Gene editing stocks have a habit of running up and down when some new piece of research underscores their potential or the risks associated with the tech.
Today the numbers were plunging into the red for CRISPR Therapeutics $CRSP, Intellia $NTLA and Editas $EDIT as some top-level investigators spotlighted a connection between CRISPR-Cas9 and an added risk of cancer associated with the technology. And soon after the studies hit, the biotechs involved began to strike back at the researchers’ conclusions.
The problem, says Professor Jussi Taipale, now at the Department of Biochemistry, Cambridge, is that editing cells with p53 is hard because it activates a system that flags the cell for DNA damage. As a results, there’s a natural preference for cells that lack the p53 pathway, which are more vulnerable to cancer, giving rise to vulnerable cell populations.
Depressing p53 activity in cells may well have the same risks, as they are stripped of their natural defenses.
Taipale worked with investigators at the prestigious Karolinska Institute in Sweden.
“Although we don’t yet understand the mechanisms behind the activation of p53, we believe that researchers need to be aware of the potential risks when developing new treatments,” Taipale says. “This is why we decided to publish our findings as soon as we discovered that cells edited with CRISPR-Cas9 can go on to become cancerous.”
Simultaneously, a group at the Novartis Institutes for BioMedical Research also raised the same issue with p53, underscoring some of the risks involved with CRISPR/Cas9 technology and spooking investors who were gambling that this technology will deliver a whole new generation of drugs.
Darren Griffin, a genetics expert at Kent University who was not involved in either study, told Reuters that the study raises “reason for caution, but not necessarily alarm”.
“Almost any treatment that has the power to do good, has the power to do harm and this finding should be considered in this broader context,” he added. “As we learn more about the CRISPR-Cas9 system and how it can be used, this study will inevitably be considered a significant finding.”
Intellia was one of the first to respond to the report, and the drooping stock price. In an email to me the biotech noted:
We’ve observed no signs of this type of toxicity or cells transforming into cancer or tumors in Intellia’s in vivo and ex vivo programs.
Intellia has not found this type of effect in any of our in vivo studies using our lipid nanoparticle delivery system, including our 52-week study of successful TTR knockdown in mice and our ongoing studies of non-human primates. For Intellia’s ex vivo work, we have achieved efficient editing (>90 percent) in HSCs and T-cells and have not seen the type of toxicity or tumorgenicity being reported in these papers. Despite extended observation in animals and in vitro cultures, we have not seen this effect. Intellia’s current approaches are directed at different cell types.
CRISPR shares were down 13% Monday afternoon, Intellia was off 9% and Editas shed 10% of its value.
https://bit.ly/2Jv7TNx
Monday, June 11, 2018
New Guide to Deprescribing Benzos and Z-Drugs
Hello. I’m Dr Charles Vega, and I am a clinical professor of family medicine at the University of California at Irvine. Welcome to Medscape Morning Report, our 1-minute news story for primary care.
Benzodiazepines and “Z” drugs (including zopiclone, zolpidem, and zaleplon) are widely prescribed as a long-term treatment for insomnia. However, the American Geriatrics Society Beers Criteria say they should be avoided,[1] and use in older adults has been associated with falls, dementia, motor vehicle accidents, and physical addiction.
A new guideline[2] provides an evidence-based algorithm to guide the deprescribing process. Most patients, when told that they can expect improvements in cognition and reduction of other adverse effects, are very willing to try to discontinue use of these drugs. And 60%-80% of patients can be successfully tapered off of these hypnotic drugs.
Clinicians should discuss the need to slowly taper in all patients aged 65 years and older, regardless of treatment duration. Younger adults who have used these drugs for longer than 4 weeks should also slowly taper off. A goal reduction of 25% of the dose every 2 weeks is reasonable. The full text of the guidelines, which includes a downloadable version of the algorithm, is available online.
Next-Gen Sequencing for Lung Cancer: Do It Early, for All of Your Patients
Hello. This is Mark Kris from Memorial Sloan Kettering in New York City, talking, once again, about the benefits of doing next-generation sequencing (NGS) at diagnosis on persons with lung cancer.
