Blocking one enzyme could help treat many chronic disorders

July 27, 2018      By Catharine Paddock PhD

Researchers have identified an enzyme that plays a key role in a biological mechanism common to many chronic inflammatory disorders.

Targeting one enzyme may lead to new treatments for many conditions.

The discovery — which has been reported in a paper now published in the journal Nature — could lead to new drugs for treating diverse inflammation-related diseases, ranging from Parkinson's and Alzheimer's to osteoarthritis and cancer.

The enzyme is called cytosine monophosphate kinase 2 (CMPK2) and it activates NLRP3, an inflammation-triggering molecule, or inflammasome.

Scientists already knew that finding a way to block NLRP3 without affecting other inflammasomes could lead to new treatments for many inflammatory conditions.

"Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases," note the authors.

But without a clear understanding of the molecular pathways involved in triggering NLRP3, it was not possible to design drugs that specifically block it.

The 'cost and benefit' of inflammation

Inflammation is an altered biological state of cells and tissues that occurs in response to infectious agents, mechanical injury, or stress. The response is complex and triggered by inflammasomes.

The state of inflammation brings potential benefits in that it can heal, restore health, and secure survival. But this happens at a cost.

During inflammation, there is a "decline in the normal function" of the affected cells and tissues while the threat is eliminated or the repair takes place.

In short-term conditions, the benefits of inflammation outweigh the costs. The infection clears, the wound is healed, and normal tissue function is restored.

But when the state of inflammation persists, the costs outweigh the benefits. For some reason, the "stimulating trigger cannot be removed" and a chronic inflammatory disease develops.

CMPK2 blockers

During the state of inflammation, there is a sharp rise in a hormone called interleukin 1 beta (IL-1B). The hormone is important for many cell events that occur during inflammation, including proliferation and death.

Inflammasomes control the production and release of IL-1B. NLRP3 is most active in this process. It senses diverse stimuli from noxious threats to tissue changes. These range from silica dust and asbestos to the microcrystals of uric acid that cause inflammation in gout.

In their study, Prof. Michael Karin — from the University of California, San Diego — and team focused on CMPK2 and the key role that the enzyme plays in triggering NLRP3 in sparking production of IL-1B and the subsequent development of chronic inflammatory conditions.

CMPK2 is a nucleotide kinase. Drug developers have already "successfully targeted" some of the enzymes in this group.

Prof. Karin suggests that CMPK2 blockers could reduce pain, inflammation, and tissue damage in osteoarthritis and gout, as well as slow the development of Parkinson's and Alzheimer's diseases.

"I predict that specific inhibitors of CMPK2 can be easily and rapidly developed."

Prof. Michael Karin

https://www.medicalnewstoday.com/articles/322601.php?utm_source=newsletter&utm_medium=email&utm_country=US&utm_hcp=no&utm_campaign=MNT%20Daily%20Full%20%28non-HCP%20US%29%20-%20OLD%20STYLE%202018-07-27&utm_term=MNT%20Daily%20News%20%28non-HCP%20US%29 

Live Broadcast of Davis Phinney Foundation Victory Summit

HOPE Parkinson's Program

Live Broadcast of Victory Summit

Friday, August 10, 2018 from 1-5 pm

Join us for a group viewing of the first ever, Live Broadcast Davis Phinney Foundation “Victory Summit®” 

We'll view the broadcast from the Cape Coral Community Room at 2430 Diplomat Pkwy. E, Cape Coral, FL 33909.

There is no cost for Hope Parkinson Program members to attend. Seating is limited; please reserve your seat today. Light refreshments will be available.

What is a “Victory Summit®”? 

This national educational event is a moving day of information and inspiration, featuring dynamic presentations from leading movement disorder neurologists and therapists across the country. It’s an upbeat, fast-paced event of community and connection, filled with laughter and conversation. You will leave feeling motivated and armed with tools to help you be more involved in your own treatment and to improve your quality of life. As one attendee said, “I left this event with the knowledge and hope of how to live well with my Parkinson’s.” 

