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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FDA Approves Ongentys as Levodopa Add-on for ‘Off’ Periods

Ongentys and FDA approval

The U.S. Food and Drug Administration (FDA) has approved Ongentys (opicapone) as an oral, add-on daily treatment for Parkinson’s disease patients experiencing off periods while on a levodopa/carbidopa regimen.

The approval is for 25 mg and 50 mg capsules, either taken once a day. It comes after Ongentys significantly reduced off periods — when the effects of a medication wear off before a new dose can be taken — and extended the periods of on-time without involuntary movements (dyskinesia) compared to placebo in two Phase 3 trials.

Neurocrine Biosciences, which owns the rights to Ongentys in North America, plans to launch the therapy later this year.

“The FDA approval of Ongentys provides patients living with Parkinson’s disease with an important new treatment option to help manage the disruptive and unpredictable motor fluctuations by decreasing ‘off’ episodes and increasing ‘on’ time without troublesome dyskinesia when taking levodopa/carbidopa,” Kevin C. Gorman, PhD, CEO of Neurocrine Biosciences, said in a press release.

Levodopa is considered the gold-standard treatment for Parkinson’s. However, several years after starting the medication, patients often begin experiencing fluctuations in their motor symptoms caused by a faster wearing off of the treatment’s effects. This means that the intervals in which symptoms are adequately controlled, called ‘on periods,’ become progressively shorter.

Levodopa can be converted to dopamine, counteracting the loss of dopamine-producing neurons in the brain, a hallmark of Parkinson’s. But dopamine cannot cross the blood-brain barrier, a semipermeable membrane that protects the brain from the external environment, so levodopa needs to reach the brain before being converted.

Ongentys works to increase the amount of levodopa reaching the brain by blocking an enzyme, called catechol-o-methyltransferase (COMT), that breaks down levodopa in the blood. This is expected to prolong levodopa’s effectiveness.

“As Parkinson’s disease progresses, first-line treatments such as levodopa begin to lose effectiveness and the beneficial effects of levodopa begin to wear off more quickly, causing more frequent and often debilitating motor fluctuations in patients,” said Robert A. Hauser, MD, a professor at the University of South Florida Parkinson’s Disease and Movement Disorders Center.

“Clinical studies have shown that adding once-daily Ongentys to levodopa therapy significantly reduced ‘off’ time, leading to better and more consistent motor symptom control,” Hauser added.

Ongentys is approved in Europe for Parkinson’s disease patients using levodopa or combinations of similar therapies, who experience motor symptoms before the next treatment dose is due. In Europe, the medicine is marketed by Bial.

The FDA’s approval was supported by 38 clinical trials, including two multinational Phase 3 trials — BIPARK-1 (NCT01568073) and BIPARK-2 (NCT01227655) — that included more than 1,000 Parkinson’s patients treated with Ongentys.

These two trials included patients diagnosed at least three years ago, who had been experiencing fluctuations in motor symptoms — off time of at least 1.5 hours daily while awake — despite being on a stable levodopa/carbidopa regimen.

In BIPARK-1, 600 patients were randomly assigned to either one of three Ongentys doses — 5 mg, 25 mg, or 50 mg — or to another COMT inhibitor called Comtan (entacapone, marketed by Novartis), or to a placebo.

Treatment was given over 14 to 15 weeks while patients continued with their levodopa/carbidopa regimen. Its main goal was to determine whether Ongentys was better than a placebo at reducing off time. Secondary objectives included additional measures of motor and non-motor symptoms, as well as sleep problems.

BIPARK-1’s results demonstrated that both 50 mg Ongentys and Comtan significantly decreased the duration of daily off periods and increased “on time” without troublesome dyskinesia, compared to a placebo. However, unlike Comtan,  opicapone led to favorable ratings in both the Patient Global Impression of Change (PGI-C) — which reflects a patient’s beliefs about the efficacy of treatment — and the Clinical Global Impression of Change (CGI-C) — which evaluates overall illness severity and clinical changes in the condition over time.

BIPARK-2 included 400 people given either a 25 mg or 50 mg dose of Ongentys, or a placebo for 14 to 15 weeks. Results were similar to those of BIPARK-1, with patients on the 50 mg dose showing an absolute on-time without dyskinesia of 1.7 hours, compared to 0.9 hours in the placebo group.

An open-label extension of BIPARK-1 and BIPARK-1 later showed that a 25 mg dose continued to show reductions in off time and increases in on periods over one year of treatment, regardless of whether patients had been randomized to Ongentys or to placebo in the double-blind part of the main trials.

The most common side effects in both studies were dyskinesia, constipation, an increase in blood creatine kinase, low blood pressure, and weight loss.

