Amazon, Xealth plan healthcare delivery pilot

CNBC sources say Amazon (NASDAQ:AMZN) and startup Xealth are planning a pilot program that would deliver doctor-recommended products after patients check out of the hospital.

Patients would gain access to discounted medical supplies and goods with home delivery through Amazon Prime or other participating e-commerce providers.

Xealth is managing the pilot with Amazon guiding bundle setup and reseller accounts. Seattle’s Providence Health Systems and the University of Pittsburgh Medical Center are also onboard as both hospital systems and Xealth investors.

The pilot program is under review and could start within months.

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Planet Fitness climbs after lawmakers pass tax break for gym memberships

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Shares of Planet Fitness (PLNT) are higher on Thursday after U.S lawmakers passed tax breaks for gym memberships. Shares are also benefiting from an analyst note out yesterday. Planet Fitness franchises and operates fitness centers under the Planet Fitness name. It operates in three segments: Franchise, Corporate-Owned Stores, and Equipment. TAX DEDUCTIONS FOR HEALTH: A special panel of the House of Representatives advanced a bipartisan bill on Thursday that would allow taxpayers to claim deductions for gym memberships, fitness classes and other workout expenses to promote a healthy lifestyle. “Americans should have the ability to save and spend their health care dollars the way they want and need,” said House Ways and Means Chairman Kevin Brady, according to a report from the Washington Examiner. According to media reports, the legislation would give individuals a $500 allowance on gym memberships and other sports and fitness expenses. ANALYST LIKES BALANCE SHEET: Piper Jaffray analyst Peter Keith raised his price target for Planet Fitness to $51 following the company’s announced debt refinance. Importantly, Planet Fitness will likely use an increased cash position to begin repurchasing stock as early as Q4, Keith told investors in a research note on Wednesday. The analyst said he finds it reasonable that the company can repurchase $400M-$900M of stock in 2019 or 10%-20% of its market capitalization. He reiterated an Overweight rating on the shares. PRICE ACTION: Shares of Planet Fitness are up 3.1% or $1.40 to $46.59 in afternoon trading.

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Zynerba Gains On Positive Phase 2 Data For Fragile X Med

Zynerba Pharmaceuticals Inc ZYNE 3.59% announced Thursday its Phase 2 trial for ZYN002 in Fragile X syndrome found sustained improvements in patients’ core behavioral symptoms.

The drug was well tolerated with no serious adverse events.

Why It’s Important

The candidate is the most advanced in Zynerba’s pipeline, and its progress promises near-term revenue opportunity.

“These data are consistent and compelling, and suggest that ZYN002 may have a clinically meaningful and durable effect on the most common observable behaviors associated with childhood and adolescent Fragile X syndrome,” Honey Heussler, lead investigator in the study, said in a press release.

Additionally, as a cannabinoid therapy, ZYN002’s success reflects positively on the cannabis industry.

What’s Next

Zynerba awaits confirmatory results from a pivotal clinical trial started Monday. Top-line data is due in the second half of 2019.

https://bit.ly/2JgZUyK

T cell engineering breakthrough sidesteps need for viruses in gene-editing

With faster, cheaper, more precise technique, authors say it’s ‘off to the races’ toward new cell therapies

In an achievement that has significant implications for research, medicine, and industry, UC San Francisco scientists have genetically reprogrammed the human immune cells known as T cells without using viruses to insert DNA. The researchers said they expect their technique — a rapid, versatile, and economical approach employing CRISPR gene-editing technology — to be widely adopted in the burgeoning field of cell therapy, accelerating the development of new and safer treatments for cancer, autoimmunity, and other diseases, including rare inherited disorders.