If you are unable to attend our live viewing session, you can register to view the event online: 

https://www.davisphinneyfoundation.org/events/live-broadcast

9470 HealthPark Circle | Fort Myers, FL 33908

(800) 835-1673 | email@hopehcs.org

8 or More Years of Contact Sports Linked to Parkinson’s-like Symptoms in Study

JULY 27, 2018 lBY IQRA MUMAL 

Athletes playing contact sports for longer than eight years are six times more likely to develop Lewy body disease — a neurodegenerative disorder causing Parkinson’s-like symptoms — compared to those playing football, ice hockey or boxing for fewer years, a study reports.

Its authors suggest that years of continual injury to the brain, rather than those causing concussions, might be a determining factor.

The study, “Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports,” was published in the Journal of Neuropathology & Experimental Neurology.

Mild traumatic brain injuries (TBI), like concussions, that occur during contact sports are a growing health concern.

Playing contact sports for multiple years — regardless of concussion history — is already associated with brain imaging abnormalities. Consequently, players are considered to be at an increased risk of developing neurodegenerative diseases such as chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis, Parkinson’s, and parkinsonism.

CTE develops as a result of repetitive head impacts, mainly through contact sports, and is characterized by abnormal changes in behavioral, mood, and cognitive and motor skills.

A 2016 study found an association between TBIs resulting in a loss of consciousness in people under age 25 and an increased risk of Lewy bodies — which correspond to aggregates of α-synuclein — in the brain.

Deposits of α-synuclein, called Lewy body disease (LBD), is associated with cognitive and motor abnormalities, and linked to later possible dementia and Parkinson’s disease.

Both trauma and CTE are also known to influence α-synuclein deposition in the brain, which can explain the motor symptoms sometimes found in athletes with chronic traumatic encephalopathy.

Researchers with Boston institutes examined whether contact sports and CTE are also linked with Lewy body disease. They assessed the presence and distribution of Lewy bodies in the brains of 269 deceased contact sports athletes (professional or amateur), 164 brain donations representing the community, and 261 from brain bank at the Boston University Alzheimer Disease Center.

The athletes had participated in sports that included American and European football, ice hockey, boxing, rugby, and the martial arts.

Contrary to what researchers expected, the regional distribution of Lewy bodies in the brains of CTE patients was similar to that seen in those with LBD.

Contact sports athletes were 1.3-fold more likely to develop neocortical LBD for each year they played. Neocortical LBD refers to deposition of Lewy bodies in the brain’s neocortex, the area responsible for such higher-order functions as cognition and motor commands.

A pooled analysis also showed that people who played contacts sports for more than eight years were the most likely to develop of neocortical LBD.

In fact, athletes in contact sports  for more than eight years were 6.24-fold more likely to develop neocortical LBD compared to those playing in them for eight or fewer years, even after adjusting for possible confounding factors.

“The number of years of play of contact sports, not concussion history, best predicts CTE stage and the severity of tau pathology in the frontal cortex,” the study states.

Researchers also found that the presence of neocortical LBD, CTE stage, and Alzheimer’s disease were all significantly associated with dementia.

But parkinsonism (a Parkinson’s-like movement disorder) was associated only with neocortical LBD –  suggesting that Lewy body disease is likely responsible for the motor symptoms seen in CTE patients.

“We found the number of years an individual was exposed to contact sports, including football, ice hockey, and boxing, was associated with the development of neocortical LBD, and LBD, in turn, was associated with parkinsonism and dementia,” Thor Stein, MD, PhD, a study author, neuropathologist at VA Boston Healthcare System and assistant professor at Boston University School of Medicine (BUSM), said in a press release.

https://parkinsonsnewstoday.com/2018/07/27/8-or-more-years-of-contact-sports-linked-to-parkinsons-like-symptoms-in-study/

Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds

JULY 27, 2018 BY JOANA CARVALHO 

The LRRK2 gene may play an important role in nonhereditary Parkinson’s disease, not just the familial form as previously thought, researchers at the University of Pittsburgh School of Medicine​ have discovered.

