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Tuesday, July 23, 2019

Doctors find differences in brains of US diplomats alleging Cuba mystery attacks

A group of U.S. government workers potentially exposed to unexplained phenomena in Cuba have less white matter in their brains and less connectivity in the areas that control vision and hearing than similar healthy people, doctors have found.
The findings from University of Pennsylvania researchers are the most specific to date about the neurological condition of the U.S. diplomats, spies and their families who reported strange sounds and sensations while serving in Havana between 2016 and 2018.
Yet while doctors found “significant differences” in their brains compared to a control group, they couldn’t say whether they were caused by whatever may have happened in Cuba, nor whether those differences account for the Americans’ symptoms.
Image: Brain scan
Maps of white matter and gray matter tissue volume were created for each participant using T1-weighted images and registering them to a template. For panel A, axial views of the brain, and panel B, sagittal views of the cerebellum and cerebrum, locations of chosen slices are shown by red lines on the template brain (first image in each panel).
The medical findings, revealed Tuesday in the Journal of the American Medical Association, come as U.S. national security officials tell NBC News that more than two years into the mystery, the government still has not determined who or what is responsible for what transpired in Havana.
The FBI, enlisted in 2017 to investigate what the U.S. has called “targeted attacks,” paid multiple trips to Havana but has exhausted its leads in the case, individuals briefed on the investigation say. While the investigation hasn’t been formally closed, no external energy source in Cuba has yet been identified that could have caused the injuries, they said. The FBI declined to comment.
Although the Trump administration has not retreated from its assertions that its workers in Cuba were attacked, officials at the FBI, the CIA and the State Department are also examining the possibility that mass psychogenic illness, or psychosomatic symptoms that spread through a community, may be to blame in at least some of the cases, officials said.
The Cuban Embassy in Washington didn’t respond to a request for comment. But Dr. Mitchell Joseph Valdés-Sosa, the Cuban Neuroscience Center chief who has been investigating the U.S. claims, said there were major “causes for concern” in the study’s methodology, including the makeup of the control group and assertions about brain changes that he said could have resulted from “many factors, including psychological states.”
“The most worrisome aspect is the attempt to link these findings with an unspecified ‘directional phenomenon,'” Valdés-Sosa said. “The research in this area has been cloaked in secrecy, and driven by cold war paranoia.”
Twenty-six Americans who served in Cuba were “medically confirmed” by the State Department to have been affected. The Penn study included most of those workers, their relatives who lived with them and other U.S. workers referred to Penn for potential exposure, bringing the total to 40.
Using a battery of advanced MRIs, researchers created a detailed map of their brains, including the pathways and connections that let parts of the brain communicate with one another. It takes a computer more than 24 hours to process the data and create the maps, officials tell NBC News. The results from all individuals in the Cuba group were combined, then custom software was used to compare those results to a map made from MRIs of 48 individuals of similar age and ethnicity.
Doctors found that in measuring white matter — nerve fibers that form the brain’s communications network — the Cuba patients had a mean volume that was 27 cubic centimeters smaller than the control patients. Overall, they had similar volumes of grey matter — rich with brain cells that process information — but in some regions of the brain, the Cuba patients had more grey matter.
Advanced neuroimaging that tracks how water molecules travel through the brain found decreased connectivity in the networks related to seeing and hearing, which tracks with many of the symptoms reported, but not in the networks that handle higher-level thinking processes. Still, doctors were unable to draw a clear connection between the findings and the patients’ symptoms, which also included problems with balance, sleep and memory.
In 2018, similar incidents were reported among U.S. government workers serving in Guangzhou, China, and one American was “medically confirmed” by the State Department to have been affected. The Penn study was limited to Americans who were in Cuba, none of whom have been publicly identified.
NBC News Medical Correspondent Dr. John Torres said the small sample size and high sensitivity of the brain scans could have produced results that appear unusual but aren’t clinically significant.
“Even though, as a group, these government personnel have changes to parts of their brains seen on MRI images, those changes cannot be tied directly to what they report happened in Cuba,” Dr. Torres said.
Starting in late 2016, U.S. diplomats and intelligence officers in Cuba started reporting strange incidents that the Penn study describes as “potential exposure to uncharacterized directional phenomena” of unknown origins, “manifesting as pressure, vibration or sound.” Some reported ear-piercing sounds in their homes at night that would suddenly disappear when they moved just a few feet away.
The mysterious noises initially led investigators to suspect a sonic weapon, but investigators ruled out the possibility sound waves could have caused the damage. Officials have explored other possibilities such as a microwave or other electromagnetic energy source, as well as potential environmental causes and psychosomatic illness.
Because of how much is still unknown about the brain’s inner workings, it’s difficult to say whether any of those theories could neatly explain the specific changes to brain matter volume and connectivity identified by the MRI study, medical experts said.
The bizarre saga has inflicted significant damage on a U.S.-Cuba relationship that was only beginning to warm in recent years following half a century of enmity.
After declaring that its diplomats had been attacked, the United States pulled most of its workers out of Cuba and warned all Americans not to travel there. Those ties have been further weakened by the Trump administration’s crackdown on Cuba and re-imposition of sanctions and travel restrictions that had been eased during the Obama administration.
In addition to Penn’s study, the National Institutes of Health is conducting its own “brain injury research study” involving the Cuba patients with help from Energy Department supercomputers and national laboratories capable of processing massive amounts of neurological data. The Defense Department has also been engaged to look into technologies that could have been used to harm the Americans, NBC News has reported.
The State Department said it was aware of the new study from Penn doctors and “welcomes the medical community’s discussion on this incredibly complex issue.”
“The department’s top priority remains the safety, security and well-being of its staff,” the State Department said in a statement.

