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Monday, December 3, 2018

Benefits of Cannabidiol for Epilepsy Fades in One-Third of Patients


About one-third of patients who used cannabidiol (CBD) to manage treatment-resistant epilepsy developed tolerance to it, researchers from Israel reported here.
In a study of 92 children and young adults with treatment-resistant seizures who used cannabis oil extract for an average of 19.8 months, tolerance to CBD emerged in 32.6% of patients, reported Shimrit Uliel-Sibony, MD, of Tel Aviv Sourasky Medical Center’s Dana Children’s Hospital, and colleagues at the American Epilepsy Society annual meeting.
“CBD is a good option for children and adults with certain kinds of epilepsy, but as with anti-epileptic drugs, it can become less effective over time and the dose may need to be increased to manage the seizures,” Uliel-Sibony said in statement. While previous research has shown that the effectiveness of cannabinoids can decrease when it is used for pain management and in the treatment of animals with seizures, this is the first large study to show it can occur with humans who use CBD to treat epilepsy, she added.
In the U.S., the FDA has approved a purified, pharmaceutical-grade formulation of cannabidiol (Epidiolex), a chemical component of the Cannabis sativa plant, for children with Lennox-Gastaut and Dravet syndromes.
In this prospective study, Uliel-Sibony and colleagues followed patients in Tel Aviv, ages 1-37 years (average age 11.8) from 2014 to 2017 with treatment-resistant epilepsy of various etiologies, ranging from Dravet syndrome and Lennox-Gastaut syndrome to epilepsy caused by stroke. All patients subsequently had been treated with one of two strains of CBD-enriched cannabis oil extract that had a 20:1 CBD-to-tetrahydrocannabinol (THC) ratio.
The researchers defined tolerance as either the necessity to increase dose by ≥30% after efficacy declined, or a response reduction of >30%. They saw tolerance in 30 patients, on an average dose of 12.6 mg/kg/day. The mean time until tolerance appeared was 7.3 months (range 1-24 months).
The researchers increased the CBD dose in most patients who developed tolerance; 12 patients achieved their previous response level and 15 did not.
“By definition, most patients with treatment-resistant epilepsy do not enjoy long-term benefits from a new anti-seizure therapy — that is, a ‘honeymoon effect,'” said Orrin Devinsky, MD, of New York University Langone Health in New York City, who was not involved with the study.
“This study found that tolerance develops in one-third of patients with treatment-resistant epilepsies who showed an initial reduction in seizures to a high CBD/low THC product after 7 months,” Devinsky told MedPage Today. “The observation that two-thirds of patients did benefit over a long follow-up period is a key finding.”
There was no statistically significant correlation between patient’s age and tolerance, but patients with shorter epilepsy duration showed a higher tendency to develop tolerance, Uliel-Sibony’s group noted. Predictive factors and mechanisms are unknown, and long-term studies to better characterize the long-term efficacy and safety of CBD are needed, they added.
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ASH Offers Early Look at Updated Sickle Cell Disease Guidelines


The American Society of Hematology (ASH) previewed clinical guidelines on sickle cell disease (SCD) here, with the intention of releasing the full set of guidelines in 2019.
The chairs from each of the five SCD guideline panels — sickle cell disease-related transfusion support; sickle cell disease-related cardiopulmonary and kidney disease; sickle cell disease-related cerebrovascular disease; sickle cell disease-related pain; and stem cell transplantation for sickle cell disease — discussed a key recommendation from each of their panels at the ASH annual meeting.
These five SCD panels, which included more than 75 experts across the field, have formulated more than 50 recommendations on SCD. Some draft recommendations veer away from standard practice, or even address issues that haven’t been addressed in previous SCD guidelines.
For example, John F. Tisdale, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, pointed out that ASH is putting out the first set of guidelines addressing transplantation in SCD, and noted the stem cell transplantation panel’s recommendation of “transplantation at a younger age over transplantation at an older age.”
The Panel on Sickle Cell Disease-Related Pain has suggested that treatment for adults and children who require hospital care for acute pain episodes should veer “in favor of hospital-based entities (i.e., day hospitals and infusion centers, all with appropriate expertise to treat pain) over typical emergency department [ED]-based care.”
