Clinical Trials

* On June 1, 2016, Santhera Pharmaceuticals announced that additional data from the pivotal phase III trial (DELOS) were published online as an article in press in Neuromuscular Disorders, the official journal of the World Muscle Society. These data show that DMD patients treated with Raxone® (idebenone) have a reduced risk of bronchopulmonary complications including fewer hospitalizations caused by such complications and a reduced need for systemic antibiotic treatment compared to patients receiving placebo.
These results originate from additional analyses of the phase III DELOS trial which was performed in DMD patients not taking concomitant glucocorticoids and showed that Raxone® reduced the loss of respiratory function in a statistically significant and clinically relevant manner (Buyse et al., The Lancet 2015 385(9979):1748-57). The data now published in Neuromuscular Disorders demonstrated that Raxone also reduced the proportions of patients falling below clinically relevant thresholds for peak cough flow, relevant for proper airway clearance, and forced vital capacity, an indicator of respiratory failure. Researchers also found that there were fewer bronchopulmonary adverse events (BAEs), including upper and lower airway infections and related complications, in patients on Raxone therapy (6 of 31 patients with 7 BAEs) compared to patients in the placebo group (17 of 33 patients with 28 BAEs). For the patients receiving Raxone, there was a 67% reduction for the risk of experiencing at least one BAE during the 1-year study period (p = 0.0187), and a 72% reduction for the risk of experiencing one or more BAEs (p = 0.0026). Additionally, the overall BAE duration for the Raxone group (82 days) was markedly shorter than for the placebo group (222 days). This result was also supported by a smaller number of hospitalizations due to respiratory complications in the Raxone group compared to the placebo group. The need for systemic antibiotic use was also lower in the Raxone group (7 or 22.6% of patients with 8 episodes of antibiotic treatment) than in the placebo group (13 or 39.4% of patients with 17 episodes).

* On November 11, 2015, Santhera Pharmaceuticals announced that it has now completed comparative analyses of the respiratory outcomes for patients in its successful Phase III DELOS trial with data from a natural history DMD patient cohort collected by the Cooperative International Neuromuscular Research Group (CINRG). These and other supporting analyses previously discussed with regulatory authorities will be included in the regulatory filings in the US (NDA) and EU (MAA) expected for 1Q 2016. In order to expand the DMD population that is the subject of these initial filings, the Company also prepares to conduct a new trial in DMD patients using glucocorticoid steroids. Following early discussions with the FDA, Santhera has now completed the following analyses and reports significant correlations between Peak Expiratory Flow (PEF), the primary endpoint of the DELOS trial, and Forced Vital Capacity, a well-validated marker of irreversible morbidity and mortality in DMD, and incidence of severe respiratory events , confirming the relevance of PEF as an intermediate clinical endpoint. Additional analyses of the DELOS trial outcome has demonstrated effect of Raxone® on bronchopulmonary events (including airway infections). The resulting hazard ratio for the number of patients reporting at least one bronchopulmonary event was 0.332 (95% CI: 0.131, 0.843; p = 0.020) and 0.271 (95% CI: 0.118, 0.623; p = 0.002) for the total cumulative number of events in favor of Raxone® treatment. Similar analysis of systemic antibiotic use showed that patients treated with Raxone® clearly used less antibiotics compared to patients receiving placebo. New data demonstrate also positive effect of Raxone® on inspiratory muscle function. Specifically, Raxone® compared to placebo stabilized the maximum inspiratory flow based on the measurement of inspiratory flow reserve and inspiratory forced vital capacity over the 52-week study period.

The first successful comparison of the outcomes for a clinical trial population (DELOS) with the outcomes for a natural history population (CINRG) matched patient-by-patient to the DELOS population. For this external validation of the DELOS study findings, CINRG compared the annual rate of change in PEF%p in its natural history population with that seen in DELOS. CINRG identified a matched patient for each DELOS patient by considering the baseline PEF%p value, previous use of glucocorticoids and the age of the patient. The matching and comparison was based on a prospective analysis plan prepared by CINRG in collaboration with Santhera and resulted in comparable baseline characteristics of the CINRG patients and the DELOS patients. The analysis of the longitudinal data met the pre-specified criterion of showing that the annual decline among the untreated CINRG natural history patients in PEF%p was at -6.3% (95% CI: -10.6% to -2.0%) closer to the decline of the placebo-treated DELOS patients at -8.5% (95% CI: -12.8% to -4.2%) than the change in those treated with Raxone -2.4% (95% CI: -6.5% to 1.7%).

The extended data sets now available are currently being compiled and integrated for use in regulatory filings. In the US, the FDA will be briefed on the extent of the new data sets in the coming weeks. Santhera expects to have a second pre-NDA meeting with the FDA in 1Q 2016 and following a supportive outcome would then submit the NDA. In the EU, these new data will be incorporated in the application for marketing authorization for DMD to be filed as Type II variation of the marketing authorization previously granted for the indication Leber's Hereditary Optic Neuropathy (LHON). The dossier is expected to be submitted also in 1Q 2016.

