Monday, April 17, 2017

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

My updates on  nilotinib


Nilotinib2DACS.svg

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

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

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

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

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

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



•The level of the Parkinson's related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and
•The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.

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

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

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

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

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



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

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

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

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

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

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

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



Friday, April 14, 2017

New research shows how cholesterol medicine has beneficial effect on immune defence system

In continuation of my update on simvastatin,  

Simvastatin.svg

The cholesterol medicine simvastatin, which is one of the most commonly used pharmaceuticals in the world, also has a beneficial effect on the immune defence system with regard to diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Danish researchers have now explored why this is so, and their findings may result in improved treatment.

New research from Aarhus University has demonstrated how simvastatin, one of the most commonly used medicines in the world - typically prescribed to reduce cholesterol - also has a direct effect on the immune defence system. This discovery opens up new opportunities for treating chronic inflammatory diseases.

Sought-after explanation of unexpected effect

The immune defence system, which normally protects the body against infections and foreign bodies, sometimes attacks the body's own tissue. This error in the immune system - whose cause is unknown - results in a chronic state of inflammation which breaks down the tissue. This, in turn, triggers diseases such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes.

In the case of multiple sclerosis, the immune defence system destroys the central nervous system, while the inflammation affects the kidneys, eyes and sense of touch in both type 1 and type 2 diabetes, leading to a variety of complications. However, simvastatin has been shown to reduce the level of inflammation in these diseases, even though it sometimes has to be administered in high concentrations to have any effect. The reason why it does so has eluded researchers thus far.

"Simvastatin - and statins in general - are not designed to have this effect. We have now identified a new mechanism that forms the basis for the effect, and this opens up new opportunities for developing a better substance to combat these inflammatory diseases. It's an interesting line to pursue because a great many people can take statins without significant side effects," relates Thomas Vorup-Jensen, Professor at the Department of Biomedicine at Aarhus University.

The reason for the positive effect is that the pharmaceutical acts as a 'plug' in the proteins that retain the immune cells in the inflammation zones. With the plug in place, the immune cells can no longer contribute to the inflammation, which is therefore reduced, leaving the patient feeling better. In the case of diabetes, for example, it can help reduce the risk of patients developing complications.

"We initially observed this mechanism in the laboratory. Of course, we now need to establish whether it works in the same way in vivo, but we think it's likely," says Thomas Vorup-Jensen.

Tuesday, April 11, 2017

FDA approves new topical retinoid gel for OTC treatment of acne

The U.S. Food and Drug Administration today approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. Differin Gel 0.1% is approved for use in people 12 years of age and older.


Adapalene structure.svg
Differin Gel 0.1% is the first in a class of drugs known as retinoids to be made available OTC for the treatment of acne, and contains the first new active ingredient for acne treatment for OTC use since the 1980s. Differin Gel 0.1% was originally approved in 1996 as a prescription product for the treatment of acne vulgaris in patients 12 years of age and older.

"Millions of consumers, from adolescents to adults, suffer from acne," said Lesley Furlong, M.D., deputy director of the Office of New Drugs IV in the FDA's Center for Drug Evaluation and Research. "Now, consumers have access to a new safe and effective over-the-counter option."

Acne is a common skin disease that affects approximately 50 million people in the United States. Acne pimples form when hair follicles of the skin clog up. Generally, pimples form on the face, neck, back, chest and shoulders. Anyone can get acne, but it is most common in teenagers and young adults. Acne can cause scarring and have adverse psychological effects (for example, poor self-image, depression and anxiety). Several OTC and prescription treatment options are available for people with acne.

Women who are pregnant, planning to become pregnant, or breast-feeding should ask a doctor before use. While topical retinoid products are often prescribed as first-line therapies for acne of all levels of severity, either alone or in combination with other treatments, Differin Gel 0.1% is the first retinoid acne treatment to be made available OTC. While there have been no adequate and well-controlled studies of Differin Gel 0.1% in pregnant women, there is no specific evidence that Differin Gel 0.1%, when used topically as directed, causes birth defects in humans. Some other retinoid drugs have been shown to cause birth defects.

