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Sunday, January 27, 2019

Pfizer Pivots to Cancer Drugs for Growth


Twenty years ago, Pfizer Inc. didn’t sell any drugs treating cancer. Now, it sells 17, including four that were approved in the U.S. at the end of last year, more than any other pharmaceutical company.
The new lineup is projected to generate $8.3 billion in sales this year, according to EvaluatePharma. For the first time, Pfizer in 2019 expects oncology products to outsell the heart and other primary-care medicines the company was long known for.
Pfizer is throwing in with other big drug companies trying to expand their footprint in cancer or gain a toehold, even as many startups hunt for new therapies, too. Driving the attraction: new insights about the disease’s biology that have paved the way for discovery of treatments, combined with major commercial potential if those therapies reach the market.
It is a significant transformation for Pfizer, whose sales of pills like Lipitor for high cholesterol, and other drugs for common ailments, powered its rise into one of the world’s biggest drugmakers. Now, the company is seeking a new round of growth by treating cancer.
“At Pfizer, oncology is one of the core components of the organization — going from an almost afterthought,” said Andy Schmeltz, who runs the business.
Drug-company marketers like the category because promoting the therapies to cancer doctors and hospitals requires a smaller sales force than was needed to sell cholesterol and hypertension medicines to the much larger cadre of primary-care physicians.
Cancer-drug sales are projected to reach $138 billion world-wide this year and are growing 11% a year, according to EvaluatePharma. A year’s treatment typically lists for more than $100,000.
“The unmet need as well as the biological advances are still so significant that there’s a lot of room for a lot of people to be successful,” said Emma Walmsley, chief executive of GlaxoSmithKline PLC, in an interview. Glaxo is trying to get back into cancer-drug sales after exiting from the market in 2014.
This month, Bristol-Myers Squibb Co. said it would buy Celgene Corp. in a $74 billion deal uniting two leading cancer-drug sellers, while Eli Lilly & Co. said it would pay $8 billion for Loxo Oncology Inc. and its drug attacking tumors with a specific genetic alteration.
Yet as more drugs come to market, their manufacturers are likely to square off against each other for patients, eating into each other’s sales. Returns could be further squeezed as the drugs target narrower slices of patients.
And high prices risk triggering cost-control efforts from health plans, especially if more of the drugs are used in combination with other expensive medicines.
“One of the big issues societies and health-care systems will face in the future is how do you finance combination therapy in oncology. It’s a big question without an easy answer,” said Christophe Weber, CEO of Takeda Pharmaceutical Co., in an interview.
New York-based Pfizer was selling billions of dollars in Lipitor pills for high cholesterol, Norvasc for hypertension and Viagra for male impotence when executives began building a dedicated cancer-drugs unit in 2008 as part of a search for new revenue to offset looming patent expirations.
The new strategy, company officials say, included hiring leading scientists like Vanderbilt University Medical Center’s Dr. Mace Rothenberg, now Pfizer’s chief medical officer, to build the company’s cancer capabilities. Pfizer also collaborated with prominent cancer experts in academia and worked to speed up drug development.
Pfizer also used deals to acquire promising drugs it could plug into its pipeline or add approved products to the company’s portfolio. Today the company is targeting three of the biggest segments of oncology patients, those with breast, prostate and lung cancer.
In 2006, the company received U.S. approval to sell a cancer drug, called Sutent, for the first time since 1970.
The 2011 approval of lung-cancer drug Xalkori stemmed from Pfizer’s efforts to join with leading cancer experts outside the company. Massachusetts General Hospital researchers helped the company find patients with a specific gene mutation thought to be a good target for the drug.
The ability to zero in on the right patients so quickly wasn’t common at the time, and it enabled investigators to avoid the normal painstaking way of finding appropriate trial subjects.
“You can imagine how hard and slow of a process that would have been,” said Alice Shaw, a Massachusetts General cancer doctor who worked with Pfizer on Xalkori’s development.
Xalkori’s approval gave Pfizer a head start studying patients whose tumors became resistant to the drug, according to company officials and Dr. Shaw. For those patients, the company, still working with the hospital, developed a new lung-cancer treatment called Lorbrena.
The new drug was approved on an accelerated timetable in November based on results from an early-stage trial, a goal of the company as it tries to speed up drug development, according to Chris Boshoff. Dr. Boshoff joined Pfizer from UCL Cancer Institute in 2013 and now oversees the company’s late-stage cancer-drug development.
Five of the last seven Pfizer cancer drugs were approved at an accelerated pace, without a late-stage trial, including Daurismo for acute myeloid leukemia in November.
Pfizer’s top-selling oncology drug, named Ibrance, treats breast cancer, and rang up nearly $3 billion in sales during the first nine months of 2018. The company’s 17 cancer drugs include three less-expensive copies of biotech drugs known as biosimilars.
Despite its success developing cancer drugs, Pfizer has struggled with an important class of treatments called immunotherapies, which unleash a patient’s own immune system on tumors.
Pfizer’s main immunotherapy, Bavencio, developed with Merck KGaA and approved last year to treat two different relatively rare cancers, has failed four late-stage studies for other tumors. The company says it plans to take advantage of the class by pairing its drugs with those from other companies.

