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 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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Benefits of Acadia’s Nuplazid Outweigh Risks for Parkinson’s Psychosis Patients, FDA Reports

Nearly half a year after news reports surfaced about deaths allegedly linked to Nuplazid (pimavanserin) — a therapy for Parkinson’s patients with disease-related psychosis — the U.S. Food and Drug Administration says it could not find any new or unexpected safety concerns with the controversial treatment.
The agency said in a Sept. 20 press release that “after a thorough review, the FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis.”
San Diego-based Acadia Pharmaceuticals, which produces Nuplazid, welcomed the announcement.
“As the only drug currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, Nuplazid is filling an important and previously unmet need,” Doral Fredericks, Acadia’s vice president for U.S. medical affairs, said in a statement emailed to Parkinson’s News Today.
She added that “we remain confident in the efficacy and safety of Nuplazid that supported its approval by the FDA and the reaffirmation the agency has given for the positive benefit-risk profile of Nuplazid in its most recent review.”
In that review, the FDA said it considered the fact that patients with Parkinson’s psychosis are more likely to die in the first place due to their older age, advanced disease, and other medical conditions.
“Moreover, Nuplazid is primarily distributed through a patient support program and a specialty pharmacy network, which increases the likelihood that deaths will be reported to the manufacturer,” said the agency, referring to its FDA Adverse Event Reporting System (FAERS). “In FAERS reports that included a cause of death (many reports did not provide sufficient information to assess drug cause and effect), there was no evident pattern to suggest a drug effect.”
It added that “overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis.”
The recommended dosage is 34 mg, taken orally as two 17 mg tablets once daily, with or without food.
The FDA’s recognition of Nuplazid’s complex safety profile after the medication’s April 2016 approval, the agency said in an April 2018 statement, “led to the inclusion of a Boxed Warning and the addition of other important warnings and precautions in the product labeling, so that healthcare professionals could have the risk/benefit information needed to make prescribing decisions.”
Concern over Nuplazid first surfaced following a CNN report in April. An article on the network’s website cited an analysis by the nonprofit Institute for Safe Medication Practices, which found that FAERS showed a total of 700 deaths — including 500 among Parkinson’s patients in which Nuplazid was the only treatment likely involved — in the nine months following Nuplazid’s June 2016 appearance on the market.
Nuplazid is targeted at treating Parkinson’s psychosis, which affects about 40 percent of the 1 million Americans believed to have the disease. According to CNN, the therapy — Acadia’s only product — generated $125 million in 2017 sales for the company.
The New York-based Michael J. Fox Foundation for Parkinson’s Research posted a bulletin about the FDA’s review on its website but offered no independent

Source: Parkinson's News Today