“This discovery is extremely consequential for Parkinson’s disease because it suggests that therapies currently being developed for a small group of patients may benefit everybody with the disease,” J. Timothy Greenamyre, MD, PhD, the study’s senior author, said in a press release. Greenamyre is the Love Family Professor of Neurology at Pitt’s School of Medicine, chief of the movement disorders division at the University of Pittsburgh Medical Center, and director of the Pittsburgh Institute for Neurodegenerative Diseases.

These new findings were reported in the study, “LRRK2 activation in idiopathic Parkinson’s disease,” published in Science Translational Medicine.

Parkinson’s disease is a chronic and progressive neurodegenerative condition caused by the loss of dopamine-producing neurons in the substantia nigra, a brain region involved in the control of voluntary movements. It is estimated to affect 1 million people in the U.S. and up to 10 million worldwide.

There are two basic types of Parkinson’s: the familial hereditary form of the disease, which is associated with genetic mutations that make individuals more prone to develop Parkinson’s; and the idiopathic nonhereditary form of the disease, where the causes are unknown.

Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the function of many others — that cause an overactivation of the protein have been associated with the familial form of Parkinson’s.

However, researchers still do not know if the normal, nonmutated LRRK2 gene could also play a role in the idiopathic form of the disease.

To answer this, investigators set out to analyze the activity of LRRK2 in postmortem brain samples from patients with idiopathic Parkinson’s, who did not have genetic mutations in LRRK2, and healthy individuals from the same age group used as controls.

But studying LRRK2 is difficult because its levels in the brains of Parkinson’s patients are extremely low and hard to detect.

To overcome this, Greenamyre’s team took advantage of a technique called proximity ligation assay, which works by attaching special fluorescent molecules to LRRK2 that glow red when the protein is active, allowing researchers to spot them under a microscope.

Investigators found that LRRK2 activity was increased in dopamine-producing neurons from the substantia nigra of patients with idiopathic Parkinson’s, in comparison with healthy controls.

Interestingly, they observed the same trend in two different rat models of the disease, suggesting that LRRK2 overactivity seems to be important not only for patients with genetic mutations in LRRK2, but also for other individuals with the idiopathic form of the disease.

They then found that LRRK2 activity is linked to alpha-synuclein — a protein that accumulates inside nerve cells, producing small structures called Lewy bodies — that is considered a hallmark of Parkinson’s disease.

Using an animal model of Parkinson’s, they discovered that LRRK2 activation actually blocks the mechanism cells use to clear excessive alpha-synuclein, eventually leading to an abnormal buildup of the protein inside nerve cells.

Researchers then treated these animals with an investigational treatment intended for patients with familial Parkinson’s that works by blocking LRRK2 activity. Remarkably, they observed that the therapy was able to prevent both the accumulation of alpha-synuclein and the formation of Lewy bodies inside nerve cells.

These findings show that, regardless of genetic mutations, the LRKK2 gene plays a role in both types of Parkinson’s disease, indicating that LRRK2 inhibitors may be useful to treat patients with the idiopathic or familial form of the disease.

“We believe that LRRK2 inhibitors may be beneficial not only for the 3 to 4% of people with [Parkinson’s disease] who carry LRRK2 mutations but also for [idiopathic Parkinson’s disease] patients who do not carry LRRK2 mutations,” the authors wrote in the study.

In the future, Greenamyre’s team aims to investigate how LRRK2 overactivity can be prevented, as well as determining the underlying mechanisms that cause its activation in Parkinson’s patients.

https://parkinsonsnewstoday.com/2018/07/27/therapies-targeting-lrrk2-may-benefit-most-parkinsons-patients-study/

Key to Effective Parkinson’s Treatment May Lie in Stem Cells, Researchers Say

JULY 26, 2018 BY JOANA CARVALHO 

One of the most promising therapeutic avenues for Parkinson’s disease is the use of stem cells to replace dopamine-producing neurons, the loss of which is a hallmark of the disease.

