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Wednesday, June 12, 2019

Hospitals look to cut opioids from surgery and beyond

Opioids used to be the go-to choice for treating surgical patients’ pain. Now some hospital officials are trying to get those patients through their surgery without ever receiving any of the highly addictive drugs.
They’re doing so by revamping surgical pain management, implementing a more thoughtful prescribing approach and relying on non-addictive and less-addictive alternatives.
Dr. Neil Martin, chief quality officer at Geisinger and chair of its neuroscience institute, said it was highly unlikely patients who undergo a surgical procedure today would receive anywhere near the number of opioids they were prescribed just a decade ago.
He said much has been learned over that time about the health risks associated with prolonged exposure to such drugs.
“Historically patients were getting opioids intraoperatively, in the recovery room, in the hospital as they recovered and at the time of discharge,” Martin said.
Danville, Pa.-based Geisinger, like many other health systems, has launched initiatives in recent years aimed at reducing the number of opioids patients receive during their care.
The focus has largely been on improving prescribing practices within the emergency department, as well 
as among primary-care clinicians and dentists, who have traditionally accounted for nearly half of all prescriptions written annually in the U.S.

Changing protocols
But a growing number of hospitals and health systems have begun to examine ways to reduce the potential for overprescribing among surgeons.
Doing so requires providers to change protocols and practices, which have been widely accepted for decades, that recognize opioids as the primary option for managing postoperative pain.
Research is supporting the expanded attention. A study published in November in the journal JAMA Surgery highlighted the problem of overprescribing among surgeons. It found they prescribed opioids for nearly four times the amount that patients actually used and that the quantity of opioids prescribed was associated with higher patient consumption of such drugs.
Martin said Geisinger’s effort overall to limit opioid use has led to a dramatic decline in prescribing at the health system, with the number of opioid prescriptions written cut almost in half from 60,000 a month in 2014 to 31,000 a month currently.
Last November, the system launched its Proven-
Recovery program to introduce best practices on opioid prescribing to more than 40 surgical procedures with an objective to implement it in more than 100 elective procedures by the end of 2019.
A key goal of the program has been to eliminate the use of opioids for postoperative pain management altogether. Patients may receive a combination of nerve-blocking anesthesia during their surgery and a combination of non-opioid medications such as acetaminophen, ibuprofen, ketamine and lidocaine to manage pain during their recovery.
But the approach also focuses on managing patients’ nutrition level before surgery, which Martin said accelerates the postoperative healing process. Martin said the program so far led to an 18% reduction in the use of opioids in surgery.
“We’re in the process of reassessing that figure right now, and I’m sure it’s going to be twice that much of a reduction,” Martin said.
“Historically patients were getting opioids intraoperatively, in the recovery room, in the hospital as they recovered and at the same time of discharge. We’re in the process of reassessing that figure right now, and I’m sure it’s going to be twice that much of a reduction,” said Dr. Neil Martin, chief quality officer at Geisinger and chair of its neuroscience institute.

