New Therapy Using Patients’ Own Cells May Halt Parkinson’s Progression, Case Study Suggests

transplanting cells

A new therapeutic approach in which patient-derived dopamine-producing neurons are transplanted into the brain may halt Parkinson’s disease progression, a case report suggests.

The approach uses patient-derived induced pluripotent stem cells (iPSCs),  which are cells collected from the skin or blood that researchers can reprogram in a lab dish to revert them back to a stem cell-like state that has the capacity to then differentiate into almost any cell type.

“Because the cells come from the patient, they are readily available and can be reprogrammed in such a way that they are not rejected on implantation. This represents a milestone in ‘personalized medicine’ for Parkinson’s,” Kwang-Soo Kim, PhD, said in a news story. Kim is co-senior author of the study and director of the Molecular Neurobiology Laboratory at McLean Hospital in Massachusetts.

Two-year data following the first of two interventions suggest the therapy resulted in at least a stabilization of the patient’s motor function and an improved quality of life. However, clinical studies with longer follow-up periods are needed to confirm the therapeutic potential of this approach in Parkinson’s patients, the researchers noted.

The case study, “Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease,” was published in the New England Journal of Medicine.

Parkinson’s is characterized by the gradual loss of dopamine-producing (dopaminergic) neurons in the substantia nigra, a region of the brain responsible for movement control. The death of dopaminergic neuron results in lower dopamine levels, affecting the regulation of muscle movement and coordination.

While the potential use of tissue transplants to replace the lost dopaminergic neurons in Parkinson’s patients has been studied since the 1980s, the creation of iPSCs offered the hope to transplant precursors of dopaminergic neurons into a patient’s brain.

In 2018, a team of researchers in Japan reported the implantation of precursors of dopaminergic neurons into the brain of a Parkinson’s patient. Six other patients were expected to receive this experimental therapy that used iPSCs developed from skin cells of an anonymous donor. Researchers plan to collect all safety and effectiveness data by the end of this year.

When implanting cells derived from other individuals, patients need to receive immunosuppressive therapies (for an undetermined period of time) to prevent the development of immune responses against the implanted cells. However, the use of a patient’s own cells would make the need for immunosuppression unnecessary.

Now, a team of researchers at the McLean Hospital and Massachusetts General Hospital (MGH) reported the case of a 69-year-old man treated with a similar approach using the patient’s own iPSCs.

The man had a 10-year history of progressive Parkinson’s disease with no signs of dyskinesia (abnormal involuntary movements that characterize advanced Parkinson’s). He was treated with extended release carbidopalevodopa tablets, Neupro patches (by UCB), and Azilect (by Teva Pharmaceuticals).

He reported poor control of his symptoms, with three hours of “off”-periods — when the medications’ effects wear off and symptoms worsen before a new dose can be taken. Higher levodopa doses caused him lightheadedness associated with a drop in blood pressure when changing to a standing position (orthostatic hypotension).

The researchers used the man’s skin cells to create iPSCs and develop them into precursors of dopaminergic neurons, which were tested extensively, including a mouse model used in human-derived transplant studies.

Using these data, Kim applied to the U.S. Food and Drug Administration (FDA) for a single-patient, investigational new drug application and also received approval from the hospital board to implant the cells into the patient’s brain.

The man underwent two surgeries, in 2017 and 2018 (separated by six months) at the Weill Cornell Medical Center in New York, and at MGH.

At each surgery, four million cells were delivered into the putamen, a large brain structure involved in movement control that is filled with dopamine receptors and receives signals from the substantia nigra. The first intervention targeted the putamen on the left hemisphere of the brain, while the second targeted the one on the right hemisphere.

The cells were delivered using a new minimally invasive neurosurgical implantation procedure developed by Jeffrey Schweitzer, MD, PhD, the study’s lead author, a Parkinson’s specialized neurosurgeon, in collaboration with other neurosurgeons at MGH and Weill Cornell. Schweitzer is director of the Neurosurgical Neurodegenerative Cell Therapy program at MGH.

The patient’s motor function was assessed through the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III and quality of life with the 39-item Parkinson’s Questionnaire.

Two years after the first intervention, imaging tests showed that the transplanted cells were alive and working correctly as dopaminergic neurons, highlighting the technical success of this personalized cell-replacement approach.

There were no reports of side effects or immune reactions against the cells (without the need for immunosuppressive therapy), or signs that the cells caused any unwanted growth or tumors.

Notably, there was at least a stabilization in the man’s motor function, with MDS-UPDRS scores varying over time, but never reaching the initial values, and he reported improvements in his day-to-day activities and quality of life.

