Parkinson's disease is a common movement disorder with prominent motor symptoms such as tremors, bradykinesia and rigidity. Many patients suffer from motor fluctuations including on off phenomena, and freezing. This presentation looks at the latest drugs for treating these.

1. 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

2. 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.

3. 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.

4. 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

5. SAFINAMIDE TRIALS (1)

6. 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

7. “ON TIME” WITH SAFINAMIDE

8. 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.

9. SAFINAMIDE TRIALS

10. 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.

11. OPICAPONE
 Novel 3rd generation catechol-O Methyl transferase
inhibitor,
 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.

12. BI-PARK I STUDY

13. 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.

14. BI-PARK 2 STUDY

15. 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.

16. 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.

17. LEVODOPA CARBIDOPA INTESTINAL GEL

18. 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)

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. LASER SHOES ALLEVIATE FREEZING OF
GAIT

26. 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.

27. 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.

28. 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.

29. 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,

30. QUERIES/COMMENTS?
THANKS
9866193953
drsudhirkumar@yahoo.com