Differin Gel's safety and efficacy were initially established based on five clinical trials in people with mild to moderate acne. To support approval for OTC marketing, the data accrued from 1996-2016 on post-marketing safety, data from consumer studies (a label comprehension study, a self-selection study, and an actual use trial), and data from a maximal use trial were submitted.

Overall, results from the consumer studies showed that consumers can understand the information on the OTC label, appropriately select whether the product is right for them, and use the product appropriately. The maximal use trial, a study of absorption of the drug through acne-affected skin when applied daily over a large surface area (face, shoulders, upper back and chest), demonstrated that absorption is limited, thus supporting safe use of Differin Gel 0.1% by people using it OTC.

Consumers should follow the Drug Facts label and consult with their health care providers if their symptoms do not improve. The drug should be applied once daily in a thin layer on the affected areas of skin, and it is for external use only. Differin Gel 0.1% should not be used on damaged skin (for example, cuts, abrasions, eczema, or sunburn). People using Differin Gel 0.1% should avoid sunburn and avoid product contact with their eyes, lips and mouth. Differin Gel 0.1% should not be used by people who are allergic to the product. In the first few weeks of use, skin may become irritated (redness, itching, dryness, burning). Consumers should stop use and ask a doctor if irritation becomes severe, if there is no improvement in acne after three months of daily use, if symptoms of allergic reaction appear, or if they become pregnant or are planning to become pregnant while using the drug.

Monday, April 10, 2017

Transplant drug rapamycin may reduce nerve damage, neuropathic pain after spinal cord injury

In continuation of my update on rapamycin

New research in mice indicates that a drug commonly used to suppress the immune system in recipients of organ transplants may also reduce tissue damage and neuropathic pain after spinal cord injury. The findings are published in the Journal of Orthopaedic Research.
Sirolimus.svg   rapamycin

Rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, has a variety of cellular functions and is known to possess both immunosuppressant and anti-tumor properties. In their previous work, investigators at the Tohoku University Graduate School of Medicine in Japan found that rapamycin treatment can reduce nerve damage and locomotor impairment after spinal cord injury. In this latest study, the team examined whether rapamycin also reduces neuropathic pain, a state of chronic pain resulting from injury to the nervous system.

Using a mouse model of thoracic spinal cord contusion injury, the researchers divided the mice into rapamycin-treated and control groups. Rapamycin treatment four hours after spinal cord injury significantly improved locomotor function and reduced mechanical and thermal hypersensitivity in the hindpaws. Close examination of the mechanisms involved revealed that treatment decreased the activity of various pathways involved in pain.

If the findings hold true in humans, rapamycin could provide considerable benefits to spinal cord injury patients, up to 80 percent of whom experience clinically significant pain that is described as burning, stabbing, and electric shock-like. "Further studies to clarify the impact and full effects of mTOR signaling are needed in order to support the clinical use of mTOR inhibitors in patients with spinal cord injury," the authors wrote.

Friday, April 7, 2017

FDA approves new topical retinoid gel for OTC treatment of acne

The U.S. Food and Drug Administration today approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. Differin Gel 0.1% is approved for use in people 12 years of age and older.


Adapalene structure.svg
Differin Gel 0.1% is the first in a class of drugs known as retinoids to be made available OTC for the treatment of acne, and contains the first new active ingredient for acne treatment for OTC use since the 1980s. Differin Gel 0.1% was originally approved in 1996 as a prescription product for the treatment of acne vulgaris in patients 12 years of age and older.

"Millions of consumers, from adolescents to adults, suffer from acne," said Lesley Furlong, M.D., deputy director of the Office of New Drugs IV in the FDA's Center for Drug Evaluation and Research. "Now, consumers have access to a new safe and effective over-the-counter option."

