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Sunovion Re-Submits Approval Request for APL-130277 to FDA for Treating Parkinson’s Off Periods

APL-130277 fda resubmission

Sunovion Pharmaceuticals has re-submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA), once again seeking the approval of its below-the-tongue formulation of apomorphine — called APL-130277 — for Parkinson’s off periods.

The re-submission is a follow-up to the FDA’s “complete response letter” from earlier this year, in which the agency requested additional information — but no new clinical trials — before deciding whether to approve APL-130277.

The new submission includes additional analysis of clinical data, and information about the intended packaging of APL-130277, according to Sunovion.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms such as tremors and dyskinesia, or involuntary movements. These effects are due to a gradual decline in the effectiveness of levodopa, which is the first-line therapy for the neurodegenerative disease. 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.

In the U.S., people with Parkinson’s currently have only Apokyn (apomorphine hydrochloride), developed by US WorldMeds, as an approved medicine for off periods. A form of apomorphine, the medicine is able to quickly penetrate the brain, where it stimulates dopamine receptors to provide short-term relief. However, Apokyn’s subcutaneous, or under-the-skin delivery may cause pain and injection-site reactions.

APL-130277 is a sublingual or under-the-tongue formulation of apomorphine, which may be easier for patients to take. It is intended to provide on-demand and fast-acting lessening of all types of off episodes — meaning those that are unpredictable, those that occur at the end-of-dose, or those occurring after awakening in the morning.

The therapy was designed to be administered up to five times a day, with a minimum of two hours from the prior dose.

This new formulation of the medication contains a two-layer film — one with apomorphine and the other with an acid neutralizer to improve absorption and reduce oral irritation. Compared with Apokyn, APL-130277 is less likely to induce nausea due to a more gradual absorption.

The new drug application for APL-130277, first filed in April 2018, was supported by a 12-week, double-blind Phase 3 trial (NCT02469090). The results showed that, within 30 minutes of dosing, APL-130277 induced 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 with placebo.

The benefits were seen as early as 15 minutes after dosing and were maintained for 90 minutes. Improvements were still detected at weeks four, eight and 12. A higher percentage of patients achieved a full-on response — or control of motor symptoms — within 30 minutes with APL-130277.

“OFF episodes in people with Parkinson’s disease can occur at any point throughout the day, often occurring in the morning after awakening and periodically throughout the day and can disrupt the ability to perform everyday activities,” Antony Loebel, MD, president and CEO at Sunovion, said in a press release.

“We look forward to continuing our dialogue with the FDA during the review period with the intention of bringing a much needed on-demand treatment option for OFF episodes to those living with Parkinson’s disease.”

An ongoing open-label extension study (NCT02542696) is testing the safety and tolerability of APL-130277 when used in the long-term. The trial is still recruiting at Los Angeles and at some European sites. More information can be found here.

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h-Patch Device for Slow Apomorphine Infusion May Ease Off Periods in Advanced Parkinson’s, Valeritas Says

apomorphine treatment

Under-the-skin infusions of low-dose apomorphine using a wearable device called h-Patch may help in avoiding off periods and improving motor function in Parkinson’s patients, Valeritas, the technology’s developer, reports.

A preclinical study found that apomorphine delivered using h-Patch could be detected in the blood within two hours, with a gradual decline upon completing the 24-hour subcutaneous infusion. Valeritas is planning to present these results at an upcoming medical conference.

Apomorphine is a derivative of morphine with effects similar to dopamine, the neurotransmitter released by specialized neurons that are progressively lost in Parkinson patients. In patients with advanced disease, apomorphine is the only approved option for the acute treatment of off episodes, or periods when the medication wears off and before a new dose can be taken. Off periods are characterized by the resurgence of motor and non-motor symptoms.

It is available in the U.S. as an under-the-skin injection (Apokyn, by US WorldMeds), but has been associated with pain and injection-site reactions.

In prior clinical trials, single-dose, subcutaneous infusions of apomorphine have shown efficacy in suppressing off periods, reducing dyskinesia — involuntary, jerky movements — and improving motor scores of Parkinson’s patients. They also enabled significantly lesser use of levodopa, which has been associated with reduced effectiveness and with impulsive and compulsive behaviors when used for a number of years.

Infusion pumps in current use can be bulky, “requiring delivery of relatively large volumes of therapeutics [to] remain a barrier” to both patients and caregivers, Valeritas states a press release.

