Products

Date: 2017-07-11

Type of information: Product launch

Product name: Xadago™

Compound: safinamide

Therapeutic area: Neurodegenerative diseases

Action mechanism: Monoamine oxidase inhibitor. Safinamide has a novel dual mechanism of action based on the enhancement of the dopaminergic function (through potent reversible inhibition of MAO-B and of dopamine uptake) and inhibition of excessive release of glutamate.

Company: Newron Pharmaceu­ticals (Italy) Zambon (Italy)

Disease:

• add-on therapy to a stable dose of a single dopamine agonist in early Parkinson’s disease patients
• add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments in mid-to late stage Parkinson’s disease patients

Latest news:

• • On July 11, 2017,  Newron Pharmaceuticals and Zambon and US WorldMeds announced that Xadago™ (safinamide) is now available as an add-on therapy for U.S. patients with Parkinson’s disease currently taking levodopa/carbidopa and experiencing “off” episodes.
• • On April 10, 2017, Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Portugal for the treatment of mid- to late-stage Parkinson’s disease. With the addition of Portugal, Xadago® is now available in twelve European countries: Germany, Switzerland, Spain, Italy, Belgium, Denmark, Sweden, UK, Luxembourg, the Netherlands and Norway.
• • On March 21, 2017, the FDA  approved Xadago® (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.
• The efficacy of Xadago® was shown in a clinical trial of 645 participants who were also taking levodopa and were experiencing “off” time. Those receiving Xadago® experienced more beneficial “on” time, a time when Parkinson’s symptoms are reduced, without troublesome uncontrolled involuntary movement (dyskinesia), compared to those receiving a placebo. The increase in “on” time was accompanied by a reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment.
• In another clinical trial of 549 participants, the participants adding Xadago® to their levodopa treatment had more “on” time without troublesome uncontrolled involuntary movement compared to those taking a placebo, and also had better scores on a measure of motor function assessed during “on” time than before treatment.
• Certain patients should not take Xadago®. These include patients who have severe liver problems, or who take dextromethorphan. It also should not be taken by patients who take a monoamine oxidase inhibitor (MAOI) because it may cause a sudden severe increase in blood pressure, or by those who take an opioid drug, St. John’s wort, certain antidepressants (such as serotonin-norepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines), or cyclobenzaprine, because it may cause a life-threatening reaction called serotonin syndrome.
• The most common adverse reactions observed in patients taking Xadago® were uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia).
• Serious, but less common, risks include the following: exacerbated high blood pressure (hypertension); serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs; falling asleep during activities of daily living; hallucinations and psychotic behavior; problems with impulse control/compulsive behaviors; withdrawal-emergent hyperpyrexia (fever) and confusion; and retinal pathology.
• • On October 21, 2016, Newron Pharmaceuticals and Zambon announced  that the FDA considers the September 2016 re-submission of the US NDA by Newron to be a complete, Class 2 response to FDA’s March 28, 2016 Complete Response Letter (CRL), and has determined the user fee goal date (PDUFA date) to be March 21, 2017.
• • On September 22, 2016, Newron Pharmaceuticals announced that the company has re-submitted the New Drug Application (NDA) for Xadago® (safinamide) to the FDA. As a class 2 resubmission, the FDA is expected to complete its review of the re-submission within 6 months of acceptance.
• • On September 1, 2016, Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Norway for the treatment of mid- to late-stage Parkinson’s disease.
• • On July 26, 2016, Newron Pharmaceuticals  and Zambon announced that the FDA and the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the FDA no longer require Newron to perform any studies to clinically evaluate the potential abuse liability or dependence/withdrawal effects of Xadago®. Thus Newron will now expedite re-submission of the New Drug Application (NDA) to the FDA.
• • On July 6, 2016, Zambon and Newron Pharmaceuticals  announced the launch of Xadago® (safinamide) in the Netherlands .
• • On May 23, 2016, Zambon and Newron Pharmaceuticals  announced the availability of Xadago® (safinamide) in the UK.
• • On April 4, 2016,  Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Belgium for the treatment of mid- to late stage Parkinson’s disease (PD).
