Rare (and Rarely Diagnosed) Diseases in Ophthalmology

In the US healthcare system, the marketplace naturally incentivizes pharmaceutical companies to develop therapies for conditions like hypertension, glaucoma, or diabetes that affect millions of people. An effective new therapy for a highly prevalent disease can generate huge revenues and a quick return on investment. Developing drugs for less common diseases is a much less compelling business proposition – no matter how dire the clinical need. To balance out this low financial incentive and encourage companies to continue to invest in new therapies, the Orphan Drug Act (ODA) was enacted more than 40 years ago, in 1983. The ODA provides faster Food and Drug Administration (FDA) review and lowers regulatory costs for manufacturers that develop drugs to treat diseases affecting fewer than 200,000 people in the US. 

More recently, in September 2025 the FDA introduced the Rare Disease Evidence Principles (RDEP) to provide even greater speed and predictability in the review of therapies intended to treat very rare and debilitating genetic diseases that affect fewer than 1,000 patients, and for which there is no other alternative treatment.

Companies seek the orphan or rare disease designation from the FDA during the early stages of development and clinical trials to ease their regulatory pathway, although the designations are by no means a guarantee of approval. Development of treatments for rare disease can be more taxing from an R&D standpoint because, with a limited patient pool, the development costs per patient are high. Additionally, it can be challenging to enroll enough patients in clinical trials when the disease is rare and patients are geographically scattered. Even within a given rare disease, there can also be significant variations in how the disease manifests and progresses. All of these factors complicate trial design and can make it harder to demonstrate a therapy’s effectiveness.

Once an orphan drug is successfully brought to market, it is often priced quite high. Because there are fewer patients afflicted with rare diseases, manufacturers of orphan drugs face considerable challenges in educating clinicians and patients about a disease that is not widespread, and they can expect far lower sales volume compared to drugs for prevalent or more easily diagnosed diseases.

In ophthalmology, for example, a full course of Tepezza (teprotumumab-trbw, Amgen) for the treatment of thyroid eye disease (TED) can cost $200,000 or more. When Tepezza was initally approved, the condition was so poorly recognized that Horizon Therapeutics (later acquired by Amgen) ran an awareness campaign on television to try to reach patients with eye bulging and other symptoms. One advantage for Tepezza, however, is that eye bulging is quite specific to TED, and recognizable to patients and doctors once they are educated about the symptom. Keratoconus, in which the primary symptom (distorted vision) can have many different causes, is not as rare as TED, but is rarely diagnosed in a timely manner because of the more general nature of its early symptoms. In general, the more severe the condition or the more powerful the treatment – such as Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), a one-time gene therapy treatment that can restore vision in patients with inherited retinal dystrophies – the higher the price tag. Luxturna, the first gene therapy approved in the US, is currently priced at more than $850,000 per treatment.

In the absence of treatments, clinicians often haven’t been trained to look for less common conditions. And even once a new therapy is developed and approved, the disease may still go untreated simply because doctors aren’t looking for early signs of the disease, they don’t know a treatment is available, or they don’t know the referral procedures for the newly developed treatment. In anterior segment care, for example, we now have highly effective treatments for neurotrophic keratitis (NK) and keratoconus that are widely covered by insurance, yet these conditions still remain grossly underdiagnosed.

Cenegermin-bkbj (Oxervate, Dompé Pharmaceuticals) is a recombinant human nerve growth factor treatment; an 8-week course of the topical drug has been shown to completely heal NK in 65%-72% of patients. NK is estimated to affect 45,000 patients, but that prevalence came from studies that looked only at stage 3 NK. Many more patients are in NK stage 1 or 2, but because they present with symptoms very similar to routine dry eye, clinicians typically don’t think about treating them with cenegermin, missing the opportunity to halt their progression to more severe stages of NK.

Similarly, keratoconus also often goes unrecognized in the early stages, when patients and primary care eye doctors fail to recognize that changing myopia and astigmatism or quality-of-vision problems are something other than normal progression of myopia. As the cornea progressively thins and warps, the patient keeps getting new spectacle or contact lens prescriptions, sending them down a path of irreversible vision loss and a lifetime of more challenging vision and disease management. Whilethe true prevalence of keratoconus remains unknown, the reality is that only a tiny fraction of patients with the disease are treated each year. A recent IRIS Registry report found that only 12% of newly diagnosed patients received cross-linking, while 5% underwent a corneal transplant, and 83% were not treated at all (1). By even the most conservative prevalence estimates, many more people would be undergoing treatment if the need for care was being effectively met.

It is largely a myth that diagnosis of these orphan ophthalmic diseases requires expensive or inaccessible diagnostic tools. For NK, we simply need to check corneal sensitivity, which can be done with something as simple as a cotton tip applicator or a piece of dental floss. Even the gold standard for corneal sensitivity testing – Cochet-Bonnet esthesiometry – is easy to use and inexpensive. I would love to see this instrument adopted more widely for NK screening. In my practice, we have made esthesiometry part of our routine point-of-care testing protocol for any dry eye patient. It is administered by a technician prior to applying numbing drops or corneal stain. That way, I see the sensitivity results right away, along with tear break-up time and other data points. If corneal sensitivity is below 50 mm, and depending on what else my examination reveals, I may consider an amniotic membrane graft as a temporizing measure while we request insurance authorization for Oxervate. This proactive screening helps us avoid bringing the patient back for more testing or attempting treatments that can’t address the underlying disease.

Confirming a diagnosis of keratoconus requires topography/tomography imaging, which is typically not reimbursed when used to screen for keratoconus. However, this disease can be detected without advanced training or equipment, even in the early stages. I encourage our in-house and referring optometrists to be on the lookout for progressive changes in manifest refraction myopia (≥0.50 D change) or cylinder (≥1.00 D change), unexplained visual quality complaints, or inability to correct to 20/20 and to use retinoscopy to identify scissoring on the retinal reflex when they see such changes or have the patient seen by the corneal specialist. Any of these signs should prompt a referral for topography/tomography. We also encourage referring optometrists outside the practice to acquire the skill to fit scleral contact lenses so that when they uncover keratoconus or refer a patient for treatment, we are able to send the patient back to them for scleral contact lens fitting (when indicated).

Effective screening for keratoconus requires much more awareness and attention to the early signs of the disease, especially in teens and young adults. This is absolutely necessary to preserve vision and reduce the lifelong impact of keratoconus on patients’ vision, mental health, educational and career prospects, and quality of life on these young patients. To improve screening in my local community, my family foundation is partnering with AdventHealth and the Lions Eye Bank on a mobile screening program for all high school seniors in Hillsborough County, FL. We intend to equip a recreational vehicle (RV) with autorefraction, topography/ tomography, and a slit lamp and have set a goal of visiting every high school in the county. While this is just a pilot program in one local area, screening programs like this should be commonplace. We know that earlier treatment can have a dramatic impact on quality of life, can prevent the need for corneal transplant surgery and its associated risks, and can also protect the ability of a young person to excel in school, join the workforce, and avoid life-long medical issues associated with keratoconus.

The FDA provides alternative approval pathways for therapies to treat rare and rarely diagnosed diseases. Once approved, it is up to us to implement better screening protocols to find the patients who can benefit most from these treatments.