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FDA Approves Kynmobi Sublingual Film to Treat Off Episodes in Parkinson’s

Kynmobi and FDA approval

The U.S. Food and Drug Administration has approved Sunovion’s Kynmobi (apomorphine hydrochloride) as an on-demand sublingual treatment for off episodes, or times when medication wears off, in people with Parkinson’s disease.

The medication, formerly known as APL-130277, is an apomorphine film that is placed under-the-tongue (sublingual administration) when patients start experiencing a worsening of their symptoms. It can be taken up to five times a day, at doses ranging from 10 mg to 30 mg.

Sunovion expects it to become available to patients in the U.S. by September.

“Today’s approval of Kynmobi advances treatment options for people with Parkinson’s disease who experience OFF episodes and the associated disruption of everyday activities,” Antony Loebel, MD, president and CEO at Sunovion, said in a press release.

“We are pleased to offer the Parkinson’s disease community a novel treatment option that we believe offers a convenient way for patients to rapidly improve impaired movements and better control their motor symptoms when they need it,” Loebel added.

Levodopa is considered the gold standard for Parkinson’s treatment. But several years after starting the medication, most patients begin experiencing fluctuations in their motor symptoms caused by a faster wearing off of the treatment’s effects. These “off” episodes can happen at any time of the day, and most patients experience more than one episode each day.

Kynmobi’s active ingredient, apomorphine, can cross the blood-brain barrier, a semipermeable membrane that protects the brain from the external environment, and mimic the effects of dopamine in the brain. As such, it can counteract the loss of dopamine-producing neurons in the brain, a hallmark of Parkinson’s.

Apokyn, by US World Meds, is an approved apomorphine injection treatment for Parkinson’s patients experiencing off episodes. Its efficacy in easing motor symptoms is established, but it can pose significant challenges to patients, such as the need for an under-the-skin injection, an initial dose titration that should be supervised in a clinic, and common side effects such as nausea and injection site complications. These challenges are thought to have limited its use.

Kynmobi is expected to provide an easier mode of administration and to be eliminate more slowly from the body, helping to ease the feeling of nausea caused by abrupt reductions in apomorphine blood levels.

“Several years after a person is diagnosed with Parkinson’s disease they may notice problems such as having trouble getting out of bed in the morning or having difficulty getting out of a chair, or that they feel frozen while trying to walk as the effect of their maintenance medication diminishes,” said Stewart Factor, professor of neurology at Emory University School of Medicine.

“The approval of Kynmobi affords health care providers with a needed option that can be added to their patients’ medication regimen to adequately address OFF episodes as their Parkinson’s disease progresses,” Factor added.

Kynmobi’s approval was based on data from a Phase 3 study (NCT02469090), in which the oral medication was compared to placebo as an on-demand treatment of motor symptoms during off periods.

The trial included 109 patients who had at least two hours of total off periods per day, including well-defined morning off episodes, despite being responsive to levodopa treatment. In an initial open-label phase, all enrolled were given increasing doses of Kynmobi (10−35 mg) until an optimal dose was identified.

Patients were then randomly assigned to either Kynmobi or placebo, taken to treat up to five off episodes throughout a day, for 12 weeks. All continued to receive their stable anti-parkinsonian medications.

The trial’s main goal was improvements in motor symptoms — defined as changes on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III — from before dosing to 30 minutes after dosing at week 12.

Results showed that patients using Kynmobi experienced an 11.1 point reduction in their MDS-UPDRS scores at week 12, while those on placebo showed reductions of 3.5 points. This 7.6-point difference between both groups was significant, and clinical improvements were seen as early as 15 minutes after dosing, and persisted for up to 90 minutes.

Kynmobi also helped more patients (31%) achieve full control of their motor symptoms — a full “on” response — within 30 minutes at week 12, compared with 14% of those given a placebo.

The treatment was generally well-tolerated, with most treatment-related side effects being mild to moderate, and reversible after its use was stopped. The most common were nausea, sleepiness, and dizziness. One person with known cardiac risk factors who was treated with Kynmobi died due to heart failure.

“We know from our research and discussions with the Parkinson’s community that OFF episodes can significantly disrupt a patient’s daily life,” said Todd Sherer, PhD, CEO, The Michael J. Fox Foundation for Parkinson’s Research. “The Foundation supported early clinical development of sublingual apomorphine, and this approval brings an important new treatment option for people with PD [Parkinson’s disease] who experience OFF [periods].”

