UT Health San Antonio researchers, working with collaborators at the University of Florida, have discovered a safe and potent next generation of drugs to fight multiple types of leukemia and lymphoma in adults and children. The journal Nature Medicine reported the findings Dec. 2.
“This is a new class of drugs called PROTACs that target an essential survival protein in cancer cells called BCL-XL,” said research co-author Robert Hromas, M.D., FACP, professor of medicine and dean of the university’s Joe R. and Teresa Lozano Long School of Medicine. “The previous drugs that have targeted BCL-XL decrease platelets dangerously, with a high risk of bleeding. Our drug markedly reduces that risk, and thus would be potentially far more useful in cancer patients.”
The PROTAC reported here would treat T-cell malignancies such as T-cell acute leukemia and T-cell lymphoma, Dr. Hromas, a noted hematologist and oncologist, said.
T cells are produced by a gland in the upper chest called the thymus. These cells are very important participants in the body’s immune response. When they turn cancerous, they rely on BCL-XL for survival.
Dr. Hromas is joined on the paper by several co-authors from the Greehey Children’s Cancer Research Institute at UT Health San Antonio.
“PROTAC drugs degrade the BCL-XL protein rather than merely inhibiting it,” said Peter Houghton, Ph.D., professor of molecular medicine and director of the Greehey Institute. “Potentially this class of drug can be developed against certain childhood cancers that have been untreatable.”
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Reference: “A selective BCL-XL degrader achieves safe and potent antitumor activity,” Nature Medicine, Sajid Khan, et al.
Funding: National Institutes of Health and the Cancer Prevention and Research Institute of Texas.
“Weight-loss medications are rarely prescribed to eligible patients,” say the authors of a newly published study of prescribing patterns in more than 2 million Americans from 2009 to 2015.
The study by David R. Saxon, MD, an endocrinologist at the University of Colorado, in Aurora, found that overall, only 1.3% of eligible patients filled a prescription for an antiobesity medication, and prescribing rates ranged from 0.6% to 2.9%. It was first reported by Medscape Medical News at Obesity Week 2017.
A key finding was that more than 75% of prescriptions for obesity drugs were for phentermine, and just a quarter of physicians surveyed prescribed 90% of all the obesity drugs.
These results “illustrate the obesity treatment conundrum: why, despite five effective FDA-approved drugs for weight loss, is the highly prevalent problem of obesity undertreated?” says Willian H. Dietz, MD, PhD, a public health expert at the George Washington University, Washington, DC, in an editorial that accompanies the published study.
Both appear in the December issue of Obesity.
Dietz goes on to suggest several reasons for the low uptake of these drugs, but he puts the onus on healthcare providers to improve this number.
“The most effective strategy may be to recognize that obesity is a disease and needs to be treated as such and to hold providers accountable for the care that they provide or don’t,” he concludes.
Main Findings From Data From PORTAL Network
Saxon and colleagues analyzed electronic health records from 2009 to 2015 from participants in the Patient Outcomes Research To Advance Learning (PORTAL) network, which is funded by the US Patient-Centered Outcomes Research Institute.
They identified 2,248,407 patients who were eligible for weight-loss medications — ie, they had a body mass index ( BMI) > 30 kg/m2 or a BMI between 27 and 29.9 kg/m2 with at least one weight-weight-related comorbidity — from eight healthcare organizations: HealthPartners, Denver Health, and Kaiser Permanente Northwest, Southern California, Mid-Atlantic, Hawaii, Colorado, and Washington state.
They also identified primary care and other providers who had written prescriptions for these drugs
The 6-year study period covered the time before, and after, the US Food and Drug Administration (FDA) announced the removal of sibutramine for the treatment of obesity from the market (October 2010) .
It also covered the time before and after the agency approved new weight-loss medications: lorcaserin (Belviq, Eisai) in May 2012, phentermine/topiramate extended release (Qsymia, Vivus) in July 2012, naltrexone/bupropion sustained release (Contrave, Currax) in September 2014, and liraglutide 3.0 mg (Saxenda, Novo Nordisk) in December 2014.
In addition to the low uptake, the main findings were as follows:
77% of the scripts were for phentermine, which, more than half of the time, was prescribed for longer than the 3 months it was approved for in 1959.
