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Monday, February 4, 2019

Raymond James says to ‘back up the truck’ on Intercept pre-Regenerate data

Raymond James analyst Steven Seedhouse upgraded Intercept to Strong Buy from Outperform and raised his price target to $184 from $125. The analyst cites his “unusually high amount of conviction in REGENERATE” trial data, noting that all the attempts to test his confidence in the investment story have only made him more bullish. Seedhouse states the Street has not fully accepted his expectation that the data will not be a headwind to the program’s success, adding that his key questions heading into the release will be around the efficacy on both primary endpoints and the safety profile of the trial.
https://thefly.com/landingPageNews.php?id=2858357

Brexit: Care home and hospital caterers stockpiling food

Major suppliers to care homes and hospitals are stockpiling food to offset the potential disruption of a no-deal Brexit.
Apetito and Bidfood, who between them supply thousands of care providers, said they were holding extra inventory in case of supply chain problems.
Both said they were prepared but Apetito said it feared others were not.
“We are in a strong position,” said Apetito UK boss Paul Freeston.
“But some firms would not be able to build up big stocks,” like his firm, he said. “Or if they are doing fresh produce they would have to stop. A Hard Brexit could cause them significant economic difficulties.”

Apetito provides pre-made meals to more than 400 hospitals and 450 care homes, as well as 100,000 vulnerable people in their homes.
Mr Freeston said it was spending £5m in building its inventory ahead of Brexit – doubling the raw materials it holds from four to eight weeks’ of stock and pre-made meals from five to six weeks’.
But if the disruption lasted much longer than 12 to 16 weeks, the firm would have “very real difficulties”, because it supplies specialist food for elderly people and those with critical conditions.
But if there are backlogs at UK ports in the event of a no-deal, “the quality of food could suffer and our product range would really narrow”, Mr Freeston said.
The other worry is that if the UK suddenly started trading on World Trade Organisation terms with the EU, the cost of raw materials could jump – and Britain imports about a third of its food from the bloc.
The concerns are shared by Bidfood, which supplies the kitchens of 4,000 care homes and 950 hospitals across the UK, as well as supermarkets, schools and prisons.
Jim Gouldie, its supply chain and technical services director, said the firm had “looked carefully” at products needed by sectors with a “duty of care” and invested in additional warehousing.
Meanwhile Anglia Crown, which manufactures meals for 100 hospital sites, told the BBC it was worried about prices rising after Brexit. A spokeswoman said the company was agreeing prices for “as many commodities as possible, especially any bought in from Europe”.

Are providers secure?

Despite the warnings, the National Care Association said most of the care homes it represents are prepared for any no-deal disruption and have enough food stocks in place – even if that means relying on dried or canned food to carry them through.
But boss Nadra Ahmed is worried that any price shocks to suppliers could end up being passed on to providers.
“Care providers are struggling with funding and recruitment issues already so any increases will increase the challenges they face.”
The Hospital Caterers Association (HCA), which represents hospital catering companies, says most of his members have been preparing for Brexit for some time. And while he is not overly worried about a no deal, he does expect some short term volatility after Brexit.
“A number are making arrangements to increase their stock holding – either on site or by securing commitments from their long-established suppliers,” he says.
“But this clearly is not possible for perishable goods. It is imperative that we ensure continuity of supply to minimise any potential disruption to patients’ menus.”
A government spokesperson said: “Our priority is to make sure that patients continue to receive the same high standard of care.
“We are working closely with the NHS, Defra and healthcare providers to ensure the uninterrupted supply of food and specialised nutritional products to patients, as part of our preparations for a no-deal EU Exit.”

