Thursday, November 1, 2018
EPA allows farmers to keep using Bayer’s controversial herbicide
The Environmental Protection Agency extended by two years its approval of XtendiMax, a version of the herbicide dicamba made by Bayer, which has been blamed for damaging millions of acres of crops over the past two years by farmers and researchers, the Wall Street Journal reports, citing the agency. The EPA will require new buffer zones and limit the hours farmers are allowed to apply the spray, in an effort to prevent drifting, but the decision will preserve an estimated $159M in profits for Bayer from dicamba in 2019, according to Bernstein analysts
https://thefly.com/landingPageNews.php?id=2815049
FDA clears the first consumer genetic test for how well your meds may work
The Food and Drug Administration on Wednesday cleared the first DNA test meant to be marketed directly to consumers to help them determine how well certain drugs may work for them.
The test was developed by 23andMe and, as with other tests from the consumer genetics giant, customers will be able to simply mail in a spit sample to get results.
23andMe’s new test will provide information on 33 genetic variants that the company says are associated with how patients respond to more than 50 commonly prescribed prescription and over-the-counter drugs. Among them: the blood thinner known as clopidogrel, which is prescribed to prevent heart attacks and strokes.
The FDA’s marketing authorization came with crucial caveats. The agency cautioned that the test cannot assess whether a drug is appropriate, or gauge a patient’s ability to respond to any specific medication. The FDA also said that patients should not look to the test for medical advice or to make treatment decisions on their own; instead, they should only use the information to guide discussions with their health care provider.
23andMe said in a press release that it has not determined when the new test will become available. The release did not say how much the test will cost.
When it does hit the market, the new product will bring a new dynamic to a crowded commercial landscape of other so-called pharmacogenetic tests meant to be ordered by a health care provider or offered by a pharmacist. Just last month, Color Genomics became the latest genetic testing company to launch such a test, as part of a $249 product, that reports on the potential effectiveness of antidepressants including Zoloft, Paxil, and Lexapro.
The genetic variants that 23andMe’s test will analyze include several that have been associated with how well the body processes medications for mental health.
But psychiatrists have pushed back on the commercial rush to use pharmacogenetics in their field, saying the application lacks supporting evidence and may not be worth the money.
23andMe had previously offered a pharmacogenetics test to U.S. consumers but, after running afoul of the FDA, pulled it back along with several other health-related tests. Earlier this year, the Silicon Valley company won FDA approval for the first direct-to-consumer test for the BRCA genes, which increase the risk of breast and ovarian cancer.
Speaking at a digital health conference in San Francisco earlier this month, 23andMe CEO Anne Wojcicki pointed to the pharmacogenetics test as something the company wanted to relaunch. “When we can bring pharmacogenomics back, then we have a complete product back,” Wojcicki said.
Treating early signs of diabetes risk may stave off the disease
People who have slightly elevated blood sugar and other early signs of risk for type 2 diabetes may avoid developing the full-blown disease if they start taking medications or make lifestyle changes that are usually used to treat diabetes, researchers say.
The study team examined data on 422 adults in southern California with slightly elevated blood sugar and an intermediate or high risk for developing diabetes based on how well they make and use insulin. All of the patients were told to make lifestyle changes like modifying their diet and exercise habits; 141 people were also asked to take two types of diabetes drugs, and 81 patients were asked to take three types of diabetes drugs.
After an average follow-up period of almost three years, the annual rate of transitioning to full diabetes was 4.1 percent among people who received only lifestyle therapy, and 1.7 percent in patients on two diabetes drugs, the study found. None of the patients on three diabetes drugs developed diabetes.
“Our study demonstrates that a personalized preventive strategy based upon physiology combining lifestyle modification and targeted medications can be extremely effective in preventing progression to diabetes,” said lead study author Dr. John Armato of the Providence Little Company of Mary Cardiometabolic Center in Torrance, California.
