obviously the operating expenses there were below pre-COVID levels. While you gave us top-line guidance for the first quarter, just would appreciate any color you could provide about how we should think about the operating expenses in aggregate as we start to flow back through the year. Obviously, assuming there's going to be some more travel, higher sales, hopefully also with that greater commission. Just trying to think about that coupled with the investments you're doing. Any kind of commentary you could provide around expenses on the operating line would be appreciated. Thank you so much.
Sure, Chris. Happy to do that. I think what you've seen now is a little bit of the pattern of how we're trying to manage our spending relative to the recovery, right? You've seen sort of the low water mark of where we could get the business to in Q2, and then how that sort of recovery has managed it from a spending standpoint relative to the sales recovery in Q3 and now Q4. What I can say is we're going to remain extremely disciplined around how we think about spending within the organization. As you saw in the fourth quarter and as I would expect to continue the course of 2021, we are continuing to forward in 2021.
Next question, line is open.
To grow sequentially over the first quarter, assuming that the favorable COVID trends 2018, 2Q was up around. Any color you can give there? Thanks.
Hi, Trevor. Yeah, that's a great question. I don't know that we're prepared to get quite that granular on it. What I'd tell you is the numbers on what we're saying for the first quarter is we've kind of gotten back to a place where we're established a little bit of growth on a pro forma basis. If you include where we're seeing a little bit of growth, and we hope to continue to expand that growth quarter and quarter as we move forward here.
Okay, great. Just another one on the guidance, or just from 2020 that is. You initially guided to $190 million, did $140 million in U.S. glaucoma business. If you do the little bit of math there, it's about $50 million to $55 million that was arguably deferred as a result of what happened. Do we think about that as being like a 2021 phenomenon just in terms of the recapture or any sort of commentary you can give there would be great?
Yeah, sure. I think that the recapture dynamics are going to be fairly elongated in the way it'll play out. I think that's going to be driven more by the ability of the accounts themselves to execute on procedural volumes. There's only so many hours in the day and so many days in the week that they can be doing procedures and bringing in these patients. I think what we're likely to see is a more prolonged market tailwind when we get on the other side of the majority of the vaccinations, as well as hopefully a lessening in the COVID cases themselves.
Great. Thank you.
Thanks. Question line of Ravi Misra with Berenberg Capital Markets.
Hi, how are you doing? Thanks for taking the question. If I can ask about the timing of maybe iStent in India and the market analysis that you have over there. Can you help us maybe size that opportunity and some of the penetration dynamics that you're thinking about in terms of timing of how you plan on kind of getting into that arena? Then I have a follow-up. Thanks.
Sure. Hey, Ravi, this is Chris. We're very pleased that we were able to secure FDA approval in India for both the iStent and iStent inject. Okay. We'll have both products. We're currently working through commercialization plans. It is our hope that we would initiate that sometime here in the near future. Beyond that, we're not in a position to be able to give more details. Obviously, given the size of the market in India, we're very excited about it and we do understand the economic and reimbursement dynamics there, and we are bullish on what we can possibly do. More to come.
Great, thanks. Maybe one on Epi-on. You're talking about segmenting the market. If I remember right, when you kind of first talked about the rationale behind the Photrexa and kind of a Avedro deal, market development was something that really needed to be done to generate awareness of the condition. I'm curious, kind of given the timing expectations around the kind of approval and commercialization that you're shooting for now on this, is this something that you're going to be kind of building in advance, or is it something kind of from an investment perspective you're going to be holding off on to drive that?
Ravi, this is Chris again. I would say that it dovetails. We're doing all those things now with Epi-off. Really have made a big investment in terms of getting out outreach with optometry and working with them to diagnose this disease earlier. Working with reimbursement to ensure stable reimbursement, all the things that I mentioned in an earlier question. I think when Epi-on comes, then there'll be the added benefit of this product being less invasive than the Epi-off procedure, and we'll continue to invest. At that time, there'll be more awareness of keratoconus and the treatment and the FDA approvals of Epi-off and then Epi-on, and we will be focusing more on the product itself and the fact that this should appeal to more patients and more surgeons given the less invasive nature of that procedure.
Great, thanks. Then maybe if I could sneak in one last one, just from the ROCK inhibitors commentary and the kind of prostaglandin, and it sounds like you're saying it's an animal model of some of the testing right now. Should we think about that kind of from a three-year window, five-year window, seven year? How to help us kind of frame when something like this could potentially come to market? Thank you.
Ravi, this is Tom. What I would tell you is that the development process is probably multi-year. I'll keep it higher level. The reason we're excited, though, is when we look at the additive value of ROCK inhibitors when used in combination with prostaglandins, we see some really significant differences in ability to be able to reach target levels in IOP reduction that hadn't been reached with other combination products. It's one of the reasons I'm bullish on being able to hunt and define the right ROCK inhibitor that we can put into the iDose vessel that will be a complementary combinatorial treatment with iDose in the future. I believe strongly that if we get this right, that we'll see the use of iDose TR in combination with Rhopressa in a number of patients with either moderate to progressive open-angle glaucoma. It's an exciting area.
We are operating within the parameters where we have to find a compound that has really high resilience in terms of stability and really potent, a highly potent, low nanomolar concentration ROCK inhibitor. That's why we're picking through a number of primary candidates. We'll find the right one, and we'll advance that. It will be multi-year, but when we have it will be, I think, an extraordinary addition to the glaucoma portfolio.