$100B settlement? Or much less? Opioid payouts a mystery until J&J judge rules

After Johnson & Johnson failed in its latest bid to toss out the opioid suit playing out in an Oklahoma courtroom, the possibility of a settlement continues to grow. For analysts watching the case as a bellwether for other opioid suits, the question is how big the payout could get.
Short answer: Who knows?
Monday, a judge threw out J&J’s final attempt to dismiss the illegal marketing lawsuit it faces in Oklahoma over sales of its opioid products in the state.
J&J, which prosecutors described as the “kingpin” of the state’s opioid epidemic in their closing arguments last week, argued its portrayal by the state as a public nuisance was invalid and violated its First Amendment rights.
The bench judge and state attorney Brad Beckworth weren’t having it.
“No man or woman has ever laid down their life for this country so that a pharmaceutical company could come out and lie or hook kids on opioids,” Beckworth said.

With the possibility of a settlement or trial loss on the horizon, analysts are closely watching the J&J case as an indicator of what could happen in other opioid lawsuits, including a massive multidistrict litigation involving more than 1,600 cities and counties.
That case is no joke: The drugmakers, distributors and manufacturers involved could be liable for up to $100 billion, according to Wells Fargo analyst David Maris.
After an interview with Yale law professor Abbe Gluck, Maris said a settlement was becoming increasingly likely as the judge in the case seeks a neat resolution to the sprawling and complicated claims. Gluck said a settlement would likely hit opioid manufacturers—and distributors and retailers, too.
“(Gluck) stated that a $100B+ master settlement is in the realm of possibility and could ultimately result in company bankruptcies if they cannot meet the obligations,” Maris said in a note to investors last week.

While it’s still unclear how a settlement of that type would work, prosecutors have floated the idea of a novel “negotiating class” for plaintiffs in which counties and cities could opt in and vote on a single negotiated settlement.
However, two former chief prosecutors in Connecticut—Attorney General George Jepsen and Deputy Attorney General Perry Zinn Rowthorn—argued in an op-ed last week that the proposed framework could provide outsized power to small municipalities and require plaintiffs to opt in without knowing a proposed settlement amount.

A nine-figure settlement could mean big payouts from drugmakers named in the suit, but at least one analyst is projecting more modest settlements for four companies—Mylan, Teva, Endo and Amneal: $8.5 billion combined.
SVB Leerink analyst Ami Fadia said Monday that Endo, Teva and Amneal could pay around $4 billion, $2.5 billion and $1.2 billion, respectively, for their liability in a range of opioid suits. While Fadia said projecting an exact settlement is “almost impossible at this point,” those three payouts would rank among some of the largest ever levied against a drugmaker in federal court.