“It is always recommended that patients embrace regular exercise, targeted weight loss, limitation of alcohol intake and getting adequate sleep because, if implemented consistently and maintained, this may be all that is needed to restore ideal health,” Armato said by email.
The study findings also suggest that some patients may want to consider the targeted use of medications in addition to lifestyle changes, Armato added.
About one in three U.S. adults have slightly elevated blood sugar that is sometimes called “prediabetes” even though it’s not high enough to warrant a diabetes diagnosis, researchers note in The Lancet Diabetes & Endocrinology. Roughly one in three of these people will progress to full-blown diabetes within five to seven years, they write.
In addition to looking at current blood sugar, or glucose, levels, and a signature of long-term glucose levels known as HbA1C, the researchers added measures of risk for progressing to full diabetes based on how well insulin is working to help cells use glucose for energy, and how well insulin-producing cells in the pancreas are functioning.
All of the patients in the study who were prescribed two medications were given metformin, an older generic diabetes drug that has long been a mainstay of treatment for this disease, and another diabetes pill, pioglitazone.
People taking three medications were given metformin and pioglitazone as well as a newer injected diabetes drug in a family of medicines that includes exenatide and liraglutide.
Compared to people who only received lifestyle therapy, patients who took metformin and pioglitazone were 71 percent less likely to develop diabetes, the study found.
Patients who took both of those drugs as well as medicines like exenatide or liraglutide were 92 percent less likely to develop diabetes than those who only received lifestyle therapy.
One limitation of the study is that people who were given only lifestyle therapy received this treatment because they refused to take medications, so the treatment groups were not random, which might influence the results, the authors note.
It’s also not clear from the study whether medications may have prevented diabetes from developing or helped to manage symptoms in people who did develop diabetes, they add.
Still, the results add to evidence suggesting that some people without full-blown diabetes may benefit from efforts to lower their blood sugar, Dr. Robert Rhyder of Sandwell and West Birmingham Hospitals NHS Trust City Hospital in the UK writes in an accompanying editorial.
But not all patients with slightly elevated blood sugar need medication, or three different drugs, to achieve optimal blood sugar levels, Rhyder cautions.
“Many would consider intervention with three pharmaceutical agents, one of which is an injectable, to be excessive in this population,” Rhyder writes. “However, the complications of type 2 diabetes can be devastating and anything that can be done to avoid diabetes and therefore its complications is worthy of consideration.”
SOURCE: bit.ly/2P4M2PV and bit.ly/2Q969ZG The Lancet Diabetes & Endocrinology, online September 14, 2018.
Can appendix initiate Parkinson’s?
A squishy, 4-inch gut organ whose function has baffled anatomists for centuries is about to have its moment of fame: The lowly appendix, scientists reported in a study on Wednesday, can initiate Parkinson’s disease.
It does so, they suspect, by serving as a reservoir of misfolded, clumping, neurotoxic proteins that travel to the brainstem via the vagus nerve, which runs from the gut all the way up to the brain. People who had their appendix removed have an almost 20 percent lower risk of Parkinson’s, according to the study in Science Translational Medicine, or a risk of 1.6 per 10,000 people over a decade compared to 1.98 in the general population.
The discovery that appendectomy might reduce but doesn’t eliminate the risk of Parkinson’s shows there are other causes of the disease, a usually-crippling brain disorder that strikes about 60,000 people in the U.S. every year. In addition, appendectomy reduced the risk only in people living in rural areas, not urban ones; not among those who inherited any of three common Parkinson’s-causing mutations, which account for about 10 percent of cases; and only if the surgery occurred early in life, well before Parkinson’s started.
Rather than weakening the study, however, those qualifications might actually support its explanation of how the appendix (which is attached to the large intestine) can trigger Parkinson’s. That explanation is based on appendectomy data as well as molecular evidence, in particular that the appendixes of Parkinson’s patients contain clumps of a protein called alpha-synuclein very similar to those in Parkinson’s-affected brains.
