Blueprint Medicines avapritinib continues effect in mastocytosis study

Blueprint Medicines (NASDAQ:BPMC) announces updated data from part 1 of a Phase 2 clinical trial, PIONEER, evaluating Ayvakit (avapritinib) in patients with indolent (slow-growing) systemic mastocytosis. The results were virtually presented at the European Academy of Allergy and Clinical Immunology Congress (EAACI).

Week 24 data showed a deepening of symptom reductions in the 25 mg once-daily treatment group compared to week 16, reported in March. Specifically, the mean change from baseline in a scale called ISM-SAF was -35% compared to -4% in the control group. At week 16, the mean reduction was -30% in the 25 mg arm. The response rate was 60% versus 0% for placebo (defined as at least a 30% reduction in ISM-SAF total symptom score).

The company has selected the response rate at week 24 as the primary endpoint for registration-enabling part 2 of the study. Recruitment (planned enrollment of 200 subjects) will commence this month.

No new safety signals were observed.

Systemic mastocytosis is a rare disorder characterized by the uncontrolled proliferation and activation of mast cells in the body which, when triggered, leads to a range of symptoms like rapid heartbeat, lightheadedness and facial flushing. It is driven by a mutation in the KIT gene called D816V.

Avapritinib is a highly selective inhibitor of D816V-mutant KIT (protein called receptor tyrosine kinase).

https://seekingalpha.com/news/3580954-blueprint-medicines-avapritinib-continues-to-shows-effect-in-mastocytosis-study

AbbVie’s Rinvoq tops Bristol Myers’ Orencia in rheumatoid arthritis study

AbbVie (NYSE:ABBV) announces positive results from a head-to-head Phase 3 clinical trial, SELECT-CHOICE, comparing Rinvoq (upadacitinib) to Bristol Myers Squibb’s (NYSE:BMY) Orencia (abatacept) in adults with moderate-to-severe active rheumatoid arthritis (RA) and prior inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (DMARDs). The results were virtually presented at EULAR.

The study met the primary endpoint demonstrating the non-inferiority of upadacitinib to abatacept as measured by the change from baseline in a scale called DAS28-CRP at week 12.

Upadacitinib showed superiority to abatacept as measured by the same scale at week 12 and the proportion of patients achieving clinical remission at week 12, both secondary endpoints.

No new safety signals were reported.

The trial is the sixth and last late-stage study in AbbVie’s SELECT RA program.

The FDA approved the JAK inhibitor in August 2019 for RA. It was approved in Europe in December 2019.

https://seekingalpha.com/news/3580955-abbvies-rinvoq-tops-bristol-myers-orencia-in-rheumatoid-arthritis-study

Cuomo accelerates reopening plans as NY coronavirus deaths drop to record low

Coronavirus deaths have hit a record low in New York, according to Gov. Andrew Cuomo, who said Saturday the “really really good news” allowed him to take steps to further reopen the state, including signing an executive order allowing commercial buildings to take the temperature of anyone entering.
COVID-19 killed 35 people across the state in the last 24 hours — down from a peak of over 700 fatalities a day in April.
“Our metrics are all, today, very good. We are going to open the valve more than we originally anticipated because the metrics are so good,” Cuomo said at his daily press conference in Albany. “Compared to where we were, this is a big sigh of relief.”
The numbers will mean an accelerated reopening of houses of worship, Cuomo said.
Synagogues, mosques and churches will be allowed to open at 25 percent capacity once the region they’re in hits the state’s phase 2 requirements, the governor said.
The religious leaders will be responsible for implementing social-distancing measures, Cuomo said.
“It doesn’t mean you go to a temple or a mosque and sit right next to a person. You have to socially distance,” he said. “We leave it to our faith-based partners to come up with a smart strategy and way to do this.

“This is an acceleration for us because we are doing so well on the metrics, but people still have to stay smart.”
Friday’s death toll, which included 26 fatalities in hospitals and nine in nursing homes, broke Thursday’s record-low of 42 deaths statewide.
New York City earlier this week for the first time reported no new COVID-19 deaths in a single day. 
As the city prepares to enter phase one of reopening on Monday, with construction, manufacturing and curbside retail returning to work, Cuomo said the executive order allows all commercial buildings to take the temperatures of anyone entering.
“When you go back to work, it doesn’t mean we are going back to the way we were. It’s about going forward and finding a new normal with new behavior and new patterns in the workplace,” he said.
https://nypost.com/2020/06/06/cuomo-accelerates-reopening-plans-as-covid-19-deaths-drop/

Potential new weapon in the war against superbugs

University of Melbourne researchers are finding ways to beat dangerous superbugs with ‘resistance resistant’ antibiotics, and it could help in our fight against coronavirus (COVID-19) complications.