“Due to the progressive nature of Parkinson’s disease, those living with the condition often struggle to control their motor fluctuations, affecting a wide range of functions, including speech, balance and movement, which adversely impact many aspects of life,” said John L. Lehr, president and CEO of the Parkinson’s Foundation.

“The Parkinson’s disease community is encouraged by the FDA approval of a new add-on treatment option to help patients further control symptoms, enabling them to better cope with this progressive disease,” Lehr added.

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FDA Approves PET Imaging Compound to Aid Early Diagnosis and Disease Monitoring

Fluorodopa F18 and FDA approval

The Feinstein Institutes for Medical Research announced that the U.S. Food and Drug Administration (FDA) has approved an imaging compound its researchers developed as a diagnostic tool for people with suspected parkinsonian syndromes, including Parkinson’s disease.

Fluorodopa F18 (FDOPA) is an injectable compound used during a PET scan to mark the dopaminergic nerve terminals that degenerate in Parkinson’s disease. Better imaging may increase the accuracy of Parkinson’s diagnoses, and aid doctors in tracking disease progression.

Fluorodopa F18 was developed at the Feinstein Institutes and is used to track the movement of dopamine. Dopamine is a type of neurotransmitter, which sends signals throughout the brain. In Parkinson’s disease, the neurons that produce dopamine decay, resulting in the motor symptoms that characterize the disease.

A PET scan is a non-invasive way of following the movement of molecules throughout the body. A radioactive tracer — in this case, Fluorodopa F18 — is attached to the molecule of interest. The PET machine then reads the radioactive signal, which is visualized on a computer screen. The type of radiation used for PET scans is of very low strength and presents little risk to the patient. Generally, whatever risk there may be is outweighed by the scan’s diagnostic value.

Because the cellular changes that lead to Parkinson’s can occur before the onset of symptoms, FDOPA may help identify preclinical or early Parkinson’s disease in seemingly healthy people. It may also help to measure the effect of various medications and procedures designed to increase the uptake of dopamine in affected brain regions. This will enable doctors and researchers to better understand the effects of various treatments, and may help guide them toward more effective therapies in future.

The FDA approved FDOPA based on results of a clinical trial involving 56 people, 38 men and 18 women, suspected of having a parkinsonian syndrome. Of these, 21 were under 65 years of age and 35 were 65 or older.

Participants received a single intravenous — into a vein — dose of FDOPA before getting a PET scan. The tracer’s benefit was assessed by comparing the accuracy of FDOPA images to detect nerve damage and/or loss with a clinical diagnosis of parkinsonian syndrome six to mine months after imaging.

In the trial, FDOPA worked the same in all participants, regardless of age or sex, with no side effects reported. Because it is a radioactive molecule, however, FDOPA may increase the risk of radiation exposure over the course of one’s lifetime.

“With this approval, PET centers across the United States can incorporate FDOPA F 18 into their diagnostic and treatment follow-up programs for patients with Parkinson’s disease,” Thomas Chaly, PhD, one of the key researchers involved in the study, said in a release announcing the approval.

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FDA Approves Generic Version of Sinemet for Parkinson’s Treatment, Company Says

Sinemet generic

The U.S. Food and Drug Administration (FDA) has approved a generic equivalent to Sinemet (carbidopa/levodopa) for the treatment of Parkinson’s disease, according to a press release.

The oral therapy, produced by India-based Alembic Pharmaceuticals, will be available as extended-release tablets containing either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa.

Sinemet, marketed by Merck, was approved by the FDA in 2014 and is sold as controlled-release tablets in three different strengths: 25 mg of carbidopa and 100 mg of levodopa; 10 mg of carbidopa and 100 mg of levodopa; or 25 mg of carbidopa and 250 mg of levodopa.

People with Parkinson’s have low levels of the neurotransmitter dopamine in the brain. Neurotransmitters are substances produced in response to nerve signals that act as chemical messengers. Direct administration of dopamine cannot be used to increase its levels because it is unable to reach the brain due to the blood-brain barrier, a thin membrane that protects the central nervous system (brain and spinal cord) from the circulatory blood system.

Levodopa and carbidopa act to increase dopamine levels in the brain. Levodopa, a molecule involved in the chemical reaction that produces dopamine, has the ability to cross the blood-brain barrier.

Meanwhile, Carbidopa inhibits enzymes known as decarboxylases that would degrade levodopa, ensuring it reaches the brain. However, carbidopa cannot cross the blood-brain barrier, which allows decarboxylases in the brain to then convert the levodopa to dopamine. Using carbidopa together with levodopa enables the use of lower doses of levodopa, which decreases its side effects, including nausea and vomiting.

