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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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FDA Accepts Resubmitted New Drug Application for APL-130277 Apomorphine Film, Sunovion Announces

APL-130277 resubmitted NDA

The U.S. Food and Drug Administration has accepted Sunovion‘s resubmitted new drug application (NDA) for APL-130277, an oral apomorphine therapy for treating off episodes in Parkinson’s disease.

The FDA had asked for additional information regarding APL-130277, following the first NDA in mid-2018. A response to this resubmission is expected by May 21.

APL-130277 is an under-the-tongue (sublingual) apomorphine film that may be easier for patients to take. The therapy is intended to provide on-demand and fast-acting lessening of all types of off episodes: periods of worsening symptoms that typically occur between the loss of a medication’s effect and when the next dose can be taken. These symptoms include tremors, rigidity, and slowness, as well as cognitive impairment and mood disorders.

Some 40% to 60% of those with Parkinson’s experience off episodes, which grow worse and more unpredictable over time.

“The unpredictable nature of off episodes can be extremely challenging and disruptive to the daily lives of people living with Parkinson’s disease as well as their care partners,” Antony Loebel, MD, president and CEO of Sunovion, said in a press release.

“We look forward to working with the FDA over the remaining review period,” Loebel added.

The agency had requested additional information — but no new clinical trials — before deciding whether to approve APL-130277. The new submission included additional analysis of clinical data, and information about the intended packaging of APL-130277, according to Sunovion.

Apomorphine crosses the blood-brain barrier — a network of blood vessels that allows the entry of essential nutrients to the brain while blocking potentially harmful substances and also some therapies — to stimulate dopamine production in the brain. Parkinson’s is biologically characterized by the loss of dopamine-producing (dopaminergic) neurons.

Other apomorphine medications, such as Apokyn, must be assembled and injected, which can pose a challenge for people with Parkinson’s. A common side effect to these medications is nausea, for which patients also must take an antiemetic.

In contrast, APL-130277 easily absorbs through the skin under the tongue and clinical trial participants reportedly tolerated it well without severe nausea. David Blum, MD, Sunovion’s global head of neurobiology, attributes this tolerance to a slower drop in the concentration of APL-130277 in patients’ blood, as compared with Apokyn. In past reporting, Blum has suggested that the sharp drop in blood Apokyn concentration may contribute to feelings of nausea. APL-130277, conversely, is absorbed quickly, but leaves the system in a slower, steadier fashion.

The treatment was seen in a Phase 3 clinical trial (NCT02469090) to ease the motor fluctuations associated with off episodes. During the study, participants received increasing doses of the compound over a 12-week period. Roughly two-thirds of 109 patients completed the trial. APL-130277 treated up to 5 off episodes throughout a given day. Some mild-to-moderate side effects, but none severe, were reported. Those reported included transient nausea, drowsiness, and dizziness.

Sunovion continues to recruit patients for an open-label extension study (NCT02542696) investigating the long-term safety and efficacy of APL-130277. Recruitment is open in Los Angeles and several European locations. More information can be found here.

If approved by the FDA, APL-130277 would be the first new treatment for off episodes in more than a decade.

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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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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

Sunovion Seeks FDA Approval of Below-the-Tongue Apomorphine for Parkinson’s Off Periods

Off-periods therapy review

Sunovion Pharmaceuticals has asked the U.S. Food and Drug Administration to begin a regulatory review of its below-the-tongue formulation of apomorphine for Parkinson’s off periods.

The request is in the form of a New Drug Application for the formulation as a treatment for the periods when standard Parkinson’s drugs have worn off. Off periods are characterized by the return of both movement and non-movement symptoms. About half of patients taking the standard therapy levodopa have off episodes, which become more frequent and severe as the disease worsens.

Off periods can occur at any time, although they frequently happen right after a patient  awakens in the morning.

Sunovion refers to its therapy as apomorphine sublingual film (APL-130277). It is intended to kick in quickly, to reduce off periods. The company designed it to be taken up to five times a day.

Off periods, “which may be characterized by symptoms such as tremor, stiffness or slow movement, may disrupt the ability to perform everyday activities and may be burdensome for patients, families and caregivers,” Antony Loebel, the executive vice president and chief medical officer of Sunovion, said in a press release.

“We are pleased to have submitted the NDA [New Drug Application] for apomorphine sublingual film for the treatment of OFF episodes and look forward to working with the FDA during the review period,” said Loebel, who is also head of Global Clinical Development at Sunovion and its parent company, Sumitomo Dainippon Pharma.