Amanda Brandow, MD, of the Medical College of Wisconsin in Milwaukee, noted that SCD may face barriers in EDs that may impact care. “So, looking at these alternative care models for acute pain management, such as day hospitals and infusion panels, was a priority to our panel,” she said.
Michael DeBaun, MD, of Vanderbilt University Children’s Hospital in Nashville, said the Panel on Sickle Cell Disease-Related Cerebrovascular Disease was committed “to maintaining cognitive function as the highest priority — and that priority was greater than being alive with minimal cognitive function.”
“All members of our panel believe very strongly that identifying silent cerebral infarcts in school-age children, and in adults with hemoglobin SS and Hemoglobin β-Thalassemia, is an important priority,” said DeBaun.
Consequently, that panel has recommended that early school-age children and adults with hemoglobin SS and hemoglobin β-thalassemia who can undergo an MRI study without sedation receive a one-time unsedated MRI to screen for silent cerebral infarcts.
On the other hand, ASH has recommended against performing routine screening echocardiograms to identify pulmonary hypertension in asymptomatic children and adults with SCD.
That recommendation is based on low quality evidence, said Sophie Lanzkron, MD, of Johns Hopkins Medicine in Baltimore. She added that it is important to make sure that people are clear on how the question of symptomatic vs asymptomatic is defined.
ASH has also recommended that new guidelines regarding blood pressure (BP) should apply to SCD as well. In 2017, the American College of Cardiology/American Heart Association updated their hypertension guidelines, which reduced blood pressure thresholds for antihypertensive therapy in high-risk adults to >130/80 mm Hg, and BP treatment goals to <130/80 mm Hg for most individuals.
“Evidence from the general population shows that intensive blood targets — initiation of therapy at blood pressure of 130/80 — resulted in decreases in cardiovascular mortality, stroke, major cardiovascular events, and heart failure,” said Lanzkron. “And the panel has no reason to believe that the SCD population would have different outcomes from the general population regarding blood pressure management.”
The Panel on Sickle Cell Disease-Related Transfusion Support looked at the question of whether patients with an acute need for transfusion, but a high risk of hemolytic transfusion reaction (HTR), should or should not undergo immunosuppressive therapy.
It suggested that immunosuppressive therapy (IVIg, steroids, and or rituximab [Rituxan]) be used “to minimize risk of a HTR in patients with SCD with an acute need for transfusion at high risk of a HTR, or with a history of multiple or life-threatening delayed HTRs.”
Robert Liem, MD, of Ann and Robert Lurie Children’s Hospital of Chicago, and chair of the ASH Sickle Cell Disease Guideline Coordination Panel, said one of the issues that complicated the formulation of many of these guidelines was the lack of quality data.
“I think the reality is we have a low level of evidence for a lot of these recommendations,” said Liem. “It doesn’t mean that we shouldn’t have tried to address these questions, because I think the way we look at these sickle cell guidelines from ASH is that it is really to look at the hard questions and challenging clinical scenarios that may or may not have been addressed by the 2014 [National Heart, Lung, and Blood Institute] guidelines.”
He explained that the panels were instructed to address questions of practice that primary care providers, hematologists, and SCD providers may have trouble with, adding that “so even in the setting of low-quality evidence, we heard loud and clear that people needed some guidance.”
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Trump Administration: Ease Scope of Practice, Certificate of Need Laws


Easing scope-of-practice laws and streamlining graduate medical education (GME) funding would make U.S. healthcare more competitive and efficient, the Trump administration said Monday.
“Reduced competition among clinicians leads to higher prices for healthcare services, and reduces choice… Government policies have reduced competition by restricting the available supply of providers and restricting the range of services they offer,” said a senior administration official, speaking on the condition of anonymity, during a call with reporters to discuss a new report called “Reforming America’s Healthcare System Through Choice and Competition.”
President Trump called for the report, issued jointly by the departments of Health and Human Services, Labor, and Treasury, in an executive order issued in October 2017; the order asked for the report to be issued “within 180 days of the date of this order, and every 2 years thereafter.”