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Long-term Gocovri Lessens Parkinson’s Motor Symptoms for at Least 2 Years, Final Phase 3 Data Show

Gocovri (amantadine)

Long-term treatment with Gocovri (amantadine) extended-release capsules was safe and led to sustained reductions in dyskinesia — involuntary, jerky movements — and off episodes in people with Parkinson’s disease, final data from a two-year Phase 3 clinical trial show.

“As the longest-running amantadine study to date, this open-label trial suggests Gocovri may provide sustained improvement in both dyskinesia and OFF [episodes] to a wide cohort of patients with Parkinson’s disease living with motor complications,” Caroline Tanner, MD, professor in the department of neurology at the University of California San Francisco, said in a press release.

“These results expand not only our knowledge of Gocovri efficacy but also of its long-term safety in these patients,” Turner said.

The study, “EASE LID 2: A 2-Year Open-Label Trial of Gocovri (Amantadine) Extended Release for Dyskinesia in Parkinson’s Disease,” was published in the Journal of Parkinson’s Disease.

While levodopa is one of the gold standard treatment to manage Parkinson’s motor symptoms, long-term use may lead to off-episodes, which are moments in which the therapy’s effects wear off and symptoms, including dyskinesia, re-emerge.

Adamas Pharmaceuticals’ Gocovri, a long-acting and extended-release oral capsule amantadine formulation, is the only U.S.-approved treatment for dyskinesia in Parkinson’s patients who receive levodopa-based therapy, with or without other dopaminergic medications. It also is the only therapy clinically proven to lessen both Parkinson’s dyskinesia and off episodes.

Taken once daily at bedtime, Gocovri levels rise slowly overnight and achieve their peak in the morning (before the patient’s first levodopa dose), maintaining its high levels throughout the waking day.

The two-year, open-label Phase 3 EASE LID 2 clinical trial (NCT02202551) evaluated the long-term safety, tolerability, and effectiveness of Gocovri in Parkinson’s patients with levodopa-induced dyskinesia for two years.

The study was designed to reflect conditions closer to a “real-world” clinical setting by including not only patients who completed previous Gocovri trials — EASED (NCT01397422), EASE LID (NCT02136914) and EASE LID 3 (NCT02274766 ) — but also those excluded from these trials because they had deep brain stimulation (DBS) therapy. It also allowed clinicians to adjust doses of levodopa and other Parkinson’s medications.

DBS is the most common surgery used to treat Parkinson’s symptoms by delivering electrical pulses to brain cells.

A total of 223 patients were recruited, including 138 who transitioned directly from previous clinical trials (60 receiving Gocovri and 78 a placebo), 61 with prior DBS surgery, and 24 who had a time gap between the prior trial and the EASE LID 2 study.

Among them, 32 patients (24 who underwent DBS and eight among those with a time gap between trials) were switched directly from amantadine immediate-release to Gocovri when entering EASE LID 2.

Most patients were white (93.3%) and more than half (58.7%) were men. Participants’ mean (average) age was 63.7 years at enrollment and they had been diagnosed with Parkinson’s for a mean of 11.8 years. Patients had been taking levodopa for a mean of 9.3 years, with reports of dyskinesia for about 5.3 years.

During the trial, participants received Gocovri once daily at bedtime for a median of 1.9 years, with 75.8% of them having completed one year of treatment and 57.8% completing two years of treatment.

The therapy’s effectiveness was assessed using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part IV (focused on motor complications). Higher scores indicate greater impact of Parkinson’s symptoms, and changes of at least one point in the MDS-UPDRS Part IV score are considered clinically important.

Results showed that Gocovri was effective in lowering dyskinesia and off episodes in all groups of patients, including those who continued treatment from prior trials and those initiating Gocovri in this trial (patients switching from placebo or amantadine immediate release, and those under DBS therapy).

Low levels of motor complications were maintained in patients continuing Gocovri treatment from prior trials. Those initiating Gocovri in this trial showed marked reductions (between two and four points) in the MDS-UPDRS Part IV score, reaching the same levels as those with continuous treatment after eight weeks (the first scheduled effectiveness assessment). These improvements were maintained throughout the two-year trial.

“The present long-term trial provides supportive evidence that 274 mg Gocovri, taken once daily at bedtime, durably reduces the daily duration, severity, and functional impact of dyskinesia as well as OFF episodes throughout 100 weeks of continued use,” the researchers wrote.