Challenging norms
The Cleveland Clinic over the past couple of years also has developed a postoperative pain management initiative that examined the potential for using narcotic alternatives and it has shown promising results.
Cleveland Clinic’s approach relies on a greater use of narcotic alternatives before, during and after surgery, according to Dr. Eric Chiang, an anesthesiologist at the Clinic. The approach involves regional anesthesia (injecting a drug directly into the surgical site or pain area), and increasing the use of medications like acetaminophen and ibuprofen.
“The science behind it shows that opioids are not the best pain medicine,” Chiang said. “We’re probably not using Tylenol and nonsteroidals enough.”
Cleveland Clinic last year began a pilot program to change postoperative pain management protocols for patients who undergo cesarean sections, one of the most common surgical procedures in the U.S.
Chiang said C-section patients were traditionally prescribed Percocet or Vicodin while in the hospital only to receive more opioids upon discharge. Under the new protocol, patients got scheduled doses of either 1,000 mg of Tylenol or a large dose of Motrin every three hours even if they did not request pain medication.
Patients were informed they could still request an opioid if their pain was too great, but within the first month of making the change, opioid use among post C-section patients fell by 70%. Upon discharge most C-section patients are no longer prescribed an opioid, and those who do receive a prescription get an average of five pills compared with the 31 pills patients typically received in 2015.
“By minimizing and prescribing appropriate amounts of narcotic medicine—that’s how you fight the opioid crisis,” Chiang said. “It’s all those extra pills sitting at home that get diverted, and those pills in the community are what fuel the crisis.”
Dr. Candace Granberg, a pediatric urologic surgeon at the Mayo Clinic, said her department since at least 2012 has adopted an opioid-free pain management approach toward postoperative patients that has been successful enough for many patients to not require any pain medications while in recovery or after discharge.
She said a key part of her approach has been the focus on anticipating the need for treatment before the patient actually experiences pain, with patients receiving doses of acetaminophen and ibuprofen on an alternating schedule throughout their visit and having a nerve block applied to surgical areas prior to their procedure.
Prior to a procedure, the surgical team discusses the best ways to block patient pain during the operation and to control it during the patient’s recovery and at home.
Geisinger’s Martin said the system’s ProvenRecovery approach has been used with more than 2,000 patients since November. But he acknowledged the goal of eliminating opioids entirely from surgery has been difficult to achieve.
He estimated only about 20% to 30% of patients undergoing certain procedures are opioid-free. “There’s very few where absolutely no opioids are prescribed—that’s an aspirational goal for us,” Martin said. “But our No. 1 goal is to make sure patients’ pain is controlled.”
The goal of prescribing zero opioids is complicated by the fact that such drugs are still needed to control pain in a minority of patients. Further complicating matters, more people in general use opioids to treat chronic pain and may build a tolerance over time and so require stronger medications to successfully manage acute pain that’s common after many surgical procedures.
Martin said some surgery patients cannot easily be taken off such medications without going through physical withdrawal symptoms. “It’s a little more nuanced issue than just going for total opioid-free surgery,” Martin said.
While illicit drugs like fentanyl have overtaken prescription opioids as the primary driver of the opioid epidemic, prescribed opioids remain a significant contributor. Nearly a quarter of all overdose deaths and more than a third of all opioid-related deaths in 2017 were related to using prescription opioids, according to the Centers for Disease Control and Prevention.
Providers and lawmakers in recent years have worked to address opioid overprescribing through greater education for clinicians as well as through laws in several states limiting prescriptions to just a few days’ supply.
As a result the number of written opioid prescriptions fell from a record set in 2012 of more than 255 million to more than 191 million by 2017, according to the CDC.
Improving prescribing practices
Yet some contend the robust number of prescriptions written in the U.S. still reflects an overprescribing problem that points to the need for even greater improvement in prescribing practices.
“Culturally, providers have always been heavy-handed with narcotics,” the Cleveland Clinic’s Chiang said. “We’re fighting against tradition, against the way things have been done for years and years in this country.”
Clinical concerns notwithstanding, Chiang’s point about breaking long-standing practices on managing pain may help to explain why even in the middle of the worst drug epidemic on record more hospitals don’t stop prescribing opioids to postoperative patients with no other pain issues or current dependence on such drugs.
Dr. John Daly, co-chair of the Patient Education Committee at the American College of Surgeons, said the decision whether or not to prescribe opioids has to be weighed with an understanding of both the benefits and risks for the patient.
“The benefit of opioids is that they do reduce pain,” Daly said. “If a surgeon is going to utilize opioid-free surgery for some procedures then they would need to adopt other mechanisms for reducing pain, because it’s not the goal to simply eliminate opioids.”
But many hospitals say the benefits of successfully managing pain for common surgical procedures without opioids can go beyond minimizing the risk of patients becoming addicted.
Dr. Charles Luke, an anesthesiologist and system director of the Acute Interventional Perioperative Pain Service at UPMC in Pittsburgh, said his system has cut in half the number of opioid prescriptions that surgeons write. He said the reduction in opioid use has been shown to decrease hospital lengths of stay, recovery times and opioid-related complications.
“Overall, long-term opioid reduction often leads to improved patient well-being,” Luke said. “The estimated cost savings to the health system is huge but not well-quantified.”
Mayo’s Granberg believes that not providing opioids for many common surgical procedures is a feasible and achievable goal for any healthcare provider. She expects more hospitals to adopt such policies as data on the efforts grows.
“I think that our communication has improved significantly in light of the opioid epidemic to say we’re going to aim to send them home without opioids,” Granberg said.