The man reported less than one hour of “off” period per day and the levodopa equivalent daily dose was lowered by 6%, “a reduction of uncertain clinical importance,” the researchers wrote.

“This strategy highlights the emerging power of using one’s own cells to try and reverse a condition — Parkinson’s disease — that has been very challenging to treat. I am very pleased by the extensive collaboration across multiple institutions, scientists, physicians, and surgeons that came together to make this a possibility,” said Bob Carter, MD, PhD, another co-senior author of the study and MGH’s chief of Neurosurgery.

Despite these apparently positive results, the researchers emphasized this is just a first step in this therapy’s development.

“These results reflect the experience of one individual patient and a formal clinical trial will be required to determine if the therapy is effective,” said Schweitzer.

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Inbrija Can Help to Improve Work Productivity and Keep Dyskinesia at Bay, Acorda Reports

study data presentations

Use of Inbrija (levodopa inhalation powder) and like medications help to more effectively manage of off episodes in Parkinson’s disease and improve work productivity in patients using it, according to a study being presented by Acorda Therapeutics at the International Congress of Parkinson’s Disease and Movement Disorders.

Another study presentation at the congress, now underway in France, will show that Inbrija treatment does not lead to a worsening of dyskinesia, or involuntary muscle movement.

Dopaminergic medications, like levodopa, help to control Parkinson’s motor symptoms. But as disease progresses, patients typically need to gradually increase their dose to maintain the same level of benefit. And even with such increases, they sometimes experience a reappearance or worsening of symptoms (off periods) due to the diminishing effects of dopaminergic therapy.

In the study, “Impact of OFF periods on aspects of employment for people with Parkinson’s disease,” presented as a scientific poster, researchers characterized the burden of off periods on work absence and productivity.

They used data from the “Financial and Social Impact of Parkinson’s Disease Survey” produced by the Michael J. Fox Foundation (MJFF) and the Parkinson’s Foundation, conducted between Sept. 17 and Oct. 8, 2018.

The online survey was directed at people with Parkinson’s, and completed by the patients, their care partners, family members or close friends. It compared the burden — in terms of work productivity — of off periods in people reporting to experience them in the past 12 months to those reporting no experience of off periods while on dopaminergic therapy.

A total 1,602 surveys were returned, 70% completed by Parkinson’s patients, and 20% by caregivers, family members, or close friend. Off periods were reported by 881 (55%) survey respondents, and an absence of off-period symptoms by 434 (27%) . Around 18% (287 people) did not know if they had experienced an off period over the previous year or failed to respond to the question.

Of the 881 patients reporting off periods, 176 (20%) worked full or part-time. Among those without such reports,  in 90 (21%) worked full or part-time. Those with off periods were more likely to report reduced work productivity, in comparison to the other patient group (72% vs. 43%).

Almost half (48%) of patients with off periods reported at least 10 days each month of low productivity, compared to the 29% of those without off period. Importantly, 34% of them missed, on average, at least three working days each month because of their disease, compared to the 21% of patients without off periods.

“PD [Parkinson’s disease] can have a financial burden on patients and their families,” the researchers noted. “More effective management of OFF periods and other PD symptoms may alleviate this burden on people with PD.”

In another scientific poster, titled “Dyskinesia Rates in Patients with Parkinson’s Disease on CVT-301 (levodopa inhalation powder),” the company summarized the results of their analysis on the effects of Inbrija (CVT-301) on Parkinson’s dyskinesia  (involuntary muscle movements).

Inbrija, developed and marketed by Acorda, is an inhaled formulation of levodopa approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of Parkinson’s disease during off episodes. When inhaled, this dry powder formulation of levodopa bypasses the digestive system and to deliver a higher and more consistent dose of levodopa to the brain.

In a 12-week, randomized and placebo-controlled Phase 3 study (known as SPAN-PD, NCT02240030) in 339 Parkinson’s patients on a carbidopa/levodopa regimen and experiencing off episodes, were treated with Inbrija or placebo. Results found that treatment at an 84 mg dose significantly eased motor symptoms as soon as 30 minutes after taking a dose.

More than half of patients (58%) given Inbrija also had control of their motor symptoms, meaning they went from an off period to an on state. They also maintained an on state when evaluated up to an hour after treatment administration, compared to 36% in the placebo group.

Researchers for this study analyzed the effects of Inbrija on patients’ dyskinesia. They obtained reports made by patients taking part in the trial, required to keep diaries of time with dyskinesia, reported as occurring over three consecutive days prior to each study visit.

Adverse events during the SPAN-PD study were also examined, as were trial investigator ratings of dyskinesia occurrence and 60 minutes post-dose, measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part IV (motor complications).

On average, patients took two doses of Inbrija (84 mg) per day during the trial.