This is the focus of a special issue on Parkinson’s disease published in the journal Stem Cells and Development available for free download until Aug. 24.

“The understandable excitement generated by recent successful phase 1 clinical trials in the treatment of Parkinson’s disease (PD) is tempered with worldwide concern for the safe translation of stem cell research to an effective treatment for this terrible disease and other neurological conditions,” Graham C. Parker, PhD, editor-in-chief of the journal, said in a press release. “The research in this special issue reflects the responsible advancement of cell therapy for PD.”

Parkinson’s disease is a chronic and progressive neurodegenerative disorder, caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

Current standard therapies for Parkinson’s disease often focus on restoring dopamine signaling in the brain to reduce the severity of symptoms and improve patients’ quality of life. However, these treatments do not cure the disease.

The most promising therapeutic approach to truly reverse Parkinson’s progression involves replacing these dopamine-producing neurons that have been lost over the course of the disease. Two articles in the special issue explore this new route, pointing out its advantages and practical challenges.

The first article, “Autologous Induced Pluripotent Stem Cell-Derived Neurons to Treat Parkinson’s Disease,” written by Jeanne F. Loring, PhD, from the Scripps Research Institute in California, discusses the use of patient-derived induced pluripotent stem cells (iPSCs) to treat Parkinson’s disease, and upcoming clinical trials to test this method.

These iPSCs are fully matured cells that researchers are able to reprogram in vitro to revert them back to a stem cell state, where they are able to grow into any type of cell, including dopaminergic neurons.

“It is a personalized therapy, in which we generate iPSCs from each patient and will transplant immunologically matched neurons. This means that there are no costs or potential side effects from giving the patients immunosuppressive drugs,” Loring wrote.

The biggest downside to this technology is its cost, which is still fairly high, but Loring says the economic burden would not be higher in comparison with other personalized cell therapies, such as CAR-T cell therapies — priced at roughly $500,000.

“We hope to begin a clinical trial by the end of next year, 2019, and our current efforts are focused on producing data for regulatory agencies that will assure them of the safety and efficacy of the autologous [patient-specific] dopamine neurons. If we are successful, the restoration of health to people living with PD will be priceless,” she said.

The second article, “Novel Approach to Stem Cell Therapy in Parkinson’s Disease,” written by Russell Kern, PhD, of the International Stem Cell Corporation in California, and colleagues, focuses on an alternative approach to stem cell therapy.

Instead of using iPSCs to generate patient-specific neurons, they propose using parthenogenetic-derived neural stem cells — stem cells obtained by chemical manipulations in unfertilized human oocytes, an immature egg cell, which are also able to grow into neurons.

The major advantages of this approach include avoiding ethical concerns since no fetus or viable embryo is used in their derivation (which is also the case with iPSCs), the reduced number of possible mutations in comparison with iPSCs, and also their low immunogenicity, which is the ability of a particular substance to trigger an immune response.

The authors are confident this alternative technique will be beneficial for the treatment of Parkinson’s patients, pointing to promising evidence in preclinical studies that supported a first human Phase 1 clinical trial (NCT02452723) evaluating the safety of a pluripotent stem cell-based treatment in Parkinson’s patients already underway.

“Our therapeutic approach is not only based on cell replacement but also on neuroprotection, neurotrophic support, and immunomodulation and has the potential to rescue the nigrostriatal and extranigral [dopaminergic] systems and significantly improve motor and cognitive functions, as well as quality of life, offering hope to patients worldwide suffering from this devastating disease,” they wrote.

https://parkinsonsnewstoday.com/2018/07/26/stem-cells-promising-parkinsons-therapy-special-issue/

Beat It! Learning to Walk to Music Reduces Falls for Parkinson’s Patients

JULY 26, 2018 BY ASHRAF MALHAS, PHD 

A training program in which patients walk while listening to regular beats can improve the velocity and cadence of Parkinson’s disease patients, while reducing their risk of falling, a study shows.

