Understanding a rare disease through the lens of real world and prevalence data

Through a comparative analysis of published LHON prevalence data and real-world evidence, this article describes a study using multiple ClarivateTM data sets to better understand disease pathology and current drug utilization for this condition.

The study was conducted collaboratively by Clarivate Senior Science Editor Shyama Ghosh, Senior Epidemiologist Shilpa Thakur, Managing Editor Stephen DuPraw and Senior Director Evelyn Davila.

LHON prevalence rates globally

Leber hereditary optic neuropathy (LHON) is a rare, maternally transmitted mitochondrial disorder that predominantly affects men in their teens and twenties and causes blindness. Degeneration of the retinal ganglion cells causes rapidly progressing vision loss, leading to permanent (non-painful) blindness within a year.

The Incidence and Prevalence Database™ (IPD) , a Cortellis solution, provides information on LHON prevalence and primary mutations, morbidity and mortality rates. Studies show a global LHON prevalence rate of 4.3 per 100,000, with Europe reporting a rate of 2.3 per 100,000. Prevalence rates vary across individual countries and regions, with higher rates in northeast England (1:31,000)[1], the Netherlands (1:39,000), Denmark (1:54,000) and Finland (1:48,000)[2], while the United States has a reported rate of 1:50,000[3]. In South India, a single study recorded a prevalence rate of 1:737[4].

LHON mutation rate variability affects therapeutic efficacy

Most LHON patients carry one of three pathogenic mitochondrial DNA mutations (11778G>A [ND4], 14484T>C [ND6] and 3460G>A [ND1]) known as primary LHON mutations. Multiple research groups have successfully used human wild-type ND4 gene transfer as a means of preventing retinal ganglion cell degeneration in patients with LHON[5]. However, mutation rates can vary between patient groups within the same region, which may affect the therapeutic efficacy across patients.

The ND4, ND6 and ND1 mutations are responsible for 80%-90% of LHON cases and are commonly seen in familial cases. Globally, ND4 is the most common mutation, followed by ND6 and ND1. The REALITY study conducted in the United States, France, Italy, Spain and the United Kingdom in 2021 reported a distribution of ND4 (61%), ND6 (20%) and ND1 (18%)[6]. Other studies have reported different percentages, with ND4 being the most prevalent mutation. In one study from Northern Ireland, the ND4 mutation had a 100% prevalence rate[7].

A notable aspect of LHON is that only approximately 50% of men and 10% of women carrying one of the three primary mutations experience optic neuropathy. The timing of initial visual loss may not be significantly influenced by mutational status, but the patient’s genetic makeup can affect spontaneous visual recovery, which can occur many years after disease onset. Patients with the ND6 mutation tend to have a less severe disease progression, while those with the ND4 and ND1 mutations have a worse prognosis and a lower chance of spontaneous recovery.

Using real world data to analyze LHON dynamics

To better understand the dynamics of LHON, including disease prevalence and drug usage in the United States, we analyzed real world data from electronic health records (EHR), claims and pharmacy data from healthcare institutions and providers. The Clarivate U.S. real world data set covers 90% of the insured population in all U.S. states. We identified patients with an LHON diagnosis using ICD-10 and ICD-9 codes H47.2 and 377.16 annually in the claims dataset for the period of 2018-2021. Once LHON patients were identified, we mapped them to EHR data to analyze racial and ethnic differences.

Our real world data analysis showed a 1.3-fold increase in LHON prevalence per 100,000, with a higher diagnosed prevalence in males and non-Hispanic white people (as shown in Figures 1 & 2). Although non-Hispanic white people made up approximately 85% of all LHON patients, Clarivate EHR data indicates lower representation among Black/African American patients (11%), other races (3%) and Hispanic (1%) ethnicities.

Figure 1. LHON prevalence trends in the U.S.

Source: Clarivate real world claims data

Figure 2. Higher diagnosed LHON prevalence in men

Source: Clarivate real world claims data

We analyzed LHON treatment patterns using pharmacy and procedure claim records identified through NDC codes, CPT, HCPCS, ICD-9 and ICD-10 procedure codes. Our analysis included prescription trends for antibiotics, steroids, vitamins and ophthalmic-intraocular pressure reducing agents (prostaglandin analogs and alpha-adrenergic agonists) from 2018 to 2021. Our RWD analysis revealed that the majority of LHON patients received antibiotics (such as amoxicillin, azithromycin, ciprofloxacin and others) alone or in combination, as well as an increased number of vitamin prescriptions (including vitamins B, C, D and others) as part of their treatment (as shown in Figure 3).

Figure 3. Drug-treatment proportion of LHON in the United States

Source: Clarivate real world claims data product

An important step in treatment and market access pathways

Both published data and our real world data analyses provide consistent information on LHON prevalence and risk. Both datasets conclude that age and gender can predict visual failure, but predicting disease onset in LHON carriers remains a challenge.

There are some promising experimental treatments in pipelines, but successful commercialization will demand an in-depth understanding of this patient population and the current diagnostic and treatment pathways[5].

The collection of real world data has become a critical pillar in the field of rare diseases, which are often characterized by scarcity and heterogeneity of data that are dispersed across countries[8]. In recent years, we’ve seen an increase in awareness among healthcare providers and better diagnosis of rare diseases, leading to improved access to care for patients with these uncommon conditions.

Learn more about the Clarivate real world data offering here.



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[5]Sahel J et al. “Gene Therapies for the Treatment of Leber hereditary Optic Neuropathy.” International Ophthalmology Clinics; V.61; No.4; 10/2021; p195; DOI: 10.1097/IIO.0000000000000364

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