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Executive Summary 

 

On 21 March 2017, Newron Pharmaceuticals and its partners Zambon and US WorldMeds announced the approval of Xadago (safinamide) for the treatment of Parkinson’s disease (PD) as an add-on therapy to levodopa/carbidopa for patients experiencing “off” periods (BusinessWire, 2017; FDA press release, 2017). This approval was long-awaited by Newron and its US partner, US WorldMeds, as it followed numerous earlier US regulatory setbacks. Newron and its partner are now looking to successfully launch Xadago, but the US approved label fell short of ideal as it did not extend to early-stage PD patients receiving dopamine agonists. Thus, Xadago’s commercial prospects will be curbed by competition from rival Azilect (rasagiline; Teva/Takeda/Lundbeck), as the latter drug is pertinent to the entire PD patient paradigm. In order to boost Xadago’s commercial appeal, Newron will need to further explore the drug’s potential to diminish dyskinesia and highlight its key clinical advantages compared to Azilect.

 

Xadago boasts a novel dual mechanism of action that is beneficial for Parkinson’s disease patients with motor fluctuations

 

Xadago is positioned as an oral, once-daily adjunctive therapy for PD patients receiving levodopa. The drug is intended to improve motor fluctuations in advanced PD patients without exacerbating dyskinesia, which Newron claims is possible due to Xadago’s novel dual mechanism of action. As a monoamine oxidase B (MAO-B) inhibitor and a glutamate release inhibitor, Xadago acts through both dopaminergic and non-dopaminergic pathways. The drug not only inhibits the MAO-B enzyme, but also blocks the activity of the voltage-dependent sodium channels and modulates glutamate release, and it is the inhibition of glutamate which helps to avoid the development of dyskinesia linked to long-term levodopa use.

 
Newron’s persistent endeavors have finally been rewarded with US approval

 

While Xadago was approved in the EU in February 2015 for the adjunctive treatment of mid-to-late-stage PD patients taking levodopa (Newron Pharmaceuticals, 2015a), the drug’s US development has been riddled with regulatory setbacks. Firstly, the US Food and Drug Administration (FDA) issued a refusal to file letter in May 2014, leading Newron to resubmit its New Drug Application (NDA) in December 2014 (Newron Pharmaceuticals, 2015b). Following an extended review period, the FDA declined to approve Xadago in March 2016. It was Newron’s second NDA resubmission, in September 2016 (BusinessWire, 2016), that was finally met with the long-awaited approval.

 

Xadago’s US approval is based on two Phase III trials (ClinicalTrials.gov identifiers: NCT01187966 and NCT00627640) which demonstrated that the drug significantly reduces “off” time without being associated with unfavorable dyskinesia events, while also increasing patients’ daily “on” time. In addition to being developed as an add-on therapy to levodopa (FDA press release, 2017), Xadago was also studied as an adjunctive therapy to dopamine agonists in early PD. However, this latter indication has not been approved by either US or European regulators.


US approval of Xadago was based on the pivotal late-phase trial data detailed below.

 

Trial

Sample size

Target patients

Study design

Dosing tested and duration

Results

Reference

Study 016 (NCT01187966) (Phase III)

669

Mid-to-late-stage PD, treated with stable levodopa therapy (with/without concomitant dopamine agonist and/or anticholinergic therapy)

R, DB, PC

Safinamide (50mg or 100mg) or placebo

Duration: 24 weeks

Significant improvement in motor function and the average amount of “on” time with no dyskinesia or with minor dyskinesia increase against placebo;

At week 24, increases in total daily “on” time with no or non-troublesome dyskinesia were 1.36 hours for safinamide 100mg per day, 1.37 hours for safinamide 50mg per day, and 0.97 hours for placebo;

The average duration of “off” time compared to placebo decreased by 0.62 hours and 0.65 hours for the 50mg and 100mg doses, respectively (p<0.05)

EMA, 2016

SETTLE (NCT00627640) (Phase III)

549

Advanced PD treated with stable levodopa therapy (with/without concomitant dopamine agonist and/or anticholinergic therapy)

R, DB, PC

Safinamide (50mg or 100mg) or placebo

Duration: 24 weeks

Significant benefit of both doses of safinamide over placebo; significant improvement of +0.96 hours in “on” time as reported by patient diaries and caregivers, and a ≥30% improvement in motor symptoms (p=0.018)

Schapira et al., 2013

DB = double-blind; PC = placebo-controlled; R = randomized

 

Xadago’s commercial potential will be overshadowed by Azilect’s broad indications



The FDA’s decision to approve Xadago exclusively as an add-on to levodopa therapy for fluctuating mid-to-late-stage patients as opposed to as an adjunct to dopamine agonists for early-stage PD patients will limit the drug’s patient potential, particularly compared with that of Azilect. Showing its confidence in Xadago’s clinical appeal, Newron had hoped for an approval across the entire PD treatment spectrum; however, the company now must settle for the potential for some off-label use earlier in the treatment algorithm encouraged by the MOTION trial in early-stage PD patients which demonstrated a significant treatment effect (ClinicalTrials.gov identifier: NCT00605683). Even so, Xadago will likely be used as a secondary choice to competitor Azilect in this setting. Therefore, in order to increase Xadago’s target population and future revenues, Datamonitor Healthcare believes Newron should investigate the drug’s potential to reduce dyskinesia in future clinical trials.

Xadago does, however, still pose some threat to its fellow MAO-B inhibitor and rival, Azilect. Xadago is poised to claim a portion of Azilect’s patient share with its high selectivity for MAO-B over MAO-A, which precludes the dietary restrictions necessary for Azilect patients. Furthermore, Xadago is an adjunctive therapy, which will circumvent the need for patients to switch therapies as their disease progresses. As levodopa therapies are now widely genericized, combined treatment costs with Xadago should still be affordable, and will not deter physicians from prescribing the drug. Moreover, Xadago stands out as particularly clinically appealing given its superior, novel dual mechanism of action, which allows it to reduce patients’ “off” time without inducing troublesome dyskinesia. If Newron and its partners can effectively highlight this in their marketing efforts, Xadago could still become a noteworthy competitor against Azilect.

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