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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

Inbrija

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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Source: Parkinson's News Today

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