“This study highlights a new subcutaneous delivery of an old drug (apomorphine) which is commonly used in Parkinson’s,” said Santosh Kesari, chair and professor of Translational Neurosciences and Neurotherapeutics at the John Wayne Cancer Institute and Pacific Neuroscience Institute, both in California.

The h-Patch approach, Kesari added, “may offer a more consistent dose throughout the day” relative to oral dosing of apomorphine, and help improve functionality and quality of life. “Drug delivery for CNS disorders is still a significant barrier for optimizing new and old drugs,” he said.

Valeritas’ V-Go Wearable Insulin Delivery device for people with type 2 diabetes, which also uses the h-Patch technology, is marketed in the U.S. with the approval of the U.S. Food and Drug Administration.

“Valeritas continues to demonstrate the versatility of, and opportunities for its h-Patch technology beyond insulin delivery,” said John Timberlake, the company’s president and CEO.

“The h-Patch is a demonstrated patient-friendly, cost-effective, and powerful delivery method for a variety of therapeutics which we believe is ideal for subcutaneous delivery of apomorphine,” he added.

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Study Highlights Importance of Personalized Parkinson’s Treatment

DBS IJLI Apokyn comparative study

Invasive treatment approaches for advanced Parkinson’s disease have differential effects on disease-associated motor and non-motor symptoms, a real-life observational study shows.

These findings suggest that selection of a treatment should be based on each patient’s particular clinical profile, researchers say.

The study, “EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease,” was published in Movement Disorders.

Parkinson’s is a progressive neurological disease mostly recognized for its motor symptoms, such as tremor, bradykinesia (impaired body movement control), and muscular rigidity. In advanced cases, oral therapies may not be sufficient to control these motor symptoms and patients often require device-aided therapies.

There are three well-established, safe, and effective treatments to improve quality of life and alleviate motor and non-motor symptoms of Parkinson’s disease: deep brain stimulation, intrajejunal levodopa infusion (IJLI), and Apokyn (apomorphine) infusion (APO).

In deep brain stimulation, electrodes are surgically implanted in certain areas of a patient’s brain. Through electrical signals received from a small device, the electrodes will stimulate these brain areas to produce dopamine — the chemical compound (neurotransmitter) lacking in Parkinson’s disease.

IJLI is one of the most influential therapies used in patients with moderate to late-stage Parkinson’s disease, shown to have positive effects on both motor and non-motor symptoms and quality of life. This approach uses a portable infusion pump that continuously dispenses levodopa gel through a tube inserted into the intestine.

Apokyn is an engineered therapy that mimics dopamine’s ability to stimulate nerve cells. Unlike other dopamine agonist agents, Apokyn is administrated by injection or continuous infusion using a pump.

Despite the demonstrated efficacy of these therapies, there is little information comparing their impact.

An international group of researchers, on behalf of the EUROPAR and the Non-motor Parkinson’s Disease Study Group of the International Parkinson’s Disease and Movement Disorders Society, compared the differential effects of DBS applied to the subthalamic nucleus (STN), IJLI, and APO in patients with advanced Parkinson’s disease.

The study included 101 Parkinson’s patients who underwent bilateral STN-DBS, 33 who received IJLI, and 39 patients who received APO treatment. Patients had a mean age of 62.3 years and had been diagnosed with the disease for a mean of 12.1 years.

Six months after receiving the treatment, patients were evaluated to determine changes in Parkinson’s symptoms.

Significant improvements concerning non-motor symptoms and motor-related complications were noted in the three groups of patients six months after receiving the treatment, as determined by the Nonmotor Symptom Scale (NMSS) and Unified Parkinson’s Disease Rating Scale-motor complications (UPDRS-IV), respectively.

Significant changes in quality of life, as assessed by the Parkinson’s Disease Questionnaire-8 Summary Index (PDQ-8 SI), were also reported by all treatment groups during follow-up.

IJLI and APO treatments were found to effectively prevent disease worsening during the follow-up period, according to Hoehn and Yahr scores, which rate severity of symptoms in Parkinson’s disease.

STN-DBS treatment reduced the amount of daily levodopa use by approximately 52%. As expected, levodopa equivalent daily dose remained stable in infusion therapies.

The three treatment approaches were found to have similar effects on dyskinesia (involuntary movements)/motor fluctuation ratios. In contrast, they had different effects on patients’ non-motor symptoms.

A more detailed analysis showed that STN-DBS had a significant positive effect on sleep and fatigue, mood and cognition, perceptual problems and hallucinations, urinary symptoms, and sexual function.