• • On March 29, 2016, Newron Pharmaceuticals and  Zambon announced  that a complete response letter from the FDA has been received for safinamide. The complete response letter requests clinical evaluation of the potential effect of safinamide on behaviors relating to abuse liability and dependence/withdrawal effects as required by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the FDA.
• • On February 29, 2016, Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Italy.
• • On February 22, 2016, Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Spain .
• • On January 12, 2016, Zambon and  Newron Pharmaceuticals  announced the launch of Xadago® (safinamide) in Switzerland, the second market after Germany.
• • On November 13, 2015, Zambon and Newron Pharmaceuticals announced that Swissmedic has approved Xadago® (safinamide) as add-on therapy to levodopa alone or in combination with other Parkinson diseases therapies for patients in mid-to late-stage and motor fluctuations.
• • On September 30, 2015, Newron Pharmaceuticals and Zambon announced that the late-cycle review meeting for the New Drug Application (NDA) for Xadago® (safinamide) has been completed with the FDA. The FDA extended the review time for the Xadago® NDA by the standard period of three months to review the late submission of additional financial disclosure forms for the MOTION and SETTLE clinical studies. This extends the PDUFA date to March 29, 2016.
• • On May 15, 2015, Zambon and Newron Pharmaceuticals announced the launch of Xadago® (safinamide) in Germany. Germany is the first country in which Xadago®, which has been approved as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson’s disease therapies for mid-to late-stage fluctuating patients, is launched.
• • On March 2, 2015, Newron Pharmaceuticals and  Zambon announced that the New Drug Application (NDA) for Xadago® (safinamide) has been accepted for filing by the FDA. Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target date of December 29, 2015 to complete its review of the NDA. The application covers the proposed use of Xadago® (safinamide) as add-on therapy in both early and mid-to-late stage Parkinson’s disease patients who are inadequately managed on their current treatment.
• • On February 26, 2015, Zambon and Newron Pharmaceuticals announced that the European Commission approved the use of Xadago® (safinamide) for the treatment of idiopathic Parkinson’s disease. Xadago® has been approved for mid-to late-stage fluctuating patients as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal products. The decision follows the Positive Opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) on December 18th, 2014 and is applicable to all 28 European Union member countries, as well as Iceland, Liechtenstein and Norway. Zambon will now proceed with the marketing authorizations in the EU countries, starting in the first half of 2015.
• • On December 29, 2014, Newron Pharmaceuticals and its commercial and development partner Zambon announced that the NDA for safinamide has been re-submitted to the  FDA. This follows the announcement last week that the CHMP has given a positive opinion on safinamide for Europe. The submission covers the indications “safinamide as add-on therapy to a stable dose of a single dopamine agonist” in early Parkinson’s disease patients and “safinamide as add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments” in mid-to late stage Parkinson’s disease patients. The first submission of safinamide to the FDA was made in May 2014. On review, the FDA issued a Refusal to File (RTF) letter based on organizational and navigational problems, largely due relating to the hyperlinking of tables, folders and the organization of the table of contents in the submission.
• • On December 19, 2014, Newron Pharmaceuticals and Zambon announced that the EU Committee for Medicinal Products for Human Use (CHMP) recommended that the European Commission approve the use of Xadago™ (safinamide) as add-on to L-dopa alone or in combination with dopamine agonists, entacapone, amantadine, and/or anticholinergics, for the treatment of patients with mid-late stage Parkinson’s disease experiencing motor fluctuations despite being stabilized on ‘Standard of Care’.
•  The EU filing was based on results of a comprehensive development program comprising over 300 preclinical studies and 37 clinical studies performed in over 30 countries worldwide, with over 3,000 subjects treated, and safinamide’s safety being documented in >1,100 patients for 1 year, >500 patients for 2 years, >220 patients for 3 years, and >160 patients for 4 years.
