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Date: 2017-09-15

Type of information: Negative opinion for the granting of a Market Authorisation in the EU

Product name: Raxone®/Catena®

Compound: idebenone

Therapeutic area: Genetic diseases - Neuromuscular diseases - Rare diseases

Action mechanism:

  • benzoquinone analog/quinone. Raxone® (idebenone), a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H:quinone oxidoreductase (NQO1), is capable of transferring electrons directly onto complex III of the mitochondrial electron transport chain, thereby circumventing the complex I defect and restoring cellular energy levels in retinal ganglion cells and promoting recovery of visual acuity. Nerve and muscle cells, including heart muscle cells, are particularly energy-demanding and are, therefore, more prone to rapid cell damage or death due to mitochondrial dysfunction. Through preserving mitochondrial function and protecting cells from oxidative stress, it is believed that Raxone®/Catena® can prevent cell damage and increase the production of energy within impaired nerve and muscle tissue in Friedreich's Ataxia and Duchenne patients.

Company: Santhera Pharmaceuticals (Switzerland)

Disease: Duchenne Muscular Dystrophy and other muscular dystrophies

Latest news:

  • • On September 15, 2017, Santhera Pharmaceuticals announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a negative opinion for its Type II extension application for Raxone® (idebenone) in Duchenne muscular dystrophy. Santhera plans to appeal the opinion and will seek a re-examination by the CHMP. Santhera gave its oral explanation to the CHMP on Wednesday this week to further support the clinical relevance of the existing data in the proposed indication. The CHMP expressed uncertainties whether the phase III DELOS trial provides sufficient evidence of efficacy to allow a Type II variation of Santhera's existing marketing authorization for Raxone. The application was filed as a Type II Variation of the existing marketing authorization for Leber's hereditary optic neuropathy (LHON), and is based on data from Santhera's phase II (DELPHI) study and the successful pivotal phase III (DELOS) study, the latter in patients not taking concomitant glucocorticoids. The outcomes of the phase III DELOS study were published in several peer-reviewed journals: Buyse et al., The Lancet 2015, 385:1748-1757; McDonald et al., Neuromuscular Disorders 2016, 26:473-480, Buyse et al., Pediatric Pulmonology 2017, 52:580-515 and Mayer et al., Journal of Neuromuscular Diseases 2017, 4: 189-198. The intended indication for Raxone is to slow the decline of respiratory function in patients with DMD who are currently not taking glucocorticoids. The indication would include patients who were previously treated with glucocorticoids or in whom glucocorticoid treatment is not tolerated or is considered inadvisable.
  •  • On September 11, 2017, Santhera Pharmaceuticals announced enrollment of first Duchenne muscular dystrophy patients with respiratory function decline not taking glucocorticoids into UK's Early Access to Medicines Scheme (EAMS) for Raxone®. To date, 15 specialist DMD centers in the UK have received training under the requirements of the EAMS. Several additional sites have expressed an interest to be trained and are currently undergoing local approval processes.
  • • On June 22, 2017, Santhera Pharmaceuticals announced that the UK's Medicines and Healthcare products Regulatory Agency (MHRA) has granted Raxone® (idebenone) a positive scientific opinion through the Early Access to Medicines Scheme (EAMS) for patients with respiratory function decline not taking glucocorticoids in Duchenne Muscular Dystrophy. The aim of the EAMS is to provide patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorization when there is a clear unmet medical need. The MHRA decision allows patients with Duchenne muscular dystrophy, who meet criteria defined under this scheme, to gain access to Raxone®. Under the EAMS, and as shown in the public assessment report, Raxone is indicated for slowing the decline of respiratory function in patients with Duchenne muscular dystrophy from the age of 10 years who are currently not taking glucocorticoids. The decline of respiratory function must be confirmed by repeated measurements prior to initiation of treatment. Raxone can be used in patients previously treated with glucocorticoids or in patients in whom glucocorticoid treatment is not tolerated or is considered inadvisable.