The new method, described in the July 11, 2018 issue of Nature, offers a robust molecular “cut and paste” system to rewrite genome sequences in human T cells. It relies on electroporation, a process in which an electrical field is applied to cells to make their membranes temporarily more permeable. After experimenting with thousands of variables over the course of a year, the UCSF researchers found that when certain quantities of T cells, DNA, and the CRISPR “scissors” are mixed together and then exposed to an appropriate electrical field, the T cells will take in these elements and integrate specified genetic sequences precisely at the site of a CRISPR-programmed cut in the genome.

“This is a rapid, flexible method that can be used to alter, enhance, and reprogram T cells so we can give them the specificity we want to destroy cancer, recognize infections, or tamp down the excessive immune response seen in autoimmune disease,” said UCSF’s Alex Marson, MD, PhD, associate professor of microbiology and immunology, member of the UCSF Helen Diller Family Comprehensive Cancer Center, and senior author of the new study. “Now we’re off to the races on all these fronts.”

But just as important as the new technique’s speed and ease of use, said Marson, also scientific director of biomedicine at the Innovative Genomics Institute, is that the approach makes it possible to insert substantial stretches of DNA into T cells, which can endow the cells with powerful new properties. Members of Marson’s lab have had some success using electroporation and CRISPR to insert bits of genetic material into T cells, but until now, numerous attempts by many researchers to place long sequences of DNA into T cells had caused the cells to die, leading most to believe that large DNA sequences are excessively toxic to T cells.

To demonstrate the new method’s versatility and power, the researchers used it to repair a disease-causing genetic mutation in T cells from children with a rare genetic form of autoimmunity, and also created customized T cells to seek out and kill human melanoma cells.

Viruses cause infections by injecting their own genetic material through cell membranes, and since the 1970s scientists have exploited this capability, stripping viruses of infectious features and using the resulting “viral vectors” to transport DNA into cells for research, gene therapy, and in a well-publicized recent example, to create the CAR-T cells used in cancer immunotherapy.

T cells engineered with viruses are now approved by the U.S. Food and Drug Administration to combat certain types of leukemia and lymphoma. But creating viral vectors is a painstaking, expensive process, and a shortage of clinical-grade vectors has led to a manufacturing bottleneck for both gene therapies and cell-based therapies. Even when available, viral vectors are far from ideal, because they insert genes haphazardly into cellular genomes, which can damage existing healthy genes or leave newly introduced genes ungoverned by the regulatory mechanisms which ensure that cells function normally. These limitations, which could potentially lead to serious side effects, have been cause for concern in both gene therapy and cell therapies such as CAR-T-based immunotherapy.

“There has been thirty years of work trying to get new genes into T cells,” said first author Theo Roth, a student pursuing MD and PhD degrees in UCSF’s Medical Scientist Training Program who designed and led the new study in Marson’s lab. “Now there should no longer be a need to have six or seven people in a lab working with viruses just to engineer T cells, and if we begin to see hundreds of labs engineering these cells instead of just a few, and working with increasingly more complex DNA sequences, we’ll be trying so many more possibilities that it will significantly speed up the development of future generations of cell therapy.”

After nearly a year of trial-and-error, Roth determined the ratios of T cell populations, DNA quantity, and CRISPR abundance that, combined with an electrical field delivered with the proper parameters, would result in efficient and accurate editing of the T cells’ genomes.

To validate these findings, Roth directed CRISPR to label an array of different T cell proteins with green fluorescent protein (GFP), and the outcome was highly specific, with very low levels of “off-target” effects: each subcellular structure Roth’s CRISPR templates had been designed to tag with GFP — and no others — glowed green under the microscope.

Then, in complementary experiments devised to serve as proof-of-principle of the new technique’s therapeutic promise, Roth, Marson, and colleagues showed how it could potentially be used to marshal T cells against either autoimmune disease or cancer.

In the first example, Roth and colleagues used T cells provided to the Marson lab by Yale School of Medicine’s Kevan Herold, MD. The cells came from three siblings with a rare, severe autoimmune disease that has so far been resistant to treatment. Genomic sequencing had shown that the T cells in these children carry mutations in a gene called IL2RA. This gene contains instructions for a cell-surface receptor essential for the development of regulatory T cells, or Tregs, which keep other immune cells in check and prevent autoimmunity.