Gilead Profiles Descovy for Potential Use as HIV PrEP Compared With Truvada

Gilead Sciences, Inc. (NASDAQ: GILD) today presented additional results from the DISCOVER trial evaluating an investigational use of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets; F/TAF) for HIV pre-exposure prophylaxis (PrEP). In a sub-analysis of the DISCOVER trial, Descovy reached intracellular drug concentration levels above the estimated protective threshold significantly more quickly than Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg tablets; F/TDF), and additional pharmacokinetic data confirm that these drug concentration levels persist longer than Truvada. The results were presented at the 10th International AIDS Society Conference on HIV Science (IAS 2019) being held in Mexico City.
“Gilead is committed to driving advances in HIV prevention and supporting broader public health initiatives that are designed to reduce HIV infections,” said Diana Brainard, MD, Senior Vice President, HIV and Emerging Viruses, Gilead Sciences. “These results presented at IAS provide further evidence supporting the potential for Descovy for PrEP™ to offer an important new prevention option for people at risk of acquiring HIV.”
In April, Gilead submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for once-daily Descovy for PrEP. A Priority Review voucher was submitted with the filing, leading to an anticipated review time of six months. Descovy was approved in the United States in 2016 for the treatment of HIV-1 infection in combination with other antiretroviral agents, and the use of Descovy for a PrEP indication is investigational. Descovy and Truvada have a Boxed Warning in their U.S. product label regarding the risk of post-treatment acute exacerbation of hepatitis B; Truvada for PrEP also includes a Boxed Warning regarding the risk of drug resistance with use of Truvada for PrEP in undiagnosed early HIV infection.

BioLife: SAVSU Partners with United Cargo on Cell, Gene Therapy Cold Chain

BioLife Solutions, Inc. (NASDAQ: BLFS), a leading developer and supplier of a portfolio of best in class bioproduction tools for cell and gene therapies, today announced that SAVSU Technologies, a leading developer of advanced cold chain management tools for cell and gene therapies, has partnered with United Cargo to offer timely, efficient, same-day airport-to-airport service of vital medical shipments when time is of the utmost importance.
Mike Rice, BioLife CEO, remarked, ‘SAVSU is continuing to build strong partnerships with best in class service providers in the cell and gene therapy distribution ecosystem. Their highly competitive approach offers the most advanced smart container and SaaS technologies, and a go-to market strategy that enables the specialty couriers to fully leverage the existing worldwide infrastructure of United Cargo. We believe SAVSU is on the verge of breaking out with significant product adoption by a marquee list of cell and gene therapy customers.’
BioLife previously announced that it had exercised its option to acquire the remaining 56% of the outstanding shares of privately held SAVSU that it currently does not own in exchange for 1.1 million shares of BioLife common stock. The acquisition will be pursuant to a share purchase agreement and is expected to close within 30 days.

MS drug helps Biogen beat Wall Street profit expectations

 Biogen Inc reported better-than-expected second quarter profit and raised its 2019 earnings forecast on Tuesday, driven by higher sales of its top-selling multiple sclerosis drug Tecfidera and lower taxes.

Shares of the U.S. biotechnology company rose more than 5% to $244.74.
Tecfidera sales of $1.15 billion (£924.21 million) topped analysts’ estimates of $1.05 billion and accounted for nearly a third of second-quarter revenue of $3.62 billion.
But Wall Street’s focus has shifted to Biogen’s newer growth driver Spinraza, a treatment for a rare, often fatal muscular disorder called spinal muscular atrophy (SMA), particularly in light of the recent failure of Biogen’s leading experimental Alzheimer’s disease treatment.
While Spinraza sales rose 15.4% from a year ago to $488 million, they fell short of lofty Wall Street estimates of $535.1 million, according to Refinitiv data.
The company said overseas sales of Spinraza came under pressure from a pricing adjustment in France, and as patients moved to a lower-priced maintenance dose from an induction dose in some mature markets.
The recent launch of Zolgensma, Novartis one-time gene therapy for SMA, is expected to further pressure Spinraza sales.
Biogen said it sees ample opportunity for growth as Spinraza has only reached 20% of adults in the United States.
“We believe Spinraza will remain a foundation of care in SMA for years to come,” Biogen research chief Michael Ehlers said.
Credit Suisse analyst Evan Seigerman said the Novartis treatment could begin to eat into Spinraza sales in 2020.
“In a vacuum, this quarter was good, but the results don’t solve a lot of our longer term concerns about the growth profile of the company,” he said.
In addition to the Alzheimer’s failure, Tecfidera is facing patent challenges and increased competition from newer treatments, such as Roche’s Ocrevus.
Biogen said it now expects 2019 adjusted earnings of $31.50 to $32.30 per share, up from its prior view of $28 to $29. Analysts were forecasting $29.70 per share.
Excluding items, Biogen earned $9.15 per share, breezing past analysts’ average estimate of $7.53. Much of the beat was due to lower costs and a tax rate of 14%, well below the expectation of 18% to 19%, analysts said.
Net income attributable to the company rose 72% to $1.49 billion in the quarter.