Gocovri’s safety profile and rate of treatment discontinuations (22%) were consistent with those reported in previous clinical trials. Common adverse side effects included falls (32.7%), hallucinations (24.2%), swelling in the legs or arms (16.1%), constipation (13.5%), and urinary tract infections (10.3%).

Not surprisingly, adverse side effects’ onset and related treatment discontinuations tended to occur earlier among those just beginning Gocovri treatment than among those continuing treatment from a prior trial.

Jean Hubble, MD, Adamas’ vice president of medical affairs, said that “given the chronic nature of Parkinson’s disease, both patients and physicians seek treatments that are effective long-term.”

“This study further demonstrates that the only FDA-approved medicine for dyskinesia may help people with PD who are struggling to manage these levodopa-related motor complications over this long period of time,” Hubble said.

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Sublingual Film Turns Parkinson’s Off Periods ‘Full On,’ Most Patients in Phase 3 Trial Report

Phase 3 trial analysis

A majority of Parkinson’s patients in a clinical trial reported achieving a fully “on” response within 30 minutes of taking Sunovion‘s under-the-tongue apomorphine film, called APL-130277, about three months after starting its use to counter “off” episodes in this disease, a post-hoc analysis of study results found.

At week 12, 79% of the 54 adults using APL-130277 in the Phase 3 trial (NCT02469090) recorded a “full on” response to the at-home treatment as the effectiveness of their stable levodopa (or similar dopamine treatment) waned, scientists reported. These responses were a secondary study goal.

Results were presented at the recent Pan American Parkinson’s Disease & Movement Disorders Congress (MDS-PAS), Sunovion said in an email that also provided the presentation. It was titled “Patient-Reported Motor Responses to Apomorphine Sublingual Film Based on Home Dosing and Response Diaries.”

Meant to provide on-demand and fast-acting relief from all types of off episodes, APL-130277 is a formulation of apomorphine in a thin film. The film is placed under the tongue (called a sublingual medication), where it is absorbed into the bloodstream. This makes it easy to self-administer at any time and any place.

Apomorphine stimulates the production of dopamine in the brain. Dopamine is a powerful messenger molecule called a neurotransmitter produced in dopaminergic neurons. Dopaminergic neurons die off in Parkinson’s disease, which leads to the loss of motor and cognitive skills characteristic of the disease.

Off episodes are periods of worsening Parkinson’s symptoms that usually occur when a medication like levodopa begins to lose effect, but before the next dose can be taken. These symptoms include tremors, rigidity, and slowness, as well as cognitive impairment and mood disorders.

The Phase 3 trial randomly assigned 109 patients, with 54 given APL-130277 for on-demand and at-home use, and 55 others a placebo. All enrolled had reported experiencing one off period each day, and were currently taking stable doses of levodopa and adjunctive medications.

The study was double-blinded, so neither the patients nor the researchers knew who received the medication and who was using a placebo.

Over the course of its 12 weeks, patients recorded the time they took APL-130277 during any off episode they chose to treat, and their resulting motor status (full on or off) 30 minutes later. This information was self-reported in diaries over the two days prior to each clinic visit, made at study weeks four, eight and 12.

Researchers measured the percentage of “full on response” reports. That response was defined as one providing benefits “with regard to mobility, stiffness, and slowness, whereby normal daily activities could be performed and were comparable to or better than normal response to [Parkinson’s] medications prior to study enrollment.”

At the study’s conclusion, 79% of patients using the investigative film reported being fully on at 30 minutes after taking APL-130277, compared to 31% of those on placebo.

Across all weeks of diary entries, 77% of patients using APL-130277 reported full-on responses, compared to 26% on a placebo. All took either the treatment or placebo a mean of 2.2 and 2.5 times each day.

Those with full-on response also said they achieved it at all times of the day, with 71% reporting it between 5 am and 9 am, and 86% overnight, between 10 pm and 5 am. This is important, as off episodes can occur at any time.

“Based on home dosing and response diaries, the self administration of APL may lead to a FULL “ON” response in most patients experiencing “OFF” episodes throughout the day,” the researchers concluded.

APL-130277 is currently under review by the U.S. Food and Drug Administration for possible approval as a sublingual treatment for off periods in Parkinson’s disease. A decision is expected on or before May 24.

Meanwhile, enrollment is continuing in an open-label extension Phase 3 study (NCT02542696) investigating the long-term safety and efficacy of APL-130277. Patients are still being recruited at sites in Los Angeles and in several European countries. More information can be found here.

