Amneal Announces Complete Response Resubmission for IPX203 New Drug Application

Amneal Pharmaceuticals, Inc. (NASDAQ: AMRX) (“Amneal” or the “Company”) today announced that it has provided a Complete Response resubmission to the U.S. Food and Drug Administration (FDA) for IPX203, a novel, oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules for the treatment of Parkinson’s disease (PD).

Carbidopa

levodopa 

The original NDA for IPX203 resulted in a Complete Response Letter (CRL) from FDA. The resubmission package included data from a healthy volunteer study which was conducted in the fourth quarter of 2023. The FDA did not request any other studies.

“We are pleased to provide our complete response resubmission for IPX203 as we look to expand our Parkinson’s franchise,” said Chirag and Chintu Patel, Co-Chief Executive Officers at Amneal. “We look forward to launching this much-needed treatment in the second half of 2024, subject to FDA approval.”

About IPX203 

IPX203 is a novel, oral formulation of CD/LD extended-release capsules designed for the treatment of Parkinson’s disease. IPX203 contains immediate-release granules and extended-release coated beads. The IR granules consist of CD and LD, with a disintegrant polymer to allow for rapid dissolution. The ER beads consist of LD, coated with a sustained release polymer to allow for slow release of the drug a mucoadhesive polymer to keep the granules adhered to the area of absorption longer, and an enteric coating to prevent the granules from disintegrating prematurely in the stomach. This formulation is distinct from RYTARY® (carbidopa/levodopa) extended-release capsules, Amneal’s extended-release CD/LD treatment for PD approved by the U.S. FDA in 2015.

About Parkinson’s Disease

Parkinson’s disease has become the fastest growing neurological disorder worldwide, with approximately 1 million patients diagnosed in the U.S. It is a progressive disorder of the central nervous system (CNS) that affects dopamine-producing neurons in the brain that affect movement.

PD is characterized by slowness of movement, stiffness, resting tremor and impaired balance.  While PD is not considered a fatal disease, it is associated with significant morbidity and disability.  The average age at diagnosis for patients with PD is 60; as people live longer, the number of patients living with PD is predicted to grow significantly over the coming decades. 

https://en.wikipedia.org/wiki/Carbidopa

https://en.wikipedia.org/wiki/L-DOPA

Amneal Announces Complete Response Resubmission for IPX203 New Drug Application

Nourianz Approved to Treat 'Off' Episodes in Parkinson Disease

In continuation of my update on Levodopa 

Nourianz (istradefylline) tablets have been approved as an add-on treatment to levodopa/carbidopa for adults with Parkinson disease experiencing "off" episodes, the U.S. Food and Drug Administration announced yesterday.

The drug is available in 20-mg or 40-mg doses, but the maximum recommended dosage in patients taking CYP3A4 inhibitors and those with moderate hepatic impairment is 20 mg once daily. The safety information for Nourianz states that use of the drug should be avoided in these patient populations.

Data from four 12-week placebo-controlled clinical studies demonstrated the effectiveness of Nourianz, a selective adenosine A2A receptor antagonist, in treating "off" episodes in 1,143 PD patients who were receiving treatment with levodopa/carbidopa. Compared with patients who received placebo, patients who received Nourianz experienced a statistically significant decrease in daily "off" time from baseline.

The most commonly reported adverse reactions with Nourianz included dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. The FDA noted that physicians should monitor patients for the development or progression of dyskinesia while taking Nourianz. A reduction in dosage or stoppage of Nourianz should be considered in the case of hallucinations, psychotic behavior, or impulsive/compulsive behavior. Nourianz should not be used during pregnancy, and women with childbearing potential should use contraception during treatment.

https://pubchem.ncbi.nlm.nih.gov/compound/Istradefylline#section=2D-Structure          https://en.wikipedia.org/wiki/Istradefylline

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Nourianz Approved to Treat 'Off' Episodes in Parkinson Disease

FDA Approves Nourianz (istradefylline) as an Add-On Drug to Treat Off Episodes in Adults with Parkinson’s Disease

Kyowa Kirin Co., Ltd., (Kyowa Kirin, TYO: 4151) announced the U.S. Food and Drug Administration (FDA) has granted approval for Nourianz (istradefylline) for use as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “OFF” episodes.