We’ve talked before about the need to get this testing done. In one fell swoop, we can easily get the complete profiling of the genetic abnormalities that can lead us to targeted therapies: point mutations, deletions, insertions, copy number alterations, fusion oncogenes. All of those things can be identified all at once, so you have the information as soon as possible to make the best choices for patients. Please work with your colleagues who obtain biopsies and your colleagues in pathology to get that done.
However, NGS also provides additional information. [In that earlier discussion,] we touched upon tumor mutational burden, a very potent indicator of benefit from immune checkpoint blockade.
Microsatellite instability is another measure for the success of immune checkpoint blockade. Although it’s not so rare to find this in other cancers (colorectal cancer being the best example), it is indeed a very rare person with lung cancer who has microsatellite instability. With NGS, you can have this information automatically available, which opens up the door for these patients. If it comes without any additional effort, it’s really well worth doing.
There is also the possibility of using NGS to determine the primary site of cancer when you have some question about whether that spot in the lung really represents lung cancer or could be another primary site. Our molecular pathologists now know what common cancers look like in the NGS panels. As a result, they can take a sample that is less well known, that you’re not sure about despite the pathologic review and immunohistochemical review, and see how the genetic profile of the tumor in your patient compares to those known tumors.
It’s an informatics exercise. It doesn’t require additional tissue or additional time. It really doesn’t even require additional money, but it can be done as part of NGS.
The other emerging area of NGS is using the same information to prognostically stratify patients. You can use panels of specific genes to identify folks with a better or worse prognosis, and establish algorithms that would define prognosis based on particular NGS results.
This is a bioinformatics exercise included within the NGS. It does not require an additional biopsy. It does require a little time and, of course, needs to be set up by your bioinformatics team. It can be another helpful piece of information that comes from NGS.
The last reminder is that NGS recently has been reviewed by the US Food and Drug Administration (FDA). Although there are still some special issues surrounding NGS testing and getting it paid for, panels have had their diagnostic reproducibility and accuracy determined, by state [department of health] panels for example, which can also be used for FDA approval.[1] The FDA has said that they would accept a number of panels—such as the one from my institution, MSK-IMPACT, and one from a commercial vendor—as an established test for a specific target, practically in lieu of a linked diagnostic test, which frankly is very rarely used.
People talk about the cost, but it is less than one PET scan. Just a small reminder that using PET scans to follow patients with soft tissue disease with an advanced malignancy, at least in lung, is not a standard of care. I know that it is done by many practitioners, including myself, who can do much more expensive tests with no clear-cut guideline recommendation. We can also use NGS testing, which has a lot of guideline-based rationale to use it, particularly for those known targets.
Please get NGS testing done on all of your patients at the time of diagnosis. Work with your colleagues to get sufficient tissue and to get [testing] done quickly, and with your bioinformatics team that analyzes this data and/or your commercial vendors to get the information you need to best care for your patients.
FluMist: Reasonable Vaccine Option or ‘Last Resort’ for Upcoming Flu Season?
Hi. My name is Paul Offit, and I’m talking to you today from the Vaccine Education Center at the Children’s Hospital of Philadelphia. I want to talk about some contention about the use of the live-attenuated influenza vaccine known as FluMist. On the one hand, you have the Advisory Committee on Immunization Practices (ACIP), which advises the Centers for Disease Control and Prevention (CDC), recommending that the FluMist vaccine be used this coming year in the same manner that one would use the inactivated vaccine. Or said another way, you could use either vaccine.
But that’s not what the American Academy of Pediatrics’ (AAP) Red Bookcommittee stated. They stated that they preferred the use of the inactivated influenza vaccine, and that the FluMist vaccine should only be used as a “last resort.”[1] Let’s talk about the data that are behind those two recommendations and see if we can make sense of them.
FluMist was first licensed for use in the United States in 2003 for those aged 5-49 years. In 2007, it was recommended for all of those between 2 and 49 years of age. The way that the vaccine is made is that it comes from two cold-temperature-adapted influenza viruses that were created in the 1960s, into which one then reassorts the hemagglutinin neuraminidase genes that are going to be prevalent for the coming season. In studies done in 2006 and 2007, that vaccine appeared to be better than the inactivated influenza vaccine.