With the non-viral CRISPR technique, the UCSF team was able to quickly repair the IL2RA defect in the children’s T cells, and to restore cellular signals that had been impaired by the mutations. In CAR-T therapy, T cells that have been removed from the body are engineered to enhance their cancer-fighting ability, and then returned to the body to target tumors. The researchers hope that a similar approach could be effective for treating autoimmune diseases in which Tregs malfunction, such as that seen in the three children with the IL2RA mutations.

In a second set of experiments conducted in collaboration with Cristina Puig-Saus, PhD, and Antoni Ribas, MD, of the Parker Institute for Cancer Immunotherapy at UCLA, the scientists completely replaced native T cell receptors in a population of normal human T cells with new receptors that had been specifically engineered to seek out a particular subtype of human melanoma cells. T cell receptors are the sensors the cells use to detect disease or infection, and in lab dishes the engineered cells efficiently homed in on the targeted melanoma cells while ignoring other cells, exhibiting the sort of specificity that is a major goal of precision cancer medicine.

Without using viruses, the researchers were able to generate large numbers of CRISPR-engineered cells reprogrammed to display the new T cell receptor. When transferred into mice implanted with human melanoma tumors, the engineered human T cells went to the tumor site and showed anti-cancer activity.

“This strategy of replacing the T cell receptor can be generalized to any T cell receptor,” said Marson, also a member of the Parker Institute for Cancer Immunotherapy at UCSF and a Chan Zuckerberg Biohub Investigator. “With this new technique we can cut and paste into a specified place, rewriting a specific page in the genome sequence.”

Roth said that because the new technique makes it possible to create viable custom T cell lines in a little over a week, it has already transformed the research environment in Marson’s lab. Ideas for experiments that were previously deemed too difficult or expensive because of the obstacles presented by viral vectors are now ripe for investigation. “We’ll work on 20 ‘crazy’ ideas,” Roth said, “because we can create CRISPR templates very rapidly, and as soon as we have a template we can get it into T cells and grow them up quickly.”

Marson attributes the new method’s success to Roth’s “absolute perseverance” in the face of the widespread beliefs that viral vectors were necessary and that only small pieces of DNA could be tolerated by T cells. “Theo was convinced that if we could figure out the right conditions we could overcome these perceived limitations, and he put in a Herculean effort to test thousands of different conditions: the ratio of the CRISPR to the DNA; different ways of culturing the cells; different electrical currents. By optimizing each of these parameters and putting the best conditions together he was able to see this astounding result.”

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Story Source:

Materials provided by University of California – San Francisco. Original written by Pete Farley. Note: Content may be edited for style and length.

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NSAIDs Plus Anticoagulants a Dangerous Combination

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and oral anticoagulants in patients with atrial fibrillation (AF) increases the risk for major bleeding and stroke, according to a new analysis of the RE-LY trial.

“Avoid NSAIDs in anticoagulated patients with AF,” senior author Michael Ezekowitz, MD, PhD, Thomas Jefferson University, Philadelphia, Pennsylvania, told theheart.org | Medscape Cardiology.

“In this post hoc analysis of the RE-LY study, we found that concomitant NSAID use with any anticoagulant increases extracranial risk particularly, as well as stroke risk in patients with AF,” he said of the study, published July 9 in the Journal of the American College of Cardiology.

In an  accompanying editorial, Sam Schulman, MD, PhD, McMaster University, Hamilton, Ontario, Canada, and James Aisenberg, MD, Icahn School of Medicine at Mount Sinai, New York, New York, write that NSAIDs along with anticoagulants represent “double trouble.”

“This study shows that both with warfarin and the newer anticoagulant dabigatran, you get more bleeding, but you can also get more thrombotic complications when you add an NSAID,” Schulman told theheart.org | Medscape Cardiology.