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Taking the Day Off from Parkinson’s

day off

I had a pretty good day recently. It was better than I’d had in a long while. I remember thinking that I could forget I had Parkinson’s disease if every day was like that day.

But every day isn’t like that one. Every other day usually begins with being slow and rigid. If I didn’t have Parkinson’s disease, I would jump out of bed and skip to the bathroom. It would be the beginning of a new day.

If I was taking the day off from having Parkinson’s disease, I would take my morning medicinal cocktail and not feel nauseous at all. But wait — if I didn’t have Parkinson’s, I wouldn’t need a medicinal cocktail.

My shower time would be halved, and I wouldn’t have to worry about being off balance in the shower or falling when stepping out of it. 

I would sit down at my computer, and instead of my fingers seizing up, feeling like popsicle sticks, and refusing to be obedient to my brain, they would begin to type. One word, two words, three words, four — just like the old times. 

What if?

But if it were like “old times,” I would most likely still be working. I would be sitting at my desk taking phone calls, encouraging people, and leading a children’s choir. Or I would be running my business again, making wooden figurines for Christmas, Thanksgiving, and Easter scenes. 

Perhaps I would have retired by now and would be watching my grandkids full-time instead of a few hours, two days a week. And I wouldn’t need a nap (or two) during the day.

If I had escaped the Parkinson’s monster, I would be able to drive myself wherever I wanted to go. I would be able to do laundry anytime and not just when I’m “on.” I could fold clothes and carry out other household chores without any help.

If I didn’t have Parkinson’s disease, I wouldn’t have to deal with my medications being “off” or “on.” I could float through my day. 

Life would be good.

Don’t misunderstand me

My life is good in spite of Parkinson’s disease. I have so much to be thankful for that I once may have taken for granted. Family and friends are so much more precious and valuable to me now.

Daily doses of dopamine may be the norm now, or adjusting deep brain stimulation settings, but I still get those priceless hours with my grandkids, and the medication still works when I take it. So, even if I can’t really take the day off from having Parkinson’s, some days are better than others, and I’ll take what I can get.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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One-year Results in 2 Given Gene Therapy at Low Dose Showing Promise, Axovant Reports

early trial results

Two Parkinson’s patients treated with AXO-Lenti-PD, an investigative gene therapy, in an ongoing clinical trial continue to show improvement 12 months later, Axovant, the therapy’s developer, said in a release.

These findings at one year after treatment are important because this timepoint allows for a better assessment of therapy durability, and a more assured differentiation between placebo effects and therapeutic response, the company added.

AXO-Lenti-PD has shown encouraging results in these two people given a first low dose in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial, which is now enrolling up to 30 patients at sites in France and England.

The treatment works by delivering three genes involved in dopamine production directly to the brain via a surgical procedure.

Dopamine is a neurotransmitter — a molecule involved in transmitting information between neurons — that is critical to coordinating movement. Dopamine-producing (dopaminergic) neurons are lost in Parkinson’s, and the resulting drop in dopamine levels is the cause of many disease symptoms.

By ‘infecting’ brain cells with the genetic instructions to increase dopamine production, AXO-Lenti-PD aims to turn other cells into dopaminergic neurons.

Current dopamine replacement therapies require continual oral doses of dopamine, whose effectiveness fades over time. The period between when one dose’s effectiveness wanes and the taking of a next dose can result in “off periods,” wherein patients report a return of symptoms such as poor motor control, stiffness, fatigue and mood changes.

Helping the brain to again produce adequate levels of dopamine would, in theory, eliminate the need for periodic oral doses, which could significantly limit off periods.

Previous studies in primate models of Parkinson’s found AXO-Lenti-PD to be safe and effective, and SUNRISE-PD results at three months’ post-treatment found that a one-time delivery of the therapy significantly improved patient scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a standard assessment of motor and non-motor symptoms associated with Parkinson’s.

The trial consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of potentially three escalating doses of the gene therapy. In part B, a new group of patients will be randomized to either the ideal part A dose or to a sham procedure as an untreated control group. SUNRISE-PD’s goal is to test the safety, tolerability, and effectiveness of the potential treatment.

Both patients here, the first two enrolled, received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD.

One-year results show positive changes of 24 points and 20 points (respectively for the two patients) on the UPDRS Part III “Off” score, representing a 37% improvement in off-period motor symptoms, Axovant reported. Improvement at six months was 29%, as measured on the same scale.