ISS thumbs down on reappoint of Takeda chief Weber

Advisory firm Institutional Shareholder Services (ISS) reportedly will recommend against the reappointment of Takeda (NYSE:TAK) President & CEO Christophe Weber according to Nikkei. It will support a shareholder proposal for the adoption of a clawback clause that would recoup executive pay in the event of large losses and the disclosure of individual directors’ pay.
The company’s annual meeting is scheduled for June 27.

AbbVie Has Long-Term Data from Phase 3 Studies in Rheumatoid Arthritis

– Data from SELECT-EARLY and SELECT-COMPARE show a significantly higher proportion of patients treated with upadacitinib monotherapy or in combination with methotrexate (MTX) maintaining clinical remission compared with MTX or adalimumab plus MTX, respectively, at 48 weeks1,2
– Findings from an integrated safety analysis across five studies in the SELECT Phase 3 clinical program support the well-characterized safety profile of upadacitinib in patients with moderately to severely active rheumatoid arthritis3
– Upadacitinib, an investigational oral agent engineered by AbbVie to selectively inhibit JAK1, is being studied as a once-daily therapy in moderately to severely active rheumatoid arthritis and across multiple other immune-mediated inflammatory diseases

NuCana Gets Orphan Drug Status for Treatment of Biliary Tract Cancer

NuCana plc (NASDAQ:NCNA) today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the Company’s investigational drug, Acelarin® (NUC-1031), for the treatment of biliary tract cancer. Acelarin is a new chemical entity and is NuCana’s ProTide transformation of gemcitabine.
“We are pleased to have received orphan drug designation from the FDA for Acelarin in biliary tract cancer,” said Hugh Griffith, NuCana’s Founder and Chief Executive Officer.  “There is a high unmet need for patients suffering from this cancer type.  Our Phase Ib study of Acelarin combined with cisplatin showed an approximate doubling of the response rate expected with the standard of care, gemcitabine plus cisplatin, with several patients achieving significant reductions in their tumor volume as well as further tumor shrinkage over time.  We believe Acelarin represents a potential significant advance in biliary tract cancer and we remain on track to open our global Phase III study in combination with cisplatin as a front-line treatment for patients with advanced biliary tract cancer in 2019.”