Acne is a common skin disease that affects approximately 50 million people in the United States. Acne pimples form when hair follicles of the skin clog up. Generally, pimples form on the face, neck, back, chest and shoulders. Anyone can get acne, but it is most common in teenagers and young adults. Acne can cause scarring and have adverse psychological effects (for example, poor self-image, depression and anxiety). Several OTC and prescription treatment options are available for people with acne.

Women who are pregnant, planning to become pregnant, or breast-feeding should ask a doctor before use. While topical retinoid products are often prescribed as first-line therapies for acne of all levels of severity, either alone or in combination with other treatments, Differin Gel 0.1% is the first retinoid acne treatment to be made available OTC. While there have been no adequate and well-controlled studies of Differin Gel 0.1% in pregnant women, there is no specific evidence that Differin Gel 0.1%, when used topically as directed, causes birth defects in humans. Some other retinoid drugs have been shown to cause birth defects.

Differin Gel's safety and efficacy were initially established based on five clinical trials in people with mild to moderate acne. To support approval for OTC marketing, the data accrued from 1996-2016 on post-marketing safety, data from consumer studies (a label comprehension study, a self-selection study, and an actual use trial), and data from a maximal use trial were submitted.

Overall, results from the consumer studies showed that consumers can understand the information on the OTC label, appropriately select whether the product is right for them, and use the product appropriately. The maximal use trial, a study of absorption of the drug through acne-affected skin when applied daily over a large surface area (face, shoulders, upper back and chest), demonstrated that absorption is limited, thus supporting safe use of Differin Gel 0.1% by people using it OTC.

Consumers should follow the Drug Facts label and consult with their health care providers if their symptoms do not improve. The drug should be applied once daily in a thin layer on the affected areas of skin, and it is for external use only. Differin Gel 0.1% should not be used on damaged skin (for example, cuts, abrasions, eczema, or sunburn). People using Differin Gel 0.1% should avoid sunburn and avoid product contact with their eyes, lips and mouth. Differin Gel 0.1% should not be used by people who are allergic to the product. In the first few weeks of use, skin may become irritated (redness, itching, dryness, burning). Consumers should stop use and ask a doctor if irritation becomes severe, if there is no improvement in acne after three months of daily use, if symptoms of allergic reaction appear, or if they become pregnant or are planning to become pregnant while using the drug.

Thursday, April 6, 2017

Ticagrelor drug shows minor added benefit for patients with history of myocardial infarction

Ticagrelor.svg


The German Institute for Quality and Efficiency in Health Care (IQWiG) assessed the added benefit of ticagrelor for patients with acute coronary syndrome already in 2011 in its very first dossier assessment, just after the Act on the Reform of the Market for Medicinal Products (AMNOG) had come into force. It was shown then that the drug provided considerable added benefit to patients with mild myocardial infarction without the typical changes in the ECG or with unstable angina pectoris. There was no corresponding proof for severe myocardial infarction.

The approval has now been expanded: Ticagrelor is approved for co-administration with low-dose acetylsalicylic acid (ASA) for prevention of atherothrombotic events after an initial one-year treatment also in specific patients whose myocardial infarction occurred at least one year ago. IQWiG investigated whether the drug has advantages in comparison with the appropriate comparator therapy also for this therapeutic indication. According to the findings, there is an indication of an added benefit with the extent "minor".

Myocardial infarction must have occurred one to three years ago

The expansion of approval applies to adults with a high risk of developing another atherothrombotic event whose myocardial infarction occurred one to three years ago. Risk factors are the following: age of at least 65 years, diabetes mellitus requiring medication, more than one previous myocardial infarction, multivessel coronary heart disease, or chronic renal impairment.

Ticagrelor at a dose of 60 mg is co-administered with ASA for prevention, whereas dosage of the initial treatment (myocardial infarction less than one year ago) is 90 mg. The Federal Joint Committee (G-BA) specified ASA monotherapy under continued basic therapy of the myocardial infarction and measures to achieve an adequate lifestyle as appropriate comparator therapy.