These patients also showed an average 13-point positive change from baseline (study start) — representing a 44% improvement — on the UPDRS Part II “Off” score, which assesses daily life activities. On the PDQ-39 score index, another quality-of-life measure in Parkinson’s disease, these two showed an average 15-point positive change, or a 30% improvement from baseline to 12 months.

Both patients tolerated AXO-Lenti-PD well, and neither reported any serious side effects. One maintained a diary of on/off periods, which is useful in evaluating changes that might be due to therapy across time.

People being enrolled in SUNRISE-PD have had Parkinson’s for at least five years, have motor fluctuations and dyskinesia (jerky, involuntary movements), and are between the ages of 48 and 70.  More information can be found here.

The company expects to soon release six-month results on the first two patients given a second and higher dose of AXO-Lenti-PD. This dose is three times higher than that given the first cohort.

If dose-escalation results allow, Axovant expects to begin the randomized and placebo-controlled part B of the SUNRISE-PD as a Phase 2 study by the close of 2020.

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Gocovri ER Capsules Ably Ease Motor Symptoms But Care Needed with Elderly, Research Shows

Gocovri and its use

Gocovri (amantadine) extended release capsules work to help lessen dyskinesia, or involuntary muscle movement, and off episodes in Parkinson’s, but special care needs to be given elderly patients with poorer kidney function, according to data presented by Adamas Pharmaceuticals, the treatment’s developer, at a science conference.

Renal insufficiency — or inadequate kidney function, often due to blood flow problems — can be common in people starting around age 70. Doctors should carefully monitor their kidney health and adjust Gocovri doses accordingly, the researchers said, to prevent amantadine from accumulating at unsafe levels in their system.

Gocovri is an extended release prescription medicine for dyskinesia, the sudden and uncontrolled movements that Parkinson’s  patients experience on levodopa therapy, with or without use of other medicines working to increase the effects of dopamine — a chemical messenger— in the brain.

Although the therapy’s exact mechanism of action is not known, Gocovri has been shown to increase dopamine release and block its re-uptake, raising overall dopamine levels and easing motor symptoms.

Data from Gocovri’s development program and post-marketing surveillance were highlighted in five scientific posters at the International Congress of Parkinson’s Disease and Movement Disorders, running in France through Sept. 26.

In the study “The Effect of Gocovri on Motor Aspects of Experiences of Daily Living: Analyses of MDS-UPDRS Part II Data from a Phase 3 Program,” researchers assessed the impact of Gocovri capsules, taken at bedtime, on motor aspects of daily life in Parkinson’s patients.

Combined data from two Phase 3 trials (NCT02136914 and NCT02274766) found that 12 weeks of Gocovri treatment significantly improved motor skills and life activities in 82 treated patients, addressing such issues as freezing, tremor, eating, and getting out of bed/car/deep chair, compared to 87 patients given a placebo. According to the researchers, the improvement noted “was both statistically significant and clinically meaningful.”

In the study “Analysis of the Shape of the Gocovri Steady-state PK Profile: Implications for an Extended Release Product,” researchers detailed Gocovri’s pharmacokinetic profile — essentially, how the body affects a medicine.

Bedtime dosing of Gocovri resulted in a delayed, slow rise in amantadine concentrations. The analysis showed concentrations to be high in the morning and sustained throughout the day, but with minimal nighttime exposure, contributing to a sustained reduction in both dyskinesia and off episodes. (Off time refers to the periods when dopaminergic medication stops working, and motor symptoms reoccur.)

Three posters assessed the Gocovri’s safety. These assessments were made during the Phase 3 trials and throughout the year after the medicine was approved and made available to patients.

These posters are: “Gocovri Dose Adjustment in Elderly Parkinson’s Patients at Risk for Renal Impairment: Implications from an Exposure Simulation Model,” “The Efficacy and Safety of Gocovri Based on Age: Special Population Analyses of a Phase 3 Study Program” and “Safety of Gocovri in Clinical Practice: One-Year Post-Launch Pharmacovigilance Data.

The most common side effects reported with Gocovri use are dizziness, hallucinations, and falls. While the treatment did ease dyskinesia and other motor complications in all age groups (under 65 to older than 75) studied, adverse events were more frequent in people age 75 and older.