“We are proud that Nourianz is now ready to help adult patients with Parkinson’s disease in the US,” said Tomohiro Sudo, Head of Global Product Management Office of Kyowa Kirin. “We believe that Nourianz could be an important contributor to improve treatment outcomes. We will keep working to bring the product to patients globally.”

“Kyowa Kirin has a commitment to global health and well-being by creating new value through the pursuit of advances in life sciences and technology particularly in oncology, nephrology, immunology, and the central nervous system,” said Tom Stratford, President of Kyowa Kirin USA Holdings, Inc. “Today's FDA approval of Nourianz is an important milestone and provides US patients with a novel non-dopaminergic once-a-day oral treatment option to be used in conjunction with levodopa/carbidopa for Parkinson’s disease.”

“Today’s approval is the culmination of decades of perseverance in exploring the science and clinical effects of istradefylline and inhibition of adenosine A2A receptor signaling in people with Parkinson’s disease,” said Jeffrey S. Humphrey, MD, Chief Development Officer of Kyowa Kirin Pharmaceutical Development, Inc. “In clinical studies, istradefylline, used as adjunctive treatment to levodopa/carbidopa in adult patients with PD experiencing 'OFF' episodes, was associated with a decrease in OFF Time and increase in ON Time without troublesome dyskinesia. We are grateful for the FDA approval and for the many dedicated scientists and patients whose participation in our research programs has resulted in a new treatment option for Parkinson's disease.”

“Istradefylline is an Adenosine A2A receptor antagonist, and is a novel non-dopaminergic pharmacologic approach to treating OFF episodes for people living with PD,” said Dr. Stuart Isaacson, MD, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida. “Based on data from four clinical studies, istradefylline taken as an adjunct to levodopa significantly improved OFF time and demonstrated a well-tolerated safety profile. Istradefylline represents an important new treatment option for patients with Parkinson's disease who experience 'OFF' episodes.”

The FDA approval of Nourianz is based on findings from randomized, multi-center, double-blind, placebo-controlled trials in patients with PD taking a stable dose of levodopa/carbidopa with or without other PD medications.

The Kyowa Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

Please see Nourianz indication and Important Safety Information below.

Indication

Nourianz (istradefylline) is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.

Important Safety Information

Warnings and Precautions

Dyskinesia: Nourianz in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

Good News, Bad News on Levodopa for Parkinson's Disease

In continuation of my update on L-Dopa

The most potent drug available for Parkinson's disease, levodopa, treats symptoms of the disease but does nothing to either ease or increase its still-mysterious underlying causes, a new clinical trial has concluded.

Doctors often delay prescribing levodopa, or L-dopa, to Parkinson's patients for fear that the drug might have toxic effects that produce jerky involuntary body movements over time.

But patients started on L-dopa nearly a year earlier than a second group did not develop significantly different rates of involuntary movement, results from the new trial show.

"The current study bolsters our confidence that levodopa is safe even in early Parkinson's disease and that patients should not fear it," said Dr. Michael Okun. He's the national medical director of the Parkinson's Foundation and chairman of neurology at the University of Florida in Gainesville.

There's disappointment here as well. While levodopa isn't toxic, it also doesn't appear to provide any protection against progression of Parkinson's in the brain, said Dr. Susan Bressman, co-director of the Mount Sinai Parkinson and Movement Disorders Center in New York City.

"The bottom line is they couldn't show neuroprotection," Bressman said. "Using this very normal dose we normally use, they couldn't show it slows the progression of the disease."

Parkinson's disease is a progressive nervous system disorder. One of its hallmarks is the loss of neurons that produce a brain chemical called dopamine. Low dopamine levels affect a person's control over their movements, causing tremors, rigid muscles and slowness.

Developed more than 50 years ago, L-dopa eases these muscular and movement symptoms. The brain synthesizes levodopa into dopamine and then puts the neurotransmitter to good use.

