CXLUSA: Show Us Your Hand

When it comes to corneal cross-linking (CXL), every single one of us is currently in the “epi-off” camp. Why? Because corneal ectasias like keratoconus need to be dealt with effectively – and, if CXL is the right approach to take for an ectatic cornea, then performing epi-off (rather than epi-on) CXL is almost always the right choice. It’s the collagen in the corneal stroma that needs to be cross-linked; riboflavin, UV-A light and oxygen need to reach the stroma to do that, but the corneal epithelial cells form a very effective barrier to riboflavin penetration and oxygen diffusion (2). That’s why the original Dresden protocol required epithelial cell debridement (3). It’s also why no epithelial-sparing – epi-on – method has come close to the effectiveness of epi-off CXL – even iontophoresis, where a small electric current is applied to enhance riboflavin penetration (4). We would all love to be able to perform an effective epi-on procedure for our patients – such an approach promises patients less pain, a reduced risk of infection and transient haze, faster recovery, easier post-procedural aftercare and more… But we don’t, because we won’t risk having to repeat the surgical procedure at a later date and having patients suffer progression from that delay. Epi-on CXL, despite all of the advances in riboflavin formulations and delivery methods, still isn’t as effective as epi-off CXL in terms of cross-linking the cornea, adding biomechanical strength, and crucially, halting the progression of corneal ectasia. Nothing the CXLUSA group have presented to date has convinced us otherwise.

Our first concern comes down to the fundamentals of the scientific method. The CXLUSA investigators have presented one-year data (5) from 341 keratoconic eyes that suggest significant improvements in uncorrected visual and corrected distance visual acuity (UCVA and CDVA) of 0.5 and 1.0 lines, respectively, a -0.45 D improvement in Kmax, and data from 217 eyes suggesting an almost 30 percent reduction in higher order aberrations (HOA) and coma (5)(6). But there was no control group  – a huge concern – and these results do not come close to what can be achieved with epi-off CXL (7). And let’s not forget that science is based on a simple principle: publish your methods and let others repeat your experiment and confirm your data. In the CXLUSA consortium’s case, the important missing factor is the nature of their bespoke riboflavin solution. The formulation remains a mystery, and other sites have not been supplied with the solution so that they may try and repeat the experiment. Until that happens, the validity of their results will remain in doubt.

Another concern relates to some of the outcome measures relied upon to show therapeutic effect: UCVA and CVDA. We’ve seen from the work of David O’Brart that even non-treated keratoconic eyes can improve in visual acuity, likely due to patients learning the chart during the trial. Therefore, in effect, the CXLUSA group cannot guarantee that their results are different to those of epi-off control populations. Worse, the consortium’s reported outcomes failed to reach the FDA’s therapeutic response endpoint of 1 D flattening of Kmax (5) – a standard that every other epi-off (standard and accelerated) protocol has reached.

Further, none of the eyes had documented keratoconus progression prior to CXLUSA cross-linking being performed. In general, about a third of patients that come to our clinics have progressive keratoconus, so the question is: how can you claim that the method works to halt keratoconus progression when you’re treating many patients who are stable? The CXLUSA consortium has presented outcomes that showed 7 percent of eyes with increased Kmax of 1 D or more at 12 months (6). If one-third of the cohort were progressive pre-CXL, then the 7 percent is equivalent to a 21 percent failure rate, which matches the failure rates described in every major epi-on study in the literature. We’d also like to see some biomechanical proof of the CXLUSA cross-linking protocol’s effectiveness soon, and more details about the demarcation line depth achieved, as a measure of how much tissue is involved in the cross-linking process.

There are regulatory concerns too. If the CXLUSA group have indeed found the “Holy Grail” of truly effective epi-on CXL, then in Europe, at least, it appears to be unlawful to have a monopoly over a medical treatment, per Article 53(c) of the Guidelines of Examination for the European Patent Office. Presumably the CXLUSA consortium wishes to commercialize its product so that it may be administered to as many patients who might benefit as possible. We asked Peter S. Hersh, the Professor of Clinical Ophthalmology at Rutgers Medical School – and the medical monitor of the clinical study that led to the FDA approval of CXL for the treatment of keratoconus – to explain what needs to be done to obtain FDA approval. His response: “The company needs to have an IND (investigational new drug) and IDE (investigational device exemption) for the FDA – the former for their riboflavin solution and the latter for the device”. In terms of clinical data to get that approval, the FDA needs “A formal clinical trial, typically with a randomized control group, carried out to demonstrate safety and efficacy of the device and drug.” So we find it strange that the epi-on functional data that consortium claims to have obtained does not appear to have been collected in an FDA-compliant manner – something that you would think renders the commercialization of the product somewhat in jeopardy. If their objective is not commercialization, what is their goal?

We all want a functioning epi-on CXL that’s as effective as epi-off CXL. If CXLUSA cross-linking proves to be that, we will all gladly embrace it. It’s not even that we don’t believe the word of the superb ophthalmologists that form part of the CXLUSA consortium when they stand at the podium and present their data. There’s a basic level of disclosure that’s expected in science and medicine, and it isn’t being met, which concerns many of us. Their justification for not doing so – commercial sensitivity – for us, is wearing thin. In our view, they should trust in their intellectual property portfolio and release the proprietary solution for validation and verification at external clinical sites. What is the point of having a wonder drug if nobody can benefit from it? On the other hand, what if CXLUSA cross-linking, when deployed in a wider patient population, isn’t as successful as it is claimed to be? If it results in significant numbers of patients needing re-treated, then we risk trashing the reputation of CXL worldwide. A wider evaluation would help spot any such lack of efficacy signal. To date, epi-off CXL with riboflavin is the only intervention in keratoconus that’s able to halt progression in many cases. If fewer patients were to receive it because of reputational damage, it would be a tragedy.

To use a poker analogy: we’re done placing bets – it’s time for the CXLUSA consortium to show their hand.