UK could ban social media over suicide images: minister


Social media firms could be banned if they fail to remove harmful content, the health secretary has warned.
Speaking on the BBC’s Andrew Marr show, Matt Hancock said: “If we think they need to do things they are refusing to do, then we can and we must legislate.”
But he added: “It’s not where I’d like to end up.”
The minister earlier called on social media giants to “purge” material promoting self-harm and suicide in the wake of links to a teenager’s suicide.
Molly Russell, 14, took her own life in 2017 after viewing disturbing content about suicide on social media.
Speaking to the BBC, her father said he believed Instagram “helped kill my daughter”.
The photo and video sharing social network has responded saying it works with expert groups who advise on their approach to the “complex and nuanced” issues of mental health and self-harm.
Based on their advice that sharing stories and connecting with others could be helpful for recovery, Instagram said, they “don’t remove certain content”.
“Instead (we) offer people looking at, or posting it, support messaging that directs them to groups that can help.”
But Instagram added it is undertaking a full review of its enforcement policies and technologies.

Facebook, which owns Instagram, said earlier it was “deeply sorry”.
The internet giant said graphic content which sensationalises self-harm and suicide “has no place on our platform”.
Papyrus, a charity that works to prevent youth suicide, said it has been contacted by around 30 families in the past week who believe social media had a part to play in their children’s suicides.
“We’ve had a spike in calls to our UK helpline since the BBC first reported this six days ago, all saying the same thing,” said a spokeswoman for the charity.
Mr Hancock said he was “horrified” to learn of Molly’s death and feels “desperately concerned to ensure young people are protected”.


In a letter sent to Twitter, Snapchat, Pinterest, Apple, Google and Facebook (which owns Instagram), the minister “welcomed” steps already taken by firms but said “more action is urgently needed”.
He wrote: “It is appalling how easy it still is to access this content online and I am in no doubt about the harm this material can cause, especially for young people.
“It is time for internet and social media providers to step up and purge this content once and for all.”
He added that the government is developing a white paper addressing “online harms”, and said it will look at content on suicide and self-harm.
Mr Hancock explained: “Lots of parents feel powerless in the face of social media. But we are not powerless. Both government and social media providers have a duty to act.
“I want to make the UK the safest place to be online for everyone – and ensure that no other family has to endure the torment that Molly’s parents have had to go through.”
Molly was found dead in her bedroom in November 2017 after showing “no obvious signs” of severe mental health issues.
Her family later found she had been viewing material on social media linked to anxiety, depression, self-harm and suicide.
Mr Russell told the BBC: “Some of that content is shocking in that it encourages self harm, it links self-harm to suicide and I have no doubt that Instagram helped kill my daughter.”
If you’ve been affected by self-harmeating disorders or emotional distress, help and support is available via the BBC Action Line.