Santhera is currently preparing to start a new clinical trial to investigate whether Raxone® treatment could also slow respiratory function loss in DMD patients treated with glucocorticoid steroids, a population previously not included in the successful DELOS trial. The new study was planned based on CINRG natural history data demonstrating that at a certain stage of disease progression patients on glucocorticoid steroids will experience the same rate of respiratory function loss as patients not using steroids, presenting an urgent medical need for treatment. Patients who will be eligible to enroll will have already started to decline on respiratory function whilst on stable glucocorticoid steroid treatment. Study participants will receive either Raxone (900 mg/day) or placebo for the duration of 78 weeks. The trial targets to enroll approximately 260 DMD patients and will be conducted in Europe and the US. Further details of the inclusion and exclusion criteria will be announced at the time of patient enrolment expected to commence early 2016. Patients completing the trial will be offered enrolment into an open label extension study.

* On October 22, 2015, Santhera Pharmaceuticals and Parent Project Muscular Dystrophy (PPMD), a U.S. advocacy organization working to end Duchenne Muscular Dystrophy (DMD), announced the results of a benefit/risk survey in patients DMD and parents of individuals with DMD. The study focused specifically on patient and caregiver preferences for treatments that address disease symptoms that are not directly related to skeletal muscle function. This first industry-supported benefit/risk study for patients with Duchenne Muscular Dystrophy (DMD) was inspired and based on data from the Phase III (DELOS) trial, which demonstrated a clinical benefit for Raxone®/Catena® (idebenone) in delaying the loss of respiratory function in patients with DMD not using concomitant glucocorticoid steroids. The PPMD Benefit/Risk Survey Study consisted of three separate research activities to assess: (i) priorities of treatment targets; (ii) treatment preferences and (iii) treatment acceptance. Best/worst scaling was used for the survey design: respondents were presented with a series of hypothetical treatment profiles and asked to choose the best and worst features of each. One hundred fifty-five individuals participated in this study. Most affected individuals had a diagnosis of Duchenne (85%). The study included caregivers of patients who were at least 10 years old, as well as teenagers and adults. Respondents prioritized treatment targets that address cardiovascular and pulmonary benefits. The greatest priority was for treatments that address weaker heart pumping. Treatments that address lung infections and cough strength were rated as the second and third-most prioritized, respectively. Stratified samples revealed that caregivers and patients had similar priorities.

The analysis of preference scores revealed greatest preference for treatments that target cough strength. Patients and their caregivers demonstrated the greatest preference for treatment that maintains cough strength underlining the importance to maintain adequate airway clearance. In the treatment acceptance analysis, in which participants answered whether they would use a hypothetical drug if it were available, respondents almost always chose to accept the treatment profile with a strong benefit and little risk, while almost three quarters would accept a treatment with a strong benefit despite the highest risk/burden profile. The results of this benefit/risk study have been forwarded by PPMD to the FDA providing the Agency with important information on the treatment priorities and risk tolerance of the DMD community for treatments that address disease symptoms not directly related to skeletal muscle function. Through this study, the regulators will have access to scientifically-robust data illustrating that study participants value interventions to slow cardiac and pulmonary disease progression highly, and would be willing to accept a higher risk of side effects and treatment burden for pulmonary benefits.

* On April 21, 2015, Santhera Pharmaceuticals announced that the full results of the double-blind placebo-controlled Phase III trial (DELOS) demonstrating efficacy and safety of Raxone®/Catena® (INN: idebenone) in patients with DMD have been published in The Lancet (Lancet 2015; 385: 1748-57). The results of the DELOS trial demonstrated that Raxone®/Catena® significantly reduced the annual decline in Peak Expiratory Flow (PEF as percent predicted, PEF%p) by 66% compared to patients taking placebo. Other respiratory function endpoints such as Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV1) corroborated these results and showed a consistent pattern with treatment differences supporting efficacy of Raxone/Catena over placebo in the preservation of respiratory function. Researchers concluded that Raxone/Catena represents a new treatment option for DMD patients. Santhera Pharmaceuticals is currently preparing the regulatory filing dossier for application of marketing authorization both in the US and Europe.

* On May 22, 2014, Santhera Pharmaceuticals reported that the results of secondary respiratory function endpoints from the on-going analysis of the DELOS trial in Duchenne Muscular Dystrophy (DMD) corroborate the positive outcome for the primary endpoint. These data provide further supportive evidence of a treatment benefit for Catena®/Raxone® in DMD. As previously announced, the DELOS trial met the primary endpoint, the difference between Catena®/Raxone® and placebo in the change from baseline to week 52 in Peak Expiratory Flow (PEF as percent predicted, PEF%p). Hospital-based spirometry assessments demonstrated that Catena®/Raxone® significantly reduced the annual decline in PEF%p by 66% compared to patients taking placebo. The average annual decline in PEF%p was 9.0% for placebo (Baseline: 54.3%; Week 52: 45.3% (n=27), p<0.001) versus 3.1% for Catena®/Raxone® (Baseline PEF%P: 53.1%; Week 52: 50.1% (n=30); p=0.13) for a treatment group difference in change from Baseline to Week 52 of 5.96% (p=0.04).