For that reason, in 2014, the ACIP gave FluMist a preferential recommendation over the inactivated influenza vaccine. Unfortunately, in the 2013-2014 season, 2014-2015 season, and the 2015-2016 season, FluMist actually underperformed compared with the inactivated influenza vaccine, especially for the H1N1 strain; and for that reason, the ACIP withdrew its recommendation to use FluMist.
This year, 2018, FluMist is back on the market. The problem that FluMist suffered is that it is a vaccine that contains four different strains and it’s given to a mucosal surface—a nasal spray vaccine. If you are going to do that, you have to make sure that all four strains replicate equally. The problem with FluMist was that the H1N1 strain (the so-called A/Bolivia strain) had a replication fitness problem. It didn’t replicate nearly as well as it needed to induce immune response.
Now, all of the data to date support the fact that the company that makes FluMist has resolved that problem. They’ve proven it by showing that this new strain, the A/Slovenia strain, as compared with the A/Bolivia strain, reproduces itself very well in human nasal epithelial cells. Previously, the company had been using Madin-Darby canine kidney cells to look for replication, which were not nearly as predictive as human nasal epithelial cells.
Second, instead of using a fluorescent focus assay, which is not a very good measure of spread of virus from one cell to another, the company now uses what is called a TCID-50 (50% tissue culture infection dose) assay, which also shows that the virus can replicate well. Furthermore, the company has shown that the immune response for the new A/Slovenia strain is much better than that of the A/Bolivia strain—similar to what had been seen before they had the H1N1 problem.
So I think the AAP was wrong, frankly, to say that FluMist should only be used as a last-resort vaccine for influenza. Rather, they should have gone along with what the ACIP said, which was that these vaccines can now be used interchangeably for persons aged 2-49 years.
https://wb.md/2y2GWLV
Amyloid PET Changes Diagnosis, Treatment for Cognitive Impairment
Amyloid positron emission tomography (PET) scans as part of a routine diagnostic work-up can change diagnoses and treatment in patients with mild cognitive impairment, a prospective diagnostic study in the Netherlands found.
Offering amyloid PET imaging to all patients in a memory clinic led to an etiological diagnosis change for 25% of patients and a treatment change for 24%, reported Arno de Wilde, MD, of VU University Medical Center in Amsterdam, and colleagues for the ABIDE project in JAMA Neurology.
Previous research about clinical use of amyloid imaging studied very select populations and did not reflect daily practice, de Wilde noted. “In contrast, we used an unselected memory clinic cohort, offering amyloid PET to all patients visiting our memory clinic. For the purpose of this study, we implemented amyloid PET in our routine diagnostic work-up,” he said.
“Our results demonstrate that amyloid PET has important consequences, in terms of diagnosis and treatment changes, for a significant number of patients in a situation that closely resembles clinical practice,” de Wilde told MedPage Today. “These results are an important step in bridging the gap between using amyloid PET in a research setting versus daily clinical practice.”
While amyloid PET scanning has been used extensively in research, few studies have assessed its usefulness in clinical practice. One study underway in the U.S. is the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) project, a collaboration of Medicare, the Alzheimer’s Association, and the American College of Radiology to study outcomes of patients with mild cognitive impairment or dementia of uncertain etiology.
An interim IDEAS analysis showed changes in diagnosis and treatment after amyloid PET scans; if improved outcomes are confirmed, the study could pave the way for Medicare and private insurance payment. Thus far, Medicare has refused broad coverage for amyloid PET scans because the agency was unconvinced that the results would positively affect patients’ outcomes.
ABIDE (Alzheimer’s Biomarkers in Daily Practice) is a 3-year project in the Netherlands that aims to apply magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and amyloid PET diagnostic tests used in research to daily clinical practice, focusing on patients with mild cognitive impairment.
In this study, researchers offered amyloid PET using fluoride-18 florbetaben to patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. They included 476 patients, plus 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic, in the study. Participants had an average age of 65 and 39% were women.
For each patient, neurologists determined a pre- and post-amyloid PET diagnosis that included both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease or not), and estimated how confident they were with their diagnoses. The neurologist also decided whether ancillary tests were needed and established a treatment plan.