The study, “Rhythmic auditory stimulation for reduction of falls in Parkinson’s disease: a randomized controlled study,” was published in the journal Clinical Rehabilitation.

Parkinson’s disease patients experience difficulties in movement that affect their ability to produce a steady gait, resulting in a high incidence of falls. More than half of all Parkinson’s patients fall recurrently.

While there are several training techniques to aid in maintaining a steady gait and avoiding falls, studies suggest that gait motor control is dependent on a patient’s internal timing and that rhythm-based training could reduce risk of falling.

The rhythmic auditory stimulation (RAS) technique is among the approaches used to synchronize gait movements with time cues. But there have been no studies assessing the benefits of RAS in Parkinson’s patients.

So, researchers in Canada set out to determine if a home-based RAS program could aid in decreasing falls in patients with that history.

The study was a randomized, controlled trial (NCT03316365) that involved 60 Parkinson’s patients, 47 of whom completed the study.

The RAS training protocol involved 30 minutes of daily walking using “click-embedded music,” which was designed to enhance rhythm perception. Essentially, patients listened to folk or classical music with embedded metronome beats while performing their walking exercises.

Participants were divided into two groups, experimental and control. Both groups received RAS training up to week 8, after which the control group stopped training and the experimental group continued. Then  training was resumed for the control group between weeks 16 and 24. Patients in the experimental group received RAS training for the entire 24 weeks.

Participants were assessed at the beginning of the study and at eight, 16, and 24 weeks following that. Assessment criteria included stride length, speed, balance, and falls.

As expected, no significant differences were seen between the two groups at week eight. However, at week 16, the experimental group showed significant improvement in velocity, cadence, stride length, decreased number of falls, and fear of falling compared to the control group.

At week 24 — after the control group had resumed RAS training — the signifiant differences in velocity, cadence, stride length, and fear of falling remained, but there were no longer significant differences in the number of falls.

Taken together, the findings indicate that “RAS gait training significantly reduced the number of falls and modified key [parameters] in gait control in patients with Parkinson’s disease,” researchers wrote.

“This clinical investigation demonstrates that RAS gait training is a potential intervention to reduce the risk of falling, since it directly addresses temporal instability, which is one of the most detrimental variables associated with falls,” they concluded.

https://parkinsonsnewstoday.com/2018/07/26/beat-learning-walk-music-reduces-falls-parkinsons-patients/

Retinal Thickness Reduced in Ipsilateral Eye in Parkinson Disease

 Neurology Advisor Contributing Writer    July 27, 2018

The superior peripapillary retinal nerve fiber layer was significantly thinner in the ipsilateral eye to the most-affected body side of the patients with Parkinson disease.

According to a study published in Parkinsonism & Related Disorders, thinning of the peripapillary retinal nerve fiber layer was revealed in the ipsilateral eye (to the body side most affected by bradykinesia) in patients with Parkinson disease, indicating the potential involvement of retinal processes in the disease mechanism.

This study sought to evaluate retinal neurodegeneration in Parkinson disease and glaucoma by comparing the thickness of the macular ganglion cell complex and the peripapillary retinal nerve fiber layer. The study sample included 146 eyes from 130 patients similar in age; participants were grouped according to a glaucoma diagnosis (60 eyes of 60 patients), Parkinson disease (46 eyes of 30 patients), and healthy control (40 eyes of 40 patients). 

Patients underwent standard ophthalmic examinations, and optical coherence tomography was used to image and segment the inner retinal layers, measuring the thickness of the macular ganglion cell complex and the peripapillary retinal nerve fiber layer. 

Correlation analyses were then performed on the ganglion and peripapillary measurements. Further relationships were evaluated between disease duration, dopamine dose, olfactory testing, and retinal thickness. Glaucoma patients additionally had their intraocular pressure tested.