• Safinamide Pivotal L-dopa Studies: The efficacy of safinamide as add-on treatment in mid-late stage PD (LSPD) patients with motor fluctuations, currently receiving L-dopa alone or in combination with other PD medications, was evaluated in two double-blind, placebo-controlled studies: SETTLE (Study 27919; 50-100 mg/day; 24 weeks; N=549), and Study 016/018 (50 and 100 mg/day; 2 year double-blind, placebo-controlled study; N=669). The results of analyses (mITT, ‘On-treatment’ population; MMRM) for Study 016/018 and the SETTLE study indicate a consistent pattern of benefit for motor fluctuations with statistically significant improvements in the Primary efficacy measure, daily ON Time (ON Time without troublesome dyskinesia), and key secondary measure of OFF Time as re-corded by the patients in the 18-hr diary. Statistically significant efficacy was also noted for secondary measures including motor symptoms (UPDRS III), Quality of Life (as indicated by changes in the patients/care-giver rated PDQ39, EQ-5D), depressive symptoms, as measured by the GRID-HAMD scale, global change from baseline (CGI-C) assessed by the clinician, and activities of daily living (UPDRS II) assessed by the patient/caregiver.
• In the SETTLE study, statistically significant improvements from baseline to endpoint were observed for safinamide, compared to placebo (LS mean difference), for ON Time (0.9 h, 95% CI [0.6, 1.2], p<0.0001), OFF Time (-1.0 h, 95% CI [-1.3, -0.7], p<0.0001), UPDRS III (-1.82, 95% CI [-3.01, -0.62], p=0.003), UPDRS II, (-0.4, p=0.0564), PDQ-39 (p=0.006) and EQ-5D (p<0.001). The proportion of patients rated as “very much/much” improved on the CGI-C at endpoint was significantly greater for safinamide (24.4%, p<0.0001) compared to placebo (9.5%). Furthermore, additional responder rate analyses demonstrated a spectrum of benefit that was reflected in a greater proportion of safinamide-treated patients, compared to placebo, having clinically important improvement (=1 hour) in ON Time and OFF Time, along with 30% improvement in UPDRS III (18.1% vs. 8.8%, p=0.0017).
• In the initial 6-month treatment period of Study 016/018, statistically significant improvements from baseline to endpoint were observed for the safinamide 50 and 100 mg/day doses, compared to placebo (LS mean difference), for ON Time (50 mg/day: 0.5 h, 95% CI [0.1, 0.9], p=0.0054; 100 mg/day: 0.7 h, 95%CI [0.3, 1.0], p=0.0002), OFF Time (50 mg/day: -0.6 h, 95% CI [-0.9, -0.3], p=0.0002; 100 mg/day: -0.7 h, 95% CI [-1.0, -0.4], p<0.0001), UPDRS III (50 mg/day: -1.6, 95% CI [-3.0, -0.2], p=0.0207; 100 mg/day: -2.3, 95% CI [-3.7, -0.9], p=0.0010) and UPDRS II (50 mg/day: -0.7, 95% CI [-1.3, -0.0], p=0.0367; 100 mg/day: -1.1, 95% CI [-1.7, -0.5], p=0.0007). The proportion of patients rated as “very much/much” improved on the CGI-C at endpoint was significantly greater for safinamide (50 mg/day: 33.2%, p=0.0017; 100 mg/day: 36.1%, p=0.0002) compared to placebo (19.8%). Furthermore, responder rate analyses showed a greater proportion of safinamide-treated patients, compared to placebo, having clinically important improvement (=1 hour) in ON Time and OFF Time, along with 30% improvement in UPDRS III (50 mg/day: 24.0%, p=0.0216; 100 mg/day: 25.9%, p=0.0061 vs. Placebo: 15.1%), UPDRS II (ADL), 100mg/day: -1.0, 95% CI [-1.7;-0.3], p=0.0060, and PDQ39 (Total Score) -16.5, 95% CI (-31.9, -1.1), p=0.0360.
• The benefits of safinamide were still significant following two years of treatment as assessed in Study 018. Statistically significant improvements from baseline to endpoint were observed for safinamide, compared to placebo (LS mean difference), for ON Time (50 mg/day: 0.6 h, 95%CI [0.1, 1.0], p=0.0110; 100 mg/day: 0.7 h, 95%CI [0.2, 1.1], p=0.0028), OFF Time (50 mg/day: -0.5 h, 95% CI [-0.8, -0.2], p=0.0028; 100 mg/day: -0.6 h, 95% CI [-0.9, -0.3], p=0.0003), UPDRS III (100 mg/day: -2.1, 95% CI [-3.5, -0.6], p=0.0047) and UPDRS II (100 mg/day: -1.1, 95% CI [-1.8, -0.4], p=0.0010), GRID-HAMD (100mg/day: -0.57, 95% CI [-1.13, -0.01], p<0.05), and PDQ39 Total Score (100mg/day: -18.36, 95% CI [-33.75, -2.97], p=0.0195).
• In the Pooled Studies 016 and SETTLE, statistically significant improvement was observed with safinamide for ON Time without troublesome dyskinesia (50 mg/day: 0.5 hr, p=0.0010; 100 mg/day: 0.7 hr, p<0.0001) and OFF Time (50 mg/day: -0.6 hr, p<0.0001; 100 mg/day: -0.9 hr, p<0.0001), compared with placebo. Statistically significant improvement was observed for the UPDRS III for both doses compared to placebo (50 mg/day: -1.5, p=0.0052; 100 mg/day: -1.5, p=0.0002). In the responder analysis for Pooled Studies 016/SETTLE, a significantly higher proportion of patients in both safinamide groups (50 mg/day: 54.8%, p=0.0106; 100 mg/day: 56.2%, p<0.0001) compared with placebo (43.1%) showed improvement of = 60 minutes in ON Time, and a significantly greater proportion of patients were rated as “very much/much” improved on the CGI-C (50mg/day: 33.2%, p=0.0002; 100mg/day: 29.6%, p<0.0001) compared with placebo (14.0%).