Elderly patients are also more susceptible to renal impairment, the researchers noted in these posters, and may have evidence of chronic kidney disease (defined by researchers here as renal function of less 50 mL/min/m2). In these cases, doctors need to adjust Gocovri doses to avoid drug accumulation, resulting toxicity, and dose- and exposure-related side effects.

“No dose adjustment of Gocovri is recommended on the basis of age alone; however, because renal impairment is common in elderly patients, care should be taken in dose selection, and it may be useful to monitor renal function,” they wrote.

Gocovri extended release is available at two different doses, as 68.5 mg and 137 mg capsules.

Side effects seen in prescription use closely mirror those observed in the Phase 3 trials, the researcher noted, including reports of hallucinations.

“Adamas’ purpose is to significantly improve the lives of people affected by neurological diseases, and we remain committed to the presentation of Gocovri data to provide further information to support robust clinical discussions,” Rajiv Patni, MD, the company’s chief medical officer, said in a news release.

“Our goal is to ensure that neurologists understand how Gocovri may be an option for their Parkinson’s disease patients with dyskinesia on dopaminergic therapies by providing them with a treatment that may increase functional on time by decreasing both dyskinesia and off,” Patni added.

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Onstryv Now Available to Patients with Parkinson’s Disease in Canada

Canada Onstryv launch

Patients in Canada with diagnosed Parkinson’s disease can now receive Onstryv (safinamide) to help manage their symptoms and their “off” episodes.

This follows the approval of Onstryv by Health Canada in January 2019 as an add-on treatment to improve motor function in Parkinson’s patients who experience “off periods” while taking other therapies such as levodopa.

The oral therapy will be available under prescription in 50 mg and 100 mg tablets, and be marketed in Canada by Valeo Pharma — under a license agreement with Zambon. Valeo has launched a physician awareness and information campaign to facilitate and expedite patients’ access to Onstryv.

“The number of Canadians afflicted with Parkinson’s Disease is expected to grow by more than 50% over the next decade as the Canadian population ages,” Steve Saviuk, CEO of Valeo, said in a press release. “Onstryv is the first new oral treatment for Parkinson’s Disease to be approved in Canada in well over a decade.”

“Valeo is committed to building and supporting relationships with healthcare professionals, patients and other stakeholders to build awareness and ensure access to this new treatment for Parkinson’s Disease,” he added.

Known as Onstryv in Canada and Xadago in the rest of the world, the compound is an oral, once-a-day add-on therapy that works by selectively and reversibly inhibiting the MAO-B enzyme that can degrade several neural signaling molecules such as dopamine, which is deficient in Parkinson’s disease. The therapy was approved in the United States in March 2017 by the U.S. Food and Drug Administration.

Onstryv was developed by Newron Pharmaceuticals and has demonstrated effectiveness in helping to control the motor symptoms and complications of Parkinson’s disease for over two years in patients. Zambon acquired rights from Newron Pharmaceuticals to develop and commercialize Onstryv globally.

Clinical trial data has shown that Onstryv can significantly reduce motor fluctuations (on/off time) when used in combination with levodopa and/or Lodosyn (carbidopa) without increasing the risk of dyskinesia (involuntary movements).

“Now, with the Canadian launch, safinamide is available across the North American region,” Stefan Weber, Newron CEO, said in a press release.

“This marks another key milestone for Newron and its commercial partners in providing availability of safinamide in Canada for the treatment of patients suffering from Parkinson’s disease,” he added.

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Gocovri Leads to Steady ‘On’ States in Parkinson’s Patients, Phase 3 Pooled Data Suggest

medications

Gocovri (amantadine) can effectively reduce the number and duration of “off” periods and dyskinesia (uncontrolled movement) episodes in Parkinson’s patients under long-term levodopa treatment, leading to a good steady “on” state, pooled Phase 3 clinical data show.

These findings were reported in a study, “Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials,” that was published in the Journal of Parkinson’s Disease.

Levodopa is a precursor of dopamine and one of the gold-standard treatments to manage the motor symptoms of Parkinson’s disease. However, patients who take it over extended periods develop off-episodes, moments in which the therapy losses its effect and involuntary movements (dyskinesia) reappear.

Some adjustments and alternative treatments, such as Gocovri (marketed by Adamas Pharmaceuticals), can help control these off-episodes and dyskinesia. But it is not clear how these treatments act as a whole.

Therefore, the researchers reviewed the effects of Gocovri from data collected during two Phase 3 placebo-controlled trials, called EASE LID (NCT02136914) and EASE LID 3 (NCT02274766).