New design for anti-influenza drugs


Researchers at LSTM and Imperial College London have designed drugs which could help combat any potential new flu pandemic, by targeting the receptors of the cells by which the virus gains entry to the human body.
In a paper published today in the Journal of Immunology the team, led by LSTM’s Professor Richard Pleass, show that by engineering a part of an antibody they can target the that allow flu to mutate and become so deadly to humans.
Last year marked the centenary of the 1918  pandemic that claimed nearly 100 million lives worldwide, thus becoming the deadliest disease outbreak in recorded history. Global annual influenza outbreaks account for 300,000-650,000 respiratory deaths, mostly in children and the elderly.
Professor Pleass explained: “Influenza vaccines have limited public health impact during pandemics, and current  are less efficacious than vaccines for many other infectious diseases. This is because influenza viruses that circulate in human and  mutate two key viral surface proteins, haemagglutinin (HA) and neuraminidase (NA), thus allowing them to escape from protective produced through natural infection or vaccination”
Both HA and NA target a sugar called sialic acid, that is found in abundance on the receptors of cells lining the mammalian respiratory tract, which the  uses to gain entry into the body. The sialic acid-binding contacts on HA and NA do not mutate readily, otherwise the virus would not be able to infect human cells.
The team has engineered antibody Fc fragments with enhanced sialic acid that target these conserved parts of both HA and NA, binding  and thus blocking their interactions with human cells.
By targeting sialic acid, these engineered biologicals may also be useful in the control of other pathogens, such as group B streptococci, Streptococcus pneumoniae, Mycoplasma genitalium, and Newcastle Disease Virus.
“Better anti-influenza therapeutics are urgently needed.” Continued Professor Pleass: “The transfer of antibodies from people recovering from influenza during the 1918 and 2009 pandemics reduced mortality from influenza by 50% and 26% respectively. However, to be useful, these antibody medicines (also called FLU-IVIG) need to be manufactured in advance of future epidemics, which is obviously problematic as there may be modest or little neutralising activity against newly emerging strains. Therefore, combinations of existing medicines, including FLU-IVIG, with sialic acid blockers could increase their efficacy while future-proofing against the next .”
Professor Sara Marshall, Head of Clinical and Physiological Sciences at the Wellcome Trust, who provided funding for this work, said: “This is a fascinating project, and one which could have really far-reaching impact not only for influenza but as a platform technology to develop new medicines for many other diseases that are currently treated by antibodies.”
The technology described is available for licensing.

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More information: Patricia A. Blundell et al, Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus, The Journal of Immunology (2019). DOI: 10.4049/jimmunol.1801337

1st US patient in novel stem cell trial for stroke disability enrolled at UTHealth


The first U.S. patient to participate in a global study of a stem cell therapy injected directly into the brain to treat stroke disability was enrolled in the clinical trial this week at The University of Texas Health Science Center at Houston (UTHealth).
“At McGovern Medical School at UTHealth, we have been studying cellular therapies as a novel treatment for  over the past 10 years. We are very excited to partner with ReNeuron and enroll the first patient into the PISCES III study,” said Sean I. Savitz, MD, the study’s global principal investigator and professor and director of the Institute for Stroke and Cerebrovascular Disease at UTHealth. “This study represents an important next step in the development of novel cellular therapies for chronic stroke and, to date, is the most advanced clinical trial to determine whether improve recovery in  chronically disabled by stroke.”
The trial, called PISCES III, is a Phase IIb, randomized, placebo-controlled, multicenter study enrolling a total of 110 eligible ischemic stroke patients, age 35 to 75, who are experiencing persistent disability six to 12 months post-stroke. They will receive either a single dose of the ReNeuron drug called CTX0E03 DP, which is injected into the brain, or they will undergo a sham surgery. The surgeries are performed at Memorial Hermann-Texas Medical Center, a teaching hospital of McGovern Medical School.
While intravenous delivery of stem cells is being studied in clinical trials for acute stroke patients, direct delivery into the brain may have more effect for patients with chronic stroke disability, Savitz said.
“Just as in a skin wound, the brain heals in different stages,” said Savitz, professer and Frank M. Yatsu, MD Chair in Neurology at McGovern Medical School. “In animal studies, direct injection in a chronic stroke setting has been shown to improve recovery and outcomes. It appears that the cells are changing the environment of the damaged area of the brain, so it is more pro-regenerative. It may be releasing factors that stimulate the repair mechanism near the area of the infarct.” An infarct is a small, localized area of dead tissue resulting from failure of blood supply.
The study brings together an interdisciplinary team that includes Peng R. “Roc” Chen, MD, associate professor in the Vivian L. Smith Department of Neurosurgery; and Monica Verduzco-Gutierrez, MD, associate professor in the Department of Physical Medicine and Rehabilitation at McGovern Medical School. Chen is on the steering committee for the trial and is the surgical lead. Chen brings years of experience to the trial in the surgical administration of stem cells. Verduzco-Gutierrez is the rehabilitation lead who will oversee the assessments of mobility and cognitive function before and after the procedure.
Like Savitz, both faculty members are part of the Institute for Stroke and Cerebrovascular Disease at UTHealth, which was founded in 2017 to use the strength of UTHealth’s multidisciplinary experts to advance research and clinical practice in acute stroke treatments, stroke prevention, stroke recovery, population health, and health services.
The intervention arm for PISCES III includes stereotactic surgery, which uses a three-dimensional coordinate system to precisely target the area of the brain to receive the injected therapy through a burr hole. In the placebo arm, patients will receive a tiny, partial burr hole in the skull. All patients will undergo a 12-week physical therapy program. The trial has been approved by the U.S. Food and Drug Administration.
The primary endpoint of the study is a comparison of the proportion of patients in the treated and placebo arms showing a clinically significant improvement on the Modified Rankin Scale, a measure of disability and dependence, at six months post-treatment compared with baseline. Top-line results from the study are expected in early 2020.