• Studies in patients with early-stage Parkinson’s disease: The efficacy of safinamide as add-on treatment to a single dopamine agonist was eva-luated in 3 double-blind, placebo-controlled studies: Study 009 (0.5 and 1.0 mg/kg/day [~40 and 80 mg/day, respectively]; 12 weeks, N=100), Study 015/017 (50-100 and 150-200 mg/day; 24 weeks followed by a 52-week double-blind, placebo-controlled extension, N=269) and MOTION (Study 27918; 50 and 100 mg/day; 24 weeks followed by a 78-week double-blind, placebo-controlled extension, N=678).
• In these studies, safinamide 50 and 100 mg/day demonstrated statistically significant improvements on the Primary efficacy measure and key selected secondary measures, however, the CHMP concluded that the medical need for additional medication for these early-stage patients, together with the magnitude of the benefit seen with safinamide in this patient group, did not provide compelling grounds for approval for this use in Europe.
• • On November 21, 2014, Newron Pharmaceuticals and its partner Zambon have confirmed that the CHMP review of the safinamide MAA is proceeding without delay, with the day 180 procedure having been completed, on time. Based on the Dec. 5, 2013 filing, the final CHMP review and decision is expected to be available subsequent to the December CHMP meeting .
• • On July 29, 2014, Newron Pharmaceuticals and Zambon announced that Newron has received a Refusal to File (RTF) letter from the FDA for safinamide. The submission  was made in May 2014. Upon preliminary review, the FDA identified some organization and navigation problems, relating to the hyperlinking of tables, folders and the organization of the table of contents in the submission, as well as the conformation of the Package Insert to FDA guidelines. The Refusal to File letter does not relate to the acceptability of the clinical data, and no judgment is made on the efficacy or safety of safinamide. Newron believes that the additional information needed to support this filing is available and is working closely with the FDA to resubmit the application as quickly as possible.
• • On May 29, 2014, Newron Pharmaceuticals and Zambon have announced that the New Drug Application (NDA) for safinamide was submitted to the FDA. The submission covers the indications “safinamide as add-on therapy to a stable dose of a single dopamine agonist” in early Parkinson’s disease patients and “safinamide as add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments” in mid-to late stage Parkinson’s disease patients. The submission was based on completion of activities agreed upon during meetings with the FDA. The submission was made by Newron, which is the NDA holder until completion of the sublicense process for the US rights to safinamide, by Zambon.
• • On May 12, 2014, Newron Pharmaceuticals informed markets that the safinamide NDA dossier has been finalized and is undergoing quality control by an external vendor. The submission of the dossier to the FDA is anticipated within the coming days.
• • On April 7, 2014, Newron Pharmaceuticals and  Zambon announced that the Application for Authorization for safinamide has been submitted to Swissmedic. The submission covers the indications “safinamide as add-on therapy to a stable dose of a single dopamine agonist” in early Parkinson’s disease patients and “safinamide as add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments” in mid-to late stage Parkinson’s disease patients. The submission was made by Zambon, who will be the authorization holder.
• • On December 5, 2013, Newron Pharmaceuticals and Zambon have announced that the Marketing Authorization Application (MAA) for safinamide was submitted to the European Medicines Agency (EMA). The submission covers the indications “safinamide as add-on therapy to a stable dose of a single dopamine agonist” in early Parkinson’s disease patients and “safinamide as add-on therapy to levodopa alone or in combination with other Parkinson’s disease treatments” in mid-to late stage Parkinson’s disease pa-tients. The submission was based on completion of activities agreed upon during meetings with a number of European national health authorities, the rapporteur and co-rapporteur for safinamide (Netherlands and the UK) as well as the CHMP. Newron will be the authorization holder.

Patents:

Submission of marketing authorization application USA : 2014-05-29/2014-12-26/2016-09-22

Submission of marketing authorization application UE: 2013-12-05

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2017-03-21

UE authorization: 2015-02-24

Favourable opinion UE: 2014-12-18

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

• • On April 5, 2012, Newron Pharmaceuticals has signed a strategic collaboration and licence option with Zambon Company., the industrial holding of Zambon, for Newron’s lead compound safinamide.

Is general: Yes