Although scope-of-practice (SOP) laws may be justified in cases where there is substantial risk of consumer harm, “Oftentimes, too, SOP restrictions limit provider entry and ability to practice in ways that do not address demonstrable or substantial risks to consumer health and safety,” according to the report. “When this happens, these undue restrictions are likely to reduce healthcare competition and harm consumers — including patients, and taxpayers more generally.”
“For example, advanced practice registered nurses (APRNs), physician assistants (PAs), pharmacists, optometrists, and other highly trained professionals can safely and effectively provide some of the same healthcare services as physicians, in addition to providing complementary services,” the report continued. It made the following recommendations:
  • States should consider changes to their scope-of-practice statutes to allow all healthcare providers to practice at the top of their license, utilizing their full skill set.
  • The federal government and states should consider accompanying legislative and administrative proposals to allow non-physician and non-dentist providers to be paid directly for their services where evidence supports that the provider can safely and effectively provide that care.
  • States should consider eliminating requirements for rigid collaborative practice and supervision agreements between physicians and dentists and their care extenders (e.g., physician assistants, hygienists) that are not justified by legitimate health and safety concerns.
The report also addressed the role of foreign-trained physicians, saying that while efforts should be made to expand domestic medical training, “easing the licensing pathway for highly qualified, foreign-trained doctors is one step that could be taken in the short run to expand the supply of medical practitioners, and thus, constrain the price of physician services and lower overall healthcare costs for American consumers.”
Currently, “there is likely an inadequate supply of physicians in the United States,” the report noted. “Moreover, there is an uneven distribution in physician supply (both geographically and across specialties), GME training slots, and in government support for GME. Yet there is inadequate information to assess overall physician needs, and for different specialties in different geographic areas.”
To address this problem, “as requested in the FY 2019 President’s Budget, the federal government should more efficiently spend taxpayer resources by streamlining federal Health and Human Services spending on graduate medical education into a single graduate medical education grant program,” the report authors suggested. “The new grant program would be funded out of the Treasury and jointly operated by the administrators of [the Centers for Medicare & Medicaid Services] and HRSA [the Health Resources and Services Administration]. This proposal is estimated to save $48.1 billion between 2019 and 2028.”
The report also called for HRSA to continue its work on assessing physician supply, and to assess the agency’s workforce development programs and identify gaps between existing programs and future workforce needs.
The authors particularly attack state “certificate of need” (CON) laws, which require healthcare providers to seek approval before opening certain types of facilities. “Not only may CON laws impose costly barriers to provider entry, but by interfering with market forces that normally determine the supply of facilities and services, they can suppress supply, misallocate resources, and shield incumbent healthcare providers from competition from new entrants. In addition, incumbent firms may use CON laws to thwart or delay entry or expansion by new or existing competitors.”
The report recommended that states repeal their CON laws “or, at a minimum, significantly scale back the scope of their CON regimes, for example, by ensuring that competitors of CON applicants cannot weigh in on these applications.”
“CON laws were put in place 40 years ago when there was a very different healthcare landscape,” an official (also speaking on condition of anonymity) said on the press call. “We think there’s a variety of anti-competitive restrictions at the state level and CON represents one of the worst, and the administration wants to get on the right side of this issue. So, to the extent we have the ability to set out a vision and to work with state policy makers to loosen up restrictions on the provider side of the market, we are excited and hopeful to do that.”
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Higher rates of use, abuse in young who received opioid in dental setting


Young people with no opioid exposure who received an opioid prescription in a dental setting had higher rates of persistent opioid use and abuse, a retrospective study found.
In a sample of opioid-naive youth, 6.9% (95% CI 6.3%-7.2%, P<0.001) of individuals who received an index opioid prescription filled at least one additional prescription between 90 and 365 days after their initial encounter compared to 0.1% of opioid non-exposed age- and sex-matched controls, reported Alan Schroeder, MD, of Stanford University in California, and colleagues.
The opioid group also had an increase in subsequent diagnoses of opioid abuse (adjusted absolute risk difference 5.3%, 95% CI 5.0%-5.7%, P<0.001), they wrote in JAMA Internal Medicine.