Sunovion based the application largely on the results of a 12-week Phase 3 clinical trial (NCT02469090) that tested the therapy’s effectiveness and safety in Parkinson’s patients whose levodopa had worn off.

Researchers assessed the treatment’s effectiveness by looking at patients’ improvement in movement 30 minutes after dosing. The study also evaluated the percentage of patients who said they achieved a full response to the treatment within 30 minutes.

A key finding was that the therapy worked better than a placebo until 90 minutes after dosing. Patients also tolerated it well.

Sunovion will present the Phase 3 results at a future scientific conference.

The FDA had previously granted the treatment Fast Track Designation to accelerate its regulatory review.

The hallmark of Parkinson’s is loss of dopamine-producing nerve cells in the substantia nigra, an area of the brain that controls movement and coordination. Apomorphine has the same effect as dopamine, a neurotransmitter that facilitates communication between nerve cells.

Other formulations of apomorphine are the only approved treatments for Parkinson’s off episodes. It is available in the U.S. as an injection under the brand name Apokyn (US WorldMeds). However, this formulation can cause pain and injection-site reactions.

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Source: Parkinson's News Today

Sunovion’s Below-the-Tongue Therapy Eases Parkinson’s Movement Difficulties, Trial Shows

Below-the-tongue therapy

Sunovion Pharmaceuticals’ below-the-tongue version of a Parkinson’s therapy was able to ease patients’ movement difficulties after the standard therapy levodopa wore off, a Phase 3 clinical trial showed.

Patients also tolerated the treatment — known as apomorphine sublingual film — well, the preliminary results showed. Sublingual means below the tongue, so the therapy’s full name refers to an apomorphine film placed below the tongue. The only approved version of the drug at the moment is administered by injection.

Parkinson’s symptoms stem from a drop in the brain’s levels of the neurotransmitter dopamine, which controls movement. Apomorphine, also known as APL-130277, works by mimicking dopamine’s activity in the brain.

Between 40 and 60 percent of Parkinson’s patients have ups and downs in their ability to control their movement. When they are responding well to a standard medication — that is, they are in an on period — they do all right. When their drug is losing its punch— or in an off period — they don’t do as well.

In an off period, patients can walk slowly, experience tremors and stiffness, and have trouble getting around. There are several types of off periods. One occurs only in the morning. Another occurs when a treatment is wearing off. And it’s impossible to predict when some off periods will occur.

Taking an oral medication is easier than other ways, so it’s the option most Parkinson’s patients prefer. But many have difficulty swallowing. Sunovion developed an under-the-tongue version of apomorphine to get around the problem of an oral version that needed to be swallowed.

“If an alternative method to deliver the medicine were approved, such as apomorphine sublingual film, it would be an important new option for healthcare providers and people with Parkinson’s disease,” Stewart Factor, the principal investigator of the Phase 3 study, said in a press release. He is chief of neurology at Emory University School of Medicine.

In the Phase 3 CTH-300 trial (NCT02469090), researchers randomly assigned 219 participants to receive apomorphine sublingual film or a placebo. The patients had been responding to the levodopa they were taking but experiencing at least one off episode per day. Their cumulative off time was at  least two hours a day.

The study’s primary goal was to see at week 12 if under-the-tongue apomorphine could improve patients’ movement within 30 minutes. A secondary objective was to identify the percentage of patients reporting a full on response within 30 minutes of treatment.

Preliminary results showed that the 109 apomorphine-film-treated patients were able to reduce their movement problems more than the placebo group within 30 minutes of putting the film under their tongue.

The therapy was still working 90 minutes after treatment, researchers. Patients tolerated it well, they said.

At week 12, more apomorphine-film-treated patients were experiencing a full on response within 30 minutes of dosing than the control group.

“For people with Parkinson’s disease and their families, OFF episodes can have a significant emotional and practical impact, and there are currently few treatment options for these events,” said Antony Loebel, the executive vice president and chief medical officer of Sunovion. “Based on these topline results, we believe that apomorphine sublingual film has the potential to be a well-tolerated, reliable, convenient and fast-acting therapeutic option for people living with Parkinson’s disease who struggle with OFF episodes.”

Sunovion plans to use the full trial results to support its New Drug Application in the United States for apomorphine sublingual film as a Parkinson’s therapy. The U.S. Food and Drug Administration has already granted it Fast Track Designation, a status aimed at accelerating its regulatory review.

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Source: Parkinson's News Today