IJLI had a positive effect on sleep, mood, and cognition, and gastrointestinal symptoms, while APO therapy significantly improved patients’ mood and cognition, lessened occurrence of perceptual problems and hallucinations, as well as improved attention and memory.

In general, STN-DBS and IJLI seemed to improve non-motor symptom burden, and APO therapy was favorable for neuropsychological and neuropsychiatric symptoms and improved quality of life.

Patients who underwent IJLI treatment had more frequent non-serious adverse events (abdominal pain and gastrointestinal symptoms) immediately after the procedure, compared to those in the other two groups.

“Distinct effect profiles were identified for each treatment option,” researchers said. “This study highlights the importance of holistic assessments of motor as well as non-motor aspects of Parkinson’s that could provide a means to personalize treatment options to patients’ individual disease profiles.”

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Sunovion Expects APL-130277 Will Ably Treat Off Episodes, Awaits FDA Decision

If the FDA approves Sunovion’s APL-130277 come January, Parkinson’s patients will have a first oral treatment — and a first new treatment in more than a decade — for off episodes, those times of difficulties with movement despite taking dopamine agonists like lepodova.
“We think that for the first time, we may have a product that can be used in a manner that is really effective, accessible, and helpful for patients who suffer from off episodes,” Antony Loebel, MD, Sunovion’s chief medical officer, told Parkinson’s News Today. The U.S. Food and Drug Administration accepted the company’s request to approve APL-130277 in June, and set Jan. 29 as a decision date.
Antony Loebel, Sunovion’s chief medical officer. (Photos courtesy of Sunovion)
Off episodes, or motor fluctuations, can come in a variety of forms. All affect a Parkinson’s disease patient’s ability to move voluntarily or cause unwanted movement (dyskinesia).
Some involve waking “up early in the morning and be frozen and not able to get out of bed until their morning dose kicks in, which can be in an hour. There are off episodes as the dose wears off,” said David Blum, MD, global head of neurology clinical research at Sunovion. “And there are more unpredictable off episodes that happen because of the internal bizarre nature of dopamine agonists like levodopa for Parkinson’s — erratic off episodes [and] delayed-on, where a patient takes a drug but it doesn’t act for a long time.”
About 40 to 50 percent of all patients experience off episodes, which generally become more severe and less predictable as the disease advances.
Parkinson’s is caused by the progressive loss of neurons that release a neurotransmitter, called dopamine, in the substantia nigra, a part of the brain that controls movement. Levodopa, an oral medication that is absorbed through a patient’s gastrointestinal tract and transported to the brain — where it is converted into dopamine — is considered the gold standard of Parkinson’s treatment.
Levodopa (combined with benserazide or carbidopa in a capsule or tablet) doesn’t stop or slow neuronal death. But it treats some of the disease’s most common symptoms, such as tremors and stiffness, by temporarily making more dopamine available.
Over time and with longer use, a patient’s response to levodopa diminishes and off periods become more frequent.
APL-130277 (apomorphine sublingual film) is not the only treatment targeting these episodes, but it may be more convenient and effective than Apokyn (apomorphine hydrochloride, US WorldMeds), approved in 2004.
Most off periods last 60 to 90 minutes, so any treatment needs to be fast-acting. Apomorphine — the active ingredient in both Apokyn and APL-130277 — can penetrate the brain quickly and stimulate dopamine receptors to provide short-term, levodopa-like relief. But it’s not easily absorbed when taken orally.
“If you deliver it in a way that bypasses oral absorption,” Blum said, “you can get a rapid rise in apomorphine levels … which kicks the patient from the off state to the on-state.”
David Blum, global head of clinical neurology at Sunovion.
Apokyn needs to be assembled and injected under the skin. Blum notes this can be a challenge for patients with movement disorders and their caregivers.
APL-130277 is a quick-acting sublingual treatment. Patients

Source: Parkinson's News Today

Sensor-Based Gait Analysis Can Enhance Individualized Evaluation of Parkinson’s Patients, Study Suggests

sensor-based gait assessment

Use of sensor-based methods to evaluate gait can improve individual assessments of Parkinson’s disease patients who are undergoing dopaminergic treatment, researchers suggest.

The study with that finding, “Sensor-based gait analysis of individualized improvement during apomorphine titration in Parkinson’s disease,” was published in the Journal of Neurology.

Gait impairment as a consequence of Parkinson’s disease progression can drastically reduce patients’ quality of life. However, available strategies to evaluate gait alterations for individual patient care are still limited.