Both eyes of patients with Parkinson disease compared with the healthy controls showed no significant differences in the overall macular ganglion cell complex; however, in patients with Parkinson disease, the retinal thickness of the ipsilateral eye to the most-affected body side with bradykinesia was significantly thinner than in the healthy controls. In all groups, the thickness of the macular ganglion cell complex and peripapillary retinal nerve fiber layer were highly correlated. Disease severity did not significantly affect the macular ganglion cell complex or the peripapillary retinal nerve fiber layer, nor was there a correlation between disease duration, dopamine dose, olfactory testing, and optical coherence tomography.

Limitations of the study included a small sample size, meaning the differences in retinal thickness between patients with Parkinson disease and control groups did not reach statistical significance. Disease duration of patients with Parkinson disease ranged from 1 to 27 years, which may have also contributed to differences in retinal thickness.

The study authors indicated that macular and peripapillary inner retinal layers were not proven as diagnostic biomarkers for predicting neurodegeneration in Parkinson disease. However, the thinning of the peripapillary retinal nerve fiber layer reported in the superior sector of the ipsilateral eye to the body side most affected by Parkinson disease was notable. A larger, more homogenous cohort is needed to detect the effects of retinal thinning over time and the retina's relationship to Parkinson disease.

Reference

Matlach J, Wagner M, Malzahn U, et al. Retinal changes in Parkinson's disease and glaucoma [published online June 21, 2018]. Parkinsonism & Relat Disord. doi: 10.1016/j.parkreldis.2018.06.016

https://www.neurologyadvisor.com/movement-disorders-advisor/parkinson-disease-glaucoma-retinal-changes/article/783427/

New Alzheimer’s Drug Slows Memory Loss in Early Trial Results

July 25, 2018

The new drug slowed cognitive decline and reduced amyloid plaques, shown lower right in a colored light micrograph of an Alzheimer’s patient.Simon Fraser/Science Source

The long, discouraging quest for a medication that works to treat Alzheimer’s reached a potentially promising milestone on Wednesday. For the first time in a large clinical trial, a drug was able to both reduce the plaques in the brains of patients and slow the progression of dementia.

More extensive trials will be needed to know if the new drug is truly effective, but if the results, presented Wednesday at the Alzheimer’s Association International Conference in Chicago, are borne out, the drug may be the first to successfully attack both the brain changes and the symptoms of Alzheimer’s.

“This trial shows you can both clear plaque and change cognition,” said Dr. Reisa Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston, who was not involved in the study. “I don’t know that we’ve hit a home run yet. It’s important not to over-conclude on the data. But as a proof of concept, I feel like this is very encouraging.”

Aside from a couple of medications that can slow memory decline for a few months, there is no effective treatment for Alzheimer’s, which affects about 44 million people worldwide, including 5.5 million Americans. It is estimated that those numbers will triple by 2050.

The trial involved 856 patients from the United States, Europe and Japan with early symptoms of cognitive decline. They were diagnosed with either mild cognitive impairment or mild Alzheimer’s dementia, and all had significant accumulations of the amyloid protein that clumps into plaques in people with the disease, said Dr. Lynn Kramer, chief medical officer of Eisai, a Japan-based company that developed the drug, known as BAN2401, along with Biogen, based in Cambridge, Mass.

Many other drugs have managed to reduce amyloid levels but they did not ease memory decline or other cognitive difficulties. In the data presented Wednesday, the highest of the five doses of the new drug — an injection every two weeks of 10 milligrams per kilogram of a patient’s weight — both reduced amyloid levels and slowed cognitive decline when compared to patients who received placebo.

Of the 161 patients in the group taking the highest dose, 81 percent showed such significant drops in amyloid levels that they “converted from amyloid positive to amyloid negative,” Dr. Kramer said in an interview, meaning that the patients’ amyloid levels dropped from being considered high enough to correlate to dementia to a level below that dementia threshold.

