D R S U D H I R K U M A R M D D M

C O N S U L T A N T N E U R O L O G I S T

A P O L L O H O S P I T A L S , H Y D E R A B A D

NEW DRUGS FOR MOTOR SYMPTOMS IN PARKINSON’S

DISEASE

SCOPE OF MY TALK

Recent drugs approved for reducing “off” time and increasing “on” time (safinamide and opicapone),

Strategies to treat “off” episodes on SOS basis (subcutaneous and sublingual apomorphine),

Apomorphine infusion for patients not fulfilling DBS criteria.

SAFINAMIDE (1)

Safinamide is the first new molecule approved by USFDA for treating PD in more than 10 years.

It was approved in March 2017, as add-on treatment for PD, who are currently taking levodopa-carbidopa and are experiencing “off” episodes.

Approval was based on two phase III trials that included 1200 PD patients with motor fluctuations.

Safinamide provided a significant reduction in the “off time” and significant increase in the “on time” without troublesome dyskinesia.

SAFINAMIDE (2)

Safinamide is an α-aminoamide,

Mechanism of action- both dopaminergic and nondopaminergic

1. Inhibition of MAO-B

2. Na+ Channel blockade,

3. Modulation of stimulated release of glutamate

SAFINAMIDE TRIALS (1)

SAFINAMIDE TRIALS (2)

Patients aged 30-80 years, with mid-late stage PD of 3 or more yrs duration, having motor fluctuations (>1.5 hours off time/day) on levodopa and other dopaminergic medications, were included

Randomized into 3 groups: 50 mg/d, 100 mg/d or placebo, OD dose, treated for 24 weeks

“ON TIME” WITH SAFINAMIDE

FINDINGS OF THIS STUDY

“On” time without troublesome dyskinesia significantly increased

“Off” time significantly reduced,

No significant treatment related adverse events were noted.

100 mg/d was better than 50 mg/d, but both doses of safinamide were better than placebo.

SAFINAMIDE TRIALS

MAIN FINDINGS OF THIS STUDY

549 patients with PD having more than 1.5 hours off time despite pharmacotherapy

Treated with safinamide or placebo for 24 weeks,

Safinamide taken once daily increased the “on” time without dyskinesia by 1.42 hours as compared to 0.57 hour with placebo.

Safinamide was well tolerated.

OPICAPONE

Novel 3rd generation catechol-O Methyl transferaseinhibitor,

Convenient once daily dosing,

Free of potential adverse effects on the liver,

Approved by European Commission in June 2016 as an adjunct therapy in patients on levodopa/DCI with end of dose fluctuations.

BI-PARK I STUDY

BI-PARK 1 STUDY

600 PD patients 30-83 year age, on levodopa with end of dose motor fluctuations were randomized to receive opicapone (5 mg, 25 mg or 50 mg OD), placebo or entacapone (200 mg with every levodopa dose).

Mean “off” time was significantly reduced with opicapone 25 mg and 50 mg OD.

Opicapone was non-inferior to entacapone.

BI-PARK 2 STUDY

BI-PARK II STUDY

427 patients were randomized to receive opicapone (25 mg or 50 mg OD) or placebo,

Were treated for 14-15 weeks, followed by 1 year open-label extension phase with opicapone,

Significant reduction in the “off” time was noted in the 50 mg OD dose (and not 25 mg OD dose) of opicapone, as compared to placebo.

This reduction in “off-time” was sustained for one year.

No significant electrocardiographic or hepatic adverse effects were noted.

LEVODOPA-CARBIDOPA INTESTINAL GEL

Studies have shown that motor fluctuations are partly due to intermittent oral doses of levodopa/carbidopa, as this results in fluctuating levels of levodopa

Continuous jejunal infusion can provide steady state levels of levodopa and reduce motor fluctuations,

Efficacy and safety of levodopa-carbidopa intestinal gel (Duodopa) was demonstrated in clinical trials

It was approved by US FDA in Jan 2015. In Europe, it was already approved in 2005.

LEVODOPA CARBIDOPA INTESTINAL GEL

LCIG STUDY

71 patients with advanced PD were randomized to receive LCIG infusion (n=37) with LC IR placebo or LC IR with LCIG infusion placebo (n=34) for 12 weeks,

LCIG infusion was given by PEG-J tube for 16 waking hours, and stopped overnight

Mean reduction in off time with LCIG infusion was 4 hours (1.9 hours more than LC IR tablets)

Mean increase in on time with LCIG infusion was 4 hours (1.86 hours more than LC IR tablets)

LEVODOPA INHALATION POWDER

Levodopa inhalation powder (CVT-301) can be used SOS during “off” episodes,

86 patients were studied for 4 weeks (Lewitt et al, Mov Disord 2016); 35-50 mg dose was used.