More recently, the development of mobile sensor-based gait analysis methods has enabled the objective assessment of gait deficits in Parkinson’s patients. Still, the applicability and effectiveness as an individualized evaluation approach has not been established.

A team led by researchers at FAU Erlangen-Nürnberg in Germany compared gait outcomes measured with standard and sensor-based methods in Parkinson’s patients undergoing dopamine replacement therapy.

The study enrolled 13 patients who had mean disease duration of about 15 years and were receiving a mean levodopa equivalent daily dose of 1,077 mg.

All participants started treatment with Apokyn (apomorphine) according to standard protocol, by injecting a defined dose subcutaneously (under the skin) every 15 minutes until achieving the best motor response. Apokyn is an injectable agent usually used to restore body movement control between doses of levodopa, during “off” periods — periods when medication wears off and symptoms reappear.

To track gait movement, researchers used sensors (3D-acceerometers and 3D-gyroscopes) attached to the shoes that could detect small changes in movement orientation and speed. These sensors measure parameters such as rotation and dynamic acceleration resulting from motion, shock or vibration, and can measure tremor in these patients.

After treatment with Apokyn, patients showed a significant improvement in gait movement, as shown by increase in certain gait parameters, including stride speed and length, maximum toe clearance, gait velocity, swing time, heel strike angle, and toe-off angle.

To better evaluate the potential of sensor-based gait analysis to perform individualized evaluations, researchers compared the data obtain between Apokyn administrations within in each patient.

This strategy allowed them to confirm that sensor-based results could effectively measure small gait differences resulting from Apokyn dosages. It could discriminate significant improvements in stride speed, length, and time, and maximum toe clearance between two sequential administrations, as well as detect when no additional improvements were achieved with higher doses.

To validate these findings, researchers compared the sensor-based data with motor scores collected with the standard measure Unified Parkinson Disease Rating Scale (UPDRS) (a 50-question assessment of both motor and non-motor symptoms associated with Parkinson’s).

Improvement in gait parameters (obtained using sensor-based gait analysis) between Apokyn injections reflected improvement in patients’ overall motor performance as measured by the UPDRS, in particular in items related to postural stability and gait.

“[S]ensor-based gait analysis provides objective target outcome measure of gait performance, reflecting apomorphine-induced improvement of motor performance in [Parkinson’s disease],” researchers wrote.

“We show that using instrumented gait analysis to measure individual changes in gait parameters … may be a powerful assessment strategy for routine clinical care in individual [Parkinson’s disease] patients,” they concluded.

However, the authors caution that additional studies in larger groups of patients are still warranted to further validate the applicability and implementation of sensor-based gait analysis as an objective and individualized diagnostic tool for real-life healthcare.

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Source: Parkinson's News Today

Sunovion’s Oral Apomorphine Film Seen to Ease Parkinson’s Off Periods in Phase 3 Trial

apomorphine trial results

Sunovion Pharmaceuticals’ apomorphine sublingual under-the-tongue film (APL-130277) — now under review for approval —  significantly improved motor fluctuations, or off episodes, in Parkinson’s patients in Phase 3 clinical trial, results show.

The double-blind pivotal study, (NCT02469090), evaluated the efficacy and safety of APL-130277 as a fast-acting oral treatment for Parkinson’s patients with off periods, including those experiencing early morning off episodes. These episodes typically occur in the period between the waning of benefits of medications such as levodopa and the time a next dose can be taken, when motor symptoms re-emerge.

A total of 109 patients were given either APL-130277 (54) or placebo (55). Their mean age was 62, and they had been diagnosed with Parkinson’s for a mean of nine years.

Results were presented at the 2nd Pan American Parkinson’s Disease and Movement Disorders Congress (MDS-PAS) that recently ended in Miami.

Compared to those on placebo, patients given APL-130277 had a statistically significant difference of 7.6 points in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score, a measure of motor skills and function. This test was preformed in patients just prior to treatment and again 30 minutes after dosing at week 12.

A statistically significant difference from placebo was seen as early as 15 minutes post-dose and persisted up to 90 minutes, the last time point measured. Similar improvements were observed in the double-blind maintenance period measured at baseline and at weeks 4, 8 and 12.

APL-130277 also led to a higher percentage of treated patients with a full on response — or control of motor symptoms — within 30 minutes at week 12.