Long-Term Prescription Opioid Use in Severe Osteoarthritis Varies by Region

Target Audience and Goal Statement: Rheumatologists, pain specialists, geriatricians, orthopedists, and primary care physicians
The goal was to examine prescription opioid use among Medicare enrollees with severe osteoarthritis who underwent total joint replacements (TJRs).
Questions Addressed:
  • What was the level of opioid use in the year preceding a TJR and overall among Medicare beneficiaries with advanced osteoarthritis and an indication for pain control?
  • Were there any geographical variations in rates of treatment with long-term opioid therapy in osteoarthritis, which was not fully explained by differences in access to healthcare providers, varying case-mix, or state-level policies?
Synopsis and Perspective:
Based on a recent U.S. News & World Report analysis, the opioid crisis is here to stay for years. This epidemic, which is affecting both children and adults, started 40 years ago and grew exponentially in the ensuing decades. The Department of Health and Human Services statedthat “increased prescription of opioid medications led to widespread misuse of both prescription and non-prescription opioids before it became clear that these medications could indeed be highly addictive.”
Many opioid prescriptions in the U.S. are written for osteoarthritis of the hip or knee — a common reason for chronic pain that today affects nearly 30 million U.S. adults. In the earlier stages of the disease, treatment usually involves non-steroidal anti-inflammatory drugs, steroids, and opioid analgesics. Patients with severe pain that is inadequately controlled by medications are usually candidates for TJRs.
Very little was known about real-world long-term use of opioids in older patients with osteoarthritis. Therefore, Rishi J. Desai, PhD, of Harvard Medical School in Boston, and colleagues, set out to conduct “an observational cohort study in a nationwide sample of Medicare enrollees with severe osteoarthritis to describe long-term opioid use and to evaluate the role of geography and healthcare access in d
Medicare beneficiaries (n=358,121; mean age 74) who underwent TJRs for the treatment of osteoarthritis at 4,080 primary care service areas from 2010 to 2014, where opioid use was reported, were included in this study. The main outcome of interest was the percentage of patients on long-term opioid therapy within each area. Desai’s group also evaluated opioid use in the year preceding each TJR procedure. Another variable of interest was opioid use by geographic region. New York was used as the reference state because of a large sample size and consistently low opioid use reported in previous investigations, the authors noted.
Average daily dose was calculated in morphine milligram equivalents (MME). According to a 2016 CDC guideline, caution should be exercised when prescribing opioids at any dosage, but special attention needs to be paid to the benefit-risk profile when the dose is increased to ≥50 MME per day. A decision to titrate dosage up to ≥90 MME should be carefully justified or avoided if possible.
Most of the patients included were women (67.8%) and white (91.9%). Back and neuropathic pain were highly prevalent among all patients. Of these study subjects, 42.3% were short-term opioid users (<90 days), 16.5% were long-term users (≥90 days), and 40.9% were non-users. Opioid consumption among long-term users was relatively stable over a 3-year period (16.8% in 2011 and 2012, 16.6% in 2013, and 16.3% in 2014).
The median length of use in the long-term group was 7 months, compared with 15 days in the short-term group. About 19% of the long-term users and 15.9% of the short-term users consumed more than 50 MME per day. Use of several opioids were higher in long-term compared with short-term users: tramadol (45.8% vs 36.8%, respectively), oxycodone (32.2% vs 21.7%), and fentanyl (6.2% vs 0.5%).
Opioid prescription rates varied across the U.S., with generally higher rates noted in the South compared with the Northeastern and Midwestern regions. The unadjusted mean percentage of long-term opioid users varied widely across states, ranging from 8.9% in Minnesota to 26.4% in Alabama.
Access to rheumatologists was not associated with long-term opioid use. When comparing areas with the highest concentration of primary care services (>8.6 per 1,000 beneficiaries) versus lowest (<3.6 per 1,000), only a modest association was seen between access to primary care physicians and rates of long-term opioid use (adjusted mean difference 1.4%, 95% CI 0.8%-2.0%).
Study limitations included not having data on pain severity or pain-related functioning for patients in this cohort, limited generalizability (TJR use among blacks was 40% lower than among whites), historical data that may not have captured post-2014 shifts in prescription opioid use patterns in this population (in response to the growing awareness about the opioid epidemic), and the fact that no evaluations were performed to see whether TJR changed opioid use in these patients.
Source Reference: Arthritis & Rheumatology, Jan. 28 2019, DOI: 10.1002/art.40834
Study Highlights: Explanation of Findings
Osteoarthritis is one of the most common reasons for chronic pain in the U.S. The current study had several strengths, e.g., comprehensive risk-adjustment based on patient demographics, comorbid conditions, as well as variation in state-level policies. One in six Medicare enrollees with osteoarthritis used long-term prescription opioids (≥90 days) for pain management in the year leading up to a TJR procedure (average duration ~7 months). Some of the long-term users (~20%) fell into the CDC-defined category of high-risk for opioid-related harms because they consumed an average daily dose of ≥50 MME.
Long-term opioid use observed in this study was more than twofold higher than previously reported estimates, according to the authors. Patients with severe osteoarthritis represent a particularly high-risk group, as they have substantially higher rates of long-term prescription opioid use compared to an average Medicare enrollee.
Results from a separate randomized trial did not support the initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. A Cochrane review of opioids for osteoarthritis stated that “for the pain outcome in particular, observed effects were of questionable clinical relevance.” Taken together with current findings, the need for caution in prescribing opioids for patients with severe osteoarthritis is vital and the authors urged that “special emphasis on periodically monitoring prescription opioid use is required to ensure benefits outweigh risks at prescribed doses.”
Geographic variations in opioid prescription practices noted in this study have also been observed by other researchers who were examining separate outcomes. Regional variations could not fully be explained by differences in access to primary care physicians or rheumatologists, variations in patient characteristics, or state-level policies, including medical marijuana and prescription drug monitoring programs. Overall, the results underscored the need for geographically targeted interventions to ensure widespread dissemination and implementation of safe opioid prescribing guidelines to make a meaningful impact on prescribing practices.
The CDC’s guidelines for the responsible prescription of opioids for chronic pain involves key criteria:
  • Use non-opioid therapies, either alone or in combination with opioid therapy, for treatment of chronic pain; and only consider opioid therapy if the benefits for pain are expected to outweigh the risks
  • Start with the lowest effective dosage and short-acting opioids instead of extended-release/long-acting opioids, when using opioids
  • Follow-up visits should include assessments of whether opioids are improving pain and function without causing harm

