OBJECTIVES: There are unmet treatment needs for patients with ultra-rare diseases—those with an estimated prevalence of <1:50.000. This deficit persists despite efforts by medicine regulators to encourage development and commercialisation of effective treatments. To explore this situation further, we sought to assess the availability of evidence-based treatments for ultra-rare respiratory diseases.

METHODS: A systematic search of Embase and Medline was conducted for studies published between 2014 and 2019 examining treatments for the following ultra-rare respiratory diseases: ataxia telangiectasia (AT); lymphangiomatosis (LYMF); pulmonary alveolar proteinosis (PAP); pleuroparenchymal fibroelastosis (PPFE); pulmonary alveolar microlithiasis (PAM); pulmonary dendriform ossification (PDO); and light chain deposition disorders (LCDD). In addition, we searched clinicaltrials.gov, orpha.net, and websites of five health technology assessment (HTA) bodies. Information from these sources was extracted and narratively synthesised.

RESULTS: No licensed treatments or HTAs were identified for any of the diseases considered. Treatment options with orphan designations in Europe and the United States, were identified for PAP, AT and LYMF, along with some related published and/or ongoing research on their clinical effects. For PPFE, PAM, PDO, and LCDD, we found no assigned orphan designations and very little published or ongoing research. Across all indications, the methodological quality of published evidence was inherently limited; typically, studies were observational, with small sample sizes (range 1–206).

CONCLUSIONS: There is an obvious lack of proven and available treatments for ultra-rare respiratory diseases. For four of the conditions reviewed, there are no treatment options with designated orphan status. For the other three, orphan designation of certain interventions and associated research reflect efforts to provide effective treatment options, but have yet to result in therapies that are licensed or approved by HTA bodies. Consequently, patients with ultra-rare respiratory diseases remain a population whose needs have been inadequately addressed by researchers, clinicians, manufacturers, and policymakers.