Provides rapid onset of action (10 min)

UPDRS Part III score favored CVT-301 by 7 points

Mean OFF time reduced by 0.9 hours

Main side effects were dizziness, cough and nausea.

PHASE III STUDY CVT 301

SPAN-PD study on 339 patients, treated with 84 mg of inhaled levodopa (CVT 301),

Poster presented at MDS conference at Vancouver (June 2017)

CVT-301 led to significant improvement in motor function (as compared to placebo) as evidenced by mean change in UPDRS III at 30 min at week 12 (-9.83 vs -5.91)

Cough was the most common AE (15% vs 2%); 2 out of 114 patients receiving CVT 301 discontinued the drug due to cough

Data submitted to FDA on June 29th 2017 regarding CVT 301 (Inbrija); resubmitted application on Dec 7th 2017.

APOMORPHINE

Subcutaneous apomorphine (Apokyn) has been approved (by FDA) for treating hypomobility episodes (end of dose wearing off or unpredictable on/off episodes) in advanced PD since 2004, as an adjunct to levodopa therapy.

Recommended dose is 0.2 to 0.6 ml, subcutaneous, delivered by metered injector pen,

Significant improvement in UPDRS motor scores and effective in ending hypomobile episodes within 20 min

Mild-to-moderate nausea/vomiting common; antiemetics are effective.

SUBCUTANEOUS APOMORPHINE INFUSION

TOLEDO phase 3 trial, presented at AAN meeting (Boston, April 2017)

106 patients with advanced PD from Europe were randomized to receive APO SCI or placebo (53 each)

APO infusion given for 16 hours (during waking time)

At 12 weeks, apomorphine group had reduction of “off” time by 2.47 hours, as compared to 0.58 hours with placebo

Available in Europe, however, US FDA approval pending.

SUBLINGUAL APOMORPHINE

Many people do not like injections; moreover, sublingual route is easier to administer,

Sublingual apomorphine (APL-130277) tested in phase 2/phase 3 studies, FDA approval pending

Dose: 10-30 mg during OFF phase,

ON state achieved in 15-30 min of dose in about 80% of patients,

Mean duration of ON phase is 50 min and 60% remain ON for >90 min

Common side effects are dizziness, somnolence and nausea.

ROTIGOTINE TRANSDERMAL PATCH

Rotigotine is an non ergoline dopamine agonist, administered as a transdermal patch, provides rotigotine for 24 hours

Approved by FDA in 2012, Dose: For early PD, initial 2 mg/24 h, can be increased

by 2 mg/24 h at weekly intervals to 6 mg/24 h. For advanced PD, dose is 4 mg/24 h, can be increased to 8 mg/24 h.

Can be used as monotherapy in early PD, or as an adjunct treatment with levodopa in advanced PD,

Low dose oral dopamine agonists (equivalent to 8 mg/24 h) can be switched overnight to rotigotine transdermal patch.

LASER SHOES ALLEVIATE FREEZING OF GAIT

LASER SHOES

21 patients with PD and Freezing of gait (FOG) were included in the study,

The number of FOG and the time spent during freezing were assessed during “on” and “off” phase.

Cueing using laser shoes significantly reduced the number of FOG episodes in both “off” phase (46%) and “on” phase (38%).

Laser shoes also significantly reduced the percent time frozen during off (56%) and on (51%) phases.

MRI-GUIDED FOCUSED ULTRASOUND

MRI guided FUS thalamotomy has been approved by FDA for ET,

MRI-guided FUS thalamotomy (via thermal ablation) has shown benefit in treating medication-resistant tremor predominant PD (Zaroor M, J Neurosurg, 2017),

30 patients (ET:18; PD:9; ET-PD:3) were treated with MRgFUS VIM thalamotomy.

Significant reduction in tremors were noted, that lasted for six months,

Side effects were minor and transient

Larger randomized trials are needed.

STEM CELL TREATMENT FOR PD

Stem cell treatment is still in experimental stage and not approved by FDA,

MDS also does not recommend using stem cell treatment in clinical practice,

Clinical trials are underway in Australia, Europe and elsewhere; and we need to await their results, before any further conclusions can be made.

CONCLUSIONS

Safinamide and opicapone are effective in reducing “off” time and increasing “on” time in patients with mid-to-late PD,

Apomorphine (sublingual or subcutaneous) are promising treatments for SOS use to treat “off” episodes,

Apomorphine infusion is a good option for patients who do not fit the criteria for DBS (can be used in conjunction with DBS too)

MRgFUS VIM thalamotomy could be a noninvasive alternative to DBS in selected patients with tremor-predominant PD,

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