As bacteria evolve, they develop strategies that undermine antibiotics and morph into ‘superbugs’ that can resist most available treatments and cause potentially lethal infections.
The Melbourne team has shown that a newly discovered natural antibiotic, teixobactin, could be effective in treating bacterial lung conditions such as tuberculosis and those commonly associated with COVID-19.
Their work could pave the way for a new generation of treatments for particularly stubborn superbugs.
Teixobactin was discovered in 2015 by a team led by Professor Kim Lewis at Northeastern University in Boston in 2015. His company is now developing it as a human therapeutic.
The new University of Melbourne research, published in mSystems journal, is the first to explain how teixobactin works in relation to the superbug Staphylococcus aureus — also known as MRSA.
MRSA is among bacteria responsible for several difficult-to-treat infections in humans, particularly post-viral secondary bacterial infections such as COVID-19 chest infections and influenza.
University of Melbourne Research Fellow in anti-infectives Dr Maytham Hussein and Associate Professor Tony Velkov’s team synthesised an aspect of teixobactin to produce a compound that showed excellent effectiveness against MRSA, which is resistant to the antibiotic methicillin.
Dr Hussein said that there was no way to stop bacteria like MSRA from developing resistance to antibiotics as it was part of its evolution. This made combatting it extremely challenging.
“The rise of multi drug-resistant bacteria has become inevitable,” Dr Hussein said. “These bacteria cause many deadly infections, particularly in immunocompromised patients such as diabetic patients or those with cancers, or even elderly people with post-flu secondary bacterial infections.”
The University of Melbourne team is the first to find that teixobactin significantly suppressed mechanisms involved in resistance to vancomycin-based antibiotics that are recommended for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and MRSA-caused meningitis.
The development could lead to new lung infection treatments and Associate Professor Velkov said it would greatly facilitate the pre-clinical development of teixobactin.
“Bacteria often develop resistance towards antibiotics within 48 hours after exposure,” Associate Professor Velkov said. “The bacteria failed to develop resistance towards this compound over 48 hours.
“These novel results will open doors to develop novel antibacterial drugs for the treatment of multi-drug resistant Gram-positive infections — bacteria with a thick cell wall — which are caused by certain types of bacteria.”

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Story Source:
Materials provided by University of Melbourne. Note: Content may be edited for style and length.

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Journal Reference:

1. Maytham Hussein, John A. Karas, Elena K. Schneider-Futschik, Fan Chen, James Swarbrick, Olivia K. A. Paulin, Daniel Hoyer, Mark Baker, Yan Zhu, Jian Li, Tony Velkov. The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study. mSystems, 2020; 5 (3) DOI: 10.1128/mSystems.00077-20

https://www.sciencedaily.com/releases/2020/06/200604111641.htm

How cancer develops resistance to treatment

Cancer cells can turn on error-prone DNA copy pathways to adapt to cancer treatment, a breakthrough study published in the journal Science has revealed. Bacteria use the same process, termed stress-induced mutagenesis, to develop antibiotic resistance.

