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Friday, May 4, 2018

Attacking treatment-resistant prostate cancer by blocking its stress response

Prostate cancer cells rely on protein synthesis to fuel their growth, but there can be too much of a good thing: Prostate tumors that are flooded with protein will actually die. Research has shown that treatment-resistant prostate cancer has a built-in stress response—an automatic brake that prevents protein synthesis from getting out of control and killing the cancer cells. Now researchers at the University of California, San Francisco, are figuring out how to interfere with that brake so prostate-cancer cells will set off on a path to self-destruction.
The scientists focused their attention on two genetic mutations seen in half of patients with treatment-resistant prostate cancer. One mutation activates the cancer-causing gene MYC, while the other disables PTEN, a tumor suppressor. They discovered that aggressive prostate tumors with both mutations have low rates of protein synthesis, and they traced that anomaly to a specific protein called P-eIF2a, which dials down overall protein production in cells.
From there, they went on the hunt for a compound that could block P-eIF2a. They found it in an unlikely place: a UCSF lab that’s studying severe brain damage. A compound called ISRIB, which was developed in that lab, prevents P-eIF2a from doing its job, they discovered. They reported their findings in the journal Science Translational Medicine.
“We have discovered the molecular restraints that let cancer cells keep their addiction under control and showed that if we remove these restraints they quickly burn out under the pressure of their own greed for protein,” said senior author Davide Ruggero, Ph.D., professor of urology and cellular and molecular pharmacology at UCSF, in a statement.

More than 1 in 10 men will be diagnosed with prostate cancer at some point in their lives, and 1 in 41 will die of the disease, making it the second leading cause of cancer death in American men, according to the American Cancer Society. Aggressive prostate tumors often respond to hormone therapy, but most become resistant to that, too.
Several companies and academic research centers are pursuing new technologies aimed at combating aggressive prostate cancer. Tmunity Therapeutics, for example, is working on a CAR-T treatment for prostate cancer and recently pulled in a $100 million series A to help fund that research. The rise of DNA sequencing has pointed to several new targets in the disease, including mutations in BRCA1 and BRCA2 that could open up the possibility of treating aggressive cases with PARP inhibitors.
To test the potential of ISRIB, the UCSF researchers implanted cells from a prostate cancer treatment into mice and showed they could shrink the tumors with the drug. ISRIB also extended survival, they reported, and normal cells were unaffected. They believe the findings should be used to design trials of ISRIB in patients with aggressive prostate tumors.

Celgene to refile MS med after FDA rebuff

Celgene suffered an embarrassing setback in February when it got a refuse-to-file letter for its multiple sclerosis drug ozanimod. Now, the company says, it expects to resubmit the NDA in the first quarter of 2019, delaying its timeline by a year.
The delay is a blow to a potential blockbuster that would, with a better safety profile, rival Novartis’ Gilenya. Celgene will have to wait a little longer to start reaping sales that could reach $5 billion a year. But it could be worse—while the 2019 timeframe isn’t great, it is still “better than worst fears of 2020 refiling and long delay,” wrote Jefferies analysts in a note to investors.
“Key questions will be around what FDA wanted for refiling (likely two-year animal cancer carcinogenicity studies due to new metabolite found at high levels in humans),” the analysts said.
The FDA sent the refuse-to-file notice because the Celgene failed to provide the necessary preclinical and clinical pharmacology information on ozanimod. At the time, management explained that the letter was not related to concerns about S1P receptor modulators and said it thought it could use existing activities to address some of the agency’s feedback.

While Celgene was optimistic, the impact of the FDA’s refusal and the ensuing delay could extend beyond ozanimod’s immediate future. It may also color perceptions of Celgene and confidence in its ability to deliver in the coming years.

Surge in ‘Deaths of Despair’ Hits the US

Gaps in mental health care services are pervasive in the United States, at a time when deaths from suicide, alcohol, and drugs have surged, according to a new report released today by the Commonwealth Fund.
The combined rate of deaths from suicide, alcohol, opioids, and other drugs — sometimes called “deaths of despair” — increased 50% from 2005 to 2016. Rates rose in all states, doubling or more than doubling in Delaware, New Hampshire, New York, Ohio, and West Virginia, the report notes.
What’s more, the pace seems to have picked up. Average annual growth in deaths of despair was 3% per year from 2005 to 2014 but tripled to 9% from 2015 to 2016.
“This is one of the most troubling mortality trends we see in this year’s report,” David Radley, PhD, senior scientist at the Commonwealth Fund, noted in a media briefing outlining key findings from the Commonwealth Fund’s 2018 Scorecard on State Health System Performance.
The report assesses all 50 states and the District of Columbia on 43 measures dealing with access to healthcare, quality of care, efficiency in care delivery, health outcomes, and income-based healthcare disparities.
“The Scorecard reports, published since 2006, are a comprehensive overview of how well the healthcare system is working for the American people,” said David Blumenthal, MD, president of the Commonwealth Fund.
Although the 2018 Scorecard report provides some “good news about the direction we are heading, we do continue to see wide disparities between states,” said Blumenthal.
“Also of concern are some areas where we see no progress or even reversal of positive trends. For example, life expectancy has fallen, in large part due to the opioid epidemic; premature deaths from preventable or treatable causes are increasing in many states; and obesity rates continue to rise representing a public health crisis of grave concern,” Blumenthal said.