Additionally, a median number of 20 pills were distributed to those who received a second opioid prescription, an “excessive” number which could result in unnecessary distribution to friends or family, the authors noted. These second prescriptions were provided by a dental clinician for 27.0% of patients. The remainder were prescribed by unknown providers, emergency medicine physicians, orthopedic surgeons, and other various healthcare providers, the authors reported.
“It’s unclear whether opioids are necessary at all after wisdom teeth extraction and there are some dental professionals that think that ibuprofen or Tylenol are sufficient,” Schroeder told MedPage Today. “But even if opioids are necessary in some cases, probably no more than a couple of pills would be sufficient.”
While not involved with the research, Chad Brummett, MD, of the University of Michigan Medical School in Ann Arbor, agreed that acetaminophen or Tylenol can usually achieve the same effect as a narcotic after dental surgery, and noted that the fact that nearly one third of adolescents in this study received an opioid from a dental clinician was “quite striking.” His past research has demonstrated that individuals specifically undergoing wisdom teeth extraction were at an increased risk for persistent opioid use as well.
“This is another paper that shows similar findings to a number of recent studies, and I hope offers another piece of evidence to make dentists and oral surgeons reflect on their prescribing habits and consider going opioid free in many cases,” he told MedPage Today.
Another previous study found that dentists were responsible for 12% of fast-acting opioid prescriptions, behind general practitioners and internists. However, Joel Funari, MS, DMD, of Advanced Oral and Facial Surgery of the Main Line in Devon, Pennsylvania, said that since these numbers were collected, most dentists have significantly changed their prescription habits. There are now certain guidelines that limit the number of narcotics that can be prescribed at one time, for example, and in some states, dental clinicians are required to receive a special certification or obtain written consent from an adolescent’s parent or legal guardian before prescribing an opioid to a patient.
“Because of the increased visibility of the opioid crisis and the actions of dental specialty groups, like the American Dental Association, the American Association of Endodontists, and state governments, there’s been a significant decrease in the percentage of dentists prescribing these quick-acting narcotics,” he told MedPage Today.
For this study, Schroeder’s team collected data from the Optum Research Database, which provides claims information for privately insured U.S. citizens across 50 states. Patients were included if they were between ages 16 to 25 at the time of the study (2015), had received an outpatient opioid prescription from a dental clinician that year, and had data in the Optum database for a minimum of 12 months to account for a year-long follow-up. Youth were excluded if they had previous histories of any opioid prescriptions or abuse, or were hospitalized up to 7 days before receiving the initial dental opioid prescription, they wrote.
Of the 14,888 young people included in the opioid cohort, most were white (75.7%) and a slight majority were women (52.9%). Researchers also collected data from 29,776 randomly-selected individuals to create a control group (67.4% white, 52.9% female). The average age across both groups was about 22, and there was one death apiece reported in each cohort.
Female patients were associated with an increased risk of persistent opioid use (aOR 1.2, 95% CI 1.0-1.4), but young adults ages 22 to 25 were less likely to have persistent opioid use than adolescents ages 16 to 18 (aOR 0.7, 95% CI 0.6-0.9).
Not surprisingly, previous non-opioid substance abuse was also linked with persistent opioid use (aOR 3.7, 95% CI 2.9-4.7) and abuse (aOR 4.5, 95% CI 3.4-5.9) after receiving a prescription in the dental setting, the authors noted.
Schroeder and his team acknowledged that some patients likely had preexisting opioid abuse not documented in the claims database. They noted that the full list of codes used to construct a comprehensive list for opioid abuse has not been “validated for medical record review,” resulting in potential misclassification. Optum also only includes privately-insured patients, so this study may not be generalizable to patients with Medicaid or other types of insurance, they wrote. Lastly, patients may have fallen out of the study, because the study required participants to have continuous insurance coverage.
Two co-authors received funding from the Department of Pediatrics of Stanford University School of Medicine.
No other disclosures were reported.