"Levodopa remains the most important and effective treatment for Parkinson's disease and its introduction has undoubtedly improved morbidity, mortality and quality of life," said Okun, who wasn't part of the trial.

But side effects in some patients cause concern that the drug might have a toxic effect on the brain, researchers noted.

A clinical trial 14 years ago that aimed to clear up the matter only muddied the waters, Bressman said.

The earlier trial found that people taking L-dopa showed improvement even after they stopped taking it, raising hopes that it might be somehow be stemming the progression of Parkinson's.

But brain scans of those patients showed some evidence that levodopa was causing potentially harmful changes to dopamine receptors in the brain, Bressman said.

"We couldn't really prove one way or the other if it's good or bad for the brain," Bressman said. "But the bottom line -- people need it. We don't have a better drug. It's the most potent drug for the symptoms, so you've got to use it, but you don't use a high dose."

The new clinical trial, led by Dr. Rob de Bie from the University of Amsterdam, hoped to clarify results of the older study.

A group of 445 early Parkinson's patients in the Netherlands were randomly assigned to either start levodopa therapy right away, or wait 40 weeks and then start taking the drug.

"The theory is if you get those extra 40 weeks of exposure to levodopa and it's neuroprotective, the earlier group will be in a better place and the late group will never catch up," Bressman said. "They'll always be a little worse because the first group got more of this neuroprotective effect."

But both groups wound up in the same place by week 80 of the trial, with essentially the same rate of disease progression, the Dutch researchers found. The drug didn't provide people in the earlier group any extra protection.

At the same time, neither group suffered greater rates of jerky movements or levodopa-related fluctuations in motor response, discounting concerns over toxic effects.

"Basically, it confirms what we currently do," said Bressman, co-author of an editorial accompanying the study. Both were published in the Jan. 24 issue of New England Journal of Medicine.

"Most people don't start levodopa at first diagnosis, when they have hardly any symptoms, because they don't need it. We don't think the drug is protecting the brain, so we don't start it right away, because it's not going to change what they're going to look like 10 years down the pike," she noted.

"But as soon as they do start to need it, we start it. We use it. And we're judicious in how we use it," Bressman continued.

Hopes for a drug that will directly treat or perhaps even cure Parkinson's now rest on research being done into suspected causes of the disease, she said.

Experts now think Parkinson's is a related group of diseases, each subtype potentially triggered by a different cause, Bressman said.

Drugs are being developed to target genes that have been implicated in Parkinson's for some patients. Future drugs might target inflammation in the brain or other potential causes.

"I think ultimately between the genetics and other biomarkers we find in the spinal fluid or in the blood, we're going to be able to group patients better and figure out the disease mechanisms," Bressman said.

https://en.wikipedia.org/wiki/L-DOPA

Good News, Bad News on Levodopa for Parkinson's Disease 

FDA Approves Inbrija (levodopa inhalation powder) for Intermittent Treatment of OFF Episodes in People with Parkinson’s Disease

In continuation of my update on Levodopa

Acorda Therapeutics, Inc. today announced that the U.S. Food and Drug Administration approved Inbrija™ for intermittent treatment of OFF episodes in people with Parkinson’s disease treated with carbidopa/levodopa. OFF episodes, also known as OFF periods, are defined as the return of Parkinson’s symptoms that result from low levels of dopamine between doses of oral carbidopa/levodopa, the standard oral baseline Parkinson’s treatment.

“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,” said Ron Cohen, M.D., Acorda President and CEO. “This milestone resulted from over two decades of research and development, beginning in the laboratory of Dr. Robert Langer at Massachusetts Institute of Technology, through years of enormous perseverance and ingenuity by the entire Acorda team.”

“Despite being on treatment, patients may experience OFF periods as Parkinson’s progresses, which can be disruptive,” said Todd Sherer, Ph.D., CEO, The Michael J. Fox Foundation. “The Foundation provided funding for the early clinical development of Inbrija because patients told us that OFF periods were one of their most serious issues. 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.”

“In the clinical study program, Inbrija established its safety profile and demonstrated clinically meaningful improvements in motor function, as measured by the UPDRS Part III,” said Robert A. Hauser, M.D., MBA, 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.”