What’s New in Biodefense

In 2001, only a week after the 9/11 attacks, members of the media and certain politicians received letters containing anthrax spores. The overall bioterror attacks killed five people and infected 17 more. Eventually, Bruce Ivins, a researcher at the federal government’s biodefense laboratories at Fort Detrick in Frederick, Maryland, was identified as the suspect. Ivins committed suicide with an overdose of acetaminophen on July 29, 2008.
There have been no major bioterror attacks in the U.S. since, although there have been a number of ricin threats—a poison sourced from castor beans—including a letter sent to the U.S. Pentagon containing ricin particles on October 2, 2018. They turned out to be castor seeds, from which ricin is created. Utah resident William Clyde Allen III was arrested and confessed.

Even more notoriously, several people were attacked in the UK by a nerve agent, Novichok, developed by the Soviet Union in the 1970s and 1980s. In March 2018, former Russian military officer and double agent for the UK’s intelligence services, Sergei Skripal, and his daughter Yulia Skripal, were poisoned by Novichok, allegedly by Russian agents, GRU Colonel Anatoliy Chepiga and Dr. Alexander Mishkin, also of the GRU.
Although bioterrorism doesn’t get the kind of attention more traditional bombings and shootings receive, the biotech industry and the federal government are paying attention and actively funding and developing countermeasures to potential bioterror, military and public health emergencies. In fact, in 2015, the global biodefense market was about $9.5 billion. Grand View Research projects that same market to grow to about $18 billion by 2025.
Here’s a look at just some of what’s going on in the biodefense arena.
BARDA
The Biomedical Advanced Research and Development Authority (BARDA) is part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response. It was established in 2006 to help keep the country safe from chemical, biological, radiological, and nuclear (CBRN) threats, in addition to a focus on pandemic influenza (PI) and emerging infectious diseases (EID).
As such, BARDA provides funding and technical assistance to a number of companies and institutions working in these areas.
One of BARDA’s initiatives is dubbed DRIVe (Division of Research, Innovation, and Ventures). DRIVe’s approach is to act more like a strategic investor in private and public companies as well as fund grants. A June 2018 Forbes article noted, “This means that the new division may be able to make direct investments into companies BARDA would like to partner with and derive value by holding equity or equity-like instruments in the venture. Investing in opportunities in this manner offers a pathway to renew funds to reinvest into other ventures deemed essential to the national interest.”
DRIVe’s portfolio includes Emory University’s DeepAISE algorithm for sepsis, Cytovale’s SeptiScan System, Biobeat’s Wrist Watch, Prenosis’ Predictive Analytic Assay and others.
A Ricin Treatment
Recently, researchers at Tulane National Primate Research Center described an experimental drug that appears to counteract the effects of ricin. The research was published in the journal JCI Insight.
The drug, developed by researchers at Tulane, Mapp BiopharmaceuticalUniversity of Texas Southwestern Medical Center, and the New York State Department of Health is a humanized monoclonal antibody against the ricin toxin. There appears, at least in primates, to be a relatively short exposure window of about four hours, when the drug was most successful. The researchers expect to work on a stronger version that could be useful further out from initial ricin exposure.
“Clinically, there is no treatment that can be administered currently to save someone in the event of an exposure to this toxin,” stated study first author Chad Roy, director of biodefense research programs at Tulane. “Our study shows proof of concept in a near-clinical animal model, the nonhuman primate, that we finally have a life-saving treatment against one of the world’s most notorious toxin agents.”
Princeton, NJ-based Soligenix also has a ricin toxin vaccine candidate, RiVax, as part of its Vaccines/BioDefense business segment. The company presented data on the vaccine in November 2018 at the Fourth International Conference on Vaccines Research & Development.
Anthrax Vaccine
On December 31, 2018, Emergent BioSolutions submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization (EUA) of its anthrax vaccine candidate, NuThrax. The FDA is expected to make a decision in the first half of this year.
NuThrax is the company’s next-generation anthrax vaccine candidate for post-exposure prophylaxis. It is a two-dose regimen. The company is hoping it can receive EUA, which would allow it to be included in the Strategic National Stockpile (SNS) this year.
In September 2016, the company received a $1.6 billion contract with BARDA to develop and deliver NuThrax. The company also markets a smallpox vaccine, ACAM2000, and an anthrax monoclonal antibody, Raxibacumab. In the fourth quarter of 2017, Sanofi acquired ACAM2000 and GlaxoSmithKline acquired Raxibacumab.