  • • On May 19, 2017, Santhera Pharmaceuticals announced an updated timeline for the ongoing assessment by the Committee for Medicinal Products for Human Use (CHMP) of its extension application for Raxone® (idebenone) in Duchenne muscular dystrophy. The application was filed as a Type II Variation of the existing marketing authorization and is based on data from Santhera's phase II (DELPHI) study and the pivotal phase III (DELOS) study, the latter in patients not taking concomitant glucocorticoids. This data demonstrated a statistically significant and clinically relevant benefit of Raxone in preserving respiratory function compared to placebo. This result is further substantiated by a natural history study, which shows that the benefits observed in the group treated with Raxone would not have been expected from the natural course of the disease.• On November 8, 2016, Santhera Pharmaceuticals announced that the Swiss Agency for Therapeutic Products (Swissmedic) has accepted for review Santhera's Marketing Authorization Application for Raxone® (idebenone) for the treatment of Duchenne muscular dystrophy in patients with respiratory function decline not taking concomitant glucocorticoids. Raxone was granted Orphan Drug Designation for Duchenne muscular dystrophy in Switzerland in 2012. Santhera submitted this marketing application in October 2016. Swissmedic has now confirmed that the dossier is sufficiently complete to permit substantive review. As part of the Swiss MAA, Santhera submitted data from its phase II (DELPHI) program and the pivotal phase III (DELOS) study, the results of which have been further substantiated by a comparative natural history study. Data from all studies demonstrate that Raxone slows the rate of respiratory function decline compared to untreated patients to a degree that is of major clinical relevance for patients with Duchenne muscular dystrophy. Raxone (900 mg/day) was safe and well tolerated with adverse event rates comparable to placebo. In parallel to the already ongoing marketing authorisation application reviews in Europe, Santhera continues to prepare for further discussions with the FDA on the most appropriate regulatory pathway to approval in the US.
  • • On September 8, 2016, Santhera Pharmaceuticals announced that the Australian Therapeutic Goods Administration (TGA) has granted orphan drug designation (ODD) to idebenone (Raxone®) for the treatment of Duchenne muscular dystrophy (DMD). The TGA defines orphan diseases as affecting fewer than 2000 individuals in Australia. The application for orphan drug designation was submitted on Santhera's behalf by TudorRose Consulting Ltd, which is acting as Santhera's legal sponsor in Australia.
  • • On July 14, 2016, Santhera Pharmaceuticals announced that it has received written correspondence from the FDA on its proposed subpart H approval pathway for Raxone® in DMD patients not taking concomitant glucocorticoids. Santhera had proposed that the planned SIDEROS trial would provide confirmatory evidence of efficacy in these patients whilst expanding the label to include the treatment of glucocorticoid-using patients. From its review of this strategy, the FDA concluded that results from the SIDEROS trial, which is powered to detect a difference in the established surrogate endpoint Forced Vital Capacity percent predicted (FVC%p) in glucocorticoid-using patients, should be provided at the time of filing to support an NDA for the treatment of DMD patients irrespective of their glucocorticoid use status.
  • The protocol of the SIDEROS trial has previously been reviewed by the FDA which confirmed that this trial has the potential, if positive, to provide the necessary efficacy data, along with data from previous trials to support NDA filing in patients with DMD. This trial SIDEROS is a Phase III double-blind, randomized, placebo-controlled trial of Raxone® in Duchenne muscular dystrophy (DMD) patients receiving concomitant glucocorticoids. Patients with declining respiratory function on any stable glucocorticoid treatment scheme irrespective of the underlying dystrophin mutation or ambulatory status will be eligible for participation. Study participants will receive either Raxone® (900 mg/day; given as 2 tablets 3 times a day with meals) or placebo for 78 weeks (18 months). The primary endpoint of the trial is change from baseline to week 78 in forced vital capacity % predicted (FVC%p). Secondary endpoints include changes from baseline in % predicted peak expiratory flow (PEF%p), time to first 10% decline in FVC, and change from baseline in inspiratory flow reserve. Patients completing the trial will be offered the opportunity to enroll in an open label extension study where all patients receive Raxone®. It is currently expected that the results of the SIDEROS trial will become available in 2H 2019.