Four (3.5%) patients on Inbrija complained of a dyskinesia-like event, in contrast to none in the placebo group. No one withdrew from the study due to dyskinesia.

At week 12, examiner-rated dyskinesia at one hour post-dose was of 16.7% among Inbrija-treated patients and 8% among people in the placebo group, all rated mild to moderate with the exception of one placebo patient whose dyskinesia was judged severe.

“In this phase 3 study of [Inbrija], adverse events and examiner ratings of mild to moderate dyskinesia were reported more frequently for [Inbrija] compared to placebo, but there was no increase in troublesome dyskinesia according to the patient reported diary and the overall impact on UPDRS part IV dyskinesia score was minimal,” the researchers concluded.

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Phase 3 Trial of Accordion Pill in Treating Parkinson’s ‘Off’ Periods Fully Enrolled


Intec Pharma announced the complete enrollment of a Phase 3 clinical trial evaluating the safety and effectiveness of its Accordion Pill Carbidopa/Levodopa (AP-CD/LD) in easing motor fluctuations in people with advanced Parkinson’s disease.

The investigative treatment will be compared to immediate release Sinemet, an approved combination of levodopa and carbidopa marketed by Merck, and to placebo in the study.

Levodopa is considered the most effective and widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that helps ease levodopa’s side effects.

Together, these two components increase the level of dopamine in the brain, which normally is low in Parkinson’s patients, leading to the motor impairments associated with the disease.

However, patients with advanced disease being treated with levodopa (or Sinemet) often develop motor fluctuations, which result from “off” periods (a return of symptoms) between levodopa doses due to its short-term effects.

This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.

Intec Pharma’s AP-CD/LD was created to solve this problem through a specific gastric retention and release system containing carbidopa and levodopa. This system is intended to allow the therapy to be released in both immediate and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over 8 to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

Previous results from a randomized Phase 2 clinical study in 60 Parkinson’s patients showed that AP-CD/LD treatment was safe and significantly reduced “off” times by 45%, giving patients two extra hours a day of controlled motor function. AP-CD/LD treatment also significantly reduced the total number of levodopa doses per day.

“By providing more uniform levodopa plasma [blood] concentrations than those provided by currently available orally-administered levodopa products, we expect to improve the duration and consistency of symptom relief provided by levodopa with a simpler dosing regimen,” R. Michael Gendreau, MD, PhD, Intec Pharma’s chief medical officer, said in a press release.

The multi-center, randomized, double-blind, Phase 3 clinical trial (NCT02605434), named ACCORDANCE, is comparing the safety and effectiveness of AP-CD/LD and Sinemet (immediate release of carbidopa-levodopa) in hundreds of adults with advanced Parkinson’s.

Prior to the 13-week randomized part of the study — which includes placebo groups — 462 patients were first stabilized and optimized on Sinemet and then on AP-CD/LD during two open-label periods lasting six weeks.

About 300 of these patients are now receiving either an AP-CD/LD capsule — containing 50 mg of carbidopa with 400 or 500 mg of levodopa — twice or three times a day or a matching placebo. Or they are being given an immediate release Sinemet tablet — consisting of 25 mg of carbidopa and 100 mg of levodopa — or a matching placebo at least four times a day.

The study’s primary goal is the reduction in the percentage of daily “off” time during waking hours, which will be considered statistically significant if it leads to at least one-hour difference between Sinemet and AP-CD/LD.

Secondary goals include the reduction of involuntary movements during “on” periods, and improvement in the scores of the Clinical Global Impression Scale-Improvement (CGI-I) — as recorded by the physician and patient — and the Unified Parkinson’s Disease Rating Scale (UPDRS), which assesses both motor and non-motor symptoms.

ACCORDANCE is taking place at about 90 clinical sites throughout the U.S., Europe and Israel (some 32% of participants were enrolled in the U.S.). At enrollment, 65% of patients were men with a mean age of 63, who have lived with the disease for a mean of 8.8 years. Participants’ mean daily “off” time was 6.1 hours, and over 40% were taking more than 800 mg of levodopa daily.

Participants who complete the 13-week randomized period can chose to move to an open-label extension study, where all patients will receive AP-CD/LD for one year. To date, more than 90% of eligible patients have chosen to enter the extension study, the company reports.

According to an Israel newspaper, results of the ACCORDANCE study are expected in mid-2019.

Intec Pharma believes these results, along with the long-term data provided by the extension study and the results of a Phase 2 clinical study (NCT03576638) evaluating how the most common dose of AP-CD/LD in the ACCORDANCE study is processed by the human body, will be essential for regulatory submission and AP-CD/LD launch.

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