FDA approval of Inbrija was based on a clinical program that included approximately 900 people with Parkinson’s on a carbidopa/levodopa regimen experiencing OFF periods. Inbrija is not to be used by patients who take or have taken a nonselective monoamine oxidase inhibitor such as phenelzine or tranylcypromine within the last two weeks.

“I’m delighted that Inbrija has been approved and may be added to patients’ existing Parkinson’s medications for on-demand use, based on individual patient need,” said Burkhard Blank, M.D., Chief Medical Officer of Acorda. “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. And we are grateful for the people living with Parkinson’s, their care partners, researchers, clinicians and advocacy groups, who have all collaborated with us to help achieve this milestone.”

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FDA Approves Inbrija (levodopa inhalation powder) for Intermittent Treatment of OFF Episodes in People with Parkinson’s Disease

Leukemia drug increases brain dopamine, lowers toxic proteins linked to Parkinson's or dementia

My updates on  nilotinib

A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson's disease or dementia with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-producing neurons in these neurodegenerative diseases.

Researchers from Georgetown University Medical Center (GUMC), say the findings, described in the Journal of Parkinson's Disease, support improved clinical outcomes observed and first reported at the Society for Neuroscience annual meeting in October 2015.

The study tested nilotinib taken daily for six months. A much smaller dose of nilotinib (150 or 300 mg once daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg twice daily). Twelve patients were enrolled in the clinical trial — one patient withdrew due to an adverse event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants who completed the study.

In addition to safety, the researchers also examined biological markers in the blood and cerebral spinal fluid as well as cognitive, motor and non-motor improvement. They found significant signs that nilotinib may provide benefit for patients with these neurodegenerative diseases.

"These results need to be viewed with caution and further validated in larger placebo controlled trials, because this study was small, the patients were very different from each other, and there was no placebo," says the study's senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherpeutics Program.

Among the biomarker findings were that:

•The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;

•The level of the Parkinson's related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and

•The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.

In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic protein that accumulates within neurons, resulting in reduced CSF levels in both Parkinson's disease and dementia with Lewy bodies.

The researchers also said that all 11 patients who tolerated the drug reported meaningful clinical improvements. All patients were at mid-advanced stages of Parkinsonism and they all had mild to severe cognitive impairment.

"Patients progressively improved in motor and cognitive functions as long as they were on the drug — despite the decreased use of dopamine replacement therapies in those participants with Parkinson's and dementia with Lewy bodies," says the study's lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital.

But three months after withdrawal of the drug, participants returned to the same reduced cognitive and motor state they had before the study began, Pagan adds.

Some serious side effects were reported including one patient who withdrew at week four of treatment due to heart attack and three incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and additional studies are needed to determine if the adverse events are related to use of nilotinib.

"Long term safety of nilotinib is a priority, so it is important that further studies be conducted to determine the safest and most effective dose in Parkinson's, says Pagan.

The researchers designed the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson's disease and dementia by turning on the "garbage disposal machinery" inside neurons.

Their published studies also showed nilotinib increases the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction due to toxic protein accumulation — and improves motor and cognitive outcomes in Parkinson's and Alzheimer's disease animal models.

"Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start," Moussa says. "If these data hold out in further studies, nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago."

He adds, "Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias."

Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson's and Alzheimer's diseases. The Translational Neurotherpeutics Program is also planning a small trial in ALS (Lou Gherig's disease).

According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was about $10,360 a month for 800 mg daily. The dose used in this study was lower — 150 and 300 mg daily.

Opicapone simplifies levodopa-related motor fluctuation treatment

Once-daily opicapone is effective for the treatment of end-of-dose motor fluctuations in patients receiving levodopa for Parkinson’s disease, phase III study findings show.

The results indicate that at a dose of 50 mg/day the drug, a potent third-generation catechol-O-methyltransferase (COMT) inhibitor, was superior to placebo and non-inferior to entacapone (200 mg with each levodopa dose) in reducing the absolute time patients spent in the off state.