“This is a very common scenario, because anticoagulants are taken by patients who have AF and those patients are typically elderly, and often have osteoarthritis and need to take something for their osteoarthritis,” he said.

Nonselective NSAIDs, including ibuprofen, naproxen, meloxicam, diclofenac, and ketorolac, all have the ability to increase the risk for bleeding and were permitted for use in RE-LY.

“Thus, we decided to do this post hoc analysis to test whether these drugs, when used with warfarin and dabigatran, carried an additional bleeding or clotting risk,” said Ezekowitz, also co-principal investigator of the RE-LY trial.

Results of the parent study in 18,113 patients with AF showed that dabigatran (Pradaxa, Boehringer Ingelheim) at the 110-mg or 150-mg dose twice daily was noninferior to warfarin for stroke or systemic embolism, although myocardial infarction (MI) risk was significantly increased with the 150-mg dose.

The new analysis, led by Anthony P. Kent, MD, Yale New Haven Health, Bridgeport, Connecticut, involved 2279 of the participants, who used NSAIDs at least once during the study period.

Patients taking NSAIDs with an oral anticoagulant (OAC) had significantly higher rates of major bleeding than those who did not use NSAIDs (5.4% vs 3.2%; hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.40 – 2.02). The finding was present across all OAC treatment groups.

NSAID use was also associated with significantly more major gastrointestinal bleeding (HR, 1.81; 95% CI, 1.35 – 2.43) and more frequent hospitalizations (HR, 1.64; 95% CI, 1.51 – 1.77).

Rates of MI and all-cause mortality were similar with and without NSAID use.

In a time-varying covariate analysis, however, the risk for stroke or systemic embolism was significantly elevated with NSAID use (HR, 1.50; 95% CI, 1.12 – 2.01).

While ischemic stroke was significantly elevated with NSAID use (HR, 1.55; P = .0102), hemorrhagic stroke rates were similar (HR, 1.08; P = .8631).

In an interaction analysis, NSAID use did not alter the ability of the dabigatran 150-mg or 110-mg dose to prevent stroke/systemic embolism relative to warfarin (P for interaction = .59 and .54, respectively).

The authors cite as study limitations the patients’ ability to periodically start and stop NSAIDs; a lack of data regarding the specific type of nonselective NSAID, dose, and reason for NSAID use; and failure to capture baseline prevalence of osteoarthritis (OA), rheumatoid arthritis, or other inflammatory conditions that might partially explain NSAID use.

The authors also point out that future research is still required to investigate the effects of NSAIDs when used with direct OACs in patients with AF.

“Doctors should tell their patients with AF  who are receiving anticoagulant therapy not to use over-the-counter pain killers,” Ezekowitz said.

He suggested that Tylenol (acetaminophen) could be an alternative but cautioned, “We have to be careful regarding the overuse of opioids.”

Double Trouble, No Single Way Out

Telling patients to take Tylenol is not a solution, contends Schulman.

“Most patients say Tylenol does nothing for my osteoarthritis, and that’s because it’s not an anti-inflammatory agent. There is an inflammatory component in arthritis and that is what needs to be treated,” he said.

NSAIDs are known to increase bleeding risk, especially in the elderly, but the bleeding was largely thought to occur in the stomach. Now, there is increasing evidence that bleeding occurs in the intestines, Schulman said.

What was surprising in the study was the fact that very few patients who were taking NSAIDs were receiving a proton-pump inhibitor, he noted.

That said, “This only protects the stomach and does not afford protection against intestinal bleeding, so it’s not a panacea.”

Until safe and effective non-NSAID, nonopioid analgesics are available, “We are stuck with the high-stakes, common question of how to manage patients with AF and OA,” Schulman said.

