Teva Pharmaceuticals this week expanded its recall of losartan potassium tablets after detecting a possible human carcinogen in the blood pressure medication.
Teva sold bulk lots of the drug to California-based Golden State Medical Supply, which packaged and shipped the medication to pharmacies in bottles that contain 30, 90 and 1000 tablets, according to a recall notice shared by the U.S. Food and Drug Administration.
Consumers affected by the recall should continue taking their medication and ask their doctor or pharmacist about alternatives or replacement drugs. Discontinuing a medication without a replacement could cause a patient more harm than continuing the drug.
Since July, two dozen drug companies have recalled hundreds of lots of commonly-prescribed blood pressure and heart medications losartan, valsartan and irbesartan after testing revealed some versions had small amounts of suspected carcinogens. The recalls of the class of drugs called angiotensin II receptor blockers (ARBs) have highlighted the complex international drug supply chain with 80 percent of drug ingredients consumed by U.S. residents made at factories overseas.
Teva said in its recall notice the NMBA impurity was traced to ingredients made at Hetero Labs Limited in India, a factory linked to multiple recalls. The FDA and European drug regulators first traced the carcinogen-tainted ingredients last July to Zhejiang Huahai Pharmaceutical in Linhai, China,
Despite the widespread recalls affecting this class of drugs, the FDA says that versions of losartan are available.
The FDA will allow losartan with tiny amounts of a nitrosamine impurities because the agency says it will not increase a person’s cancer risk. The measure is designed to avert a shortage of the critical medication – the nation’s ninth-most commonly prescribed drug.
Back in 2016, Helen (a pseudonym) took three different direct-to-consumer (DTC) genetic tests: AncestryDNA, 23andMe and FamilyTreeDNA. She saw genetic testing as a way to enhance her paper trail genealogy research, and it panned out when she matched with several new relatives.
Helen is one of over 26 million individuals who have reportedly taken a DTC genetic test. That’s a lot of spit in tubes being mailed to companies that promise customers information about their health, ancestry and family trees.
Notably, the search for genetic insights doesn’t always stop with the interpretations provided by the DTC companies. One of Helen’s matches on AncestryDNA told her how she could stretch her personal genomic information further: by downloading her raw genetic data, that long list of As, Cs, Gs and Ts at each of the DNA sites the DTC company measured, and then uploading it to third-party interpretation tools online such as GEDmatch and DNA.land to find more relatives.
Helen enthusiastically did so and joined Facebook groups dedicated to helping people use their genetic data to flesh out their family trees. While Helen wasn’t initially seeking health information, on these forums she learned about the third-party tool Promethease and decided to upload her data there as well. She thought, “Well, for five dollars—we’ll see what it says.”
Researchers don’t have a very clear or comprehensive picture of how DTC customers use their raw data and these kinds of third-party tools. As a genetics researcher interested in the ethical and social implications of genomics in research, clinical care and everyday life, I think it’s important to address this knowledge gap—particularly given questions about whether and to what extent these third-party tools are or should be regulated.
My colleagues and I conducted a survey of about 1,100 DTC customers recruited via social media and followed up with interviews of 10 respondents—to our knowledge, the largest survey of this topic to date.
Eighty-nine percent of our survey participants had downloaded their genetic data from a DTC company, and most of those downloaders (94%) had also used one or more third-party interpretation tools—three tools on average. The most commonly used tools were GEDmatch (84% of tool users), Promethease (63%) and DNA.land (55%).
One notable aspect of our results is that over half of tool users (56%) used both health-related and non-health-related, such as ancestry and genealogy, tools. We called this phenomenon “crossover” use. These crossover users were significantly different from people who used only one tool type in terms of demographics, which DTC tests they had taken and what initially motivated them to do DTC testing.
Credit: The Conversation
For example, the percentage of users who had ordered 23andMe increased from the non-health-only to crossover to the health-only group, with a reverse trend for both AncestryDNA and FamilyTree DNA tests. While this trend is as you might expect, it was surprising how many respondents initially ordered DTC tests focused on ancestry and genealogy—like from AncestryDNA and FamilyTree DNA—who went on to use their genetic data from these companies in health-related third-party tools.