Regeneron: Euro Panel Recommends OK of Praluent for Cardiovascular Disease

Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for Praluent® (alirocumab) Injection, recommending a new indication to reduce cardiovascular risk by lowering low-density lipoprotein cholesterol (LDL-C) levels as an adjunct to correction of other risk factors in adults with established atherosclerotic cardiovascular disease (ASCVD). Praluent should be used in addition to maximally-tolerated statins or can be used alone in patients intolerant to or inappropriate for statin therapy.
ASCVD is an umbrella term, defined as a build-up of plaque in the arteries that can lead to reduced blood flow and a number of serious conditions such as stroke, peripheral artery disease and acute coronary syndrome (ACS), which includes heart attack and unstable angina.
The CHMP opinion is based on data from ODYSSEY OUTCOMES, a Phase 3 cardiovascular outcomes trial that assessed the effect of Praluent in 18,924 patients who had an ACS between 1-12 months (median 2.6 months) before enrolling in the trial. Results from the ODYSSEY OUTCOMES trial were published in The New England Journal of Medicine in 2018.
The European Commission is expected to make a final decision in the coming months. Data from ODYSSEY OUTCOMES have also been submitted to the U.S. Food and Drug Administration (FDA), with a target action date of April 28, 2019.

FDA Action Alert: Sanofi, Motif Bio and Merck

Over the next two weeks, the U.S. Food and Drug Administration (FDA) has three upcoming decisions. Here’s a look.
Sanofi’s Biologics License Application for Caplacizumab for aTTP
France’s Sanofi has a target action date of February 6 for its caplacizumab for acquired thrombotic thrombocytopenic purpura (aTTP), a life-threatening, autoimmune-based blood clotting disorder. The disease is marked by extensive blood clot formation in the small blood vessels of the body. This can lead to severe thrombocytopenia, which is a very low platelet count, microangiopathic hemolytic anemia, which is red blood cell destruction, and restricted blood supply throughout the body, or ischemia. This can cause widespread organ damage, particularly in the heart and brain.
The drug was approved under the brand name Cablivi by the European Commission in August 2018. The drug was developed by Ablynx, a Sanofi company. It is the company’s first Nanobody-based drug to receive approval and the first newly approved product that is part of Sanofi Genzyme’s Rare Blood Disorders franchise.

Motif Bio’s Antibiotic for Skin Infections
Motif Bio, with offices in New York and London, has a target action date of February 13 for its New Drug Application (NDA) for iclaprim, a targeted, Gram-positive investigational antibiotic for the treatment of acute bacterial skin and skin structure infections. The company also plans to develop the antibiotic for hospital-acquired pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP). A Phase II trial in patients with HABP has been completed and a Phase III trial is planned.
Iclaprim has received Qualified Infectious Disease Product (QIDP) designation from the FDA along with Fast Track designation for the ABSSSI indication.
The company presented iclaprim data in October at the IDWeek conference in San Francisco, showing it was non-inferior to vancomycin in a pooled analysis of a subgroup of patients in the REVIVE Phase III clinical trials in patients with wound infections.
G. Ralph Corey, Gary Hock Professor at Duke University School of Medicine and principal investigator of the REVIVE-2 trial, stated at the time, “Wound infections, including surgical site infections, can be difficult to treat and it was important to see that iclaprim was non-inferior to standard of care in treating these types of infections. Additionally, in the iclaprim treatment arm, there was no evidence of nephrotoxicity, while two patients in the vancomycin arm demonstrated high serum creatinine levels.”
Merck’s Checkpoint Inhibitor Keytruda Up for Another Indication
Merck & Company has a target action date of February 16 for its supplemental Biologics License Application (sBLA) for Keytruda, its anti-PD-1 therapy. It is being reviewed as adjuvant therapy in patients with resected, high-risk stage III melanoma. The sBLA is based on data from the pivotal Phase III EORTC1325/KEYNOTE-054 trial, which showed significant benefit in recurrence-free survival. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting 2018 and published in The New England Journal of Medicine.
In June, when the acceptance of the sBLA was announced, Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories, stated, “EORTC1325/KEYNOTE-054 was the first trial with Keytruda to demonstrate a recurrence-free survival benefit in the adjuvant setting, and we continue to actively investigate Keytruda in the adjuvant or neoadjuvant setting across our broad clinical development program.”
On Jan. 3, Merck announced that Keytruda had been approved for this indication by the Japan Pharmaceuticals and Medical Devices Agency (PMDA), as well as for four other indications: in combination with pemetrexed and platinum-based chemo for first-line unresectable, advanced/recurrent nonsquamous NSCLC regardless of PD-L1 expression; in combination with carboplatin and paclitaxel or nab-paclitaxel for first-line treatment of unresectable, advanced/recurrent squamous NSCLC regardless of PD-L1 expression; monotherapy in first-line treatment of PD-L1-positive unresectable, advanced/recurrent NSCLC; and as monotherapy for advanced/recurrent MSI-H solid tumors that have progressed after chemotherapy.