Benefit assessment on the basis of the PEGASUS study

The assessment was conducted based on the three-arm randomized study PEGASUS-TIMI 54. All patients received unblinded ASA as basic therapy and, blinded, ticagrelor in dosages of 60 mg or 90 mg or placebo. Data from the 60 mg arm and the placebo arm were compared for the benefit assessment. About three quarters of these patients complied with the approval, thus constituting the subpopulation relevant for the assessment.

Advantages in mortality and morbidity, but also disadvantages

An indication of an added benefit of the combination in comparison with ASA monotherapy was shown in all-cause mortality. There were also indications of an added benefit in the morbidity outcomes "cardiovascular mortality, nonfatal myocardial infarction and nonfatal stroke" as well as "myocardial infarction".

Data on health-related quality of life were not recorded in the study. In the outcome category of side effects, there was an indication of greater harm from ticagrelor regarding both discontinuation due to adverse events (including bleeding) and severe bleeding, and proof of greater harm from ticagrelor regarding dyspnoea.

These disadvantages did not completely outweigh the advantages, particularly in all-cause mortality. In summary, there is an indication of a minor added benefit of ticagrelor in combination with ASA in comparison with ASA monotherapy for the prevention of atherothrombotic events in patients at risk and a history of myocardial infarction.

Inhalable ibuprofen holds potential to treat cystic fibrosis

Ibuprofen2DCSD.svg

In continuation of my update on Ibuprofen 

Ibuprofen: You can buy it at any drug store, and it will help with that stabbing headache or sprained ankle. One of the ways it does so is by reducing inflammation, and it is this property that may also help patients with cystic fibrosis.

Research has found that ibuprofen, when taken at high doses, helps slow the progression of lung function decline in people with cystic fibrosis, a disease caused by having two 'bad' copies of a gene that codes for a protein important in fluid secretion. Improved lung function is important, given that most people diagnosed die by their early 50s, usually due to chronic lung infections caused by their inability to move particles, including bacteria, up and out of the lungs. The downside is that ibuprofen doses that high, when taken routinely, can result in gastrointestinal (GI) bleeding and—when combined with the antibiotics that these patients often have to take for their recurring lung infections—acute kidney injury.

But what if you could get the drug just to the area that needs it: the lungs? You could harness ibuprofen's benefits without the negative side effects.

Carolyn Cannon, MD, PhD, an associate professor at the Texas A&M Health Science Center College of Medicine, is working on a way to do just that.

"We feel that nanoparticle ibuprofen delivered by aerosol to the lungs would be a fantastic therapeutic," Cannon said. And because it is essentially a repurposed drug—only the delivery method is different—the development and regulatory approval process should be relatively easy, in comparison to the requirements for a novel therapeutic.

"The researchers who performed the original ibuprofen study thought it was working solely by inhibiting the migration of a type of white blood cell, called the neutrophil, to the lung. It goes hand-in-hand with acute inflammation," Cannon said. "However, although this may be one mechanism of action, at the high doses that were being given to the cystic fibrosis patients, the drug also has antimicrobial properties."

The inhaled ibuprofen would work in conjunction with the antibiotics the patient is already being given for the underlying infection. "We determined that not only does ibuprofen act as an antimicrobial itself, it is also synergistic with the antibiotics we already give to these patients," Cannon said.


"Together, they kill the pathogens much better than either one does alone and we could get the same great effects of the high concentrations of ibuprofen without the side effects."
Cannon and her team are pursuing international patent protection on this technology and, in the next year or so, hope to begin discussions with the Food and Drug Administration (FDA) about working towards receiving Investigational New Drug (IND) status to allow for future clinical trials.
"We have several nanoparticle formulations, one of which, developed by our collaborator, Dr. Hugh Smyth at the University of Texas in Austin, is almost pure ibuprofen," Cannon said. "We are excited about this formulation, but we still have to prove that it achieves our goal of high lung concentrations of the drug and low systemic concentrations."