Imagine a DTC customer such as Helen who first focused on genetic genealogy. After matching with some new relatives on GEDmatch, she went on to plug her data into Promethease. There she saw thousands of reports of potentially increased genetic risk for diseases ranging from age-related macular degeneration to restless legs syndrome—quite a distance from where her genealogy quest started.
Uploading genetic data to a variety of third-party tools makes sense when you consider that DNA carries multiple kinds of information: health risks, family relations and more distant genetic ancestry. The genome is like a Swiss Army knife in that you can draw on different characteristics depending on what you want to do or know.
Through our follow-up interviews, my research group learned how crossover users arrive at such different third-party tools. As with Helen, a common reason was hearing about multiple tools on social media venues such as Facebook groups or subreddits.
And once you’ve started plugging your raw data into one tool, there is relatively low activation energy required to use additional tools. Other reasons people tried additional third-party tools included initial lack of interesting findings in one domain and general curiosity to extract as much information as possible.
Credit: The Conversation
More interpreters, more implications
Once relatively obscure, third-party tools have come into the spotlight over the past year. The third-party genealogy website GEDmatch helped crack the Golden State Killer murders and subsequently dozens of other cold cases. The health-related tool Promethease garneredheadlineswhen individuals were incorrectly told they were at increased risk for serious diseases—though these false positives ultimately came down to errors in the DTC genetic data, rather than Promethease’s interpretation.
Though my colleagues and I were able to reach over a thousand DTC customers in our study, we cannot say that our findings generalize to all DTC customers. Because of how we recruited participants, it’s likely that we sampled a very motivated and engaged group of people. The DTC testing and third-party tool landscape is also changing rapidly. Just in the past year, for instance, GEDmatch changed its terms of service regarding use by law enforcement more than once, My Heritage expanded into health-related offerings, and Gencove retired its consumer-oriented product. Any research in this area is on shifting sands.
But this kind of study can also help inform genetics professionals who are considering delivering raw DNA data in other contexts. This includes researchers, such as those planning to return raw data to participants in the National Institutes of Health’s All of Us precision medicine project. Clinicians who order genome sequencing tests may enable raw data access; patients have the legal right to their full laboratory reports. Our study can shed some light on what individuals who receive raw data via these other routes might do with it.
Overall, our study illustrates the complexity and variety of third-party tool users’ motivations, experiences and actions. These findings should inform, but probably won’t simplify, the job of any regulators grappling with whether and how to respond to this growing field of genetic interpretation.
Amgen (NASDAQ:AMGN) today announced the five-year overall survival (OS) analysis from the single-arm, Phase 2 BLAST study that evaluated BLINCYTO® (blinatumomab) in patients with minimal residual disease (MRD)-positive acute lymphoblastic leukemia (ALL). The study found that with a median follow-up of 59.8 months, the median OS for BLINCYTO-treated patients was 36.5 months (95 percent CI: 22 months – not estimable [NE]). More than half of patients who achieved a complete MRD response following the first cycle of BLINCYTO treatment were alive at five years. These results from the largest prospective trial ever conducted in MRD-positive ALL were presented today during an oral presentation at the 24th Annual Congress of the European Hematology Association (EHA) in Amsterdam.
‘As the only CD19-targeted immuno-oncology therapy with five-year survival data, BLINCYTO continues to demonstrate compelling results for ALL patients,’ said David M. Reese, M.D., executive vice president of Research and Development at Amgen. ‘We are proud of the science behind our BiTE® technology. These data in an MRD-positive ALL patient population give us increased confidence in the clinical benefit of BLINCYTO, especially when these patients are treated earlier.’
The Phase 2 open-label BLAST study enrolled 116 patients with MRD-positive Philadelphia chromosome-negative (Ph-) B-cell precursor ALL in first or subsequent complete hematologic remission after at least three intensive chemotherapy blocks of treatment. Of the 116 enrolled patients, OS was evaluated for 110 patients with less than five percent leukemic blasts, including 74 patients who received hematopoietic stem cell transplantation (HSCT) in continuous complete remission (CCR) after BLINCYTO treatment.