  • • On June 21, 2016, Santhera Pharmaceuticals announced that the European Medicines Agency (EMA) has validated its Marketing Authorization Application (MAA) for Raxone® for Duchenne muscular dystrophy (DMD) in patients with respiratory function decline who are not taking concomitant glucocorticoids. Validation confirms that the submission, which was filed as Type II variation of the Company's existing marketing authorization for Raxone, is complete and that the review process by the CHMP (Committee for Medicinal Products for Human Use) has begun. Santhera expects an opinion from the CHMP in the first quarter of 2017.
  • • On May 31, 2016, Santhera Pharmaceuticals announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Raxone® (idebenone) for the treatment of Duchenne muscular dystrophy in patients with respiratory function decline and not taking concomitant glucocorticoids. The regulatory dossier now submitted as Type II Variation of the existing marketing authorization summarizes data from Santhera's phase II (DELPHI) program and the successful pivotal phase III (DELOS) study which demonstrated a statistically significant and clinically relevant benefit of Raxone treatment in slowing the rate of respiratory function loss compared to placebo in patients with DMD not taking concomitant glucocorticoids. This benefit also translated to fewer bronchopulmonary events (e.g. airway infections), shorter event duration and less antibiotic treatment in the Raxone-treated patients. The data have been substantiated by a natural history study showing that the significant decline of respiratory function observed in the placebo group of DELOS reflected the natural course of the disease whilst the outcome for Raxone-treated patients did not. The MAA also includes data from a patient-centered benefit-risk survey which highlighted the importance of treating pulmonary disease in patients with DMD. The findings showing that Raxone slows the rate of respiratory function decline, decreases the proportion of patients crossing clinically relevant functional thresholds and increases the time until such thresholds are reached, represent an important treatment effect and are of major clinical relevance for patients with DMD. Raxone (900 mg/day) was safe and well tolerated with adverse event rates comparable to placebo. The intended indication for Raxone is for patients with DMD in whom respiratory function has started to decline and who are currently not taking concomitant glucocorticoids. The indication would include patients who previously were treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. Patients with respiratory function decline currently not using glucocorticoids account for approximately 40% of DMD patients above the age of 10 years. There is currently no treatment available for this group of DMD patients. In the USA, Santhera has submitted comprehensive briefing material to the FDA in preparation for discussion on the filing of a New Drug Application (NDA) for idebenone under Subpart H for the same indication as in the MAA. Feedback from the FDA is currently expected by the end of July.
  • • On May 3, 2016, Santhera Pharmaceuticals announced that it has submitted comprehensive briefing material and a meeting request to the FDA to discuss the filing of a New Drug Application for Raxone® (idebenone) for the treatment of DMD patients not taking concomitant glucocorticoids. The FDA-meeting request included a very comprehensive data package intended to prepare for discussions with the Agency on an accelerated NDA approval (under Subpart H) for Raxone in patients with DMD not taking concomitant glucocorticoids. The intended indication is for patients in whom respiratory function has started to decline and would include patients who previously were treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. The data package provided to the FDA summarizes data from Santhera's phase II (DELPHI) program and the successful pivotal phase III (DELOS) study, which demonstrated a clinically relevant and statistically significant benefit of idebenone treatment in slowing the rate of respiratory function decline compared to placebo. Importantly, the package also includes data from the Cooperative International Neuromuscular Research Group's (CINRG) Duchenne natural history study (DNHS), which, in collaboration with CINRG, were used to conduct the first prospectively planned external control group study to compare outcomes for patients participating in DELOS with matched, contemporaneously-observed patients from the CINRG DNHS. The results demonstrate that the respiratory function