The magnitude of effect with opicapone was greater that than of entacapone, with a 26.2 minute greater reduction in the time spent in the off state after 14–15 weeks of treatment and a 60.8 minute greater reduction compared with placebo.

Opicapone 50 mg “is, therefore, the only once-daily COMT inhibitor to provide a mean reduction in time in the off state that is clinically relevant,” say Patrício Soares-da-Silva (BIAL, Coronado, Portugal) and team.

The average changes from baseline in time spent in the off state over a 24-hour period were 116.8 minutes in 115 patients taking opicapone 50 mg/day, 96.3 minutes in 120 patients taking entacapone and 56.0 minutes in the placebo group.

Opicapone 25 mg and 5 mg were also tested in 116 and 119 patients, respectively, but the effects of these doses on the time patients spent in the off state did not differ significantly from that of placebo.

The researchers note in The Lancet Neurology that, in addition to greater reductions in the time patients spent in the off state, opicapone 50 mg was associated with greater increases in the percentage of time patients spent in the on state without troublesome dyskinesia, with a 5.4% difference compared with placebo and a 1.2% difference compared with entacapone.

Improvements in global symptoms were seen in significantly more patients taking opicapone 50 mg than in those taking entacapone, and while numerical improvements in motor symptom scores were seen in all groups, differences between active treatment and placebo groups were not significant.

Opicapone simplifies levodopa-related motor fluctuation treatment

Drug used to treat Parkinson's and related diseases may delay or prevent macular degeneration

In continuation of my update on L-DOPA

In a major scientific breakthrough, a drug used to treat Parkinson's and related diseases may be able to delay or prevent macular degeneration, the most common form of blindness among older Americans.

The findings, published in the American Journal of Medicine, are a groundbreaking effort in the fight against age-related macular degeneration (AMD), which affects as many as 11 million Americans. AMD hinders central vision, and even when it does not lead to blindness it can severely reduce the ability to read, drive, and recognize faces.

In the study, supported in part by BrightFocus Foundation, researchers discovered a biological connection between darker pigmented eyes, which are known to be resistant to AMD, and increased levels of a chemical called L-DOPA in those eyes. Since L-DOPA is frequently prescribed for Parkinson's patients, the researchers wanted to know whether patients who received the drug L-DOPA as treatment for Parkinson's or other diseases were protected from AMD. By combing through massive databases of medical chart data, they reported that patients receiving L-DOPA were significantly less likely to get AMD, and when they did, its onset was significantly delayed.

Drug used to treat Parkinson's and related diseases may delay or prevent macular degeneration

L-DOP A drug may delay or prevent age-related macular degeneration

In continuation of my update on L-DOPA

A drug already used safely to treat Parkinson's disease, restless leg syndrome and other movement disorders also could delay or prevent the most common cause of blindness affecting more than 9 million older Americans - age-related macular degeneration (AMD).

Researchers have discovered that patients who take the drug L-DOPA are significantly less likely to develop AMD, and if they do get AMD it's at a significantly older age, according to the study published online Nov. 4 in the American Journal of Medicine. The retrospective study was led by researchers at Marshfield Clinic Research Foundation, University of Arizona, Medical College of Wisconsin, University of Miami, Essentia Health, Stanford University and University of Southern California.

"Research points to this as a pathway to regulate and prevent this most common cause of blindness in adults," said Murray Brilliant, Ph.D., director, Marshfield Clinic Research Foundation Center for Human Genetics, Marshfield, Wisconsin. "Imagine telling patients we potentially have medication that will allow them to see and continue enjoying life, their family and perform every day activities as they age. That is very powerful."

AMD, the No. 1 cause of legal blindness in adults over 60, is a progressive eye condition affecting as many as one in three adults. The disease attacks the macula of the eye, where the sharpest central vision occurs, causing central blindness. This vision is used to drive, read, recognize faces and perform daily tasks. AMD spares the peripheral vision, leaving dim images or black holes at the center of vision.

L-DOPA is a natural by-product of pigmentation and is made in a layer of cells in the back of the eye that functions to promote health and survival of retinal tissues. Researchers asked the question if people taking L-DOPA as a medicine are protected from AMD.