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Common pain reliever can improve survival in head and neck cancer


Regular use of a common type of medication, such as aspirin and ibuprofen, significantly improves survival for a third or more patients with head and neck cancer, a new study led by UC San Francisco has found.
Non-steroidal anti-inflammatory drugs, or NSAIDs, improved the overall five-year survival rate from 25 percent to 78 percent for  whose  contained a specific altered gene, known as PIK3CA, the researchers reported. The survival for patients whose gene was not altered in their tumor, was unaffected by NSAID use.
This is the first study to show a strong clinical advantage of regular NSAID use for head and neck cancer patients with mutations in the PIK3CA gene and may indicate a clear, biological reason to implement NSAID therapy in certain cases of the disease, said the authors.
The paper is published January 25, 2019 in the Journal of Experimental Medicine.
“Our results suggest that the use of NSAIDs could significantly improve outcomes for not only head and neck cancer patients, but also patients with other cancers that contained the PIK3CAmutation,” said Jennifer R. Grandis, MD, a UCSF professor of otolaryngology, head and , and senior author of the paper.
“The magnitude of the apparent advantage is strong, and could potentially have a positive impact on human health,” Grandis said.
Within head and neck PIK3CA is the most commonly altered oncogene, with 34 percent of all tumors carrying mutations that activate the PIK3CA gene. In head and neck cancer associated with the human papillomavirus (HPV), PIK3CA is mutated in more than half of tumors.
Head and neck squamous cell carcinoma is a complex malignancy that carries a poor prognosis: the five-year survival rate is about 45 percent. According to the American Cancer Society, head and neck cancer accounts for approximately 4 percent of all cancers in the United States, with an estimated 65,000 people developing it annually.
While the disease can occur in the young, most patients are above age 50 when diagnosed. Primary risk factors include smoking, alcohol use, and HPV infection.
NSAIDs, which include over-the-counter drugs such as ibuprofen and aspirin, are known to relieve pain and reduce inflammation, fever and blood clots. They are the most frequently-prescribed medication for conditions such as arthritis.
In the new research, 266 patients from the University of Pittsburgh Medical Center whose tumors were surgically removed were investigated by the study authors. The majority (84 percent) smoked and 67 percent received post-surgery chemotherapy and/or radiotherapy. Median overall survival was 66 months.
Altogether, 75 tumors (28 percent) in the study had an activating alteration of the PIK3CA gene.
Among the patients who regularly used NSAIDs, 93 percent used aspirin as a component of the NSAID regiment, and 73 percent took aspirin exclusively. Most of the regular users started on the aspirin therapy following their head and neck cancer diagnosis.
The investigators learned that regular use of NSAIDs for at least six months provided “markedly prolonged” improved survival compared to non-use for patients whose PIK3CA gene was mutated or amplified—in these patients, NSAIDs raised overall five-year survival from 25 to 78 percent. However, patients without alterations in their PIK3CA gene were no better off by taking NSAIDs.
Through analysis of both cell line and mouse studies, the researchers speculated that NSAIDs likely blocked tumor growth by reducing the production of an inflammatory molecule called prostaglandin E2.
The researchers pointed out that their results need to be corroborated in a prospective trial. Additionally, they noted limitations, including the small size of the study group, as well as the type, timing, and dosages of NSAIDs taken by patients.
“NSAID use likely confers a statistically and clinically significant advantage in overall survival in PIK3CA-altered head and neck cancer through direct interaction between the PI3K and COXpathways,” said Grandis, a member of the UCSF Helen Diller Family Comprehensive Cancer Center.
“Given the marked mortality of this disease,” she said, “the researchers have designed a prospective, randomized clinical trial to address the initial study’s limitations and assess the clinical significance of this therapeutic use.”