Results presented at EHA showed that in 84 patients who achieved a complete MRD response (had no measurable MRD), median OS was not reached (95 percent CI: 29.5 months – NE) compared to 14.4 months for those who had measurable MRD (n=23; 95 percent CI: 3.8 – 32.3 months). Among patients with MRD in first complete remission (CR1), median OS was not reached for those who achieved a complete MRD response (95 percent CI: 29.5 months – NE) versus 10.6 months (95 percent CI: 2.7 – 39.7 months) for those who did not achieve complete MRD response (n=13; p=0.008).
A breast cancer drug with the potential to replace traditional chemotherapy is accelerating through clinical development and could soon offer patients who previously had limited options an effective treatment.
Over 400,000 people are diagnosed with HER2-positive breast cancer each year, a type of cancer that learns to resist the drugs designed to attack it. Women with HER2 can start by taking the breast cancer drug Herceptin, then often move to Kadcyla once the cancer becomes resistant.
After the disease overpowers Kadcyla, there is no standard course of action, according to Dr. Ian Krop, clinical research director of the Breast Oncology Center at Dana-Farber Cancer Institute.
That’s where the DS-8201 cancer treatment, developed by Japanese company Daiichi Sankyo, comes in.
The drug works by attaching chemotherapy to antibodies that offer a targeted attack on cancer cells and milder side effects compared to traditional chemotherapy.
Krop said that in clinical trials, 90% of patients saw some degree of tumor shrinkage. The treatment has also been seen to double survival time for advanced breast cancer patients to 20 months from 10 months.
Krop called the results “precedent-setting.”
“People run out of treatments that work eventually and then we are kind of stuck,” said Krop. “What’s really kind of special about this new drug is that it seems to start working when all the other drugs have stopped working.”
“I think this drug can definitely replace chemotherapy,” said Krop.
Clinical trials of DS-8201 started at Dana-Farber three years ago and Krop has seen the results in his own patients, some who travel a great distance for access to the treatment.
“It’s been a great experience to be involved with this because it looks like it will be a real breakthrough for these patients,” said Krop. He added that his patient’s pain levels and symptoms have improved while on the drug and CAT scans show the cancer has regressed considerably.
Krop said there are still some side effects for patients taking DS-8201, like hair loss, some nausea and some lowering of blood counts, however they are more mild than the side effects of traditional chemotherapy.
Cheryl Osimo, a breast cancer survivor and executive director of the Massachusetts Breast Cancer Coalition, knows the devastating side effects of chemotherapy all too well.
“My chemotherapy affected my vision. I lost all my hair. For some women, it affects every part of their being, every part of their body,” said Osimo. “It can be debilitating because you feel nauseous a lot.”
Osimo said, “A treatment that has milder effects and is more effective can provide people with hope, once you run out of treatment options … you become hopeless, so the more options the better.”
Daiichi Sankyo is currently accelerating its biologics license application, meaning that the drug could be approved by the Food and Drug Administration sooner than expected. Krop said it could be approved sometime in 2020.
Krop said looking toward the future, DS-8201 also has the potential to work in lung or stomach cancers.
The breakthrough drug is also expected to prompt major changes in the market as the company announced it will partner with AstraZeneca to develop and commercialize DS-8201 in many countries worldwide. The deal sees AstraZeneca paying Daiichi Sankyoup to $6.9 billion in total.
— 5F9 Well-Tolerated in Combination with Rituximab — — Durable Responses Observed in DLBCL and Indolent Lymphoma; Median Duration of Response Not Yet Reached — — Overall Response Rate (ORR) of 36% Observed in DLBCL and ORR of 61% Observed in Indolent Lymphoma — — FDA Feedback Suggests Single-Arm Pivotal Trial May Support Registration of 5F9 in Combination with Rituximab in Heavily Pre-Treated DLBCL Patients, Including Those Ineligible for CAR-T Therapy — — Forty Seven to Host Conference Call and Webcast at 8:00 am ET on Monday, June 17, 2019 —
Forty Seven, Inc., a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, today announced updated data from its ongoing Phase 1b/2 clinical trial evaluating 5F9 in combination with rituximab for the treatment of relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL), including diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma. The data will be presented in an oral session at the 24th Congress of the European Hematology Association (EHA) in Amsterdam, Netherlands. Also at EHA, Forty Seven will present data from its ongoing Phase 1b clinical trial evaluating 5F9 as a monotherapy and in combination with azacitidine for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which were previously presented at the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting.