Santhera also announced that this finding has been corroborated by the results of secondary endpoints assessing respiratory function in all randomized and treated subjects. When measured weekly by the patient at home using the hand-held ASMA-1 device (secondary endpoint), Catena®/Raxone® significantly reduced the annual decline in PEF%p by 80% compared to patients taking placebo. The ASMA-1 device showed a significant 9.0% decline in PEF%p occurred between Baseline and Week 52 in the placebo group (n=31; p<0.001), compared to a non-significant decline of 1.8% in the Catena®/Raxone® group (n=31; p=0.44), for a treatment group difference in change from Baseline to Week 52 of 7.2% (p=0.03). Furthermore, for Forced Expiratory Volume in 1 second (as percent predicted, FEV1%p), an additional endpoint for respiratory muscle strength, Catena®/Raxone® significantly reduced the annual decline by 78% compared to patients taking placebo. The annual decline in FEV1%p in the placebo group was 10.7% compared to 2.4% in the Catena®/Raxone® group (p=0.03).

Importantly, the outcome for Forced Vital Capacity (as percent predicted, FVC%p), a measure of restrictive lung disease predictive of morbidity and mortality in DMD, also supported a treatment benefit of Catena®/Raxone®. The annual decline in FVC%p was reduced by 37% in Catena®/Raxone®-treated patients (9.0% decline in FVC%p in the placebo group versus a 5.7% decline in the Catena/Raxone group; p=0.08). No differences were observed between treatment groups in Maximal Inspiratory or Expiratory Pressures or in Peak Cough Flow.

In summary these outcomes provide clear evidence of a clinical benefit for Catena®/Raxone® in delaying the loss of respiratory function in patients with DMD compared to placebo. As also reported previously, treatment with Catena®/Raxone® was safe and well tolerated. A total of 93.8% of Catena®/Raxone®-treated and 94.1% of placebo-treated patients experienced at least one Adverse Event (AE). Serious AEs were reported in 6.3% of Catena®/Raxone® treated and in 14.7% of placebo-treated patients. Nasopharyngitis (25.8%) and headache (19.7%) were the most common adverse events but there were no differences in the incidence of these events between the treatment groups. Diarrhoea was slightly more commonly observed in Catena®/Raxone®-treated patients (25.0% versus 11.8%), whilst upper respiratory tract infections were more frequently observed in placebo-treated patients (17.6% versus 6.3%). Overall adverse events were mild to moderate in intensity.

* On May 13, 2014, Santhera Pharmaceuticals announced that its Phase III DELOS study of orally administered Catena®/Raxone® (idebenone) in patients with Duchenne Muscular Dystrophy (DMD) met the primary endpoint and achieved its primary objective of delaying the loss of respiratory function compared to placebo. The study randomized 65 DMD patients who were 10-18 years of age and who were not using concomitant corticosteroids. The study met the primary endpoint, the difference between Catena®/Raxone® and placebo in the change from baseline to week 52 in Peak Expiratory Flow (p=0.04). Peak Expiratory Flow is a measure of respiratory muscle strength, the decline of which is a major contributing factor to morbidity and mortality in DMD. Catena®/Raxone® (900 mg/day) was safe and well tolerated with adverse event rates comparable to placebo. Other endpoint analyses are ongoing and results of these will be disclosed shortly.

"On the basis of these results we will approach the US and European authorities for discussions on the most expeditious regulatory pathway to approval," said Thomas Meier, CEO of Santhera.

* On November 26, 2013, Santhera Pharmaceuticals has announced that the Phase III DELOS study of orally administered Catena®/Raxone® (idebenone) in patients with Duchenne Muscular Dystrophy (DMD) remains on track to deliver pivotal data early in 2Q 2014 and is unaffected by recent clinical and regulatory developments related to exon skipping-based treatment strategies. Santhera's randomized, placebo-controlled DELOS study completed the enrolment of 65 steroid non-using DMD patients at the end of 2012 and in April 2013 successfully passed a planned futility analysis for safety and efficacy for the primary respiratory function endpoint.

* On April 16, 2013, Santhera Pharmaceuticals has announced that the Phase III DELOS study of orally administered Catena® in patients with Duchenne Muscular Dystrophy (DMD) successfully passed a planned futility and safety analysis. The independent Data Safety Monitoring Board (DSMB) for DELOS informed Santhera that the study has a reasonable chance of achieving its primary endpoint for improving or delaying the loss of respiratory function in Duchenne patients not using corticosteroids and since no safety issues were detected, recommended that the study should continue as planned.