Big Boys Don’t Whine

asking for help

“Oh, poor me. I have lost so much,” I moan, hanging my head down and shuffling my feet.

My partner looks up from her book. “Did you say something, dear?”

“Just another rough period,” I say with an affect as flat as the tarmac at LaGuardia Airport. It’s a personal choice to continue working on acceptance without the self-pity. Some days are better than others, but I resist the cacophony of emotions of grief, sadness, anger, frustration, and anxiety. Mostly, I don’t believe their narrative.

I don’t want to whine about an inner dialogue that is based on old voices from a dysfunctional family past. I replace the “whine” with “I’m defining.” Not, “I’m OK, you’re OK.” Or, “Go to your happy place and you will be all better.” Or the Pollyanna philosophy of, “Really, I’m doing fine with it all. I really am. Believe me.” Instead, it’s an honest assessment that the glass is half-full and half-empty at the same time. If I am whining, then I am not defining all the possibilities to be found.

Moving to a new house at a new location causes stress. So far, my threshold management practices help about 90 percent of the time. There is no room for whining in my schedule these days. I don’t have enough personal resources to manage my chronic disease and finish all of the tasks needed to prepare for our move. Realizing this did cause some internal dissonance in the form of bemoaning the situation, but mostly it was because I didn’t know how to ask for help. So, I felt trapped — and that can get dark very quickly.

I mentioned that I am at the edge of my wellness map, an explorer surveying the wild frontiers of an unexplored wisdom regarding living well with a chronic disease. I ran out of answers. Stuck again.

Wait! Maybe other people have written about living with a chronic disease. Why have I been so slow to grasp the obvious? Or, as my partner says, “Uh, duh …” To my surprise, I found many books. I dove into one called “Dancing with Elephants” by Jarem Sawatsky.

As the author says, the book is not about frolicking with pachyderms. It is about how we, as individuals and as a community, address the elephant in the room: chronic disease. The author says that most of us don’t know how to offer help or ask for it.

I learned something through all of this. Asking someone for help is most likely to be successful when the request is fully understood, joyfully accepted, and matches the abilities of the person giving the help. It sounds like common sense. However, the answers are not straightforward.

Success is linked to the degree of fit between the one in need, the tasks to be done, and the talents of the other. This degree of fit has several parameters shaping its outcome, something I have spent more than three decades examining. Yet, when it came to the simple task of asking for help, I was stymied.

Maybe it’s like when guys don’t ask for directions and drive around for hours “mansplaining” that they are not lost while their partner fumes in the passenger seat. The problem is the cost of being lost inside my chronic disease has too high a price. I had to ask for help.

The result: My brother’s help was instrumental in getting us ready to move, and my stress level decreased, which reflected to my partner an improved ability to deal with the stress of moving. It was the first time in my life when I could not, due to the chronic disease, complete tasks by myself that were important to the well-being of my partner and me.

The turmoil that swirls around when even considering asking for help is linked to self-image. One of the problems of chronic disease is that it tears at the flesh of self-image. In the beautifully written book “When Breath Becomes Air,” author Paul Kalanithi speaks about the shifting sands of identity when the tsunami of chronic disease keeps knocking you down.

With a PhD in rehabilitation counseling, I know about adaptability, about making accommodations that are adjustments to the physical and cognitive changes of chronic disease. I just wasn’t ready to dive under the tsunami into the deep water of the human psyche to find ways of bolstering my new identity. I’m not a very good swimmer.

So, I’m replacing whining with defining those things most important to a self-identity that has meaning and purpose. This includes asking for help. My partner is smiling at me.

Do you have trouble asking for help? Please share your experience in the comments below.

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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Scientists Uncover New Therapeutic Molecule BT13 That May Possibly Protect Against Neurodegeneration

therapeutic molecule BT13

Scientists have uncovered a new therapeutic molecule, called BT13, that can get to the brain to boost dopamine levels — the brain chemical that’s in short supply in Parkinson’s disease — and could potentially protect against neurodegeneration.

While the research is in the early stages, and the molecule has only been tested in mice and cellular models of the disease, the researchers say BT13 shows promise as a way to slow or stop Parkinson’s instead of just treating its symptoms.

The findings were described in the study, “Glial cell line–derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo,” published in Movement Disorders.

Evidence shows that a small protein known as glial cell line-derived neurotrophic factor, or GDNF, supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease.

In animal models of Parkinson’s, as well as in human clinical trials, GDNF has shown neuroprotective effects.

However, due to its large size, GDNF is not able to cross the human blood-brain barrier (BBB), and complex surgery is required to deliver the treatment to the brain. The BBB is a semipermeable membrane that protects the brain against the external environment, but is a major barrier for the efficient delivery of therapies that need to reach the brain and central nervous system to work.

BT13, another molecule that binds the same signaling receptor — or RET receptor — for the GDNF molecule family, is much smaller in size than GDNF. Researchers say BT13 has the potential to produce the same neuroprotective effects as GDNF and should be able to more easily cross the blood-brain barrier.

Now, a team of scientists from the University of Helsinki in Finland set out to study this small molecule’s effects in immortalized nerve cells — neurons that are engineered to proliferate indefinitely — and in live mice.

The results revealed that after binding to RET, BT13 triggered molecular signaling cascades related to cellular survival and growth in normal dopamine-producing immortalized neurons. However, when cells were engineered to lack the RET receptor, BT13 had no effect.

BT13 was found to protect against Parkinson’s-related neurodegeneration, which was simulated in the lab by exposing dopaminergic neurons in dishes to 6-OHDA and MPP+ — both neurotoxins that induce cell death and mimic disease symptoms. Importantly, BT13 only protected these neurons when they expressed the RET receptor.

In addition, when BT13 was administered to mice — through an injection directly into the brain — it was able to cross the blood-brain barrier. When in the brain, the molecule activated cell survival and growth pathways and promoted the release of dopamine from the animals’ striatum, a motor control brain area primarily affected by Parkinson’s.

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms. One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s,” David Dexter, PhD, deputy director of research at Parkinson’s UK and professor of neuropharmacology at Imperial College London, said in a press release.

“We are constantly working on improving the effectiveness of BT13,” said Yulia Sidorova, PhD, the study’s lead researcher. “We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years,” Sidorova said.

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Researchers Work to Map LRRK2 Cell Interactions for Parkinson’s Clues, Study Says

LRRK2

Researchers characterized the structure and interactions of proteins connected to the leucine-rich repeat kinase 2 (LRRK2) gene, the most common genetic cause of Parkinson’s disease, opening up new avenues for the development of new treatments for the disease.

The study,” Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2,” was published in the journal Structure.

Parkinson’s is characterized by the loss of neurons in a region of the brain called the substantia nigra. These neurons produce dopamine, a neurotransmitter, or chemical messenger, that allows brain cells to communicate. Damage and loss to these neurons leads to lower dopamine levels and the characteristic symptoms of the disease.

“The only treatment for Parkinson’s disease in the last 20 years has been dopamine replacement therapy,” which is “not completely effective and can wear off over time,” Amir Khan, associate professor at the School of Biochemistry and Immunology at Trinity College in Dublin and senior author of the study, said in a press release.

The absence of effective treatments may be due to lack of understanding of how neurons become damaged and die. The study focused on the LRRK2 gene, which provides instructions for the production of an enzyme called leucine-rich repeat kinase 2, also known as dardarin.

Some 10% of Parkinson’s cases have an underlying genetic base, and the most common involved gene is LRRK2. The protein also plays a role in sporadic cases of Parkinson’s.

“In other words, afflicted individuals may not have an LRRK2 mutation, but the enzyme ‘runs amok’ in their neurons anyway,” Khan said. “Inhibitors of this enzyme are now in late clinical trials for treatment of Parkinson’s disease.”

The researchers studied the enzyme and its network of substrates (the molecule upon which an enzyme acts) in the laboratory.

In the cell, LRRK2 is involved in important processes like autophagy (cells’ clean-up system), mitochondria functioning (cells’ powerhouses) and protein processing.

Small proteins known as GTPases are physiological substrates, or targets, of LRRK2. These include so-called Rabs — part of a protein superfamilly called Ras, which are essential to cell growth, differentiation and migration, and trafficking of molecules in and out the cells. These enzymes alternate between an active and inactive state.

Previous findings have “place[d] LRRK2 at the center of a Rab signaling cascade that is key to understanding the molecular pathways that underpin [Parkinson’s disease],” the researchers wrote.

The modification of Rabs by LRRK2 modulates their interaction with different molecules, by promoting the interaction of Rabs with two poorly studied proteins termed RILPL1 (Rab interacting lysosomal protein-like 1) and RILPL2, which have been associated with the regulation of ciliogenesis (the assembly of cilia, cells’ structures that sense and process signals).

The researchers used  X-ray crystallography — a technique that provides information about protein structure — to study the 3-D structure of the complex formed by Rabs and RILPL1 and RIPL2 and understand how LRRK2 can affect the brain and lead to Parkinson’s disease.

“The research allowed us to visualize the 3-D structure of a protein complex that is formed when LRRK2 is overactive,” Khan said. “From these structural studies of proteins, we can understand how LRRK2 is able to impose its profound effects on neurons. We are the first group to report the effects of LRRK2 in 3-D detail using a method called X-ray crystallography.”

“An overactive LRRK2 runs loose in neurons and wreaks havoc on motor and cognitive abilities,” Khan said. “In a way, we are chasing the footprints that LRRK2 leaves in the brain to understand what it does, and find ways to stop it.”

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Long-term Gocovri Lessens Parkinson’s Motor Symptoms for at Least 2 Years, Final Phase 3 Data Show

Gocovri (amantadine)

Long-term treatment with Gocovri (amantadine) extended-release capsules was safe and led to sustained reductions in dyskinesia — involuntary, jerky movements — and off episodes in people with Parkinson’s disease, final data from a two-year Phase 3 clinical trial show.

“As the longest-running amantadine study to date, this open-label trial suggests Gocovri may provide sustained improvement in both dyskinesia and OFF [episodes] to a wide cohort of patients with Parkinson’s disease living with motor complications,” Caroline Tanner, MD, professor in the department of neurology at the University of California San Francisco, said in a press release.

“These results expand not only our knowledge of Gocovri efficacy but also of its long-term safety in these patients,” Turner said.

The study, “EASE LID 2: A 2-Year Open-Label Trial of Gocovri (Amantadine) Extended Release for Dyskinesia in Parkinson’s Disease,” was published in the Journal of Parkinson’s Disease.

While levodopa is one of the gold standard treatment to manage Parkinson’s motor symptoms, long-term use may lead to off-episodes, which are moments in which the therapy’s effects wear off and symptoms, including dyskinesia, re-emerge.

Adamas Pharmaceuticals’ Gocovri, a long-acting and extended-release oral capsule amantadine formulation, is the only U.S.-approved treatment for dyskinesia in Parkinson’s patients who receive levodopa-based therapy, with or without other dopaminergic medications. It also is the only therapy clinically proven to lessen both Parkinson’s dyskinesia and off episodes.

Taken once daily at bedtime, Gocovri levels rise slowly overnight and achieve their peak in the morning (before the patient’s first levodopa dose), maintaining its high levels throughout the waking day.

The two-year, open-label Phase 3 EASE LID 2 clinical trial (NCT02202551) evaluated the long-term safety, tolerability, and effectiveness of Gocovri in Parkinson’s patients with levodopa-induced dyskinesia for two years.

The study was designed to reflect conditions closer to a “real-world” clinical setting by including not only patients who completed previous Gocovri trials — EASED (NCT01397422), EASE LID (NCT02136914) and EASE LID 3 (NCT02274766 ) — but also those excluded from these trials because they had deep brain stimulation (DBS) therapy. It also allowed clinicians to adjust doses of levodopa and other Parkinson’s medications.

DBS is the most common surgery used to treat Parkinson’s symptoms by delivering electrical pulses to brain cells.

A total of 223 patients were recruited, including 138 who transitioned directly from previous clinical trials (60 receiving Gocovri and 78 a placebo), 61 with prior DBS surgery, and 24 who had a time gap between the prior trial and the EASE LID 2 study.

Among them, 32 patients (24 who underwent DBS and eight among those with a time gap between trials) were switched directly from amantadine immediate-release to Gocovri when entering EASE LID 2.

Most patients were white (93.3%) and more than half (58.7%) were men. Participants’ mean (average) age was 63.7 years at enrollment and they had been diagnosed with Parkinson’s for a mean of 11.8 years. Patients had been taking levodopa for a mean of 9.3 years, with reports of dyskinesia for about 5.3 years.

During the trial, participants received Gocovri once daily at bedtime for a median of 1.9 years, with 75.8% of them having completed one year of treatment and 57.8% completing two years of treatment.

The therapy’s effectiveness was assessed using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part IV (focused on motor complications). Higher scores indicate greater impact of Parkinson’s symptoms, and changes of at least one point in the MDS-UPDRS Part IV score are considered clinically important.

Results showed that Gocovri was effective in lowering dyskinesia and off episodes in all groups of patients, including those who continued treatment from prior trials and those initiating Gocovri in this trial (patients switching from placebo or amantadine immediate release, and those under DBS therapy).

Low levels of motor complications were maintained in patients continuing Gocovri treatment from prior trials. Those initiating Gocovri in this trial showed marked reductions (between two and four points) in the MDS-UPDRS Part IV score, reaching the same levels as those with continuous treatment after eight weeks (the first scheduled effectiveness assessment). These improvements were maintained throughout the two-year trial.

“The present long-term trial provides supportive evidence that 274 mg Gocovri, taken once daily at bedtime, durably reduces the daily duration, severity, and functional impact of dyskinesia as well as OFF episodes throughout 100 weeks of continued use,” the researchers wrote.

Gocovri’s safety profile and rate of treatment discontinuations (22%) were consistent with those reported in previous clinical trials. Common adverse side effects included falls (32.7%), hallucinations (24.2%), swelling in the legs or arms (16.1%), constipation (13.5%), and urinary tract infections (10.3%).

Not surprisingly, adverse side effects’ onset and related treatment discontinuations tended to occur earlier among those just beginning Gocovri treatment than among those continuing treatment from a prior trial.

Jean Hubble, MD, Adamas’ vice president of medical affairs, said that “given the chronic nature of Parkinson’s disease, both patients and physicians seek treatments that are effective long-term.”

“This study further demonstrates that the only FDA-approved medicine for dyskinesia may help people with PD who are struggling to manage these levodopa-related motor complications over this long period of time,” Hubble said.

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RTB101 Well-tolerated, Crosses Blood-Brain Barrier in Therapeutic Quantities, According to Interim Results

Parkinson's trial, RTB101

RTB101, an investigational therapy being developed to treat Parkinson’s disease, is well-tolerated, can cross the blood-brain barrier, and reaches potentially therapeutic concentrations in cerebrospinal fluid (CSF), according to interim results of a Phase 1b/2a study.

Developed by resTORbio, RTB101 is an orally-administered compound meant to induce autophagy in neuronal cells by inhibiting a protein called target of rapamycin complex 1 (TORC1).

Autophagy is the process by which cells clear away defective and unnecessary components, such as toxic misfolded protein aggregates. This process is vital to cellular health and survival, and defective autophagy is thought to contribute to the progression of Parkinson’s disease.

A key clinical finding in Parkinson’s is the presence of protein aggregates called Lewy bodies in dead and dying nerve cells.

Multiple preclinical models have shown that TORC1 inhibition alleviates the symptoms of neurodegenerative diseases, including Parkinson’s.

“Preclinical data suggest that induction of autophagy has the potential to slow the progression not only of Parkinson’s disease but also of multiple other neurodegenerative diseases that are characterized by the accumulation of toxic protein aggregates in cells such as Huntington’s and Alzheimer’s disease,” Joan Mannick, MD, co-founder and chief medical officer of resTORbio, said in a press release.

To date, three separate treatment cohorts in the trial have shown evidence that RTB101 reaches concentrations that inhibited TORC1 activity and induced autophagy in neuronal cells in preclinical models.

The trial is evaluating the safety and tolerability of RTB101 among Parkinson’s patients, either alone or in combination with sirolimus (brand name Rapamune, among others). The company plans to enroll 45 patients with mild Parkinson’s disease, with or without mutations in the GBA gene, and who are being treated with standard therapies.

Trial participants have so far been randomized into three cohorts and dosed once weekly with 300 mg of RTB101 alone, 2 mg of sirolimus alone, or a combination of 300 mg RTB101 and 2 mg of sirolimus. The trial will also evaluate escalating doses of 2 mg, 4 mg, and 6 mg of sirolimus in combination with 300 mg of RTB101.

Interim results show that all three dosing regimes have been well-tolerated and RTB101 successfully crossed the blood-brain barrier (BBB), a semipermeable membrane that protects the brain and spinal cord from the external environment. The BBB is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

Furthermore, RTB101 was measured at concentrations in the CSF (the liquid that surrounds the brain and spinal cord) that have the potential to induce autophagy based on past preclinical trials.

Enrollment into the study group receiving 300 mg of RTB101 in combination with 4 mg of sirolimus once weekly is ongoing.

In addition to easing other symptoms of the disease, resTORbio hopes that by inducing autophagy, RTB101 will ease the levodopa-induced dyskinesia experienced by many patients.

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Could CBD Help to Ease Parkinson’s Symptoms?

CBD

As a Colorado resident, I often wonder about the healing power of plants. We live in a time when the pharmaceutical industry is booming. Pills exist to tame nearly any symptom, but they often can have unwanted side effects. The side effects of plants, however, may be less harsh, or even nonexistent. Cannabidiol (CBD) is a great example of this phenomenon.

What is CBD?

CBD is a compound derived from the cannabis plant and is commonly sold in oils and foods. Depending on the product, CBD could potentially treat pain, anxiety, depression, insomnia, and inflammation, among other issues. Additionally, research suggests that CBD potentially could be useful for other conditions, including improving well-being and quality of life in Parkinson’s disease (PD).

Unlike tetrahydrocannabinol (THC), CBD generally has relaxing effects. Users do not feel “stoned” or intoxicated.

Why is CBD controversial?

The use of CBD is legally gray, as marijuana is illegal at the federal level. However, the 2018 U.S. Farm Bill legalized the use of CBD produced via the cultivation of hemp with THC levels below 0.3 percent.

You also can use a medical marijuana card to obtain CBD in some states. Nevertheless, a few states currently forbid the use of CBD. Check to see if CBD is legal in your state here. 

Because CBD is unregulated at the federal level, it can be difficult to determine the amount of THC in certain products. Purchasing CBD products from reputable brands that conduct third-party testing is currently the safest option.

What might CBD do for Parkies?

CBD has shown potential in early studies for reducing dyskinetic activity in people with PD and treating motor symptoms in various neurodegenerative conditions.

According to a 2018 review study published by the journal Frontiers in Pharmacology, “Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects.” Data also suggest that CBD could potentially play a protective role in the treatment of certain movement disorders. Results are promising, but further studies are needed to clarify the efficacy of CBD.

Our experience

My dad kept hearing about the potential benefits of CBD. He doesn’t like the sensation of getting high, so he investigated products that would yield similar benefits without the possibility of intoxication. Eventually, he purchased two tinctures that he consumed orally for several weeks. He doesn’t believe the tinctures had a substantial impact on his everyday life, but I’m not ready to let him stop hoping.

Of course, it is important to consult your physician before trying CBD or any other treatment.

Has CBD helped you in any way? Please share in the comments below. 

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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Parkinson’s Boxers Have the Greatest Cheering Section Around

cheering section

I attend a Rock Steady Boxing class twice a week. Rock Steady Boxing is a program founded in 2006 by Scott Newman, who has Parkinson’s disease, along with his friend, Vince Perez, who does not have Parkinson’s. 

The class is more than merely exercising or getting “Parkinson’s fit.” Fellow attendees become friends committed to doing their best to fight this disease. They are friends who are all in the same boat and encourage one another verbally, emotionally, and by example. But the class also has another dimension: a personal cheering section.

Many of us who attend these classes have someone to drive us to them, including husbands, wives, other family members, and friends. Most stay and watch our workouts. Some participate in their own way.

The other evening, Penny, who is the wife of one of our guys, offered to help me put on my gloves. Someone commented that this is Penny’s purpose — helping participants of our boxing class to put on their gloves. She agreed. 

You may think that her assistance is insignificant or believe that perhaps I am making light of it. You would be mistaken. Penny’s purpose extends far beyond closing the velcro on boxing gloves. 

She takes a front-row seat on a metal stool behind the half-wall of the gym, sitting alongside a small group of other family members and friends of Parkinson’s boxers. This is our time to strengthen our bodies and their time to reinforce their reserve as caregivers. While we are hopping, jogging, and doing pushups, they are exchanging caregiving war stories or just sharing some downtime with others who understand their plight.

They watch us run, jump, squat, and punch. They laugh with us. (Please note that I wrote, “They laugh with us,” not “at us.”) They root for us when we jog by and count repetitions for us so we don’t have to use our valuable brain cells to stay on track. They encourage us to keep going when we show signs of fatigue or feel like quitting.

Each week, they bring healthy snacks to share with one another and with us, too. Instead of taking our gloves off so that we can take a carrot stick, grape, or strawberry, they happily “feed” them to us.   

Anyone with a chronic illness knows that being a caregiver is tough. After all, we are the ones they are caring for. We can be grumpy because of the constant pain that ravages our bodies, and we may appear ungrateful at times. But one thing is certain: Though we may not always show our appreciation for them, we have the greatest cheering section around. 

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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Oncodesign and Servier Hit First Milestone in Developing LRRK2 Inhibitors for Parkinson’s

Parkinson's, partnership

Oncodesign and Servier have reached the first key milestone months ahead of schedule in their partnership to develop LRRK2 inhibitors for Parkinson’s disease, the companies announced in a press release.

“The collaboration works perfectly and both teams are up to the challenges,” said Philippe Genne, PhD, Oncodesign’s founder and CEO. “The results were obtained sooner than expected which allowed us to reach our first milestone several months in advance.”

Mutations in the gene leucine rich repeat kinase 2 (LRRK2) are one of the most common genetic causes of Parkinson’s disease. Furthermore, even when there isn’t a disease-causing mutation, the LRRK2 protein tends to be overly active in the brains of people with Parkinson’s. This abnormally high activation causes problems in the molecular machinery that brain cells use to recycle proteins, which is thought to be involved in Parkinson’s by promoting the abnormal aggregation of proteins such as alpha-synuclein.

Preclinical research has suggested that blocking LRRK2 activity could be therapeutic in Parkinson’s disease, and such investigational therapies are in early clinical trials.

Servier and Oncodesign entered into a partnership to design new LRRK2 inhibitors in March 2019. The partnership involves the use of Nanocyclix, a proprietary technology owned by Oncodesign, which facilitates the discovery of small molecules that can block the activity of protein kinases such as LRRKs.

“Reaching this first important milestone in such a challenging program speaks to the potential of the Nanocyclix series of molecules that we pursue,” said Jan Hoflack, PhD, scientific director at Oncodesign. “[T]heir potency and selectivity within very small molecular weight compounds are ideal assets for this difficult CNS [central nervous system] program. It also speaks to the highly collaborative approach between Servier and Oncodesign.”

Hitting the first milestone triggered a payment of 1 million euros (about $1.08 million USD) to Oncodesign.

“We are very pleased with the rapid progress we have made together with Oncodesign in this collaborative program, with a very efficient and dynamic joint team, and look forward to continuing success over the coming years to reach our common goal of bringing a new treatment for patients,” said Christophe Thurieau, executive director of the Servier Research Institute.

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Motion Machine’s Ability to Ease Motor Symptoms in Parkinson’s Entering Trial in Australia

Parkinson's and balance

A trial in Australia will test a motion machine, called the Reviver, to understand whether it can improve balance, mobility and sensory-motor coordination in people with moderate to advanced Parkinson’s disease and atypical parkinsonism.

Exercise has been shown to help ease Parkinson’s symptoms. The Reviver machine, by Isodymanics, is designed to stimulate the vestibular system, the sensory system that provides a sense of balance and information about body position.

The machine works by placing the user at a tilted angle and rotating them in a slow and radial, wave-like motion.

The reaction to being tilted off-balance can induce a brain response that activates muscles across the body, including those that may be dormant as a result of age, infrequent use, damage, or disability. Specifically, it activates nerve pathways that then aid in balance, enhance muscle strength, and help resist the effects of gravity.

Isodynamics reports early evidence suggesting the Reviver’s use can improve mobility and lessen Parkinson’s symptoms, with patients demonstrating a 22% increase in mobility; namely, quicker “up and go” test times over an average of 26 days. This test measures the time it takes for a person to rise from a chair, walk three meters (about 10 feet), turn around and return, then sit down again.

“The anecdotal results with our patients have been very positive,” Geoffrey Redmond, Reviver’s developer, said in a press release. “We’re really glad to see the Reviver being used in a formal trial.”

The trial will assess whether a 12-week program using the Reviver machine improves balance, mobility, and sensory-motor coordination. It plans to enroll 30 patients with moderate to advanced Parkinson’s disease or atypical parkinsonism. People with atypical disease have some evident Parkinson’s symptoms, like muscle stiffness or balance issues, but who do not respond well to standard medications. Their symptoms are caused by other disorders.

The trial is being overseen by Terry O’Brien, a neurologist at Monash University and led by Ben Sinclair, a brain imaging expert at Monash and with Alfred Health. Participants will be required to attend twice weekly sessions for 12 weeks at The Alfred in Melbourne.