“Despite advancements in the treatment of newly-diagnosed NHL, there are very limited options for patients with advanced forms of the disease, who have failed multiple lines of treatment or are ineligible for existing therapies due to advanced age, numerous co-morbidities, and/or the diagnosis of aggressive, proliferating disease,” said Justin Kline, M.D., University of Chicago, Department of Medicine, an investigator for the clinical trial. “In treating these patients, our goal is to achieve durable responses and stave off the rapid disease progression that can limit overall survival to a matter of months. As such, I am encouraged by the updated data for 5F9 in combination with rituximab, which showed consistent clinical benefit across a range of patient populations — including patients who are heavily pre-treated, ineligible for CAR-T therapy or suffering from primary refractory disease — as well as durable responses in both DLBCL and FL. I am eager to continue evaluating this combination as a well-tolerated, chemotherapy-free regimen, with the potential to induce long-term remissions even in the sickest patients.”
“Today’s announcement marks a significant milestone in our development of 5F9 for the treatment of r/r NHL,” said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of Forty Seven, Inc. “The design of our Phase 1b/2 clinical trial allowed us to continue to explore the clinical benefit of 5F9 in combination with rituximab in patients with DLBCL and indolent lymphoma, while also expanding into a subset of older, sicker DLBCL patients who have been deemed ineligible for CAR-T therapy. We are particularly gratified to see meaningful activity in this newly-defined population, which has never before been evaluated in clinical trials, and for whom there are few, if any, effective treatment options available. Importantly, following recent interactions with the U.S. Food and Drug Administration (FDA), we believe we may be able to pursue approval in a heavily pre-treated population, including DLBCL patients who have failed at least two prior lines of therapy or who are ineligible for CAR-T therapy, with a single-arm pivotal study serving as the basis for our BLA filing. These developments bring us closer to achieving our vision of establishing 5F9 as a cornerstone immunotherapy for the treatment of a broad range of cancers.”
Investor Conference Call and Webcast Information
Forty Seven will host a live conference call and webcast on Monday, June 17, 2019 at 8:00 a.m. ET to review the clinical data presented at EHA. The conference call may be accessed by (866) 953-0780 (domestic) or (630) 652-5854 (international), and by referring to conference ID 3236239. A webcast of the conference call will also be in the Investors section of the Forty Seven website at www.fortyseveninc.com. The archived webcast will be available approximately two hours after the conference call and will be available for 30 days following the call.
Atif Zaman, MD, MPH reviewing Simon TG et al. Clin Gastroenterol Hepatol 2019 May 8
Daily aspirin use reduced risk for fibrosis progression.
One of the key predictors of increased liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD) is the development and progression of liver fibrosis. Recent studies have shown that aspirin may have antifibrotic effects in NAFLD. In murine models, aspirin limits hepatic stellate cell activation by inhibiting the cyclooxygenase-2 (COX-2) enzyme, and antagonism of COX-2 seems to improve nonalcoholic steatohepatitis (NASH)–related fibrosis. In humans, much of the literature has been limited to cross-sectional studies.
Now, investigators have conducted a prospective cohort study involving 361 adults with biopsy-proven NAFLD, 151 of whom were daily aspirin users. Participants underwent evaluation every 3 to 12 months for development of fibrosis, using serum fibrosis markers.
At baseline, daily aspirin users versus nonregular users had lower odds of having NASH (adjusted odds ratio, 0.68) or fibrosis (aOR, 0.54). During a median of 3692 person-years, daily aspirin users had lower rates of advanced fibrosis (adjusted hazard ratio, 0.63), with the greatest benefit occurring in those taking daily aspirin for ≥4 years (Ptrend=0.026). Nonaspirin NSAID use did not affect fibrosis rates.