The carbidopa and levodopa extended-release tablets also are approved for treatment of postencephalitic parkinsonism, a progressive neurodegenerative disease with clinical features of Parkinson’s, likely caused by an infection, and for people with Parkinson’s symptoms following intoxication by carbon monoxide or manganese.

Brief exposure to air pollution, including to carbon monoxide, has been suggested to increase the risk of Parkinson’s disease and other neurological diseases.

Exposure to the metal manganese may trigger the development of Parkinson’s by promoting the release from nerve cells of the alpha-synuclein protein. The clustering of this protein causes inflammation and neurodegeneration.

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Inbrija Approved in US to Treat Off Periods in Parkinson’s Patients on Carbidopa/Levodopa


The U.S. Food and Drug Administration has approved Inbrija (levodopa inhalation powder)‎ for the treatment of Parkinson’s off periods in patients on a carbidopa/levodopa regimen.

Acorda Therapeutics’ therapy is expected to be available by prescription in the first quarter of 2019. It will be distributed through a network of specialty pharmacies in the U.S.

“Today’s approval of INBRIJA marks a major milestone for both Acorda and the Parkinson’s community, for whom we are gratified to have developed this much needed therapy,” Ron Cohen, MD, Acorda’s president and CEO, said in a press release. Cohen noted the more than “two decades of research and development” needed for this approval, as well as the “enormous perseverance and ingenuity” by Acorda’s team.

Inbrija is a self-administered, orally inhaled levodopa treatment for off periods, which are characterized by the re-emergence of Parkinson’s motor symptoms due to low levels of dopamine between doses of standard treatment. These off episodes are typically more common as the disease progresses.

The Michael J. Fox Foundation helped to fund the early development of Acorda’s medication, a decision based on the impact off periods have on patients’ lives, according to Todd Sherer, PhD, the foundation’s CEO.

“We knew we had to help address this unmet need, and this approval is a significant step forward for the community as it provides a new option to manage these gaps in symptom control,” he said.

Inbrija uses Acorda’s ARCUS technology, a system designed to deliver medication to the lungs through inhalation. ARCUS transforms molecules into a light, porous, dry powder, enabling the delivery of much higher doses of medication.

The FDA’s decision was based on a clinical program that included approximately 900 Parkinson’s patients. The pivotal Phase 3 SPAN-PD trial (NCT02240030) evaluated the efficacy and safety of 84 mg and 60 mg of Inbrija in 351 participants with mild to moderate Parkinson’s who were experiencing off periods.

Results of the double-blind study showed a statistically significant improvement in motor function at the final 12-week visit, seen by a reduction in the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score with Inbrija’s higher dose, compared with placebo, at 30 minutes post-dose. Inbrija’s effects were seen as early as 10 minutes after treatment.

The most common adverse reactions with Inbrija were cough, upper respiratory tract infection, nausea, and discolored sputum, which may indicate a bacterial infection.

Treatment with Inbrija was also analyzed in a one-year, randomized, open-label Phase 3 trial with 398 participants (NCT02352363). Results showed a similar average reduction in forced expiratory volume in one second — a measure of pulmonary function — in the Inbrija (84 mg) and observational groups.

Inbrija also eased Parkinson’s symptoms at all time points, as measured with the UPDRS-III scale, enabled symptom control within 60 minutes of the dose and reduction of total daily off times, and led to improved Patient Global Impression of Change scores in 75% of patients, which reflects the patients’ assessment of treatment effectiveness.

“In the clinical study program, Inbrija established its safety profile and demonstrated clinically meaningful improvements in motor function,” said Robert A. Hauser, MD, a professor of neurology and director of the Parkinson’s Disease and Movement Disorders Center at the University of South Florida. “Inbrija helps address a significant unmet need for people with Parkinson’s, and we look forward to adding this new treatment option to our armamentarium.”

Inbrija is not to be used by patients currently on or treated with a nonselective monoamine oxidase inhibitor, such as the antidepressants and anxiolytics phenelzine or tranylcypromine, within the last two weeks.

The company is currently seeking EU approval for Inbrija.

Burkhard Blank, MD, Acorda’s chief medical officer, said he was “delighted” with Inbrija’s approval and its upcoming availability for on-demand use, based on each patient’s needs.

“We thank the FDA for a constructive dialogue throughout the development program and their partnership during the review cycle. We especially thank all those who volunteered for the Inbrija clinical trials, without whose commitment new medications could not be developed,” he said.

He further noted the important role played by “people living with Parkinson’s, their care partners, researchers, clinicians and advocacy groups,” to achieve FDA approval.

A webcast of a recent conference call hosted by Acorda is available here.