To test this, this summer Cannon and Smyth and their teams plan to deliver the ibuprofen nanoparticles to the lungs of animal models and measure the drug concentrations in the lungs and serum at different time points. "This type of experiment addresses the pharmacokinetics of the drug and aims to investigate our hypothesis that we can achieve high local concentrations in the lung while maintaining low systemic concentrations," Cannon said. She and her collaborators will also investigate the capacity of the ibuprofen nanoparticles to improve pneumonia survival rates in animal models.

"The staff in the Office of Technology Translation at the Health Science Center have been wonderful through the whole process," Cannon said. "They have served as advocates for our projects with the Texas A&M Technology Commercialization (TTC) team, which has helped actualize our vision to move our inventions from the lab into use by patients."

Wednesday, April 5, 2017

Diabetes drug metformin could help reduce toxic acid levels linked to MSUD

In continuation of my update on metformin 


Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine. Left untreated, infants die from a toxic buildup of resulting keto-acids within weeks of birth. Those who are diagnosed early can live a normal life, but are forced to eat a very controlled, formula-based diet. The only proven treatment for the disease, which is characterized by sweet-smelling urine, is a liver transplant. Publishing in Scientific Reports, researchers at the Buck Institute show that the widely-used diabetes drug metformin reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

Senior author and Buck faculty Arvind Ramanathan, PhD, says metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction," he said. "There is a definite need for novel interventions."

Ramanathan, who specializes in metabolomics, came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of aging. The work could provide a mechanistic explanation for metformin's success in controlling diabetes and possibly extending healthspan in both animals and humans. The research also highlights similarities between a rare pediatric disease and normal aging - and shows how studying one can inform the other.

Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal aging. Ramanathan says decreased BCKDH is implicated in obesity and diabetes; he believes it may be involved in a number of other age-related conditions as well. Ramanathan also studied an enzyme upstream of BCKDH - called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. "We think the same process may be afoot with age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle."

"This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA," said Brian Kennedy, PhD, senior co-author and Buck Institute CEO. "In this case, we hope our discovery will help those living with MUSD. We plan on building on these insights to further our research aimed at extending the healthy years of life for all of us."

Tuesday, April 4, 2017

Deutetrabenazine may help improve chorea symptoms in patients with HD




People with Huntington disease (HD) experienced improvements in chorea while taking deutetrabenazine (SD-809) compared to placebo, according to a paper published today in the Journal of the American Medical Association (JAMA). Although the topline results of the trial have been released previously, the complete peer-reviewed publication about the First-HD clinical trial is now published in a premier medical journal.

Deutetrabenazine was investigated in the First-HD study, a Phase 3 clinical trial which was led by the Huntington Study Group (HSG) on behalf of Teva Pharmaceuticals. In the double-blind, placebo-controlled trial, deutetrabenazine significantly decreased chorea, the involuntary movements that many individuals with HD experience.

"Patients' chorea and motor scores improved compared to placebo over the course of 12 weeks," said Samuel Frank, MD, HSG's principal investigator of First-HD and director of the Huntington Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center in Boston. "In addition, both the participants and their study physicians reported overall improvement."

First-HD enrolled 90 patients at 34 HSG research sites between August 2013 and August 2014. The trial followed patients for 12 weeks on the medication and measured their chorea, as well as patients' and clinicians' impression of improvement.

"As a physician who cares for people with HD, it's gratifying to see positive results from a well-designed, fully enrolled trial. Until we find a cure, we aim to bring our patients more treatment options to relieve symptoms," Frank said. "We are grateful to the people who participated in this trial and their families and support systems that made their participation possible. Research in the HD community depends on volunteers enrolling in trials."
At the end of May, Teva Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) asked for more data on deutetrabenazine, which had been under review to treat chorea associated with HD. The request for more data is common when the FDA is asked to approve new medications, and this is the first deuterated compound to be reviewed by the FDA. Michael Hayden, M.D., Ph.D., Teva's president of Global R&D and chief scientific officer said Teva plans to respond to the request in the third quarter of 2016.