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This is the first prospective study to evaluate the potential benefits of daily aspirin use in NAFLD patients. Although this is not a randomized study, the duration-dependent relationship of aspirin to NAFLD-related fibrosis, coupled with the biologic plausibility of the antifibrotic effects of aspirin in NAFLD patients, makes the results compelling. Given the growing body of literature around the association of NAFLD and cardiovascular disease, the use of aspirin in NAFLD patients seems appropriate to consider in clinical practice.
Recent research from the Hannover Medical School in Germany has found telemonitoring of exercise to be effective in treating patients with metabolic syndrome. These patients were given Garmin smartwatches to monitor physical activity over a six-month period and were observed to have significant increases in overall health, work ability, and quality of life. These findings were published in The Lancet Public Health on June 13.
What is Metabolic Syndrome?
Metabolic syndrome is defined as the clustering of obesity, high blood pressure, and elevated fats, cholesterol, and sugar in the bloodstream. The condition increases one’s risk of developing type 2 diabetes, cardiovascular disease, and associated mortality, and is more likely to affect older populations. There is a 25% prevalence of metabolic syndrome globally, with the highest and fastest growing rates occurring in the U.S. Being that the condition is correlated to absence at work, decreased productivity, and increased healthcare costs, it presents as both a socioeconomic and healthcare issue.
Regular physical activity is known to promote overall health in those with metabolic syndrome, however it is difficult to continually monitor a patient’s adherence to an exercise program. Wearable technologies like the Apple Watch that monitor one’s physical activity and heart rate have presented as a way for physicians to track their patient’s exercise. Using smartwatches and telemonitoring methods, these Hannover researchers conducted a study to evaluate how well such interventions can improve outcomes in patients with metabolic syndrome.
Background of the Hannover Study
The researchers conducted a randomized, controlled trial with participants from Volkswagen AG to evaluate the impact of exercise and telemonitoring in people with metabolic syndrome. To be included in the study, the workers had to meet the criteria for metabolic syndrome and not be enrolled in any occupational health programs. They hypothesized that this regimen would not only decrease the magnitude of their condition but increase their work ability as well.
The participants were randomly assigned to either an exercise group or a control group. Those in the exercise group were given an exercise supervisor, nutritional counseling, and a Garmin smartwatch to monitor their activity. This wearable devicefunctioned to measure their daily steps, heart rate, and general activity and report such data to the researchers. Participants were also able to communicate with their exercise supervisors via phone call or email. A companion smartphone app was used to link data from the participants to the researchers as well.
These workers chose a form of exercise that best fit their lifestyle and were told to meet a requirement of 150 minutes of exercise per week. Participants in the control group were instructed to continue their current lifestyle and were informed of the possibility to go through the exercise regimen after the study.
Baseline metrics were taken from each group, including bodyweight, body fat percentage, BMI, and levels of glucose and lipids in the blood. This data was used to compile an overall metabolic syndrome score for each participant. In addition, the workers had their heart rate and blood pressure evaluated using an exercise bike to measure exercise capacity. These measurements were taken before the trial to set a baseline and remeasured after 6 months of intervention to compare outcomes.
Success of Exercise and Smartwatch Monitoring
The researchers found that those in the exercise group had significantly lower metabolic syndrome scores than those in the control group. The group averaged 9,612 steps per day and 147 minutes of exercise per week, with 48% of the participants meeting or exceeding the recommended 150 minutes of daily exercise. Among those who exercised, average waist circumference decreased by 4 cm, triglyceride levels by 25 mg/dL, systolic blood pressure by 2.7 mm Hg, and fasting glucose concentration by 5.4 mg/dL. In addition, those who went through exercise intervention displayed increased work ability index scores and overall improvements in their quality of life.
The researchers conclude that these findings indicate the potential benefits of personalized and digitally monitored activity programs in treating patients with metabolic syndrome. They note that further research is needed to examine connections between the health effects of exercise and socioeconomic benefits in the workplace.
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