Moderna’s Not the Only One: A Look at the mRNA Market

Although Moderna gets the lion’s share of attention in the mRNA market, it’s not the only company working to break away with this potentially disruptive technology.
Messenger RNA (mRNA) is a family of RNA molecules that transport genetic information from DNA to the ribosome, where it specifies the amino acid sequence that creates proteins. In theory, by coding your own mRNA, it should be possible to insert it into the cells and turn them into protein factories churning out whatever drug or molecule you program it to.

Moderna is the most prominent player in the field although it has yet to get a product to market. In December, the company went public, raising $604 million with its IPO. The company’s value is tagged at around $7.5 billion.
The company has a development pipeline of 21 programs. Ten are in the clinic and another three have open Investigational New Drug (INDs) submissions. Nine of those in the clinic are in Phase I and one is in Phase II, according to a July 2018 update.
But Moderna is not alone.
In August 2018, Pfizer entered a collaboration deal with Mainz, Germany-based BioNTech to develop mRNA-based vaccines to prevent influenza (flu). The two companies will jointly conduct research and development to advance the vaccines. Pfizer paid BioNTech $120 million upfront along with equity and near-term research payments. Another $305 million in milestones is up for grabs and if the vaccines make it to market, BioNTech will receive up to double-digit tiered royalties.
Earlier this month, Paris-based Sanofi extended a deal with BioNTech to co-develop and co-commercialize a cancer vaccine based on mRNA. And this deal follows a July deal Sanofi made with Lexington, Mass.-based Translate Bio to develop an mRNA vaccine for up to five infectious diseases. Sanofi Pasteur paid Translate Bio an upfront payment of $45 million. Translate Bio is eligible for up to $805 million in payments, including a $45 million upfront payment and various milestone payments and royalties.
On January 3, Translate Bio announced that its Phase I/II clinical trial of MRT5005, an mRNA treatment for cystic fibrosis, was ongoing. It also announced that its MRT5201, an mRNA candidate for patients with OTC deficiency, a common urea cycle disorder, was advancing, with the trial expected to begin in the first half of this year. However, on January 22, the company indicated the U.S. Food and Drug Administration (FDA) had requested more information about the IND submission for MRT5201.
Another company making waves in the mRNA market is CureVac, based in Tubingen, Germany and Boston. On October 23, 2018, the company announced it had initiated its Phase I dose-escalation trial of its mRNA-based rabies vaccine, CV7202. CV7202 is a “prophylactic mRNA-based vaccine encoding the rabies virus glycoprotein, RABV-G, formulated with the next generation LNP.”
LNP stands for Lipid Nanoparticle, which is a type of delivery system for mRNA.
On Jan. 8, 2019, the U.S. Patent and Trademark Office (USPTO) granted CureVac a fundamental patent for the use of MRNA for the Respiratory Syncytial Virus (RSV) F-protein to be used to vaccinate infants.
CureVac also has deals with Sanofi, Eli Lilly, and Boehringer Ingelheim.
In theory, mRNA could be used to treat any disease. However, it’s not all that simple. The major challenge is getting the mRNA to the right cells in order to express the protein. As a result, companies have tended to focus on what is often deemed “low-hanging fruit,” such as vaccines and cancer immunotherapies. That’s the case of CureVac, BioNTech and Moderna, but Translate Bio is focusing on a significantly more difficult challenge of cystic fibrosis.