Rubio, Grassley: HHS Should Probe Payments to Chinese-Linked Companies

This week, U.S. Sen. Marco Rubio, R-Fla., and U.S. Sen. Chuck Grassley, R-Iowa, wrote U.S. Department of Health and Human Services (HHS) Acting Inspector General (IG) Joanne M. Chiedi requesting oversight on potential payments made to U.S. entities with partnerships to genomics companies affiliated with the Chinese government, including WuXiand BGI. Both WuXi and BGI have publicly touted their partnerships with the Chinese telecom company Huawei, a state-directed actor used by the Chinese government and Communist Party to undermine U.S. companies and steal intellectual property and trade secrets.
Rubio and Grassley asked the HHS IG for the following:
A review of Centers for Medicare and Medicaid Services (CMS) payments to determine whether it has made payments for Americans’ genetic testing to U.S. entities with partnerships to BGI, WuXi and any other company with ties to the Chinese government; To determine whether CMS considers national security risks when determining whether payments are permissible to providers with partnerships with these Chinese-affiliated companies; and, That the IG make recommendations to CMS and to Congress on ways to mitigate national security risks related to Americans’ genomic data with respect to CMS payments.
The full text of the letter is below:
Dear Acting Inspector General Chiedi:
According to a February 2019 report released by the U.S. Department of Health and Human Services Office of the Inspector General (OIG), the Federal Bureau of Investigation (FBI) has identified national security risks related to sharing genomic data, and recognizes China as a country as a primary source of those risks. The report raises concerns that the National Institutes of Health (NIH) gave access to U.S. genomic data to for-profit companies from China, including WuXi Nextcode Genomics (WuXi) and Shenzhen BGI Technology Company (BGI), “even though the FBI has identified those companies as having ties to the Chinese Government.” We agree with your office’s recommendations for the NIH to work with national security experts to assess the potential consequences of providing foreign entities access to Americans’ genomic information. We also support your efforts to bring this issue to the NIH’s attention and its recommendation that NIH work to mitigate these risks.
We are equally concerned that CMS may be providing payments for genetic testing or analysis to U.S. entities that have domestic partnerships with WuXi, BGI, and other genomics companies with ties to the Chinese government.  In 2016, WuXi was the first genetic sequencing facility in China to gain CLIA (Clinical Laboratory Improvement Amendments) certification from CMS.  It has since gained a foothold in the U.S. Similarly, BGI has publicly announced partnerships with leading American health care systems, including those that accept Medicare and Medicaid patients. In 2013, BGI acquired Complete Genomics, a U.S. company which later became part of MGI Tech (MGI), a BGI subsidiary. In March 2019, MGI announced plans to expand into the U.S. market by the end of 2019, making it all the more necessary for the OIG to determine whether CMS has the proper security protocols in place to protect Americans’ genetic information.
Both BGI and WuXi also have publicly touted their partnerships with Huawei to expand genomic analytics. As you know, Huawei is a State-directed Chinese telecommunications company that, according to the heads of six U.S. intelligence agencies including the CIA, FBI, NSA, and the Director of National Intelligence, possesses the capabilities to “maliciously modify or steal information” and “to conduct undetected espionage.” This is the same company that the U.S. recently charged with conspiring to defraud our nation and stealing trade secrets, among other crimes. WuXi and BGI’s U.S.-based partnerships give them unique access to genomic data, including Americans’ genomic data. Therefore, it is particularly alarming that these two companies have partnered with Huawei.
As of March 2019, the Congressional Budget Office estimates that the federal government’s gross spending on Medicare in 2018 was $712 billion, while federal Medicaid expenditures were $389 billion, not including the states’ Medicaid spending. Together, these two programs totaled more than $1.1 trillion in federal outlays in 2018 – far more than federal funding to the NIH. Taxpayers cover the costs of CMS payments. Accordingly, they have every right to know if their money has gone to entities connected to the Chinese government.
We therefore request that the OIG, in coordination with relevant Intelligence Community agencies, review CMS payments to determine whether it has made payments for genetic testing to U.S. entities with partnerships to BGI, WuXi and any other company with ties to the Chinese government.  We also request that the OIG determine whether the CMS considers national security risks when determining whether payments are permissible to providers with partnerships with these Chinese-affiliated companies.  Finally, we ask that the OIG make recommendations to CMS and to Congress on ways to mitigate national security risks related to Americans’ genomic data with respect to CMS payments.