Diethylpropion, orlistat, sibutramine, and locaserin accounted for 12.2%, 4.3%, 2.8%, and 2% of scripts, respectively.
Women, blacks, and patients with higher BMIs were more likely to receive a prescription.
24% of the prescribers accounted for 90% of all filled prescriptions.
In 2015, just 2.7% of the prescribed drugs were for one of the newer agents.
Possible Reasons for Undertreatment
Dietz suggests that the following factors may contribute to the very low rates of prescribing of antiobesity drugs that Saxon and colleagues found:
Lack of recognition in the patient’s chart that the patient has obesity: “If obesity is not recognized, it should be no surprise that it is not treated,” Dietz writes.
Lack of patient demand: patients may not expect or ask their provider for advice regarding weight loss.
Provider knowledge: in a 2016 survey, “only 8% of providers correctly identified the recommended threshold for the initiation and continuation of pharmacotherapy for obesity.”
Provider bias: “69% of people with obesity reported experiencing weight-loss bias from physicians.”
Time and cost: “Few providers and patients may be able to meet the recommendation of the US Preventive Services Task Force (USPSTF) that patients with obesity receive intensive behavioral therapy delivered in 12 to 26 visits over the course of a year” and insurance plans may limit counseling and may not cover pharmacotherapy.
Provider and patient knowledge: Even if antiobesity pharmacotherapy is covered, “providers and patients may not be aware of the benefit.”
How to Remedy This?
The main strategy to stop the obesity pandemic is for providers to treat obesity as a disease, stresses Dietz.
In addition, patients need to ask for appropriate care, in shared decision making with providers.
And federal and state policy makers need to ensure that public health insurance programs cover FDA-approved drugs for obesity.
The study was funded by Kaiser Permanente, HealthPartners, and Denver Health through a Patient-Centered Outcomes Research Institute (PCORI) award. Saxon and other coauthors were also supported by grants from the NIH and the Veterans Affairs (VA). The authors have disclosed no relevant financial relationships. Dietz reports receiving research grants from Novo Nordisk and the Kresge Foundation, holding consulting positions with the National Academy of Medicine Roundtable on Obesity Solutions and WW (formerly Weight Watchers), and serving on boards for Partnership for a Healthier America and the JPB Foundation.
U.S. Food and Drug Administration staffers reviewing Correvio Pharma Corp’s heart drug said on Friday they did not believe the benefits of the therapy outweighed its risks, sending the company’s shares down nearly 38%.
The drug, Brinavess, approved in Europe and other countries including Canada, aims to correct erratic heart rhythm in the upper heart chambers due to a condition known as atrial fibrillation or AFib.
Although Correvio has provided evidence of benefits, Brinavess comes with “serious liabilities” including low blood pressure, irregular heartbeats in the lower heart chambers, and death, the FDA staffers said in documents released on Friday.
They also said the risk and management data provided by Correvio did not provide reassurance about the safe use of Brinavess.
A panel of independent experts to the FDA is set to convene on Tuesday to vote on the drug’s approval – an influential factor in the agency’s final decision that is expected by Dec. 24.
“While the company and its advisors will present its side… and bring experts to the (meeting) who will say that Brinavess is needed and can be used safely, we believe based on the FDA review to date, the odds are stacked against Brinavess,” Bloom Burton Securities analyst David Martin said.
Safety concerns led the FDA to decline approval to Brinavess in 2006 and later put trials on clinical hold as a patient with no apparent heart issues died after being administered Correvio’s drug. The hold still remains in place.
AFib, a common cardiac rhythm disturbance, is a leading cause of stroke. The condition affects about 2.7 million to 6.1 million Americans every year, according to the American Heart Association.
“Despite the cautious tone of the materials, we still believe there is a large unmet need for a drug like Brinavess and we are hopeful the Agency can find a path to approval,” Cantor Fitzgerald analyst Louise Chen said in a client note.
Current treatments for AFib include medication to regulate heart rhythm, blood thinners to prevent clot formation, and even, electric shocks to reset the heartbeat.
U.S.-listed shares of the Canadian drugmaker were trading lower at $1.32 in early morning trading.