Doctors should consider using a cyclooxygenase-2 inhibitor such as celecoxib (Celebrex, Pfizer), which is associated with less bleeding and does not decrease platelet function but still has anti-inflammatory properties, he suggested.

The RE-LY trial was funded by Boehringer Ingelheim. The post hoc analysis did not have a funding source. Ezekowitz reports receiving consulting fees from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Portola, Daiichi-Sankyo, and Armetheon and grant support from Boehringer Ingelheim and Pfizer. Schulman reports receiving honoraria and a research grant from Boehringer Ingelheim. Aisenberg reports no relevant financial relationships.

J Am Coll Cardiol. 2018;72:255-267, 268-270. Abstract, Editorial

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Proton Therapy Trials ‘at Risk,’ Slow to Enroll Patients

The big question about proton beam radiotherapy — is it any better than conventional radiotherapy? — is being addressed in seven ongoing randomized clinical trials sponsored by the National Cancer Institute (NCI).

But these trials, which cover cancers of the breast, lung, prostate, esophagus, liver, and brain, are all enrolling more slowly than expected, report a trio of experts.

The trials are “at risk” mainly because of this poor accrual, say Justin Bekelman, MD, of the University of Pennsylvania in Philadelphia, and Andrea Denicoff, MS, RN, and Jeffrey Buchsbaum, MD, PhD, both from the NCI.

Unfortunately, “restrictive” insurance coverage is dragging down the entire research effort and is “a principal barrier to enrollment,” they write.

Their report was published online July 9 in the Journal of Clinical Oncology.

The trials are essential to compare the efficacy and toxicity of the newer, experimental proton therapy to conventional radiotherapy based on photon therapy, which includes intensity-modulated radiotherapy (IMRT).

However, there are problems with getting patients to receive proton therapy.

“Nearly all commercial insurers and state Medicaid plans do not cover proton therapy for the indications under study,” the authors report. Proton therapy has not been proven superior and is more expensive, claim insurers.

The authors talked to physicians, patient advocates, and insurers and reviewed commercial insurers’ coverage policies.

On a positive note, the authors found that Medicare “typically does cover the treatment through local coverage determinations, which may include clinical study participation requirements.”

Another hopeful sign is that some insurers, including Cigna, Independence Blue Cross, and Blue Cross Blue Shield of Florida, cover proton therapy for selected cancers under study or have established coverage with study participation policies.

In other good news, some proton centers, including those at the University of Pennsylvania, the Mayo Clinic, and the University of Maryland, offer discounts to patients in which the price of proton therapy is equal to that of IMRT. Other centers, such as Northwestern Proton Therapy and Seattle Cancer Alliance, have payment programs in which the center absorbs the treatment cost if proton therapy is not covered upon appeal to an insurer.

These “compromises” from both insurers and proton centers “signal progress,” say the report authors, but they are “uncommon.” Overall, the situation is at an “impasse.”

The result is very slow enrollment. For example, in the breast cancer trial, which involved 893 clinically eligible patients screened through September 2017, 582 patients (65%) had insurance policies that did not cover proton therapy. Bekelman is the principal investigator in this breast cancer trial, and his home institution, the University of Pennsylvania, owns and operates a photon therapy center.

So, as the slate of seven clinical trials drags on, no answers are generated about comparative efficacy and toxicity of the two rival radiotherapy technologies.

“If we can complete the trials in a timely fashion, the results will enable patients to make more informed treatment decisions,” said Denicoff in a press statement.

Proton therapy has been aggressively marketed by centers, but, to date, final efficacy results are available for only one randomized clinical trial, in lung cancer. (The lung cancer trial was not among the seven trials in the current study.) In that trial, proton therapy was no better than standard radiotherapy, as reported by Medscape Medical News.

One thing is certain about proton therapy: it costs more. The average Medicare reimbursement per course of treatment, say the report authors, is approximately $10,000 to $20,000 more for proton therapy than for conventional photon-based IMRT, depending on indication.

