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Table 2 Studies with potentially breakthrough findings

From: Italian program for independent research on drugs: 10 year follow-up of funded studies in the area of rare diseases

• The project coordinated by Tiziano Barbui was aimed at comparing, in patients with polycythemia vera, two therapeutic strategies (based on pharmacological and non-pharmacological interventions) in the prevention of thrombotic events. In a RCT that included 365 patients, the strategy aimed at maintaining the hematocrit target at less than 45 % (aggressive strategy) was associated with a significantly lower rate of cardiovascular death and major thrombosis in comparison with the group of patients with a hematocrit target of 45 to 50 % (hazard ratio in the high-hematocrit group, 3.91; 95 % CI, 1.45 to 10.53) [25].
• In patients with acute myeloid leukaemia, the standard myeloablative conditioning treatment of busulphan plus cyclophosphamide is associated with a substantial non-relapse mortality. An alternative combination of busulfan and fludarabine has been proposed to reduce the incidence of these events. In a multicenter study, Rambaldi and coll. randomized 252 patients (aged 40-65 years) with acute myeloid leukaemia to compare the two regimens [26]. The 1-year non-relapse mortality was 17.2 % in the busulfan plus cyclophosphamide group and 7.9 % in the busulfan plus fludarabine group (Gray's test p=0.026). No difference was observed in terms of serious adverse events. The Authors concluded that, in older patients with acute myeloid leukemia, the busulfan plus fludarabine regimen “should be regarded as standard of care during the planning of allogeneic transplants”.
• This example refers to a multicenter, randomized, study that compared plasma-derived (PD) with recombinant (R) factor VIII with regard to the risk of developing autoantibodies that neutralize the coagulant activity of factor VIII [19]. Between 2010 and 2014, 251 previously untreated patients with severe hemophilia A were randomized to the recombinant or the plasma-derived products. The cumulative incidence of developing factor VIII inhibitors was higher in the recombinant than in the plasma-derived group (hazard ratio 1.87; 95 % CI 1.18-2.97). These findings are of special importance also for low- and middle-income countries when considering that the plasma-derived factor VIII is far less expensive than the recombinant product.
• In this study, AIFA co-founded a project (already supported by Telethon charity) with the aim to extend the number of patients receiving a gene therapy for the treatment of an extremely rare and severe congenital immunodeficiency due to adenosine deaminase deficiency (ADA) [27]. Aiuti and coll. were able to demonstrate that the treatment could radically modify the prognosis of these patients. After 4 years of follow up, all ten patients were alive and for 8 of them the enzyme-replacement therapy was not required. The findings of the study originated an agreement between Telethon and a pharmaceutical company for the developing and marketing of an “industrialized” product and the recognition of an orphan drug designation by EMA http://www.pharmafile.com/news/396244/gsk-files-ultra-rare-disease-application-ema.