Thanks. Question line of Anthony Petrone with Jefferies.
Hi, good afternoon. Hope everyone's doing well. I have two quick ones in there based on channel checks we've done. First on iStent W, our understanding is that-
Solution, the major feature there is surgeon ease of use. I'm wondering, A, how many iStent inject users have actually transitioned to W? Do you believe W will be market expansive on the surgeon adoption end because of ease of use? The second is on reimbursement coding. Our understanding is new coding for OMNI is allowing OMNI to be used with the MIGS stent implants, and that can go down the severity curve. I'm just wondering how that's going to play out in the marketplace when you consider the additional reimbursement for surgeons. Thanks.
Hey, Anthony, this is Chris. Let me start with W. I think your channel checks are right. I think people do see the W as a big improvement over iStent inject. That is because of the flange being larger. That's the component that is visible within the angle of the eye. With that brings more predictability. What a lot of doctors maybe haven't told you in your channel checks is that we've also improved the insertion device itself, and that has made for more predictability. We feel like this has been a big advancement, excuse me, and that the acceptance level of this product has been very high. I do believe that this has helped us to recapture share and is helping to expand the market with this product. To be clear, iStent inject W is replacing iStent inject.
Right now in the U.S., the two choices are iStent and iStent inject W. Moving to your thoughts on OMNI, that is a visco delivery system. There are doctors who are utilizing this product in combination with trabecular bypass. This is a new trend, it's complementary to what we have. Some people do it in standalone as well. The concept there is that you expand the canal and you place a trabecular bypass device in as well. Two separate codes. They're able to be used in harmony with each other. We think that given all the advantages of iStent inject W, that it's the ideal trabecular bypass device to be utilized with this technology because of its predictability, its visibility, its efficacy, and its superlative safety profile, and perhaps even ease of use. I think that addresses your question.
Yes, very much. Thank you very much. I'll hop back.
Anthony. Yeah, Anthony, no, go ahead. This is Tom. I'll just add a few things. One, I'd like to believe this is something we foresaw. When we look at the NCCI edits, which precluded surgeons from using visco canaloplasty codes in conjunction with goniotomy, we presumed and thought that there'd be a natural pivot to using the visco canaloplasty device in conjunction with stents, in this case, the trabecular bypass stent. It wasn't lost on us. I believe we've been prescient now. If you can see our development plan and product development plan, we now have iPRIME under development. iPRIME, then you can fast-forward and think about it in use in conjunction with iStent inject or iStent infinite to treat these patients.
It gives us tremendous flexibility either using a visco canaloplasty device or viscodilation device as a standalone treatment or in combination with a plethora of products that we have. It's expanding our algorithm. I think it's going to give us the ability to continue to generate robust growth within the glaucoma area in the future.
Very helpful. Thank you.
Your final question comes from the line of Steven Lichtman with Oppenheimer & Co.
Thank you. Hi, guys. Just a couple from me. Heading into 2020, you targeted 500-plus physicians trained on MIGS. Obviously, COVID changed that. Wondering where you wound up coming in last year and any goals you're willing to provide on physicians trained in 2021?
Hi, Steve. It's Joe. Yeah, I think first with respect to the 2020 target, you're right. Obviously, COVID took a chunk out of that. I will say, without getting too specific, we ultimately landed much closer to that number than I would have predicted back in the March, April, May timeframe. It really speaks to the commercial organization, the creativity that they engaged virtually in bringing forward a lot of physicians who had maybe a little extra time on their hands, and ultimately bringing it forward. I think that we were encouraged by that. As you heard in the prepared remarks, we were very encouraged by the fourth quarter in particular, hopefully the realization of the full year of work. As we turn the corner in 2021, I think we're not giving a specific number.
There's too many variables there in play with COVID and the like. Our guys continue to get increasing access. Hopefully we can continue to drive that important market driver.
Great. Thanks, Joe. Just secondly, also heading into 2020, you had guided to your $300 million of OpEx spend, but you were able to keep that well under in response to COVID. I know you've mentioned that you're going to keep a close eye on OpEx spend given the variability in the marketplace. Is that still a place where a number we should be targeting on a run rate when things get normalized o r have you found some underlying cost savings that perhaps won't get you back up to that $300 million in the near future?
I think it's a fair question, Steve. The way I would think about that is $300 million represented obviously ex-COVID, where we saw that the business and our investments trending. That's based upon fundamentals, both in terms of our commercial infrastructure expansion as well as our R&D pipeline. I think that still remains a pretty good bogey in terms of where the spending can go. Where we get between our current run rate and there has more to do, obviously, with the pace of the recovery from a COVID standpoint as well as the normal things, right?
I mean, anytime you're trying to bring forward exciting new technologies especially from a development standpoint, the pace in which some of those things click and where they increase their spending as you move into the clinic and things like that can really drive how close you get to that $300 million in any given point in time. Clearly that's the direction that we're heading. There's, as you know, been no significant change in our overall strategic plan and what we're trying to accomplish from an R&D standpoint.
Makes sense. Thanks, Joe.
I would now like to turn the call back over to Chris Lewis for closing remarks.
Okay, this is actually Tom. I want to thank all of you for your time and attention today. We hope and trust that everyone is staying safe, and we want to thank you for your continued interest in Glaukos Corporation. Goodbye.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.