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FDA Approves Xeomin to Treat Excessive Drooling, Common in Parkinson’s Patients

Xeomin FDA approval

Xeomin (incobotulinumtoxinA) has been approved by the U.S. Food and Drug Administration to treat adults with chronic sialorrhea, or excessive drooling, a condition often experienced by Parkinson’s disease patients.

Merz Neurosciences, a division of Merz North America, announced that its supplemental biologics license application for Xeomin was granted FDA approval to treat adults with sialorrhea, making it the only approved neurotoxin for this indication in the U.S.

Approval came under priority review by the FDA, a status given to therapies with the potential to significantly improve the safety or effectiveness of treatment, diagnosis, or prevention of serious conditions.

“Until now, there has not been an FDA approved treatment for this debilitating condition,” Kevin O’Brien, vice president and U.S. head of neurosciences at Merz North America, said in a press release. “This approval represents a significant milestone in addressing the unmet needs for more than 600,000 adults who suffer from chronic sialorrhea, and underscores our commitment to improving the lives of those living with movement disorders.”

Excessive drooling occurs in 50-80 percent of Parkinson’s patients, especially in men, and can lead to consequences such as social isolation and embarrassment. Patients with other neurological conditions, such as cerebral palsy or those who have had a stroke, may also have this disorder, which is most commonly caused by poor oral and facial muscle control. Excessive production of saliva and postural problems are other possible causes.

Xeomin is injected directly into muscles and glands, and can block nerve cell signals that cause altered muscular responses.

Its approval was based on results from the randomized, double-blind, placebo-controlled Phase 3 SIAXI clinical trial (NCT02091739).

The study assessed the effectiveness and safety of two different doses of Xeomin, compared with placebo, in reducing the salivary flow rate, and the severity and frequency of chronic sialorrhea.

A total of 184 adults with excessive drooling associated with parkinsonism, stroke, or traumatic brain injury received either 75 Units (U) or 100 U of Xeomin, or a placebo.

Compared with pre-treatment assessments and with placebo, 100 U of Xeomin significantly reduced the unstimulated salivary flow rate (uSFR) and the severity and frequency of excessive drooling — as assessed by the Global Impression of Change Scale (GICS), routinely used in studies of neurological disorders — at four weeks.

The frequency of adverse events was similar between placebo and Xeomin at both doses, and no new or unexpected adverse events were reported.

Merz had already reported that both doses improved uSFR and GICS at weeks eight, 12, and 16 of treatment. Other analyses, including the Drooling Severity and Frequency Scale, confirmed the effectiveness of both treatment regimens.

Xeomin was previously approved to treat adults with abnormal head position and neck pain due to involuntary contraction of neck muscles, abnormal spasm of the eyelids (blepharospasm) in patients who were previously treated with Botox (onabotulinumtoxinA), and to reduce upper limb spasticity, or muscle stiffness.

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FDA Accepts New Drug Application for Acorda’s Parkinson’s Therapy Inbrija

FDA review for Inbrija

The U.S. Food and Drug Administration has accepted Acorda Therapeutics’ New Drug Application for Inbrija (CVT-301) as a potential treatment for Parkinson’s disease.

Accepting the application means the agency is ready to start its regulatory review of the therapy. It expects to make a decision by Oct. 5, 2018.

Inbrija is an inhaled powder formulation of levodopa for the times when the punch of Parkinson’s patients’ oral levodopa and carbidopa regimen wears off. Doctors refer to such times as off periods.

Although levodopa is the most effective oral Parkinson’s therapy, many patients experience movement difficulties during off periods, which become more common as the disease progresses.

“Off periods greatly disrupt the lives of people living with Parkinson’s, and there is a significant need for new treatments in this community,” Dr. Burkhard Blank, Acorda’s chief medical officers, said in a press release.

The New Drug Application included results of the 12-week Phase 3 SPAN-PD clinical trial (NCT02240030), which covered 351 patients. It showed that a high dose of Inbrija administered up to five times a day improved patients’ movement during off periods, compared with a placebo. The results were in line with those of a Phase 2b trial.

FDA officials initially refused to accept the application for Inbrija — not because of safety or effectiveness concerns, but because of questions about its manufacturing process. Acorda addressed the questions in its resubmitted application.

“People with Parkinson’s and physicians need more options to manage this disease,” said Dr. Todd Sherer, the CEO of The Michael J. Fox Foundation. “Inhaled delivery of levodopa could help the many people living with Parkinson’s facing the complication of off periods as their disease progresses.”

The foundation funded some of the work of the therapy’s original developer, Civitas. Acorda acquired Civitas later.

Acorda uses its ARCUS delivery system to get Inbrija powder into patients’ lungs. From there it travels to the brain.

Oral and nasal-passage-delivered medications are administered through the digestive tract, getting to the brain slower.

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Source: Parkinson's News Today