And on a battery of cognitive and functional tests measuring memory and skills like planning and reasoning, the performance of the high-dose group declined at a rate that was 30 percent slower than the rate of decline in the placebo group.

Dr. Sperling, who briefly advised Eisai last year on a different drug, called the reductions in amyloid “dramatic,” but said the cognitive results were less momentous. Still, she said, “If you could really slow decline by 30 percent for people who are still normal or very mildly impaired, that would be clinically important.”

Dr. Samuel Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center, said that for the drug to really be effective, it would have to allow patients to function longer independently without needing caregivers to help them with basic daily activities. That kind of practical application was not reflected in the data presented Wednesday.

“I wouldn’t say this is a quantum leap,” he said. “It is a convincing moving of the needle. But it’s not clear that the needle has moved far enough to make a difference in people’s lives.”

Dr. Kramer said the results were statistically significant 18 months after patients began taking the drug, but improvement began to be noticed after about six months. The 253 patients in the group receiving the second-highest dose also had amyloid and cognitive results that followed a similar trend.

In December 2017, the companies reported that a statistical analysis of the trial at the 12-month mark projected that the drug would not result in a statistically significant slowing of dementia. That meant that the trial did not meet its primary benchmark, which caused some experts and investors to voice skepticism about the drug. The 18-month results allayed some of that skepticism, although the Alzheimer’s Association issued a statement expressing caution and saying the results were “not large enough to definitely demonstrate cognitive efficacy.”

The results came from a Phase 2 trial, which measures both the safety and the efficacy of a drug, but is typically considered an intermediate step to larger and more extensive Phase 3 trials. Other drugs have shown promise in Phase 2, only to disappoint in Phase 3.

In this trial, patients were randomized into six groups, with 247 patients receiving placebo injections while the other five groups received varying doses of the drug.

One unusual aspect of the trial raised questions for some experts. Eisai and Biogen used a cognitive assessment they devised. Called the Alzheimer’s Disease Composite Score (Adcoms), it draws on elements from three other, more established cognitive tests.

Dr. Kramer said Adcoms was developed to compile the measures from those three tests that were sensitive enough to measure change at such an early stage of dementia. The data presented on Wednesday indicated that the patients also showed positive results on two of the three established tests, when those were looked at separately.

Some potential Alzheimer’s treatments have resulted in serious side effects that may cause dangerous swelling or bleeding in the brain. Fewer than 10 percent of the patients taking the new drug experienced such effects, the companies reported, making it relatively safe.

The drug works by attacking the stringy amyloid tendrils that form before they begin sticking together into plaques. The results of the trial add evidence to the idea that treatment for Alzheimer’s is most likely to succeed if it starts early in the disease process, because the brain begins to deteriorate years or even decades before full-blown dementia occurs. Some other drugs have failed because they were tried on patients with more advanced Alzheimer’s; others attacked the amyloid at later points in its progression.

Even if study results continue to be positive, making the drug widely available to patients could take years. Dr. Kramer and Ivan Cheung, the chairman and chief executive of Eisai, said that the companies recently submitted a request to meet with the Food and Drug Administration to learn what steps they need to get the drug approved.

“It’s a bit premature to talk about at this point, but our goal is to bring BAN2401 to patients and families as soon as possible,” Mr. Cheung said.

The F.D.A. typically requires Phase 3 clinical trial data to demonstrate safety and effectiveness. However, the agency does have processes for expediting the review of drugs, said a spokeswoman, who declined to comment on this drug or on conditions that would be taken into consideration for an Alzheimer’s drug.

Eisai is the maker of Aricept, which is one of the few drugs that can help slow early memory decline, but which is effective for only about six to nine months. Biogen is the maker of another Alzheimer’s treatment, aducanumab, that has shown early promise in a small Phase 1 trial in both reducing amyloid and slowing cognitive decline. Many in the Alzheimer’s field are intently anticipating the outcome of two large clinical trials of aducanumab, expected to be able to report results in 2020.