Hikma, Civica Rx in long-term agreement to reduce US generic drug shortages

Hikma Pharmaceuticals PLC(Hikma, Group) (LSE: HIK) (NASDAQ Dubai: HIK) (OTC: HKMPY) (rated Ba1 Moody’s / BB+ S&P, both stable), the multinational generic pharmaceutical company and Civica Rx (Civica, Inc.) today announce a five-year agreement to manufacture and supply Civica’s growing membership of US health systems with medications that are often in short supply in US hospitals.

Under the agreement, Hikma will produce 14 essential sterile injectable medications for Civica as a private label distributor, using Hikma’s Abbreviated New Drug Applications (ANDAs) and Civica’s labeling and National Drug Code (NDC). These medicines are used daily by hospitals in emergency care, surgery, pain management and in treating hypertension. The list of products included in the agreement will be publicly announced in the near future, and initial shipments are expected to begin before the end of 2019.
Civica was founded in 2018 by leading US hospital systems concerned about generic drug shortages and philanthropic organizations passionate about improving healthcare. To date, more than 30 health systems are Civica members, representing more than 900 US hospitals and approximately 30 percent of all licensed US hospital beds.
Hikma is the third largest US supplier of generic injectable medicines with a growing portfolio of more than 100 injectable products. Today, one in every six generic injectable medicines used in US hospitals is a Hikma product. During the last three years, Hikma has launched more than 20 medications into US shortage situations and in 2016 the company received a Drug Shortage Assistance Award from the US Food and Drug Administration (FDA) for its role in preventing or alleviating drug shortages.

Merck Presents Early Data on Extended Delivery Subdermal Anti-HIV-1 Agent

Merck & Company (NYSE: MRK), known as MSD outside the United States and Canada, announced today results from a Phase 1 study evaluating the pharmacokinetics and safety of a prototype subdermal drug-eluting implant for extended administration of islatravir, the company’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), in healthy volunteers. The early findings of this prototype were presented as a late-breaking oral presentation (Abstract TUAC0401LB) at the 10th International AIDS Society Conference on HIV Science (IAS 2019) in Mexico City and featured in the official IAS 2019 press program.
“We are encouraged by the results of this proof of concept study exploring the potential of delivering meaningful doses of islatravir over a 12-week period,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “At Merck, we recognize multiple options are needed to address the needs of individuals at risk of HIV-1, and we are committed to investigating those options. Through the application of our established expertise in drug delivery, we are seeking to capture the potential of islatravir for HIV-1 pre-exposure prophylaxis (PrEP).”
Merck is conducting a broad development program to evaluate the potential of islatravir for the treatment and prevention of HIV-1 infection. The lead program in treatment of HIV-1 infection is assessing a once-daily, oral, 2-drug regimen. The company is also exploring several potential options for PrEP, including a drug-eluting implant, as noted above, and a once-monthly oral formulation. The investigational once-daily, 2-drug regimen for the treatment of HIV-1 treatment will be presented as a late-breaking oral presentation tomorrow (July 24) and is in the official press program at the IAS 2019. For the once-monthly oral formulation for PrEP, Merck plans to initiate a Phase 2, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of investigational oral islatravir once-monthly in participants at low- risk for HIV-1 infection (ClinicalTrials.gov: NCT04003103). The trial is due to commence recruitment in September 2019.