Unmet Mental Health Care Needs

The report confirms that accessing mental health care is tough in the United States. Up to one quarter of adults with a mental illness reported a need for care that was not met during the 2013-2015 period, and up to one third of children needing mental health treatment in 2016 did not receive it. Across states, 41% to 66% of adults with symptoms of a mental illness received no treatment in 2013-2015.
Deaths from treatable conditions are also moving in the wrong direction. After trending downward for most of the past decade, there has been an uptick nationally in premature deaths from preventable or treatable causes — a measure called “mortality amenable to health care.”
Two thirds of states saw an increase in 2014-2015 in this measure. In six states — Colorado, Maine, Nebraska, Oklahoma, Vermont, and Wyoming — the increase was greater than 5%.
“Premature deaths are on the rise in states across the country. Some of this is driven by deaths from substance abuse, but increases in deaths from treatable conditions is a sign that healthcare systems are also falling short,” said Radley.
Obesity remains an ongoing public health threat as well, the report notes. In Mississippi and West Virginia, the proportion of adults who are obese reached 39% in 2016. Even in states with the lowest rates, a quarter of all adults are obese.

Best, Worst Performers

Still, on balance, the 2018 report shows that across all dimensions of performance of state healthcare systems, there was more improvement than worsening from 2013 to 2016 — a reversal of what happened during the 2000s, when progress stalled or perfomance worsened.
By region, New England, the Upper Midwest, and several states in the West are at the top of the overall rankings. Southern states generally rank at the bottom.
By individual state performance, Hawaii, Massachusetts, Minnesota, Vermont, and Utah are the top-ranked, and Louisiana, Oklahoma, and Mississippi are the bottom-ranked.
California and Oregon made the greatest gains, jumping 9 and 10 spots, respectively. Both states expanded eligibility for Medicaid.
New York improved on 18 of the 37 indicators tracked over time, the most of any state. Arkansas, Louisiana, Oklahoma, and West Virginia each improved on 17 indicators.
The report also shows that the expansion of Medicaid has led to gains in access to care. In 47 states, the rate for adults aged 19 to 64 who are uninsured was at least five percentage points lower in 2016 than it had been in 2013. Eleven of the 13 states in which there was at least a 10-point drop had expanded Medicaid overage by January 2016. During this time, there was also a drop in the percentage of people reporting that they had not gone to the doctor when needed, owing to cost. States that expanded Medicaid coverage saw greater improvement, on average, than states that did not.
“Scaling back or even repealing pieces of the Affordable Care Act could put many of those improvements that we see in the Scorecard in jeopardy across states,” Radley warned.
The report concludes that if every state achieved the performance of the top-ranked state on each indicator, the gains in healthcare access, quality, efficiency, and outcomes would be “dramatic.” With the current rates of improvement, however, it may take many years or decades for states and the nation to see such progress.
Table. National Gains If All States Achieved Top Rates of Performance
18 million more adults and children insured
14 million fewer adults skipping care because of cost
26 million more adults with a usual source of care
11 million more adults undergoing recommended cancer screenings
837,000 more young children receiving all recommended vaccines
1 million fewer Medicare beneficiaries receiving a high-risk prescription drug
440,000 fewer hospital readmissions
5.7 million fewer unnecessary emergency department visits
89,000 fewer deaths before age 75 from treatable disease

The full report is available online.

Orasure selloff overdone: Canaccord

OraSure selloff looks overdone, says Canaccord. Canaccord analyst Mark Massaro noted OraSure shares traded down following its Q1 beat. The analyst thinks the weakness is overblown as he notes molecular collections grew revenues 72% year-over-year and continues to win new business in a huge market. He also noted the leadership changes and the ongoing strategic review. Massaro maintained his Buy rating and lowered his price target to $20 from $24 on OraSure shares.

Health Insurance Innovations stays top pick after beat, raise: Canaccord

Health Insurance Innovations remains a top pick, says Canaccord. Canaccord analyst Richard Close said the magnitude of the pullback in Health Insurance Innovations following its beat and raise Q1 report was surprising. He said it the company remains a top pick as the outlook is improving with a likely near-term resolution to the multi-state investigation, probable reversal of the 3-month duration limit on short term medical, and the individual mandate penalty going away in 2019. Close reiterated his Buy rating and $55 price target on Health Insurance Innovations shares

Cerner target cut by SunTrust

Cerner price target lowered to $58 from $68 at SunTrust. SunTrust analyst Sandy Draper lowered his price target on Cerner to $58, saying the downside from his previously expressed concerns about a difficult market, high multiple, and optimistic consensus came “quicker than expected”. The analyst states that the company should consider share repurchases in order to generate double-digit EPS growth given the “difficult macro environment”.

Herbalife target upped by SunTrust

Herbalife Nutrition price target raised to $105 from $76 at SunTrust. SunTrust analyst Michael Swartz raised his price target on Herbalife to $105 following its Q1 earnings beat that also showed “improving trends in the U.S.” The analyst notes however that China volume fell dramatically by 23% after last year’s price increase. Swartz keeps his Hold rating on Herbalife and recommends that investors don’t chase the stock price after its year-to-date gains.