decline observed in the placebo group of the DELOS study is consistent with the rate of decline observed in matched patients from the CINRG DNHS and therefore with the expected natural history of DMD. However, the slower rate of decline observed in idebenone-treated patients in DELOS was not observed in matched patients from the CINRG DNHS, indicating that the rate of respiratory function decline in idebenone-treated patients in DELOS differs from the expected natural history of DMD. Submission documents using the same data sets are currently being finalized for a Type II-variation of the existing Marketing Authorization granted for Raxone® for Leber's hereditary optic neuropathy in Europe to add the treatment of DMD patients not using glucocorticoids to the label. The Company also reported that the SIDEROS protocol for a new phase III study in DMD patients using glucocorticoids has successfully completed the FDA review process. The Company will make a further announcement as soon as the study starts enrolling patients. Patients with declining respiratory function on any stable glucocorticoid treatment scheme will be eligible. Study participants will receive either Raxone (900 mg/day) or placebo for 78 weeks. The trial targets to enroll approximately 260 DMD patients and will be conducted in Europe and the US. Patients completing the trial will be offered the opportunity to enroll in an open label extension study. Santhera intends to position this study to provide confirmatory evidence (under Subpart H) of the efficacy of idebenone in patients both taking and not taking concomitant glucocorticoids.
  • • On August 19, 2015, Santhera Pharmaceuticals announced that the FDA has granted rare pediatric disease designation for Santhera's lead orphan drug candidate, idebenone, for the treatment of Duchenne Muscular Dystrophy (DMD). The rare pediatric disease designation supplements the orphan drug designation granted by the FDA for idebenone to treat DMD in February 2007.
  • • On June 10, 2015, Santhera Pharmaceuticals announced that it has discussed its plans to submit a New Drug Application for Raxone®/Catena® (idebenone) in DMD with the FDA in a pre-NDA meeting. The Agency and Santhera agreed that data presented at the meeting, including natural history data obtained under collaboration with the Cooperative International Neuromuscular Research Group (CINRG), and the possible implications of the natural history data on plans for this NDA will be further discussed during a second meeting. Idebenone has been granted orphan drug designation for DMD in Europe and the US and has use patent protection until 2026 in Europe and 2027 in the US. The FDA recently granted Fast Track designation for Raxone/Catena (idebenone) for the treatment of DMD (See below).
  • • On April 9, 2015, Santhera Pharmaceuticals announced that the FDA has granted Fast Track designation for Santhera's Raxone®/Catena® (idebenone) for the treatment of Duchenne Muscular Dystrophy. Santhera previously announced that the Phase III trial (DELOS) in DMD met its primary endpoint and demonstrated that Raxone/Catena delayed the loss of respiratory function. DELOS was a Phase III, double-blind, placebo-controlled trial which randomized and treated 64 European and US DMD patients not receiving concomitant corticosteroids. Patients 10-18 years of age received either Raxone/Catena tablets (900 mg/day) or matching placebo for 52 weeks. The primary endpoint was change in Peak Expiratory Flow % predicted (PEF%p) from baseline to week 52. PEF%p declined significantly (-9.01%p; 95% CI: -13.2, -4.8; p<0.001) from baseline to week 52 in the placebo group compared to a non-significant decline (-3.05%p; 95% CI: -7.1, 0.97; p=0.134) in the Raxone/Catena group, resulting in a statistically significant difference between treatment groups of 5.96%p (95% CI: 0.16, 11.8; p=0.044) at week 52 and representing a 66% reduction in loss of PEF%p. A statistically significant treatment effect was also seen at week 26 (p=0.007) and week 39 (p=0.034) and across all assessment timepoints (p=0.018).

Patents:

  • • On August 24, 2011, Santhera Pharmaceuticals announced that the United States Patent and Trademark Office granted patent protection for the use of idebenone (Catena®) in the treatment of Duchenne Muscular Dystrophy and other muscular dystrophies. The patent in the United States is supplemented by a similar patent in the European Union granted in 2010.

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization:

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA: 2007-02-16

Orphan status UE: 2007-03-20

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes