Soaring Neurological Retail Prescription Drugs: By Dr. De Leon

 April 20, 2019   By Dr. De Leon

As I have

battled with Parkinson’s disease and my illness has gotten more complex so have

my challenges in obtaining medication. I am sure I am not alone in this. Every

time I go to the pharmacy as of late, the joy seems to be knocked right out of

my soul for at least an hour. I have to brace myself and be in a sound state of

mind to be able to navigate through all the hurdles a routine visit to the

pharmacy can pose. It used to be that I could just call and have my

prescriptions delivered to my office/home no questions asked. No let’s see if

your insurance will allow it nor let’s see how many pills insurance will allot

this time around. Each time, I step into the pharmacy, I wonder if the quantity

be enough to cover my needs? 

While I was

practicing prior to Medicare part D (intended

for patients to have better access to treatments they needed) patients had

greater access to treatments even those that were costly in the form of subsidy

programs, samples and other pharma assistance programs. However, with the

advent of Medicare part D many of these programs disappeared, at least in my

area, leaving patients high and dry without medications for months at a time.

The reason being the soaring price of medicines which typically places a

patient into a ‘donut hole’ (where insurance does not cover cost of

medication). In some cases, this period can extend for months, as it does me. An

estimated 17% are said to skip doses or stop treatment all together because of

cost.

With the advent of the Affordable Care Act I found myself, like many others with chronic neurodegenerative illnesses, forced out of plans.  As the number of medications began proliferating, due to my Parkinson's diagnosis, I had to start allotting a good chunk of time just to visit the pharmacist (at times it is almost as lengthy as a doctor visit!). 

All the

while, as I stand there at the counter arguing yet again about the importance

of getting my medicines on a timely basis, I see person after person of all

ages and walks of life get the same comment..."Sorry, your insurance did not approve this prescription,"

"you must get authorization from

your physician first “or my favorite “if

you want it costs such and such you have to pay…usually an exorbitant price and

rarely for a full months prescription, which no one ever seems to be able to

afford!  The great majority of

individuals have a sinking saddened look as they walk away from the counter without

their much needed prescriptions others like myself may have a sudden rise in

blood pressure causing severe head pain. 

 In the last several years’ retail prescription

prices have increased six times faster than 1.5 % inflation. This is according

to the new AARP Public Policy Institute (PPI) report. Even the prices of

so called generic drugs has escalated to the point of being more expensive or

as expensive as  ‘brand name’ drugs, one

such example is Rasagiline (Azilect) .

The average annual prescription cost has reached new heights of over $11,000,

which according to the experts is nearly 75% of the average annual Social

Security benefits. This is madness!

If these trends continue people are simply going to stop taking medications which are no longer affordable increasing the taxpayer’s burden in the long run. This is because as I have experienced many times as a practicing physician as well as a patient when the appropriate medications are not given or taken routinely due to financial constraints there is a subsequent increase number of institutionalized in our case Parkinson’s patients due to worsening of symptoms including falls, strokes, hypertensive crisis, along with pain, aspiration pneumonia's, and cognitive status changes.  Other times, as I have recently experienced, when medications are altered to save insurances money, patients end up suffering needlessly and in the long run also end up costing not just insurances but inflict a monetary burden on patients as well. This is not even taking into account the time along with emotional distress caused on the entire family. 

Placing a system of check and balance on the rising cost of medications is long overdue. Currently the rise in cost of medication is the fastest growing over any other health cost according to US News report of December 2017. To make things worse the drug cost in neurological illnesses like PD are disproportionately high. Medicare drug expenses for neurology has an annual spending of roughly 5 billion, the fourth highest in Medicare drug expenses. The hardest hit are those on Medicare and Medicaid due to Federal anti-kickback Statute, which prohibits pharmaceutical companies from offering shared assistance to beneficiaries of government subsidized health plans. With the majority of PD patients being on Medicare including younger patients due to medical disability this can be a great deterrent and challenge for many.

However, there

are a few things we can do to ease our stress and burden in obtaining necessary

medications:

1. Be vocal- self advocate – let your needs be known to affect change. Talk to your lawmakers about the challenges and need for changes to health care to truly make affordable and accessible to all who live with PD. For me, this has been my biggest coping strategy. Although extremely time consuming at times for the most part it ensures I maintain a constant supply of medications
2. Team up with a clinical pharmacists, social workers and doctors to find the BEST treatments keeping in mind your personal financial situation. In my case having a clinical pharmacist through my insurance has been of little service. However, having my personal designated local pharmacist has been a great asset. Further, my biggest advocate and key team advisor has been my own MDS who advocates on my behalf continuously and provides me with the necessary medications and authorizations in a timely fashion. (She Rocks and I am extremely grateful for her). Some of the questions you should be asking yourself when discussing options with doctors, pharmacist, insurance etc. How many side effects, drug trials, and out of pocket cost am I willing to tolerate before I become proactive or vocal in demanding or asking for what I need? Do I have a choice and will I allow substitution of medications for a cheaper alternatives which may not be in same class as the ones I am taking. Can I pay extra to reduce or cut ‘donut hole’ altogether and are there supplement insurances or programs I can qualify for to aid in the cost of drugs?
3. Consider generics only when available and appropriate keeping in mind there is a difference – but if you decide to stay with generics remember to keep same generic each time. Plus, if you get generic initially and do not get a positive response before discarding medication try a different generic or even brand ( highly recommend) to truly know whether it works or not. For instance, some drugs like Neurontin (gabapentin) do not work as well for tremors as brand name – this is years of experience treating patients with tremors.
4. Use resources like national organizations to find assistance.
5. Use additional resources like pharma assistance programs/NORD

 Remember that the solution lies in all of us working together for better health.

References:

Melville, Nancy. "Soaring Neurological Drug prices: How docs can help" (Feb. 17, 2019) Medscape Neurology

The facts about rising prescription drug cost. https://www.csrxp.org/.../2016/04/CSRxP_Facts-of-Rising-Rx-Prices.pdf

The high cost of rising drug prices. https://http://www.usnews.com/.../the-high-cost-of-rising-drug-prices

Dr. De Leon

https://defeatparkinsons.com/2019/04/20/soaring-neurological-retail-prescription-drugs-by-dr-de-leon/

Researchers are testing ultrasound to treat neuropathic pain

• By Sarah Meehan The Baltimore Sun (TNS)
 
• Apr 18, 2019

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• BALTIMORE — Steroid injections, nerve stimulators and spinal fusions were no match for the chronic pain in Tammy Durfee’s left side — never mind the “searing-hot poker” sensation that would jab her leg without warning. After a decade searching for relief, a four-hour procedure in Baltimore put her pain to rest.
  Durfee, of Higginsville, Mo., was the first U.S. patient to be treated for neuropathic pain using focused ultrasound in a medical trial being conducted by University of Maryland School of Medicine researchers. Just as a magnifying glass can concentrate sunlight to burn holes in leaves, focused ultrasound concentrates sound waves to singe a small area of the brain, preventing neurons from overreacting and triggering pain.
  Durfee’s treatment is part of a broader trial in which Maryland medical school researchers are studying the use of focused ultrasound on neurological conditions including essential tremor, Parkinson’s disease and other movement disorders. Proponents of focused ultrasound expect the non-invasive therapy could become a mainstream treatment for dozens of conditions ranging from cancer to Alzheimer’s disease in the years ahead.
  Often associated with pregnancy sonograms, ultrasound is a technique that sends sound waves through the body, often to create medical images. Focused ultrasound pinpoints the sound waves to a specific area to burn tissue.

  The technique looks to be a promising treatment for neuropathic pain, a fairly common condition that is notoriously difficult to treat. The sensation is caused by damage to nerves, the spinal cord or neurons in the thalamus, the part of the brain that relays information from the body’s sensory receptors.

  Neuropathic pain encompasses a range of diagnoses, and symptoms affect an estimated 7-10 percent of the population. It can manifest in different ways, with both continuous and intermittent pain. The condition does not usually respond to pain medications, and surgical remedies only work for some patients.

  “Even if it responds early on, the treatments eventually fail. And the side effects of treatments are many and very, very serious. Many medications lose their effectiveness,” said Dr. Dheeraj Gandhi, the University of Maryland’s director of interventional neuroradiology and the study’s principal investigator. “Most patients don’t have very many options and they have to live through this constant pain and the effect it has on the rest of their brain, including cognition, the effect on mood and unemployment. The majority of patients are not able to live their lives to their fullest.”

  Durfee spent her days avoiding movement after her pain began in 2010. She stayed in bed as long as possible in the morning before leaving for her job as a pharmacy technician at Walmart. In the evenings, she tried to find a comfortable seat on the couch until she went to sleep.

  “It made my days very, very long,” Durfee said. “I never knew when the deep, searing poker pain was gonna hit.”

  Steroid injections, spinal fusions, pills and nerve stimulators helped, but the effectiveness of each treatment faded eventually.

  Tim Clanton, 54, had seven knee surgeries, an ankle surgery, three spinal sympathectomies — in which a nerve is cut or clamped — and three nerve blocks after a belt-loader crushed his knee as he was hauling luggage onto a commercial jet more than 30 years ago.

  “Over the years I’ve had probably every anti-inflammatory that is known to man, along with lots of other medication,” the Dallas resident said. “Being on medication is not good. I prefer not to be, but I also have to work and provide a living for my family.”

  Fatal overdoses, mostly related to fentanyl, continue to climb in Maryland

  Gandhi said focused ultrasound could provide more lasting relief for neuropathic pain patients and help reduce their reliance on pain medications — including opioids, which are often used to manage neuropathic pain.

  “If you look at overall health costs for pain-related treatments, the U.S. probably spends more than $500 billion annually on treatments related to pain,” Gandhi said. “So if this procedure works well in these types of patients, it could be a very significant alternative to what we have today.”

  Dr. Neal Kassell, founder and chairman of the Focused Ultrasound Foundation, said the University of Maryland trial could prove that such treatment fills the “holy grail” of improving health outcomes while decreasing costs. The risk of infection is low because there are no surgical cuts. And, because it’s a one-time treatment, focused ultrasound could reduce costs for pain patients, too.

  For now, Gandhi said, the procedure’s cost is comparable to open-brain surgery because so many researchers are involved.

  The study is one step in an arduous process toward regulatory approval. The current trial allows researchers to treat five patients with one of three types of neuropathic pain: shooting pain that does not respond to neurosurgery, pain from spinal cord injuries or phantom limb pain after an amputation.

  If the treatment’s safety is proven, the research team will review results with the U.S. Food and Drug Administration and request permission to treat more neuropathic pain patients.

  Neuropathic pain is among more than 100 conditions being studied for treatment with focused ultrasound.

  “Fields like this grow exponentially and I believe we’re right now at the inflection point of that curve,” said Kassell, whose organization is funding the University of Maryland trial. “Focused ultrasound will be as revolutionary to therapy as (magnetic resonance) scanning was to diagnosis.”

  Some doctors caution that more research is needed before focused ultrasound can be lauded as a cure-all.

  Dr. Art Sedrakyan, a professor of healthcare policy and research for Weill Cornell Medical College, said such therapies as focused ultrasound, cryotherapy and microwave ablation may show promise, but their long-term effects are unknown.

  “We need to ensure that we don’t get too excited about them in terms of their effectiveness,” Sedrakyan said.

  He’s developing a database of patients treated with such emerging technologies, so they can be tracked for years.

  “We need to clearly encourage innovation,” Sedrakyan said. “But what’s critical is to ensure evaluation.”

  Though treating neuropathic pain with focused ultrasound is experimental in the United States, it’s gained more traction in Europe, where Dr. Daniel Jeanmonod pioneered the technique in Switzerland. His team referred Durfee to the Maryland trial after she came across his work.

  For the procedure, a patient’s shaved head is affixed to a steel frame to immobilize it as they lay in an MRI machine. The top of the head is submerged in a water bath and coupled to a focused ultrasound transfuser — a helmet-like contraption with more than 1,000 elements that direct sound waves to burn a 5-6 millimeter section of the brain. Doctors constantly monitor the patient, who is awake during the procedure.

  “We’re actually, if you will, cooking a small group of nerve cells,” said Dr. Howard M. Eisenberg, chair of Maryland’s neurosurgery department, who is conducting the trial.

  It was uncomfortable at times, Clanton said — like a headache. But it was a small price to pay for relief from 33 years of pain that left him limping, stopped him from playing with his three children and stole his quality of life.

  “As a kid, you hear people that are older and you think, how can someone live with pain? I found out at (age) 20,” Clanton said. “It’s been tough. And if more patients can do this, it could be life changing.”

  Clanton’s pain has not disappeared since his treatment in December, but he said it’s dulled. He’s limping less and doesn’t shy away from stairs. Best of all, he said, he’s lowered his medication doses — something he wants for other patients in his position.

  “When pain is bad you kind of sit there and you’re hurting and it’s an all-day thing and all night. You never get out of it,” Clanton said. “So if at minimum they do the procedure and the medication that they’re on works more efficiently, that’s worth it. And I can tell you that that’s happening with me.”

  Durfee had the procedure Sept. 13, and her results were immediate. After the procedure ended, she sat up on the table without assistance and did something she hadn’t done in years — she danced out of the hospital room.

  “I’ve been pain-free ever since,” she said.

  Gandhi, Eisenberg and their team are monitoring the patients for a year with the aim of seeing at least a 40 percent reduction in their pain intensity and a 30 percent reduction in disabilities related to their pain. So far their patients have seen positive results, though it’s too soon to tell how effective the treatment will be in the long term.

  Clanton said his friends and family have commented that he’s moving more easily. And Durfee can now wrestle with her dogs, play with her grandchildren and sit through a movie without wiggling to find a comfortable position.

  “I like being pain-free,” she said. “It’s fabulous.”

• https://www.heraldmailmedia.com/news/nation/researchers-are-testing-ultrasound-to-treat-neuropathic-pain/article_5359caf7-10c3-5e09-8c56-988d4bc04a06.html

Kinston Parkinson's Support Group holds annual walk

JUNIOUS SMITH III     APRIL 19, 2019

The Kinston Parkinson’s Support Group has been together for 13 years, raising money and awareness for a cure to the disease. Photo by Junious Smith III / Neuse News

April is recognized as Parkinson’s Disease Awareness Month and a local group wanted to shed additional light for those affected.

The Kinston Parkinson’s Support Group held its annual walk Wednesday at UNC Lenoir Hospital. The group, which has been together for 13 years, is facilitated by Judy Heath, who wanted to provide support for those afflicted by the disease and their families.

According to Parkinson.org, Parkinson’s disease affects 1 million people in the United States and 10 million worldwide. The progression of symptoms are different between those affected and some of the signs are tremors, limb rigidity and balance problems. The causes for the disease remain largely unknown.

Heath said last year the organization was able to raise $6,000 for Parkinson’s awareness.

“We’re all about awareness and helping each other out,” Heath said. “We also meet at the Wellness Center on the third Wednesday of each month at 2 p.m. and it’s free for anyone to join. This was our state walk and our national one is Nov. 3.”

The support group has several teams — Team Henry, Alberta and David — named for members who succumbed to complications from Parkinson’s. Irene Herring, who lost her aunt, Alberta, during Christmas 2018, said she joined the group four years ago with her family.

“My aunt and mother both have Parkinson’s disease, but they wouldn’t let the disease bring them down,” Herring said. “My aunt had it for 21 years and my mom’s had it for about seven — it’s been a privilege to be a part of this group and amazing the determination my mother and aunt had. There are so many things that are affected from Parkinson’s, like speech and walking. Little things like picking up a napkin can be a struggle.

“Caregivers have been amazing, and we’re thankful to have the support of them as well.”

Shelby Phillips, Herring’s mother, said she’s been appreciative of all the love within the group. Phillips had deep brain stimulation surgery in 2014 and has undergone treatment every six months.

“It means a lot to have this group and I’m fortunate to have received surgery,” Phillips said. “I’m one of the lucky ones and there have been difficulties from time to time. I am truly thankful for Judy and the others in this group, who truly show love and care.”

For anyone looking to send a donation, mail it to Heath at 2089 Briarwood Drive, Kinston N.C. 28501. All donations are tax-deductible.

https://www.neusenews.com/index/2019/4/19/kinston-parkinsons-support-group-holds-annual-walk

Antioxidants Protect Against Levodopa Toxicity, Mouse Study Shows

APRIL 18, 2019  BY CATARINA SILVA 

Antioxidants like vitamin C may protect against the toxic effects of levodopa, researchers report.

Their study, “Reducing oxidative toxicity of L-dopa in combination with two different antioxidants: an essential oil isolated from Rosa Damascena Mill., and vitamin C”, was published in Toxicology Reports.

Levodopa (L-DOPA) treatment effectively reduces early motor symptoms in Parkinson’s disease, but conflicting evidence suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules.

In theory, combining levodopa therapy with antioxidants may decrease treatment-related side effects and help relieve symptoms.

Investigators from Trakia University in Bulgaria investigated whether L-DOPA-induced oxidative stress could be reduced by combining two distinct antioxidants — an essential oil isolated from Damask rose, and vitamin C.

To do so, healthy mice were divided into four groups. All animals, except the ones in the control group, received two intraperitoneal injections (injected directly into the body cavity) of L-DOPA and, after that, benserazide, a compound that increases the amount of L-DOPA crossing into the brain and its subsequent conversion to dopamine.

Two of the four study groups were pre-treated with injections of either rose oil or vitamin C before they were treated with L-DOPA and benserazide.

Scientists then screened for the presence of oxidative stress by measuring blood concentrations of particular proteins and lipids (fatty acids) that are known oxidative stress markers.

In comparison to the control sample, L-DOPA-only treated animals had a significant increase in molecular markers of oxidative stress, meaning that levodopa treatment induced oxidative stress in healthy animals.

Importantly, those same markers were significantly decreased in both groups pre-treated with antioxidants, compared to control animals.

“It must be emphasized, that Rosa damascene [Damask rose] oil exhibited behavior very similar to the classic antioxidants – vitamin C, making it potential candidates for extensive experimental research to their possible use as protectors against oxidative toxicity triggered by drug therapy of neurodegenerative diseases,” researchers concluded.

https://parkinsonsnewstoday.com/2019/04/18/antioxidants-protect-against-levodopa-toxicity-mouse-study-shows/

Pilot Project Tests Wrist Device That Monitors Symptoms at Home

 APRIL 18, 2019     BY PATRICIA INACIO, PHD

A pilot project in the United Kingdom is testing a wrist device that is worn like a watch, called Personal Kinetigraph (PKG), to help Parkinson’s patients and their specialist healthcare providers to monitor their condition at home.

The PKG, developed by Global Kinetics, will be tested in the “Developing Home-based Parkinson’s Care” project, led by researchers at the University of Plymouth and University Hospitals Plymouth NHS Trust (UHPNT).

The wearable technology monitors patients’ motor symptoms, using a proprietary algorithm to process the data. Participants also are asked about their non-motor symptoms, including changes in mood, to supplement the movement data delivered by the PKG.

Patients will wear the device for six-day stints, during which their care team will identify and implement necessary treatment changes. The specialist Parkinson’s team will work remotely to ensure necessary help — calls or clinical appointments — is offered when needed.

In the U.K., current guidelines recommend that Parkinson’s patients see a specialist every six months, no matter the stage of their condition. Care is usually provided by a consultant and community Parkinson’s disease nurse specialist (PDNS).

However, results from a recent survey showed that almost half of these appointments (46%) are delayed by more than six months. In 60% of the cases, patients can go an entire year without an appointment. Some regions of the U.K. don’t have the specialist service, and 50% of vacant PDNS positions are due to long-term sick leave or resignation, the audit showed.

“The UK prevalence of Parkinson’s disease will increase by a fifth by 2025, so the challenges associated with providing a timely and patient-centered service will also be much higher,” Camille Carroll, the project leader and an associate professor at the University of Plymouth’s Institute of Translational and Stratified Medicine (ITSMed), said in a press release.

“The existing service puts a lot of pressure on nurses, and attending clinics is arduous for both patient and carer as it presents logistical and physical challenges that add to burden and distress,” said Carroll, also a consultant neurologist at UHPNT.

“We want to help people with Parkinson’s to live the best lives they can for as long as they can, and this project aims to empower patients to take control of their own condition,” she added.

The project will start with 150 patients from Plymouth city, West Devon and East Cornwall.

“The new project is designed to reduce the burden of attending hospital clinics; improve motor and non-motor Parkinson’s symptoms; ensure appropriate and timely contacts to health-care services; and result in improved quality of life for people with Parkinson’s and their carers,” Carroll said.

“If successful, the intervention will prove a means of providing a resilient and sustainable service faced with the future demands of a condition that is increasing in prevalence and complexity,” she added.

The project also will bring together both clinicians and caretakers by providing “co-design workshops” to ensure that patients’ needs and expectations are assessed and met.

A Parkinson’s patient from Looe who is enrolled in the project is pleased with the device’s ease of use.

“Using the PKG is simple and gives the specialist an easy and quick way of monitoring my Parkinson’s disease remotely. Hopefully the new service design will make life easier for others like myself living with the condition,” John Whipps said.

“One of the hardest things with Parkinson’s is trying to decide when your Partner needs their extra doses of medication. The PKG results help take the guesswork out of that, which is really valuable for ensuring the best care possible,” said Sue Whipps, his wife and caregiver.

The pilot project is being delivered in partnership with the Cure Parkinson’s Trust, Flourish Workplace, Sheffield Hallam University, Global Kinetics Corporation, Parkinson’s UK, Fre-est, Radboud University, the South West Academic Health Science Network (SWAHSN) and UCB Pharma.

It’s been funded with £75,000 ($97,619) from the Health Foundation and £15,500 ($27,176) from a Parkinson’s UK Excellence Network Service Improvement Grant.

“The PKG is an exciting example of how technology has the potential to transform care in conditions like Parkinson’s,” said Julie Dodd, director of Digital Transformation at Parkinson’s UK.

“People tell us that one of the most frustrating things about the condition is how unpredictable it is, no two days are the same, which makes it incredibly hard to plan,” Dodd added.

https://parkinsonsnewstoday.com/2019/04/18/parkinsons-project-tests-wrist-device-monitors-symptoms-home/

Neuroimaging method measures disease severity in Parkinson’s patients

April 18, 2019 | Matt O'Connor | Advanced Visualization

Dopamine transporter (DAT) SPECT may be a useful imaging biomarker to determine the severity of Parkinson’s disease, according to an April 17 study published in the American Journal of Roentgenology.

Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) area of the brain, resulting in presynaptic nigrostriatal dopamine dysfunction. The dopaminergic neurons release neuromelanin into surrounding brain areas which directly contributes to the progression of Parkinson’s. 

Neuromelanin MRI and DAT SPECT have both shown promise for evaluating neuromelanin, which is central for understanding “PD pathogenesis, assessing PD progression, and monitoring PD therapeutics,” wrote first author, Hiroto Takahashi, Osaka University Graduate School of Medicine in Osaka, Japan, and colleagues. 

“In the current study, we compared neuromelanin MRI with DAT SPECT to discern the relation between dopamine neurons in the SNpc and presynaptic striatal dopamine capacity while evaluating the conditions of the nigrostriatal dopaminergic system in accordance with disease severity in PD,” the researchers added. “We also aimed to explore the use of these imaging biomarkers to quantify disease severity during progression of PD.”

The researchers included 40 patients with Parkinson’s disease who underwent neuromelanin MRI and DAT SPECT in the study. On MRI images, Takahashi et al. recorded the signal-to-noise (SNR) ratio in the SNpc while noting the striatal specific binding (SBR) ratio on DAT SPECT images. 

Overall, SNR and SBR were much greater in early-stage patients compared to the advanced stage group. Of note, there were 40 patients in stages 1-3 and 10 patients in stages 4-5. 

Additionally, the ROC AUCs for differentiating early and advanced stage groups was 0.73 for SNR and 0.89 for SBR. The coefficients of correlation were −0.47 for SNR versus Hoehn and Yahr (HY) stage and −0.67 for SBR versus HY stage.

“The current study shows that it is possible to quantify the degeneration of dopaminergic nigrostriatal transporters in PD using striatal SBR derived from DAT SPECT with good correlation with the HY stage,” Takahashi and colleagues wrote. “The results are consistent with the results of previous studies indicating that DAT SPECT provides a quantitative biomarker for the severity of nigrostriatal dopaminergic degeneration in PD.”

https://www.healthimaging.com/topics/advanced-visualization/neuroimaging-measures-disease-severity-parkinsons

Can Neurotrophic Factor Be Neuroprotective in Parkinson's Disease?

Talan, Jamie  April 18, 2019

Despite Some Doubts, UK Scientists Push for a Phase 3 Study for Answers

Representative F-DOPA images from two patients, shown at baseline and at the end of the double-blind study. Top images are from a patient who was receiving placebo infusions every four weeks; 10 placebo infusions in total. Bottom images are from a patient who was receiving GDNF infusions every four weeks; 10 GDNP infusions in total.

Investigators are pushing for a phase 3 trial to test the efficacy of infusing glial cell line-derived neurotrophic factor in patients with Parkinson's disease, despite negative findings from a phase 2 trial. They believe the results have promise, though independent experts do not agree.

Researchers have spent almost two decades studying the infusion of glial cell line-derived neurotrophic growth factor (GDNF) into the brains of patients with Parkinson's disease (PD) to see whether the growth factor would protect dopamine neurons and their support cells from dying. Despite some promising results in animal models of the disease, study after clinical study has failed to meet the primary outcome measures in humans, no matter how the drug was delivered.

Now, two new studies by researchers in the United Kingdom were just published with similar negative results from a phase 2 double-blind study, but the research team is pushing to move into a phase 3 study with hopes that the benefits they observed in patients are more than just a robust placebo response.

“Does it work?” asked Steven Gill, MD, a neurosurgeon the Translational Health Sciences at the Bristol Medical School in the United Kingdom and senior author of the studies published in Brain on March 1 and the Journal of Parkinson's Disease on February 26.

Dr. Gill said that the standard rating scales do not adequately reflect disease severity and are a poor method of evaluating efficacy. He said that many of the patients on active drug were carrying out activities that they hadn't been able to do in years. Moreover, the brain scans showed that the drug reached the target. “PET scans showed 100 percent increase in 18F DOPA in the motor putamen demonstrating restoration of dopamine neurons,” he said.

“There is no other explanation for the patients' improvements,” said Dr. Gill. “It took us a long time to figure this out. We found the right materials, flow rate and delivery method, and we had no infections during the study.”

But independent experts, some of whom have conducted their own research involving GDNF, said media hype around the latest findings have led to some misunderstanding of the findings and what they mean.

The History Leading to Current Trials

Dr. Gill and his colleagues published findings from their first GDNF study—a phase 1 safety study comprising five patients in an open-label study—in 2003. The neurotrophic growth factor was infused continuously through micro-catheters into each putamen, which is deprived of dopamine in Parkinson's disease. They reported that this led to a 39 percent improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61 percent improvement in the activities of daily living sub-score.

The research team followed the patients for another two years and reported that the improvements continued and that there were no serious clinical side effects or significant changes in cognition. Functionally, the patients were reporting improvement in their activities of daily living. One patient who died of an unrelated heart attack was shown to have restoration of dopaminergic neurons at the site of infusion in the putamen as well as in the substantia nigra consistent with the clinical benefit.

Excited by the open-label findings, Amgen, makers of GDNF, launched a double-blind placebo-controlled trial in 2003 using a different catheter system. The multicenter study enrolled 34 patients. A year later, the company announced they were stopping the study. The patients on the active drug did not reach the predetermined endpoint to show significant benefit and the scientists had detected neutralizing antibody in two of the study participants, and this was worrisome. The company had other reasons to stop the trial: Preclinical findings from non-human primates found a loss in neurons in the cerebellum following high dose exposure and subsequent GDNF withdrawal. Patients and the Parkinson's disease community were upset, and lawsuits were filed to try to force the company to provide the drug through a compassionate use application. The courts ruled in favor of Amgen.

Failure of the Amgen study was attributed to inadequate delivery because the larger catheter used resulted in much of the GDNF refluxing back along the catheter/tissue interface and not adequately penetrating the brain tissue, said Dr. Gill. In the non-human primate study, the catheter leak back resulted in a significant dose of GDNF entering the cerebrospinal fluid and collecting around the skull base causing toxic damage to the cerebellum, he added.

Dr. Gill was still convinced that the growth factor would work given the right delivery method and the optimal dose. The problem with the method used was that the continuous slow infusion would result in a build-up of GDNF at the catheter tip causing local toxicity and poor distribution covering no more than 10 percent of the putamen, he said. The solution that he came up with was to drive the drug throughout the putamen using controlled pressure via micro-catheters and then stop the infusion. This would need to be repeated every four weeks to maintain a biological effect.

Findings in Brain

To achieve this, Dr. Gill designed a drug delivery system comprising four micro-catheters that were implanted with a surgical robot into the putamen and connected to a small bone-anchored port that emerges through the skin behind the ear. The drug was delivered by connecting external infusion pumps to individual catheters via an administration set that is connected to the port when required.

In 2013, with charitable funding from Parkinson's UK, the Cure Parkinson's Trust, and Funding Neuro, the team in Bristol commenced a randomized double-blind trial and recruited 41 patients between the ages of 35 and 75. The study participants had motor symptoms for at least five years and their symptoms during the off- and on-state UPDRS ratings were in the moderate disease severity range. Half the patients were enrolled in active drug or placebo for nine months and then all patients received active drug for another nine months. The once-a-month delivery method was enough for the half-life to clear from the brain. Blood samples were taken throughout the study to look for GDNF plasma concentrations and any antibodies that might develop in response to the treatment. The findings from this study were published in Brain.