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Kura Oncology remains ‘favorite smallcap oncology name’: Piper Jaffray


Piper Jaffray analyst Tyler Van Buren kept his Overweight rating and $25 price target on Kura Oncology following the company’s update on the development of tipifarnib in highly refractory PTCL patients where a significant association between CXCL12 expression and clinical benefit was observed. The analyst notes that the data were “particularly impressive given the patients’ refractory states and importantly, one patient was even able to receive a potentially curative transplant”. Van Buren further contends that Kura Oncology is positioned for $500M or more in long-term sales for tipifarnib in HRAS-driven cancers, adding that its “shares are significantly undervalued based on that opportunity alone”.
https://thefly.com/landingPageNews.php?id=2831617
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Athene in significant pension risk transfer transaction with Bristol-Myers


Athene Holding  announced a first-of-its-kind pension plan termination transaction with Bristol-Myers Squibb (BMY) covering more than 24,000 active employee participants, retirees, beneficiaries, and former Bristol-Myers Squibb employees who have not yet commenced their benefits. Under the agreement, Athene’s wholly-owned Iowa-domiciled life insurance subsidiary, Athene Annuity and Life company, agreed in advance to provide an annuity contract covering all obligations of Bristol-Myers Squibb’s U.S. Retirement Income Plan for which the plan participants do not elect to receive a lump sum payment. Subsequent to payout of the lump sum obligations in July 2019, it is expected that AAIA’s annuity contract will cover as much as $3.8B of remaining pension liabilities when the transfer is completed in August 2019, subject to customary closing conditions. “We are pleased to have been selected as a trusted partner by Bristol-Myers Squibb, a global leader in the biopharmaceutical industry, to serve all of their U.S. Plan participants through this innovative transaction,” said Sean Brennan, Senior Vice President and Head of Pension Risk Transfer at Athene. “This transaction represents the largest full-plan termination to date that includes both retirees and non-retirees, and we believe this approach may provide a blueprint for plan sponsors considering full plan terminations in the future.” Upon completion of the transaction, Athene will provide irrevocable commitments to all Plan participants and will assume full financial responsibility, including required administration, for annuity and lump sum payments. Plan participants have received information packages and do not need to take any action at this time. “As a leader in pension risk transfers, Athene is able to provide plan sponsors with customized solutions to achieve their desired pension risk and financial objectives while ensuring the financial security of their plan participants,” said Bill Wheeler, President of Athene. “Our differentiated investment, actuarial, risk-management, and operational capabilities, combined with our strong balance sheet, position us well to serve the $3 trillion defined benefit marketplace.” Athene is a leader in the pension risk transfer industry, managing pension payments for more than 80,000 annuitants. During 2018, Athene has closed six pension risk transfer transactions totaling more than $1.8 billion.
https://thefly.com/landingPageNews.php?id=2831587
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Incyte: Jakafi for Graft-Versus-Host Disease Shows Rapid, Durable Benefit


  • Updated data to be presented today at the 60th annual ASH meeting
  • REACH1 study formed the basis of sNDA, now under Priority Review by the FDA
Incyte Corporation (Nasdaq:INCY) announces updated results from its pivotal Phase 2 REACH1 study evaluating ruxolitinib (Jakafi®) in combination with corticosteroids as a treatment for patients with acute graft-versus-host disease (GVHD) who have had an inadequate response to corticosteroids. As previously announced, the study met its primary endpoint, demonstrating an overall response rate (ORR) of 55 percent (n=39/71) at Day 28, along with a best overall response rate (BORR) – patients achieving a response at any time point during the study – of 73 percent (n=52/71).
Many of the patients (68 percent) had Grade III or Grade IV disease at baseline, illustrative of an at-risk patient population, and responses were observed irrespective of grade or steroid refractory (SR) criteria. Responses to ruxolitinib were rapid and durable; the median time to response was seven days and the median duration of response (DOR) for patients who had a minimum of six months of follow-up was 345 days. Adverse events reported were consistent with the safety profile established in prior ruxolitinib studies, and in patients with SR acute GVHD.
These results are being presented at the American Society of Hematology (ASH) Annual Meeting 2018 in San Diego, California, in an oral session today, Monday, December 3, from 7:00 a.m. PT to 8:30 a.m. PT (Location: Manchester Grand Hyatt, Grand Hall A; Oral Session 722, Abstract #601).
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