Three Solutions?

The NCI and the Patient-Centered Outcomes Research Institute (PCORI) have made “major investments to fund” these seven randomized trials, say the report authors. However, those investments evidently did not include paying for patient treatment with the various technologies.

To address this shortcoming, the report authors propose a set of three solutions.

The first emphasizes the need for insurance. The trio says that all stakeholders should come together to establish insurance coverage with a trial participation program for patients who enroll in the NCI- or PCORI-funded randomized radiotherapy treatment trials.

Radiotherapy manufacturers should be a part of the effort and should offer financing, the report authors say.

“It has been noted that linear accelerator and proton therapy manufacturers have not underwritten the costs of treatment during evidence development as drug makers might for new drugs because proton therapy units are considered class II devices by the FDA and approved through the 510(k) program,” they observe.

The second solution is to improve enrollment rates and recognize clinicians who are good at enrolling patients.

The third solution is to engage patients more deeply so that they want to enroll.

However, even with patient-friendly trials, enrollment “would be even more fruitful if there was a clear solution to restrictive insurance coverage for proton therapy,” say the report authors.

The report was partially funded through a PCORI award and grants from the NCI. The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online July 9, 2018. Full text

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DEA Moving On Reclassification of CBD Ahead of GW’s Launch of Epidiolex

The U.S. Drug Enforcement Agency is in the midst of readdressing cannabis following the regulatory approval of the first cannabinoid-based drug for the treatment of some epilepsy patients.

In June, the U.S.Food and Drug Administration (FDA) gave the nod of approval to GW Pharmaceuticals’ Epidiolex as a treatment for seizures associated with two rare forms of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome. The FDA’s approval marked two firsts. The first was the fact that Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana. Secondly, Epidiolex was the first drug approved specifically for patients with Dravet syndrome, a rare form of epilepsy.

While Epidiolex has been approved for use in the United States, there is still one significant hurdle that has to be met before the drug can be available to patients – the DEA. Currently, all derivatives of the cannabis plant, including those that are not addictive, are classified as a Schedule I drug – something that is considered to have high abuse potential with no medical use. Marijuana was included on the Schedule 1 list alongside other drugs such as heroin and cocaine. That though is changing, per the approval of the GW Pharma drug, as well as the fact that some states have legalized the use of marijuana for medicinal purposes.

The new drug is derived from Cannabidiol (CBD), a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication like the illicit use of marijuana. It’s the first in a new category of anti-epileptic drugs (AEDs), GW Pharma said.

When Epidolix was approved, GW said the DEA was going to address its Schedule 1 ruling within 90 days. That would mean the U.K.-based company will be able to begin selling its new medication later this year, the company said at the time of the approval. The DEA appears to be on track for making that change. A spokesperson for the agency told Business Insider at the end of June that the DEA was on its way to reclassifying CBD as a Schedule II or Schedule III drug. Unlike Schedule I drugs that are not considered to have any medicinal use, Schedule II and Schedule III drugs are considered addictive (to differing degrees per the Schedule) but have medicinal use. Schedule II drugs include opioid treatments for chronic pain, which are readily subject to abuse, while Schedule III drugs include things like testosterone therapies and Tylenol with Codeine.

When it was approved, FDA Commissioner Scott Gottlieb said Epidiolex “serves as a reminder” that understanding and advancing development programs from the active ingredients in marijuana can lead to important medical therapies.

GW isn’t the only company awaiting the reclassification of CBD. Other companies are also developing CBD-based treatments for various therapeutic uses. For example, CURE Pharmaceuticals is developing cannabinoids for the treatment of a wide range of sleep disorders. On Wednesday, CURE acquired the non-pain assets of Therapix Biosciences. Therapix is developing a cannabinoid-based pipeline with drug development programs using dronabinol, a synthetic cannabinoid already approved by the FDA, CURE said in its announcement.

https://bit.ly/2ma33Y2