“It’s a really nice study, and all of their ideas are biologically plausible,” said James Beck, chief scientific officer of the Parkinson’s Foundation, which was not involved in the research. “It connects the epidemiology, about appendectomy reducing the risk of Parkinson’s, with the basic science.”
Although the appendix is often described as useless or vestigial, it plays a role in the immune system, including by affecting the composition of the gut microbiome and detecting and removing pathogens.
The findings do not mean that everyone worried about Parkinson’s should have an appendectomy, cautioned the study’s senior author, Viviane Labrie of the Van Andel Research Institute in Grand Rapids, Mich. Nor does it mean that everyone with an appendix is likely to develop the disease. It is “a” site of origin for the disease, she said, “but it likely has many sites of origin, including the brain.”
The research does, however, suggest new, appendix-centered approaches to preventing or treating Parkinson’s, which destroys dopamine-making cells in the brain’s substantia nigra. Today’s drugs can replace the lost dopamine but not the destroyed neurons, so although they partly (and temporarily) alleviate symptoms such as tremor and stiffness, they do nothing to stop disease progression.
The new study marshals two lines of evidence for an appendix-Parkinson’s connection, which started off as what Beck calls “a weird idea” in 2003.
The first evidence comes from large databases. One, with medical and demographic information on 1.6 million Swedes going back to 1964, showed that people who’d had an appendectomy were 19.3 percent less likely to develop Parkinson’s. When the scientists analyzed urban and rural residents separately, however, they found no such protective effect in the former. Another data set, of 849 Parkinson’s patients, showed that in those who had an appendectomy, the disease appeared an average of 3.6 years later than in patients who still had their appendix — but again, only for rural residents.
The second line of evidence comes from scrutiny of dozens of appendixes. Parkinson’s patients’ had clumps of alpha-synuclein virtually identical to those in Parkinson’s brains. So did healthy people, but Parkinson’s patients had 4.5 times as much of the short form of alpha-synuclein, which is more prone to clumping into the neurotoxic aggregates than the long form.
“The appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins,” the exact same aggregates found in Parkinson’s brains, said Bryan Killinger, the study’s first author and a postdoctoral fellow in Labrie’s lab.
Clumps of alpha-synuclein don’t seem to harm the appendix. But “the protein doesn’t like to stay put,” said Labrie. “It travels from neuron to neuron, including into the vagus nerve” from the appendix up to the brainstem. As it happens, where the vagus enters the brainstem is one of the first brain regions to contain alpha-synuclein. And it’s probably no coincidence that cutting the vagus, as was once done to cure ulcers (it didn’t), reduced the risk of Parkinson’s, according to previous studies. “That was an aha moment,” Beck said. “It added weight to the gut-brain hypothesis of Parkinson’s.”
The presence of pathogenic forms of alpha-synuclein in the appendixes of people both with and without Parkinson’s shows that a “second hit” — which Labrie has started to look for — is necessary for the disease to develop: More than 99 percent of people manage to avoid Parkinson’s, appendix or not.
It’s anyone’s guess what the second hit is. One hint, though, comes from the urban-rural divide in the protective effect of appendectomy, as well as the finding that it’s protective only in people with a non-genetic family history of the disease. A non-genetic cause with a family history suggests shared environments, not shared DNA.
Those facts suggest that alpha-synuclein in the appendix becomes more abundant, more pathogenic, or more upwardly mobile in the presence of something found in the countryside more than cities. Pesticides, well water, and farming, for instance, have been linked to a higher risk of Parkinson’s since 1998.
For new drug possibilities, the Van Andel team suggests compounds that cut alpha-synuclein in the gut. Alpha-synuclein-targeted drugs to treat Parkinson’s have been in development for years, but almost always with the idea of delivering them to the brain. It would almost certainly be easier and safer to target the gut.