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More informationJournal of Experimental Medicine (2019). doi.org/10.1084/jem.20181936

Fewer Docs Taking Medicaid Compared With Other Plans


Psychiatrists’ lack of acceptance of new patients who have Medicaid is “alarming,” Sheldon Retchin, MD, MSPH, said Thursday at a meeting of the Medicaid And CHIP Payment And Access Commission (MACPAC).
“I found this very alarming, that 65% of psychiatrists do not take new Medicaid patients at a time when we just expanded Medicaid and the nation is paralyzed by substance use disorder and mental health problems,” said Retchin, who is a MACPAC commissioner and professor of medicine and public health at Ohio State University, in Columbus. “I can’t tell if this is leading to a significant barrier or an access-to-care problem for this population, but it certainly suggests that. This is really impacting this population.”
Retchin was commenting after MACPAC staff members presented research that MACPAC had contracted to find out how often physicians were accepting new Medicaid patients, and what might influence their decision. The study was performed by the State Health Access Data Assistance Center at the University of Minnesota, in Minneapolis; researchers there analyzed data from the annual National Ambulatory Medicare Care Survey (NAMCS). That survey, conducted by the National Center for Health Statistics, uses information collected from office-based physicians nationwide. Results were based on data from 1,410 physicians.
Survey researchers asked each practice whether they were currently taking new patients and, if so, which insurers they accepted payment from. The researchers found that 70.8% of respondents were taking new patients covered by Medicaid, compared with 85.3% who were taking new patients with Medicare and 90.0% who were taking new patients with private insurance. Family physicians and general medicine doctors were less likely to accept new patients with Medicaid, at 68.2%, than to accept patients with Medicare (89.8%) or private insurance (91.0%), they found. Psychiatrists had markedly lower acceptance rates: 35.7% accepted new patients with Medicaid, while 62.1% accepted new Medicare patients and 62.2% accepted new privately insured patients.
There was no difference in overall acceptance of new Medicaid patients based on the Medicaid expansion status of the state in which the physician was practicing, or based on the rate of managed care penetration in the area. The only factor that appeared to influence acceptance rates, the researchers found, was the Medicaid fee — as the Medicaid fee grew closer to the amount paid by Medicare, which reimburses at a higher rate, more physicians would accept Medicaid patients.
These results “say something about psychiatry; we just tend not to value it,” said commission member Fred Cerise, MD, MPH, of Parkland Health and Hospital System in Dallas. “That’s particularly worrisome to me.”
Some commissioners offered possible explanations for the low Medicaid acceptance rates. “In a lot of rural communities, primary care in particular is provided by nurse practitioners and physician assistants; that has to factor in here somewhere,” said commissioner Martha Carter, DHSc, CNM, founder and CEO of FamilyCare Health Centers in Scott Depot, West Virginia. As for the psychiatrists, low payment rates from Medicaid and other insurers may be one reason why psychiatry residency programs have a hard time filling their slots, she said.
Commissioner Bill Scanlon, PhD, an independent consultant in Oak Hill, Virginia, noted that managed care plans also may play a role. “How are managed care plans managing physician access? They may have strategies to say, ‘I’m going to deal with fewer physicians and get a better response rather than having it open to everybody’ … it could result in what seemingly are lower participation rates but be a deliberate strategy.”
Commissioner Kisha Davis, MD, a family physician in Gaithersburg, Maryland, noted that in her own practice, “The reason our practice takes Medicaid is because in our state there is Medicare/Medicaid [rate] parity; that was a big [impact on the] financial decision on whether or not we would take Medicaid.”
Other types of practice settings also may play a role, said commissioner Christopher “Kit” Gorton, MD, MHSA, former president of public plans at Tufts Health Plan, in Boston. “At a broader level, there might be data in the NAMCS dataset about employment … groups, employed physicians, private practice physicians. In some cases these doctors [may say], ‘I never worked for myself; I never decided which patients I took or didn’t take; somebody else decided that,'” he said. “I think that may be a [data] slice that is illuminating.”
MACPAC chairwoman Penny Thompson, MPA, a consultant from Ellicott City, Maryland, said the commission would continue working on the issue. “There have been a fair amount of good ideas for expanding on this [in an] issue brief with additional information,” she said. “We ought to think about where this takes us and some areas where we want to dive deeper, whether it is psychiatry or [other] areas we want to find out more about. Payment policy is something Medicaid agencies can do something about; workforce supply they could maybe have an impact on, although not so directly.”
One possible idea is that “if a state paid at the Medicare rate … maybe it would excuse them from doing more reporting,” Thompson said. “That may be a recommendation for scrutinizing accessibility and access, focusing on areas of the country where the payment rates are substantially below Medicare. Maybe that’s something we can give some thought to as well.”