"The obvious question was if the L-DOPA no longer produced was supplemented via pill form, does it have the potential to serve as a preventive medicine against AMD," Brilliant said. "We need more research, but this first step is promising."

L-DOPA drug may delay or prevent age-related macular degeneration

Newron, Zambon announce re-submission of safinamide NDA to FDA

In continuation of my update on safinamide 

Newron Pharmaceuticals S.p.A. ("Newron"), a research and development company focused on novel CNS and pain therapies, and its commercial and development partner Zambon S.p.A., an international pharmaceutical company, announced  that the NDA for safinamide has been re-submitted to the US FDA. This follows the announcement last week that the CHMP has given a positive opinion on safinamide for Europe.

The submission covers the indications "safinamide as add-on therapy to a stable dose of a single dopamine agonist" in early Parkinson's disease patients and "safinamide as add-on therapy to levodopa alone or in combination with other Parkinson's disease treatments" in mid-to late stage Parkinson's disease patients.

The first submission of safinamide to the US FDA was made in May 2014. On review, the FDA issued a Refusal to File (RTF) letter based on organizational and navigational problems, largely due relating to the hyperlinking of tables, folders and the organization of the table of contents in the submission.

Ravi Anand, Newron's CMO, stated: "Newron has been in frequent contact with the FDA to propose solutions to the technical issues and obtain their concurrence with the proposals. These discussions lead Newron to conclude that the RTF issues have been addressed in this submission."

Newron, Zambon announce re-submission of safinamide NDA to FDA

New drugs may improve quality of life for people with Parkinson's disease

In the study, 225 people were randomized to receive either eight weeks of stable dose treatment with a placebo or the drug droxidopa, (see structure)  

 

which converts to norepinephrine. After one week of stable treatment, those who received the drug had a clinically meaningful, two-fold decrease in the symptoms of dizziness and lightheadedness, when compared to placebo. They also had fewer falls, or 0.38 falls per patient per week, compared to 1.73 for those receiving a placebo on average over the entire 10-week study duration.

The second study looked at treatment with a new drug for "wearing-off" that occurs with people who have been taking levodopa for several years. As each dose wears off, people experience longer periods of time where the motor symptoms do not respond to levodopa. For the study, 420 people who were experiencing an average of six hours of "off" time per day received a placebo or one of four dosages of the drug tozadenant in addition to their levodopa for 12 weeks. People receiving two of the dosages of the drug had slightly more than an hour less off time per day at the end of 12 weeks than they had at the start of the study. They also did not have more troublesome involuntary movements during their "on" time, called dyskinesia, that can occur. 

 
The third study looked at 321 people with early Parkinson's disease whose symptoms were not well-controlled by a dopamine agonist drug. For the 18-week study, the participants took either the drug rasagiline or a placebo in addition to their dopamine agonist. At the end of the study, those taking rasagiline had improved by 2.4 points on a Parkinson's disease rating scale. In addition, rasagiline was well tolerated with adverse events similar to placebo.

New drugs may improve quality of life for people with Parkinson's disease

New Drugs May Offer Hope to Parkinson's Patients - Drugs.com MedNews

"Progress is being made to expand our use of medications, develop new medications and to treat symptoms that either we haven't been able to treat effectively or we didn't realize were problems for patients," said Dr. Robert Hauser, professor of neurology and director of the University of South Florida Parkinson's Disease and Movement Disorders Center in Tampa.

Parkinson's disease, a degenerative brain disorder, affects more than 1 million Americans. It destroys nerve cells in the brain that make dopamine, which helps control muscle movement. Patients experience shaking or tremors, slowness of movement, balance problems and a stiffness or rigidity in arms and legs.

In one study, Hauser evaluated the drug droxidopa (see the structure right),  which is not yet approved for use in the United States, to help patients who experience a rapid fall in blood pressure when they stand up, which causes light-headedness and dizziness. About one-fifth of Parkinson's patients have this problem, which is due to a failure of the autonomic nervous system to release enough of the hormone norepinephrine when posture changes.