The Swiss government approved on Friday health insurance coverage for CAR-T cell therapies from Novartis and Gilead Sciences, which can cost hundreds of thousands of dollars per patient.
In this form of therapy, patients’ white blood cells are genetically modified to attack cancer cells.
The health department said the decision covered Novartis’s Kymriah and Gilead’s Yescarta.
“The contract between hospitals and the health insurers will be approved until the end of 2020, granting the affected patients immediate access to these therapies,” the government said after a cabinet meeting.
Spain’s Grifols said on Friday the latest results from a clinical trial of its Alzheimer’s treatment show positive effects by achieving a reduction of the disease’s progression in patients with mild and moderate conditions.
The results of its AMBAR trial were unveiled at a conference in San Diego, the Barcelona-based company said in a statement to the Spanish stock regulator.
The trial aims to evaluate whether Alzheimer’s disease can be slowed down by periodically extracting plasma from the patient’s body and replacing it with albumin, a protein. It has been conducted in people with mild or moderate Alzheimer’s disease in Spain and the United States.
The latest results strengthen Grifols’ research on plasma protein replacement therapies, the company said.
The trial showed that those patients treated with albumin and immunoglobulin had less of a reduction of the brain’s glucose metabolism after the 14-month-treatment, suggesting a reduction of the patients’ neuronal damage, it added.
U.S. Department of Veterans Affairs delivered more than 2.6 million episodes of telehealth care in fiscal year 2019, up 17 percent from last year, according to a Nov. 22 news release.
Three things to know:
1. More than 900,000 veterans used VA’s telehealth services this year.
2. VA’s telehealth application VA Video Connect usage increased 235 percent in 2019.
3. More than 200,000, or around two-thirds, of VA Video Connect appointments were for telemental health visits this year.
In histories written about Alzheimer’s disease, 2019 will turn up as a landmark year, one in which researchers, clinicians, patients, and their families were whipsawed from crushing despair to giddy optimism.
The year unfolded with a string of disappointments. One of the biggest came on March 21 when Boston-based Biogen announced it had pulled the plug on two clinical trials of aducanumab, a promising treatment for individuals with Alzheimer’s disease. The drug had failed a “futility analysis,” meaning it would not be able to achieve its objectives. More bad news came in the weeks and months to follow. An entire class of drugs called BACE inhibitors (pronounced “base” as in baseball) had failed.
By the annual international meeting of Alzheimer’s investigators in Los Angeles in July, a pervasive disappointment was enmeshed with embarrassment, heightened by the meeting’s timing on the 50th anniversary of the successful Apollo mission to the moon. A half a century ago, we were able to send someone to the moon, have him walk about, and return home but, despite all our time and effort and money since then, despite all the advances in genomics, proteomics, and other “omics,” despite precision medicine, we haven’t been able to make a dent in this disease.
Five months later, at the Clinical Trials in Alzheimer’s Disease (CtAD) conference on Thursday, December 5, I and other Alzheimer’s researchers gathered once again in California. This time the mood was giddy. The crowd in the Indigo ballroom at the San Diego Bayfront Hilton behaved more like a gathering at an awards ceremony than an early morning session at a scientific meeting. There were hugs, laughter, and backslaps.
Why the change? Biogen had somehow flipped the switch on aducanumab. According to its reanalysis of the clinical trial data, aducanumab wasn’t a flop but a success, and the company had decided to ask the FDA to approve aducanumab for the treatment of Alzheimer’s disease.
Samantha Budd Haeberlein, who heads late stage clinical development for Alzheimer’s disease at Biogen, spent 45 minutes explaining the complicated events leading up to and following the futility analysis. One key message was that the company had gathered more data in the three months between the start of the futility analysis and the decision to end the trial, but that data hadn’t been part of the analysis. After adding it into the analysis, a different picture emerged: The highest dose of aducanumab just might slow down the cognitive and functional decline caused by Alzheimer’s disease.
The much-used phrase “a shot heard ’round the world” comes from the dawn of the American Revolution. It evokes when war first broke out in and around Boston between British troops and American rebels. It sent a message to Britain’s George III and every other monarch and the aristocracies they sustained: Your days are numbered.