Forty-one patients were randomized to receive bilateral infusions of GDNF (120 mg per putamen) or placebo for the first 40 weeks. Then everyone received the drug for the next 40 weeks. Every eight weeks before the next infusion, patients were asked to complete three-day diary recordings and they had assessments of motor function in their off state, which was followed by a levodopa challenge. The researchers had MRIs of the patients done to ensure that the doses were administered bilaterally. The researchers took baseline recordings on 18F-DOPA PET and again at the end of the study.

The primary outcome measure was the percentage change from baseline to week 40 in the off-state motor UPDRS score, with the study powered to demonstrate a 20 percent difference between the groups. The change in the mean off-state score in the UPDRS motor score was 17.3 percent in the GDNF group and 11.8 in the placebo group, which was not statistically significant.

The PET findings at baseline were what they expected to find in the pathology of PD. At 40 weeks, those in the placebo arm showed no changes. Those who were receiving GDNF showed significant changes in both sides of the posterior putamen, central putamen, and anterior putamen, said Dr. Gill. “Unfortunately, these changes did not correlate with the motor UPDRS scores, which were not significantly different.”

The secondary endpoints—including an absolute change from baseline in off-state UPDRS motor scores, absolute and percentage change from baseline in UPDRS score in the on state, UPDRS activities of daily living and changes in the disease diary ratings over time, timed motor tests, and changes on non-motor symptoms—were also no different between patients receiving the drug or those on placebo.

Dr. Gill said that they went back to conduct a post-hoc analysis and found that nine (43 percent) of the patients in the active medication arm had at least a 10-point improvement in their off motor score, which he said was clinically meaningful. There were no patients in the placebo arm that achieved this level of benefit, he said, adding that the infusions were well-tolerated and there were no drug-related serious adverse side effects that differed between the placebo and active drug group.

No one in the GDNF group discontinued the medication during the study, although one patient had a mildly symptomatic putamenal stroke with the initial test dose and another a small asymptomatic hemorrhage in both putamina during the initial test infusion. Both were withdrawn from the study before randomization.

The scientists also reported three device-related side effects, including one infection around the port site that required hospitalization and oral antibiotics, and two hypertrophic skin reactions that required surgical thinning. During the early part of the study, several patients reported some loosening of the port fixation, and this led Dr. Gill to modify the design with a stabilizing element to retro fit it in a few individuals. The team realized that more education was needed on how to keep the port site clean.

“Overall, the success of the implantable drug delivery system opens the possibility for its use in delivering other medications safely into the brain,” said Dr. Gill.

The question, of course, is why the delivery of this particular growth factor did not have a significant clinical effect in these patients despite effective delivery and evidence of increased dopamine uptake on the PET scans. Do they need to design this intervention for patients in an earlier stage of disease? Was it an adequate dose? Was nine months long enough? They could show a bimodal distribution of absolute responders and non-responders on the UPDRS measures, but there were no clues about what made some patients improve and not others. The scientists concluded that “further GDNF investigations will need to address potential reasons why our clinical primary endpoint was not reached despite apparently optimizing putamenal therapeutic delivery.”

Adding an Open-Label Extension Study

The open-label extension study, reported in the Journal of Parkinson's Disease, was designed to give everyone in the study the active drug from week 40 to week 80. The researchers did not know the results of the double-blind study when they began this second phase. Patients who accepted enrollment into the open-label study did not know whether they had received the active drug in the first study. Trained raters were also blinded to the patient's condition, prior treatment assignment, and outcome measures.

Every patient in the extension trial received ten doses of GDNF at four-week intervals. (Patients in both studies were maintained on their initial Parkinson's medications.) The clinical measurements were the same in this study at baseline and every eight weeks.

All 41 patients opted to continue in the extension phase of the study. They all completed the trial, as well. Almost 98 percent of the group kept to the infusion schedule. Twelve percent of the infusions were interpreted or terminated early due to mechanical pressure increases in the infusion lines.

Again, there were some differences in those who had 80 weeks of active medicine versus those with 40 weeks, including the observation that patients in the active/active GDNF arm had fewer increases in the levodopa medications they were taking compared with those on placebo/GDNF. It was impossible to know whether this was due to a placebo response because everyone knew they were getting the active drug.

The investigations also said that investigator bias in the extension phase could also have led to the changes noted between 40 and 80 weeks.

“There was a 30 percent improvement in UPDRS motor scores, which is clinically meaningful,” said Dr. Gill. “There was progressive improvement month by month. The PET scans showed improvement and patients were getting better. If you look at the data, it's difficult to attribute this to a placebo effect alone. Hard as I have looked, I've not found any study where patients continue to improve month-by-month over 18 months on a placebo.”

The investigators said that the unexpectedly large 11.8 percent improvement in the motor scores of the placebo arm could in part be explained by the mechanical disturbance of the putamen from the infusions. Micro trauma is known to stimulate the release of neurotrophic factors such as GDNF and brain-derived neurotrophic factor. These could lead to increased synaptogenesis and axonal sprouting in dopaminergic neurons. If so, said Dr. Gill “one should consider including a best medical therapy arm as a control group in future studies, which has been done in studies of deep brain stimulation.”