Dr. Gandy said the BAN2401 results were encouraging for the prospects of aducanumab because it suggests that there are at least two compounds that may be able to attack both amyloid buildup and cognitive decline.

In early July, when the companies announced they would soon present positive results from the BAN2401 trial, the stock prices of both companies rose by about 20 percent. They have since stayed roughly at that level.

A version of this article appears in print on July 26, 2018, on Page A1 of the New York edition with the headline: Promising Alzheimer’s Drug Attacks Brain Changes and Symptoms.

https://www.nytimes.com/2018/07/25/health/alzheimers-dementia-drug-treatment.html

Qualification of first Parkinson's biomarker represents major milestone in clinical trials

 July 27, 2018

The biomarker is used to determine the presence of dopamine transport deficiency in the brain, and has been qualified as an enrichment biomarker for clinical trials targeting early stages of Parkinson's, soon after diagnosis. The qualified biomarker involves the intravenous injection of a small amount of a radioactive tracer before the brain images are acquired, and can be done at any one of many specialist imaging centers. The imaging agent binds very specifically to dopamine transporter sites on the neurons that are lost in Parkinson's disease. 

The use of this biomarker can help better identify patients that are more likely to exhibit significant progression in their motor signs and symptoms, thus helping select patients for clinical trials. The CPP consortium is a global public-private partnership consisting of industry, academics, advocacy organizations, and government agencies collaborating to develop solutions to optimize drug development for Parkinson's. 

This qualification represents a major milestone in this regard, as the first biomarker for Parkinson's to receive such a regulatory designation. In 2015, the U.S. Food and Drug Administration issued a letter of support for the use of this imaging biomarker for use in Parkinson's clinical trials.

"This endorsement from the European Medicines Agency represents many years of hard work and incredible collaboration among companies, universities, and charities facilitated by the Critical Path Institute," says Dr. Diane Stephenson, Executive Director of CPP, who led the work. "These brain scans in themselves are not new, but until now there has not been a clear consensus that they can and should be used to select participants for clinical trials. Through our global project, we've been able to bring all the data and expertise together to make a powerful case, so we're delighted that this endorsement from the EMA will improve the quality and chances of success for future trials of Parkinson's treatments. This success is just the first in a suite of new tools that we hope to deliver for Parkinson's."

Studies suggest that up to 15% of individuals taking part in clinical trials for new Parkinson's treatments may not exhibit a measurable progression in motor signs and symptoms over the course of such trials. Furthermore, the rate of uncertainty in predicting disease progression is higher at earlier stages of the condition. These individuals are extremely unlikely to benefit from the new therapies being tested, and their inclusion can affect both the trial results and, ultimately, the future of the potential treatment.

Professor David Dexter, Deputy Research Director of Parkinson's UK, which funds CPP, comments, "Scientific breakthroughs mean that there is now a new wave of exciting treatments that genuinely could slow, stop, or reverse the condition, but it's crucial that we're able to test them properly in clinical trials. Being able to rule out individuals who are unlikely to have Parkinson's could be the difference between a successful trial and failure. This is a vital step forward in our mission to deliver, as quickly as possible, better treatments, and one day a cure, to people living with Parkinson's."

Because Parkinson's is a progressive condition caused by the gradual loss of cells in the brain, the best chance to intervene with treatments that can slow, stop, or reverse damage is during the earliest stages of the condition. During these early stages, however, signs and symptoms tend to be mild, which makes selecting the right people to participate in trials very difficult.

"The use of these brain scans is already being included in new clinical trials at Biogen." said Dr. Michael Ehlers, Executive Vice President of Research and Development at Biogen. "We believe that this new approach will introduce greater efficiency in terms of cost and speed, while ensuring that the right patients are being included in our trials."

Source:

https://c-path.org/first-ever-biomarker-qualified-for-parkinsons-is-a-vital-step-toward-improved-clinical-trials/

https://www.news-medical.net/news/20180727/Qualification-of-first-Parkinsons-biomarker-represents-major-milestone-in-clinical-trials.aspx