Hereditary hemochromatosis behind many cancers and joint diseases


A British study has found that “stealth disease”, also known as hemochromatosis, could be the reason behind several disease conditions including cancers and joint diseases. These diseases were earlier thought to be a part of ageing, but this new study finds that hemochromatosis or build up of iron within the body is a prominent reason behind these conditions. The study reports were published in the latest issues of the journals BMJ and Journal of Gerontology.
Hemochromatosis is a hereditary condition that is found among people of European descent commonly and was thought earlier to affect only around 1 percent of the population. This condition is caused by a genetic mutation.
This latest study is one of the largest till date in the UK and US. It finds that around one in five men and one in ten women are affected with this genetic mutation carrying one or both affected genes. This condition leads to iron overload. This new study finds that 1.6 percent of hip replacements and 5.8 percent of liver cancers among males are linked to hemochromatosis. The common early problems these men face include fatigue and joint pain. In the UK around 250,000 people suffer from this condition. One in 200 individuals in Europe have this condition with a prevalence among the Irish, Scottish and the Welsh. This has nicknamed the disease “Celtic curse”.
This new study looked at 2,890 patients enrolled the UK Biobank scheme. They all carried a mutation in their HFE C282Y gene that led to their condition. Professor David Melzer from Exeter University, who led the research, said in a statement, “The hemochromatosis mutations were thought to only rarely cause health problems… We’ve shown that hereditary hemochromatosis is actually a much more common and stealth disease, including in older people.” He urged researchers to come up with better screening systems and methods to detect this condition early. ‘
He explained that people with hemochromatosis tend to absorb twice as much iron from their diet compared to those who do not have this condition. Some of this iron is used to form the red blood cells and others get deposited around the body especially in the liver, experts add. This iron overload leads to increased risk of liver disease (four times) and arthritis (two times). It also raises the risk of chronic pain and diabetes.
Co-author Dr Luke Pilling in a statement said, “We found that diagnosis of hemochromatosis is often delayed or missed. That’s not surprising as symptoms such as joint pains and tiredness are frequently mistaken as signs of ageing. Yet it is likely that these potentially deadly health risks could be treated and avoided, transforming lives, especially at older ages.”
Public Health England lauded this research. Professor Debra Lapthorne, of PHE said, “We really welcome this study and think the work will be clinically very important as the results could have implications for clinical practice and help us find people much earlier, before significant damage is done. This work shows the real benefit to the population of linking academic research to policy and clinical practice.” The UK National Screening Committee has said in a statement that they would “look at the evidence to screen for hemochromatosis in 2019/20, as part of their routine three yearly review.”