Achieve goes up in smoke

Achieve Life Sciences gets a reality check despite largely positive smoking cessation data.
What looked on the face of it like decent mid-stage data from Achieve Life Sciences were not enough to stop the company’s stock sinking for a second day. Shares opened 10% lower this morning, after sinking 25% yesterday.
The company believes that its smoking cessation candidate cytisinicline has shown enough promise to justify going into phase III. But worries about the project’s patentability, Achieve’s capital structure and the company’s cash position probably all contributed to the selloff.
Some investors also questioned a high placebo response seen in the phase II Orca-1 trial, which tested four dosing regimens of cytisinicline: declining titration schedules starting at 1.5mg and 3mg, and 1.5mg and 3mg three times per day.
The primary endpoint was patients’ self-reported reduction in daily smoking. Over the 25-day treatment period and across all four dosing arms patients on cytisinicline reported a 74-80% median reduction in the number of cigarettes smoked, compared with a 62% drop in the placebo arms.
The high number with placebo might be explained by the self-reported nature of this endpoint, which could be open to abuse. The trial also looked at expired carbon monoxide, a biochemical measure of smoking activity and therefore a more objective endpoint; across the groups this declined by a median of 71-80% with cytisinicline, versus 38% with placebo.
The discrepancy between the two sets of results suggests a relative under-reporting of cigarettes smoked by patients in the placebo group, according to Achieve.
3mg three times daily
On the primary endpoint, only three of the four dosing arms met statistical significance, but this might not matter: Achieve plans to take forward just one of the successful doses, 3mg three-times daily, which it said was the “clear winner” in terms of performance.
The company will discuss the Orca-1 data with the US FDA in the next few weeks, and hopes to start its phase III programme in the second half of 2019. This will comprise two trials, the sizes of which are still to be determined. They had originally been set to enrol up to 2,300 patients in total, but Achieve said on a conference call yesterday that it might revise statistical powering assumptions based on the latest data.
The primary outcome in phase III will be the continuous abstinence rate over 5-8 weeks, confirmed by expired carbon monoxide levels – this is the endpoint preferred by regulators, according to Achieve.
On this measure the 3mg three-times-daily dose showed 30% of patients abstaining, versus 8% in those receiving placebo, with a p value of 0.005. Achieve’s chief executive, Rick Stewart, claimed that the study had not been designed to show this level of smoking abstinence.
Still, these results make cytisinicline look slightly less efficacious than an approved anti-smoking drug, Pfizer’s Chantix, which according to its label has shown continuous abstinence rates through 9-12 weeks of 40-51% – although the usual caution about cross-trial comparisons applies.
And Chantix has its own issues, having been linked with suicidal ideation. Adverse events with cytisinicline looked more benign, with the most common being abnormal dreams, insomnia, upper respiratory tract infections and nausea, all seen in 6% of patients in the 3mg three-times-daily arm.
The hope is that cytisinicline, an alkaloid produced from the seeds of the laburnum plant, could be safer than Chantix, which was still a $1bn drug last year despite its side effects.
Patent questions
But Chantix is set to come off patent next year, which could eat into cytisinicline’s potential market. And Achieve has intellectual property issues itself: being a natural product, cytisinicline is not eligible for a composition-of-matter patent.
Achieve is trying to get around this, and was recently granted a patent covering a novel salt form of cytisinicline. The company has also pointed out that it would receive five years’ data exclusivity protection on FDA approval, while an EU green light would secure 10 years.
Cytisinicline has long been available in eastern Europe, at the 1.5mg downward titration dose, where it is also known as Tabex, but Achieve plans to pursue approval in the EU. It hopes that the 3mg three-times-daily dose could differentiate its product.
Other worries for the company include its capital structure. A high number of outstanding warrants leaves current shareholders at risk of being diluted.
If Achieve can get cytisinicline approved it might address a huge market: there are nearly 40 million smokers in the US and over a billion worldwide. Whether the company can get this far is another matter. The group had just $13.9m at the end of March, which will not be enough to fund its phase III trials.
Achieve has said it is looking for a partner; it will have to hope the Orca-1 data are enough to tempt a suitor, as a fundraising looks out of the question for now.

Arcadia up as White House streamlines approval process of new GMO crops

Shares of Arcadia Biosciences Inc (NASDAQ:RKDA) increased by double-digits Wednesday after the Trump administration ordered three federal agencies to ease their rules for approving genetically modified crops and other agricultural biotechnology.
President Trump on Tuesday signed an executive order instructing the Agriculture Department, the Food and Drug Administration and the Environmental Protection Agency — which oversee genetically engineered agricultural products — to review their biotech regulations to streamline the approval processes.
Arcadia, based in Davis, California, is an agricultural biotech company that develops high-value food ingredients and nutritional oils that aim to meet the demand for healthier diets. It also produces a GMO soybean.
The company’s stock closed up 19.6% to $5.91 a share.

The White House wants to bring new agricultural biotechnology to the marketplace faster and with less cost for companies. Also the Trump administration hopes to encourage more investment in GMO crops.
Trump’s executive order comes after the US Agriculture Department last week proposed sweeping changes to biotech rules that would exempt from regulation genetically edited farm products with traits “similar in kind” to modifications that could be produced through traditional breeding techniques.
Arcadia operates in specialty genomics and has a proprietary approach combining conventional breeding and gene editing.
And on Friday the US told the World Trade Organization that it was planning to revise its regulations on importing, transporting and releasing GMOs.
“As a leading U.S. crop improvement company, Arcadia Biosciences is focused on enhancing the nutritional value and quality of food ingredients while improving crop productivity to allow America’s agricultural industry to be more sustainable and prosperous,” a company spokesperson said. “We’re supportive of any legislation that fosters public confidence in science-based crop innovation and streamlines regulatory approaches in order to reduce undue financial and logistical burdens on farmers.”