As it happens, compounds called metalloproteases, which have been tested against cancer (unsuccessfully), might be repurposed to inhibit enzymes that cut alpha-synuclein into the short, clumping, disease-causing form. It might “be an effective strategy for the treatment or even prevention” of Parkinson’s, the scientists wrote.
A more karmic argument for the appendix-Parkinson’s link: Dr. James Parkinson (1755 to 1824), for whom the disease is named, was the first English physician to describe a case of appendicitis.
Abbvie cuts Humira to the quick to retain European share
Breaking news from Bernstein analyst Ronny Gal yesterday afternoon on the Humira biosimilar fight in Europe: Abbvie has managed to win the first national biosimilars tender by agreeing to supply the product at a huge 80% discount to the brand’s existing price. Biosimilar discounts of more than 50% are not unusual in Europe, but 80% from the offset for the new Humira market is much steeper than expected. Abbvie’s aggressive move took its stock down 4%; executives had previously guided to a 20% drop in European Humira sales by the end of 2019, an estimate that is likely to be retracted on Friday when the company reports earnings, Mr Gal commented. The makers of Humira biosimilars are also likely to be nervously looking at their assumptions – five companies including Mylan and Amgen have won approval for copycat versions of the antibody, though consensus forecasts are only available for Amgen’s Amjevita. The European biosimilars market is considered a bright spot for manufacturers of these lower-cost biologicals, who have largely been thwarted in the US and will be alarmed by this rapacious move to retain market share. Other brand name manufacturers facing similar competition will be watching how this situation develops with interest.
The sellside’s view of European sales
Source: EvaluatePharma.
Sanofi, Denali to develop treatments for neurological and inflammatory diseases
* Candidate molecules have the potential to treat multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and systemic inflammatory diseases
* Denali to receive $125 million upfront payment and future milestone payments that could exceed $1 billion
* Denali to receive $125 million upfront payment and future milestone payments that could exceed $1 billion
Sanofi plans to collaborate with Denali Therapeutics Inc. on the development of multiple molecules with the potential to treat a range of neurological and systemic inflammatory diseases.
The two lead molecules (DNL747 and DNL758) target a critical signaling protein known as the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the TNF receptor pathway, which regulates inflammation and cell death in tissues throughout the body. The companies plan to study DNL747 in multiple sclerosis (MS), Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS), and DNL758 in systemic inflammatory diseases such as rheumatoid arthritis and psoriasis.
Under the terms of the agreement, Sanofi will make an upfront cash payment to Denali of $125 million, with future development and commercial milestone payments that could exceed $1 billion. Sanofi and Denali will share commercial profits and losses from DNL747 in the U.S. and China equally, while Denali will receive a royalty from Sanofi for other territories for DNL747 and worldwide for DNL758.
Phase 1b and 2 clinical development costs for DNL747 will be fully funded by Sanofi for MS, ALS, and other neurological indications, except in Alzheimer’s disease, which will be funded by Denali. Phase 3 trials for all neurological indications will be jointly funded by Sanofi (70%) and Denali (30%). Sanofi will fully fund the clinical development costs for DNL758 in systemic inflammatory diseases.
“This collaboration with Denali is yet another example of Sanofi’s commitment to accelerate the development of transformative and best-in-class treatments for patients living with serious illnesses,” said Rita Balice-Gordon, Ph.D., Global Head of Rare andNeurologic Diseases Research at Sanofi. “We look forward to working with Denali on the RIPK1 program as we explore the potential of this mechanism in neurologic and inflammatory diseases.”
“RIPK1 is a promising target with the potential to bring disease modifying medicines to patients suffering from neurodegenerative diseases as well as systemic inflammatory diseases. We are very excited to partner with Sanofi and expand our RIPK1 program into new indications,” said Ryan Watts, Ph.D., CEO of Denali. “With its considerable infrastructure and experience in both clinical development and commercial functions, Sanofi is an ideal partner for Denali to maximize the clinical and commercial success of our RIPK1 program.”
Subscribe to:
Posts (Atom)