Enrolled patients will be split into two groups, based on their diagnoses. One group will undertake the Reviver exercise regime on top of their standard of care, and the second (a control group) will continue with standard of care without using the Reviver.

Those interested in participating or receiving more information about the trial can call Isodynamics at 02-9524-2188 (in Australia, country code +61) or email the company.

“We now need to see what kind of results can be generated during a formal, randomised controlled trial,” Sinclair said.

“It’s an exciting project because people affected by Parkinson’s have a limited range of treatment options. This study provides a rare opportunity to explore and uncover a new possible treatment pathway for people affected by Parkinson’s,” he added.

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Sublingual Film Turns Parkinson’s Off Periods ‘Full On,’ Most Patients in Phase 3 Trial Report

Phase 3 trial analysis

A majority of Parkinson’s patients in a clinical trial reported achieving a fully “on” response within 30 minutes of taking Sunovion‘s under-the-tongue apomorphine film, called APL-130277, about three months after starting its use to counter “off” episodes in this disease, a post-hoc analysis of study results found.

At week 12, 79% of the 54 adults using APL-130277 in the Phase 3 trial (NCT02469090) recorded a “full on” response to the at-home treatment as the effectiveness of their stable levodopa (or similar dopamine treatment) waned, scientists reported. These responses were a secondary study goal.

Results were presented at the recent Pan American Parkinson’s Disease & Movement Disorders Congress (MDS-PAS), Sunovion said in an email that also provided the presentation. It was titled “Patient-Reported Motor Responses to Apomorphine Sublingual Film Based on Home Dosing and Response Diaries.”

Meant to provide on-demand and fast-acting relief from all types of off episodes, APL-130277 is a formulation of apomorphine in a thin film. The film is placed under the tongue (called a sublingual medication), where it is absorbed into the bloodstream. This makes it easy to self-administer at any time and any place.

Apomorphine stimulates the production of dopamine in the brain. Dopamine is a powerful messenger molecule called a neurotransmitter produced in dopaminergic neurons. Dopaminergic neurons die off in Parkinson’s disease, which leads to the loss of motor and cognitive skills characteristic of the disease.

Off episodes are periods of worsening Parkinson’s symptoms that usually occur when a medication like levodopa begins to lose effect, but before the next dose can be taken. These symptoms include tremors, rigidity, and slowness, as well as cognitive impairment and mood disorders.

The Phase 3 trial randomly assigned 109 patients, with 54 given APL-130277 for on-demand and at-home use, and 55 others a placebo. All enrolled had reported experiencing one off period each day, and were currently taking stable doses of levodopa and adjunctive medications.

The study was double-blinded, so neither the patients nor the researchers knew who received the medication and who was using a placebo.

Over the course of its 12 weeks, patients recorded the time they took APL-130277 during any off episode they chose to treat, and their resulting motor status (full on or off) 30 minutes later. This information was self-reported in diaries over the two days prior to each clinic visit, made at study weeks four, eight and 12.

Researchers measured the percentage of “full on response” reports. That response was defined as one providing benefits “with regard to mobility, stiffness, and slowness, whereby normal daily activities could be performed and were comparable to or better than normal response to [Parkinson’s] medications prior to study enrollment.”

At the study’s conclusion, 79% of patients using the investigative film reported being fully on at 30 minutes after taking APL-130277, compared to 31% of those on placebo.

Across all weeks of diary entries, 77% of patients using APL-130277 reported full-on responses, compared to 26% on a placebo. All took either the treatment or placebo a mean of 2.2 and 2.5 times each day.

Those with full-on response also said they achieved it at all times of the day, with 71% reporting it between 5 am and 9 am, and 86% overnight, between 10 pm and 5 am. This is important, as off episodes can occur at any time.

“Based on home dosing and response diaries, the self administration of APL may lead to a FULL “ON” response in most patients experiencing “OFF” episodes throughout the day,” the researchers concluded.

APL-130277 is currently under review by the U.S. Food and Drug Administration for possible approval as a sublingual treatment for off periods in Parkinson’s disease. A decision is expected on or before May 24.

Meanwhile, enrollment is continuing in an open-label extension Phase 3 study (NCT02542696) investigating the long-term safety and efficacy of APL-130277. Patients are still being recruited at sites in Los Angeles and in several European countries. More information can be found here.

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