Biogen’s reinterpretation of its data must still be subjected to FDA and peer review, of course. But if it holds up, I believe that aducanumab will be a shot heard round the world: the beginning of the end of Alzheimer’s disease.
It won’t end Alzheimer’s because it cures the disease. It doesn’t do that. Aducanumab appears to slow, but does not stop, and certainly does not reverse, patients’ cognitive and functional declines. Given the past disputes over the effects of earlier Alzheimer’s drugs, experts will vigorously debate aducanumab’s benefits.
When a disease is common, has unknown causes, and no effective treatments, stigma flourishes. The stigmas of Alzheimer’s are intense. They cause people to avoid seeking a diagnosis. They nudge some clinicians to hide the diagnosis. Patients who do learn their diagnosis experience self-stigma. They start to doubt their abilities and worth to others. Friends disappear. Caregivers worry about the future.
Stigma causes all kinds of language games. When Ronald Reagan announced his diagnosis of Alzheimer’s disease, he in fact didn’t say he had it. In a handwritten letter to his fellow Americans in 1994, the Great Communicator explained, “I have recently been told that I am one of the millions of Americans who will be afflicted with Alzheimer’s disease.” The “will be” stands out. It distanced him from his diagnosis.
What makes aducanumab so powerful is that it targets one of the pathologies of Alzheimer’s disease, and it does so in persons who are not yet diagnosed with dementia. A bit of history is needed to explain this novel way of labeling people with Alzheimer’s disease and why it is so significant.
For much of the 20th century, Alzheimer’s disease and dementia were enmeshed. A person had to have dementia to be diagnosed with Alzheimer’s disease. This made sense. You have to be ill to have a disease.
Most of the participants in Biogen’s trials, however, did not have dementia. They had what’s called mild cognitive impairment, known widely as MCI. Characterized in 1999 by researchers at the Mayo Clinic, MCI describes changes in individuals’ cognitive abilities that, while noticeable and often annoying, are not disabling. They don’t have dementia, nor do they have normal aging. They’re sort of in between.
The reason why the field cared about MCI was that the Mayo team showed it was a risk factor for developing Alzheimer’s disease, like smoking or obesity. The Mayo investigators reported that an individual with MCI had about a 15% per year chance of declining from MCI to dementia.
One other event is important. In 2002, investigators at the University of Pittsburgh stunned the Alzheimer’s field when they announced the discovery of a radiotracer they called Pittsburgh compound B that could visualize amyloid in the brain of a living person. Before this, the only way to see this characteristic pathology of Alzheimer’s disease was with a brain autopsy. A person with dementia had to die so their caregivers could learn the cause of their dementia. Amyloid imaging ended that Gothic horror story.
Which brings me back to Biogen’s trials. Eighty percent of the participants did not have dementia. They had MCI and PET scans that showed elevated amounts of amyloid in their brains. Some Alzheimer’s experts label this as “prodromal Alzheimer’s disease,” others as “MCI caused by Alzheimer’s disease.” Still others prefer the blunt label “Alzheimer’s disease.”
Patients will reject each of these labels. There’s maddening ambiguity around what MCI actually is. It’s like a semi-boneless ham. The term Alzheimer’s disease is unacceptable to individuals with MCI. It is hidebound to dementia, which they do not have.
Alzheimer’s is the senility of the 21st century. Patients and their families will give their own names to what they have and why they are getting treated. Perhaps they’ll say they have abnormal amyloid or, in a word, amyloidosis.
This renaming is sensible. A drug that targets a pathology targets stigma. It offers some explanation for what’s wrong, the hope of treatment, and a means to rethink and even rename a disease.
The statin drugs that reduced cholesterol, first tested in the 1980s, recast heart disease into a test for “good” and “bad” cholesterol. After fluoxetine was baptized Prozac and psychiatrist and author Peter Kramer counselled America to listen to it, antidepressants recast depression. Prozac and its many cousins didn’t just treat American depression and anxiety. Being on Prozac transformed depression into a problem of serotonin balance. A stigmatizing mental illness became a near universal experience.
So too shall be the recasting of Alzheimer’s disease. Because aducanumab isn’t just a drug — it’s also an idea. Just like the American Revolution and the shot heard ’round the world.
Jason Karlawish, M.D., is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania and co-director of the Penn Memory Center.