Hauser studied 225 people with this blood-pressure problem, assigning half to a placebo group and half to take droxidopa for 10 weeks. The drug changes into norepinephrine in the body.

Those on the medicine had a two-fold decline in dizziness and lightheadedness compared to the placebo group. They had fewer falls, too, although it was not a statistically significant decline.

In a second study, Hauser assessed 420 patients who experienced a daily "wearing off" of the Parkinson's medicine levodopa (see structure left), during which their symptoms didn't respond to the drug. He compared those who took different doses of a new drug called tozadenant, which is not yet approved, with those who took a placebo. All still took the levodopa.

At the start of the study, the patients had an average of six hours of "off time" a day when symptoms reappeared. After 12 weeks, those on a 120-milligram or 180-milligram dose of tozadenant (see structure below) had about an hour less of "off time" each day than they had at the start of the study.

Tozadenant, which works on brain receptors thought to regulate motor function, merits further study in future trials, Hauser said.

In another study, Hauser looked at 321 patients with early stage Parkinson's whose symptoms weren't handled well by a medicine called a dopamine agonist, typically the first drug prescribed for Parkinson's patients. During the 18-week study, Hauser assigned them to take either their usual medicine plus an add-on drug called rasagiline (brand name Azilect see below structure) or their usual medicine and a placebo.

Azilect is approved for use in patients with early stage disease as a single therapy or as an add-on to levodopa, Hauser said, but not yet as an add-on to dopamine agonists.

Those taking the Azilect   but not those taking the placebo   improved by 2.4 points on a standard Parkinson's disease rating scale.

Costs of the still unapproved drugs are not known. Azilect costs about $200 monthly at the 1-milligram daily dose used in the study.

Each of the studies was funded by the pharmaceutical company making the particular drug: Chelsea Therapeutics paid for the blood-pressure study; Biotie Therapies Inc., supported the "wearing-off" study; and Teva Pharmaceutical Industries sponsored the Azilect study. Hauser is a consultant for all three companies.

New Drugs May Offer Hope to Parkinson's Patients - Drugs.com MedNews

Positive Results from Clinical Study of CVT-301, an Inhaled L-dopa for Parkinson’s Disease..

In continuation of my update on Levodopa....

The Phase 1 study (by Civitas Therapeutics, Inc) showed that CVT-301 achieved sufficient plasma levels of L-dopa through inhaled delivery to the lung, resulting in a pharmacokinetic profile that supports its therapeutic potential.  Immediate absorption and dose proportional pharmacokinetics were seen across all doses tested.  In addition, all doses tested of CVT-301 were safe and well tolerated.  

More....

Ref : http://civitastherapeutics.com/cms/sites/default/files/news/CVT-301%20Clinical%20results%20press%20release%20FINAL%2006Jan2012_0.pdf

Safinamide for advanced Parkinson's disease.!

Safinamide

We knew that ‘Safinamide” is a candidate drug against Alzheimer's disease. In 2007, a Phase III clinical trial, was started by Merck-Serono for Safinamide as add-on to dopamine agonist for early idiopathic Parkinson's disease. Now thanx to the same companies for having second phase III trial of Safinamide in advanced Parkinson's disease. Interestingly the same compound has been tested for restless legs syndrome (RLS) and epilepsy As of 2008^[update], they are in Phase II.

Safinamide is believed to have a novel dual mechanism of action based on the enhancement of the dopaminergic function (through reversible inhibition of monoamine oxidase-B [MAO-B] and dopamine uptake) and reduction of glutamatergic activity by inhibiting glutamate release.

The earlier trials revealed that safinamide significantly improved motor function in patients with advanced Parkinson's disease. And also the results are encouraging and suggest that safinamide could have benefits beyond motor symptoms. The earlier results not only substantiates the claims but also established something interesting factors like ability of safinamide to improve depressive symptoms are important aspects of PD in addition to the other benefits. Hope after few days safinamide as an add-on therapy to levodopa will come in the market as a boon to those who are mid-to late-stage idiopathic Parkinson's disease (more than five years of disease duration).....

Ref : http://www.merckserono.com/corp.merckserono/en/images/20090507_en_tcm112_41170.pdf