He said that his team is pushing for a phase 3 study that will include a dose escalation. The dose delivered in the study was constrained by the toxicity data that they had at the commencement of the trial, however recent toxicology studies have indicated that they can now safely increase the monthly dose by four-fold, Dr. Gill explained.

“People misunderstand a failed study. Science is about the balance of probabilities,” he added. “When you fail to meet a pre-determined endpoint, it may mean that you have asked the wrong question, failed to deliver sufficient drug to the correct location at the optimal frequency, failed to observe the patients for long enough, or even produced a biological effect in your control group. This is an extremely difficult problem to solve and translate into a therapy. Nevertheless GDNF is the only molecule with the potential to restore dopaminergic, serotoninergic, noradrenergic, and cholinergic neurons, all of which are affected in Parkinson's. Having seen remarkable improvements in all aspects of the disease in individual patients, I will not give up until I get it right.

“Many of the patients say that they know they are better,” he added. “Now that the study is finished they are desperately trying to get access to the drug.” He said that patients and private foundations are helping to raise money for the phase 3 study. Dr. Gill said that they are also talking about implementing an alternative evaluation of the patients in the study. Dr. Gill invented the surgical system and is on the advisory board for Renishaw, the company that makes the device. Other scientists are using the technology to test the delivery of other growth factors into the brain.

Expert Commentary

Independent experts were less sanguine about the findings, however. “It is another GDNF trial that has failed,” said Jeffrey H. Kordower, PhD, the Alla V. and Solomon Jesmer professor of neurological sciences and director of the section of neurobiology at Rush Medical College. “It failed in all of its endpoints except fluorodopa PET, and fluorodopa PET has no clinical association with functional outcome. There are numerous patients who have had increased fluorodopa PET in other trials without clinical benefit. For scientists to tell their patients that ‘I know it works’ is totally misleading and unsupported by the science. Also, these types of unsubstantiated statements drive expectations and the placebo effect, which was substantial in this trial.”

C. Warren Olanow, MD, chairman emeritus of the department of neurology at Mount Sinai School of Medicine, agreed. “To say it works in the lab is a great leap of faith to say it will work in humans. Every single GDNF trial has failed. If double-blind studies are negative, it speaks louder than the proclamation of a neurosurgeon saying that he knows it works.”

On February 28, BBC aired the first in a two-part series called The Parkinson's Drug Trial: A Miracle Cure? BBC spent six years documenting the latest UK study, speaking to patients and the scientists, including Dr. Gill and neurologist Alan Whone, MD, the lead author of the studies.

“Unfortunately, the failure of this study has been lost in the hype by the investigators saying that they know the drug works,” added Anthony E. Lang, MD, FAAN, the Jack Clark chair for Parkinson's disease research and director of the Edmond J. Safra program in Parkinson's disease at the University of Toronto. Dr. Lang has carried out GDNF trials, which also had negative results.

“Scientists must have equipoise when they plan a clinical trial and talk about their findings. I have been dealing with this a long time,” he said of GDNF's negative findings. “The methodology that Drs. Gill, Whone, and their colleagues used to test the drug was excellent. The design of the device was very novel and seemed to appropriately address the criticisms they had about the previous trials. They seemed to do all the right things, and if the treatment was truly efficacious it should have worked, but it didn't. Now they are saying it was the dose. Maybe it didn't work because it doesn't work.”

“I personally believe that this treatment should now be allowed to die a natural death,” Dr. Lang said. “Even if the very modest positive signals emphasized by the investigators generated sufficient enthusiasm to fund another expensive trial, I don't think that a more positive result would encourage widespread use of this treatment given the cost and technically demanding, invasive nature of its application.”

“There have been many attempts to deliver GDNF in humans to see if the laboratory findings in animals can be replicated in humans,” said John G. Nutt, MD, FAAN, professor of neurology and physiology/pharmacology at Oregon Health and Science University. “The clinical results of this blinded, 40-week comparison of placebo and GDNF study followed by the open (unblinded) 40 weeks found no difference between placebo and GDNF. The discussion is about whether this is an adequate test of GDNF as treatment for PD with the conclusion that because of only one dose tested it is not.”

Disclosures

Dr. Gill is the medical director of Renishaw PLC and is the inventor of the drug delivery system from which he may have a future royalty share. He serves on the scientific advisory board of MedGenesis Therapeutix Inc, for which he is reimbursed with share options. Drs. Nutt, Olanow, and Kordower had no competing interests.

Dr. Lang has received fees for consulting with Lundbeck, Sun Pharma, Kallyope, Retrophin, Paladin, Seelos, Theravance, Roche, and Corticobasal Degeneration Solutions. He serves on advisory boards for Jazz Pharma, PhotoPharmics, Sunovion, and has received honoraria from Sun Pharma, AbbVie, and Sonovion.

Neurology Today: April 18, 2019 - Volume 19 - Issue 8 - p 26–30

doi: 10.1097/01.NT.0000558059.57664.71

In the Pipeline

https://journals.lww.com/neurotodayonline/Fulltext/2019/04180/Can_Neurotrophic_Factor_Be_Neuroprotective_in.7.aspx