The analysis included data from 162 Parkinson’s patients who participated in these trials, of whom 77 received Gocovri and 85 received a placebo for 12 weeks. The patients had a mean age of 64.5 years, had been diagnosed with Parkinson’s disease for 9.9 years, and had been taking levodopa for about 7.6 years.

During the trials, patients kept diaries in which they were asked to detail their daily on- and off-periods, and events of dyskinesia. Patients divided their awake time into 30-minute intervals and reported the state they were in at each interval.

Three main states were considered: “on” without troublesome dyskinesia (good “on”), “on” with troublesome dyskinesia (troublesome dyskinesia), and off-periods. Troublesome dyskinesia referred to involuntary movements that impaired, at least partially, the performance of daily functions.

Most patients (67%) reported waking up in an off-state, which decreased to 13% of patients during the first two awake hours. Thereafter, the number of patients in each state remained constant throughout the day.

A lower number of patients (5%) woke up experiencing troublesome dyskinesia, which in contrast increased up to 24% within the two hours after being awake, then fluctuated between 20% and 44% through the rest of the waking day.

Patients were found to experience a mean of 3.0 episodes of troublesome dyskinesia and about 2.2 off-episodes during the day. The mean duration of each episode was approximately two hours for dyskinesia and 1.1 hours for an off-episode.

After taking Gocovri for 12 weeks, the proportion of patients reporting no episodes of “on” with troublesome dyskinesia was 57.1%, compared with 24.7% in the placebo group. The treatment also reduced the mean duration of the episodes and the mean number of transitions between states during the day, leading to a steadier good “on” state during the day.

In general, the treatment was found to be safe, with less than 10% of patients experiencing adverse events. The most common adverse events were dizziness, constipation, hallucinations, dry mouth, edema, swelling of the extremities, and urinary infections.

“Our results demonstrated a treatment effect of Gocovri for dyskinesia and OFF [states] throughout the waking day,” the researchers wrote.

“In the future, wearable sensors and other types of monitors may provide continuous monitoring through the day and allow more sensitive assessment of mild motor fluctuations and dyskinesia,” they said.

Of note, most of the researchers received compensation from or are employees of Adamas Pharmaceuticals.

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#AANAM – L-DOPA Nasal Delivery System May Offer New Way to Manage Parkinson’s OFF Episodes

POD device powder L-DOPA

Impel NeuroPharma has developed an inhaler to administrate a powder formulation of levodopa (L-DOPA) so people with Parkinson’s disease can more easily manage their symptoms.

Evidence of the potential of this new treatment strategy was presented at the 2019 American Academy of Neurology (AAN) annual meeting in Philadelphia, in a poster titled “Preclinical Development of a Novel Precision Olfactory Delivery (POD®) – L-dopa Drug- Device Combination Product for the Treatment of OFF Episodes in Parkinson’s Disease.”

Levodopa is the gold-standard strategy used to achieve motor symptom relief in Parkinson’s disease. It is associated with the greatest improvement in motor function in these patients when compared with other available therapies designed to work in similar ways, and overcome the low dopamine levels in the brain that cause Parkinson’s.

Dopaminergic medications, including levodopa, enable Parkinson’s motor symptom control. However, as disease progresses, patients typically need to gradually increase treatment dose for maximum benefit and even after that they may still experience reappearance or worsening of symptoms (OFF periods) due to diminishing effects of the therapy. Evidence indicates that patients need to achieve 400 ng/mL L-DOPA levels circulating in the blood for their motor symptoms to ease.

The complexity of neurological disorders, the difficult access to the brain, and the high risks and costs of drug development represent serious disadvantages for improving therapies. Nose-to-brain drug transport offers an attractive alternative strategy attempting to enhance drug penetration into the central nervous system.

The Precision Olfactory Delivery (POD) device is a nasal therapy delivery system that allows easy access to a large tissue surface well-suited for rapid and consistent absorption of therapeutic compounds. Researchers manufactured more than 50 powder L-DOPA formulations and 30 of those were evaluated in preclinical animal models.

Researchers showed that using the POD system, it was possible to achieve 400 ng/mL L-DOPA levels circulating in the blood (the amount found to be clinically necessary to effectively ease motor symptoms) in about 5 to 12 minutes in non-human primates. This represents three- to five-fold improvement in levodopa delivery in comparison to currently available formulations.