The average Mini-Mental State Examination score of the cohort was 25. Of the total sample, 32.3% received a pretest diagnosis of Alzheimer’s disease dementia, 13.8% non-Alzheimer’s disease dementia, 22.5% mild cognitive impairment, and 31.3% subjective cognitive decline.
Amyloid PET results were positive for 47.7% of patients. The suspected etiology changed for 24.7% of patients after amyloid PET, more often stemming from a negative (31%) than positive (18%) result (P<0.01). Diagnostic confidence increased from 80% to 89% (P<0.001).
In 24.3% of cases, neurologists changed patient treatment post-PET, mainly making medication changes — starting cholinesterase inhibitors and referring patients to clinical trials — for patients with positive scans.
This research shows that amyloid PET improves diagnostic accuracy and can help patients and families make important decisions about medications, employment, finances, and clinical trial participation, noted Stephen Salloway, MD, MS, of the Alpert Medical School of Brown University, in an accompanying editorial. But there are issues to consider: patients in this study were younger than many people with Alzheimer’s disease and had fewer comorbid illnesses than many patients with cognitive impairment in clinical practice.
“There is some concern about generalizing these results to primary care or memory clinic settings,” Salloway wrote. “The introduction of a cohort with subjective cognitive decline is novel, but it is unclear how to interpret the meaning of a negative amyloid scan in a 61-year-old with subjective cognitive decline, and we do not yet have reliable prognostic markers to estimate the likelihood and timing of cognitive decline in patients with subjective cognitive decline who have a positive amyloid scan.”
The researchers listed other possible limitations to their study. Its main outcome measure was change in diagnosis which reflects, in part, clinicians’ beliefs. And the study setup deviated from regular clinical practice in several important ways: the researchers offered amyloid PET to all patients, not just diagnostically uncertain cases; the primary neurologist may or may not have seen the patient; and patients did not always receive the results of their scan.
This study was performed within the framework of the Dutch ABIDE project and was supported by a ZonMW-Memorabel grant and a grant by Piramal Imaging (positron emission tomography scan costs) to the Stichting Alzheimer & Neuropsychiatrie, Amsterdam.
Researchers reported relationships with Avid, Boehringer Ingelheim, Piramal Imaging, Janssen Stellar, Combinostics, Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzyme, Sanofi-Aventis, TEVA, Novartis,Toshiba, BV Cyclotron VU, GE Healthcare, Danone Research, Merck, Lilly, Sanofi, Nutricia, Probiodrug, Biogen, Avraham, and EIP Pharma.
The editorialist reported no disclosures.
LAST UPDATED
Primary Source
JAMA Neurology
Secondary Source
JAMA Neurology
NMC HEALTH: JV to create Saudi healthcare platform
NMC Health has announced the signing of a non-binding agreement to form a joint venture healthcare platform with Hassana Investment Company, the investment arm of the General Organisation for Social Insurance (Gosi), which is the largest pension fund in Saudi Arabia.
The proposed joint venture would create one of the largest private healthcare platforms operating in KSA today. The venture would have a strong foothold in Riyadh, as well as in multiple smaller, underserved cities. The enlarged organisation is expected to benefit from economies of scale, allowing more efficient deployment of capital, increasing patient choice and optimising returns across multiple assets.
Prasanth Manghat, CEO of NMC, said: “We identified KSA as a key strategic priority for NMC and the proposed partnership between NMC and Gosi/Hassana would offer a tremendous opportunity for both the companies to better serve the KSA healthcare market. The Saudi government’s forward-looking and investor-friendly policies make the Kingdom one of the most attractive destinations in the region for investment in the healthcare sector.”
Citron sees 130% short-term upside in shares of Fitbit
Citron Research, known for being a short-seller, posted on its website today a bullish research report on shares of Fitbit (FIT). The firm has a $15 “short-term target” for the stock, which represents upside of 130%. Fitbit in midday trading is up 41c, or 6.5%, to $6.76. “What was once a pinata for short-sellers (since IPO) has transformed itself to one of the most underappreciated med-tech stories in the market with a balance sheet and brand equity that gives investors a tremendous investing opportunity,” Citron writes. The firm sees the stock reaching $15 in 2018, “if not acquired first.”
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