There is only one drug currently approved to treat chorea associated with Huntington disease: tetrabenazine. Deutetrabenazine is structurally related to tetrabenazine with deuterium atoms placed at key positions in the molecule, prolonging plasma half-life and reducing metabolic variability, without changing target pharmacology. This can translate into effective symptom control with fewer medication doses a day, lower total daily doses, and improved tolerance. In First-HD, both patient and clinician overall assessments were significantly better in the deutetrabenazine treated group compared to placebo after 3 months. The deutetrabenazine group improved in a quality of life measure while the placebo group worsened.

"Overall status and quality of life measures are especially relevant in chorea, where no single number captures what is clinically meaningful to patients themselves," said Claudia Testa, MD, PhD, HSG's co-principal investigator for First-HD and director of the HDSA Center of Excellence at Virginia Commonwealth University. "It's exciting to see how treating an HD symptom can make a real-life positive impact."

Monday, April 3, 2017

Liraglutide drug lowers blood sugar levels in diabetic patients taking large doses of insulin

In continuation of my update on   Liraglutide

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Dr. Ildiko Lingvay, Associate Professor of Internal Medicine and Clinical Sciences at UT Southwestern Medical Center, designed the clinical trial, which looked at the effectiveness of liraglutide in patients who were taking high doses of insulin. 

"We have a growing population of obese patients who require larger and larger doses of insulin. The insulin causes them to put on more weight, which in turn means their glucose levels remain out of control. We wanted to test whether treating such patients with liraglutide would have an effect," said Dr. Lingvay.

Liraglutide, produced by Novo Nordisk, has several effects on the body: It increases insulin secretion; it reduces hunger; and it decreases glucagon secretion. Insulin and glucagon are molecules produced by the pancreas that have opposing effects, with insulin reducing blood sugar levels and glucagon increasing blood sugar levels. Insulin is secreted by beta cells in the pancreas and glucagon is secreted by alpha cells in the pancreas.

The study enrolled 71 Type 2 diabetes patients who were injecting large amounts of insulin each day, in most cases four or five shots a day. All of the patients had HbA1C levels that were 7.5 or higher (the goal for patients with diabetes is 7 or below). All of the patients were also overweight.

The patients in the study were randomly assigned to give themselves a daily injection of either a placebo or liraglutide in addition to their current therapy with a high dose of insulin. The results of the trial were clear, with the average HbA1C level of patients taking the drug dropping from 8.9 to 8, while long-term blood sugar levels were unchanged in the placebo group. The liraglutide patients also lost 4 ½ pounds on average, while the placebo group gained a small amount on average.

"This is less improvement than we normally see with liraglutide in patients who are not on insulin, but this is a huge improvement in a population that is so difficult to treat," said Dr. Lingvay.

Although the study was blinded - neither patients nor researchers knew which group a patient was assigned to - Ms. Sweat said that after a few weeks of being in the study she was sure that she had been assigned to the liraglutide group because her blood sugars were dropping dramatically.

"I thought I was doing the drug because my sugar finally went to normal," she said. "From the day I was diagnosed, my sugar was always high. After I started the study, for the first time in my life, my HbA1C went down, and I kept thinking, 'I must be taking the drug.' "

When the study ended, her physician prescribed liraglutide for her-whose attempt with other drugs were not successful."I give myself a shot every morning," the Garland woman said, adding that not only is her blood sugar level consistently better than it had been at any time before the study, but she has maintained a modest weight loss since the study began as well.

The study that Dr. Lingvay designed also looked at the mechanisms of action of liraglutide on this group of patients and the effect of the drug on the underlying disease, measuring insulin and glucagon blood levels following a meal.

The findings: Insulin production went up.

"The results were counterintuitive," said Dr. Lingvay. "One might expect that patients with such long-standing disease would have little or no residual beta-cell function and improvements would be driven through suppression of glucagon. To the contrary, we found that liraglutide exerted its hypoglycemic effect through improving insulin secretion."