Regarding anatomy or response to therapies, no other animal species is as close to humans as primates, so they are often used to test the safety and viability of therapies. They also allow an easier and truer extrapolation of findings to the “human reality,” making scientists better equipped to identify therapies that may reverse OFF episodes in Parkinson’s patients.

These preliminary results demonstrate that “a powder formulation of L-DOPA delivered to the vascular-rich upper nasal cavity with the POD device” can provide a way for self- or caregiver- administrated therapy and “achieve consistent and rapidly effective treatment to abort OFF episodes,” researchers said. “This work has led to the selection and further evaluation of a novel formulation in a Phase 2a clinical study.”

The study (NCT03541356) is currently recruiting patients with Parkinson’s disease at four clinical sites in Australia. For more information, visit the registry page here.

Up to 36 Parkinson’s patients, age 40 and up, will be randomized to take levodopa or a placebo administrated by a POD device. Researchers will assess the ability of the new formulation to manage OFF periods of motor symptom control, as well as its safety and tolerability.

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FDA Declines to Approve APL-130277 for Treating ‘Off’ Periods; More Information Requested

APL-130277.

The U.S. Food and Drug Administration (FDA) has told Sunovion Pharmaceuticals that it is unable to approve APL-130277 (apomorphine sublingual film) in its present form for the treatment of Parkinson’s disease “off”  periods.

Sunovion submitted new drug application for APL-130277 in April 2018. Now the FDA has now issued a “complete response letter” in which it requests additional information, but no new clinical trials.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms — such as tremors and dyskinesia (involuntary movements) — due to a gradual decline in levodopa’s effectiveness as a therapy. About half of all patients on levodopa experience off episodes, which, although frequent in the morning after awakening, may occur multiple times throughout the day. These episodes become more frequent and severe as the disease progresses.

Noting the frequency and scarce treatment options for off periods, Antony Loebel, MD, Sunovion’s executive vice president and chief medical officer, said in a press release that “Sunovion remains committed to working with the FDA to address its requests so that we can bring apomorphine sublingual film (APL-130277) to patients as expeditiously as possible.”

Currently, Parkinson’s patients in the U.S. have only apomorphine — brand name Apokyn (apomorphine hydrochloride, US WorldMeds), as an approved medicine for off periods. Apomorphine is able to enter the brain quickly and, similar to levodopa, stimulate dopamine receptors to provide short-term relief. However, Apokyn’s subcutaneous (under-the-skin) delivery may cause pain and injection-site reactions.

In turn, APL-130277 is a sublingual (under the tongue) formulation of apomorphine, intended to provide on-demand and fast-acting lessening of all types of off episodes, meaning those that are unpredictable, and those that occur at the end-of-dose or after awakening in the morning. It was designed  to be taken up to five times a day, no sooner than two hours from the prior dose.

APL-130277 contains a two-layer film, one with apomorphine and the other including an acid neutralizer to improve absorption and reduce oral irritation. Compared to Apokyn, APL-130277 is less likely to induce nausea due to a more gradual absorption, said Loebel, who is also the head of global clinical development for Japan-based Sumitomo Dainippon Pharma Group (which owns Sunovion) in an October 2018 interview with Parkinson’s News Today.

The FDA new drug application for APL-130277 was supported by a 12-week, double-blind Phase 3 trial (NCT02469090). The results showed that, within 30 minutes of dosing, the treatment enabled a clinically meaningful reduction in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 3 score, a measure of Parkinson’s motor symptoms, in comparison to placebo.

The benefits were seen as early as 15 minutes post-dose and were maintained for 90 minutes, when the last analysis was conducted. Similar improvements were seen at weeks four, eight and 12. A higher percentage of patients achieving a full-on response — or control of motor symptoms — within 30 minutes with APL-130277 also was observed.

The therapy was well-tolerated, with most treatment-related side effects being mild to moderate and reversible.

Most patients took the treatment two or three times each day, though no minimum dose was required. “So that indicates they’re getting a benefit and … it’s not given on a prescribed schedule — they chose to use it two or three times a day,” David Blum MD, Sunovion’s global head of neurology clinical research, said.

The company is still recruiting for a 24-week, open-label extension study (NCT02542696) at multiple locations. A total of 226 participants are expected to use APL-130277 at 10-35 mg. Outcomes focus on the safety and tolerability of longer-term use, including patient response without Tigan (trimethobenzamide), an antiemetic (a medicine against vomiting and nausea) required as pretreatment to Apokyn.

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