Apomorphine sublingual (under-the-tongue) film was generally well-tolerated, with most treatment-related side effects being mild to moderate, and reversible, after its use was discontinued. Nausea, sleepiness, and dizziness were the most frequent adverse effects reported in the maintenance phase.

“Off episodes are disruptive to a person’s daily routine, so a possible treatment that can help alleviate these periods is important for the Parkinson’s disease community and healthcare providers,” Fernando L. Pagan, MD, director of the Movement Disorders Program at Georgetown University Hospital, said in a press release.

Pagan added that the results show promise for APL-130277 “as a fast-acting medicine for on-demand treatment of all types of motor off episodes.”

Sunovion intends APL-130277 to be a treatment for all types of off episodes, those that are unpredictable as well as those that occur at the end-of-dose or in the morning hours after awakening. The formulation is designed to be taken up to five times a day.

About half of all Parkinson’s patients taking levodopa experience off periods, which become more frequent and severe with disease s progression. Apomorphine is the only approved medication for off episodes in the U.S., available as Apokyn (apomorphine hydrochloride, US WorldMeds). But Apokyn is an injection treatment.

Sunovion recently announced that the U.S. Food and Drug Administration has accepted for review its request to approve APL-130277 to treat off episodes in Parkinson’s. The FDA’s decision is expected by Jan. 29, 2019.

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Source: Parkinson's News Today

Sunovion’s Request for Approval of Under-the-Tongue Apomorphine to Treat ‘Off’ Periods Under FDA Review

off periods and Parkinson's

The U.S. Food and Drug Administration (FDA) has accepted for review its request to approve apomorphine sublingual film (APL-130277) as a quick-acting, oral treatment of the motor fluctuations, or off episodes, associated with Parkinson’s disease.

Sunovion, which is developing the potential therapy, submitted a new drug application, or NDA, to the agency in April and the FDA’s decision is expected to by Jan. 29, 2019.

“We are encouraged that the FDA has accepted our NDA for apomorphine sublingual film,” Antony Loebel, executive vice president and chief medical officer at Sunovion, said in a press release.

“There are currently few treatment options available to Parkinson’s disease patients for the as-needed treatment of OFF episodes. We look forward to working with the FDA during the review period,”Loebel added.

Parkinson’s patients treated for long periods with levopoda, the most common first-line treatment for disease symptoms like tremors and stiffness, can develop motor fluctuations — “off-time” periods characterized by the return of these symptoms — as well as dyskinesia, or involuntary movements. These episodes occur as the result of the drug wearing off.

About half of all patients taking levodopa eventually experience off episodes, which become more frequent and severe as the disease worsens. Off periods can occur at any time — unpredictably or as a dose nears its end — although they frequently happen shortly after a patient awakens in the morning.

Despite its impact, therapies targeting off episodes in advanced patients are limited – the only approved medicine in the U.S. is apomorphine, marketed under the brand name Apokyn (apomorphine hydrochloride, US WorldMeds), administered as a subcutaneous injection. Its mode of administration can cause pain and injection-site reactions.

Sunovion’s apomorphine (APL-130277) was developed as an oral (under the tongue), on-demand and fast-acting therapy to lessen all types of motor off episodes. The company designed it to be taken up to five times a day.

It works by mimicking the action of dopamine, a neurotransmitter that facilitates communication between nerve cells. Parkinson’s motor impairments are caused by the death of dopamine-producing nerve cells in the brain.

Sunovion’s supported its FDA application with data from a 12-week Phase 3 study (NCT02469090) that tested the therapy’s effectiveness and safety in Parkinson’s patients whose levodopa had worn off.

Researchers measured its efficacy within 30 minutes after dosing, and looked at the percentage of patients who achieved a full response within that time window. The treatment met the study’s study goal, with initial results of 109 treated adults showing at 30 minutes a statistically significant mean reduction in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 score, a measure of Parkinson’s motor symptoms, compared to placebo at week 12.

Results also showed the therapy was well-tolerated, and continued to show persistent effects through 90 minutes after dosing, when a final measure was taken.

“Through our ongoing work with people living with Parkinson’s disease, we know the community is eager for more treatment options that may help alleviate OFF episodes, which are often disruptive to their daily lives,” said Todd Sherer, PhD, CEO of The Michael J. Fox Foundation for Parkinson’s Research. “We’re heartened to see apomorphine sublingual film is successfully continuing through the regulatory process, and we are hopeful for its approval and future availability.”

The clinical development of apomorphine was partly supported by the Fox Foundation.

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Source: Parkinson's News Today