The cells of the human body are constantly dividing, and each time need to copy a three billion-letter DNA code with high precision to ensure cell survival. The same is not true for cancers, researchers have discovered.
A team led by Professor David Thomas at the Garvan Institute of Medical Research has shown how a broad range of cancers, including melanoma, pancreatic cancer, sarcomas and breast cancer, generate a high number of errors when they copy their DNA when exposed to cancer treatments, leading to drug resistance.
“Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail. We have uncovered a fundamental survival strategy that cancer cells use to develop resistance, and which has given us new possible therapeutic strategies,” says Professor Thomas, Garvan’s Cancer Research Theme Leader and Director of The Kinghorn Cancer Centre.
Resisting cancer treatment
Resistance to cancer therapy affects hundreds of thousands of cancer patients every year, leading to devastating health outcomes even for the most advanced treatments.
Researchers have long known that cancer cells accumulate genetic variations that make it possible for them to evade treatment. But how this happens — and whether the process could be targeted to improve cancer treatment — has been elusive.
The authors of the current study began to investigate the underlying drivers of treatment resistance by analysing biopsy samples from cancer patients, before and after they were treated with targeted cancer therapies. Targeted therapies block the growth of cancer by interfering with molecules that are needed for tumour growth, and are a common treatment for many forms of cancer.
They were surprised to discover that the cancer cells from patients that had received targeted therapies showed much higher levels of DNA damage than pre-treatment samples — even when these treatments did not directly damage DNA. Further, the researchers used whole genome sequencing to analyse how treatment resulted in accelerated evolution of the cancer genome.
“Our experiments revealed that cancer cells exposed to targeted therapies undergo a process called stress-induced mutagenesis — they generate random genetic variation at a much higher rate than cancer cells not exposed to anti-cancer drugs,” says first author Dr Arcadi Cipponi.
“This process is ancient — single-celled organisms, such as bacteria, use the same process to evolve when they encounter stress in their environment.”
Cancer’s two-step strategy for resistance
To pinpoint the mechanisms underlying stress-induced mutagenesis in human cancer cells, the researchers carried out a large-scale screen to silence every gene in cancer cells individually, looking to identify the specific pathways contributing to drug resistance.
When they silenced the gene for MTOR — a stress sensor protein — they discovered that cancer cells stopped growing, but paradoxically accelerated evolution in the presence of a cancer treatment.
“MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment. But we found that in the presence of a cancer treatment, MTOR signalling allowed cancer cells to change expression of genes involved in DNA repair and replication, for example shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases,” says Dr Cipponi. “This resulted in more genetic variation, ultimately fuelling resistance to treatment.”
The shift to low-fidelity DNA repair and replication was temporary — once cancer cells acquired resistance to a cancer treatment, they reactivated high-fidelity pathways.
“Genomic instability can itself be harmful to cells — which is why some of our chemotherapies and therapeutic radiation work. We found that once cancer cells had developed resistance to a treatment, they switched back to high-fidelity DNA polymerases to ensure the cells that had evolved resistance to treatment could survive,” explains Dr Cipponi.
New approach for cancer treatments
Combining conventional targeted cancer therapy with drugs that target DNA repair mechanisms, the researchers say, may lead to more effective therapeutic strategies.
As a proof-of-principle, the researchers tested such a drug combination in a mouse model of pancreatic cancer. By combining the cancer treatment palbociclib with rucaparib, a drug which selectively targets cells with impaired DNA repair, they were able to reduce cancer growth by almost 60% over 30 days, compared to palbociclib alone.
“Our findings have opened up new potential strategies that either prevent stress-induced mutagenesis in cancers, or are more effective in cancers that have already developed resistance,” says Professor Thomas.

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Story Source:
Materials provided by Garvan Institute of Medical Research. Note: Content may be edited for style and length.

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Journal Reference:

1. Arcadi Cipponi, David L. Goode, Justin Bedo, Mark J. McCabe, Marina Pajic, David R. Croucher, Alvaro Gonzalez Rajal, Simon R. Junankar, Darren N. Saunders, Pavel Lobachevsky, Anthony T. Papenfuss, Danielle Nessem, Max Nobis, Sean C. Warren, Paul Timpson, Mark Cowley, Ana C. Vargas, Min R. Qiu, Daniele G. Generali, Shivakumar Keerthikumar, Uyen Nguyen, Niall M. Corcoran, Georgina V. Long, Jean-Yves Blay, David M. Thomas. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer. Science, 2020; 368 (6495): 1127 DOI: 10.1126/science.aau8768

https://www.sciencedaily.com/releases/2020/06/200604152052.htm

Restoring vision by gene therapy in macular degeneration

Humans rely dominantly on their eyesight. Losing vision means not being able to read, recognize faces or find objects. Macular degeneration is one of the major reasons for visual impairment, round the globe, close to 200 million people are affected. Photoreceptors in the retina are responsible to capture the light coming from the environment through the eye. Diseased photoreceptors lose their sensitivity to light, which can lead to impaired vision or even complete blindness.

Scientists of the Institute of Molecular and Clinical Ophthalmology Basel (IOB) together with colleagues from the German Primate Center (DPZ) — Leibniz Institute for Primate Research in Göttingen have developed a completely new therapeutic approach based on gene therapy. They managed to activate degenerated photoreceptors using near-infrared light. Their findings are published in the journal Science.
The main cause of blindness in industrialized countries is the degeneration of photoreceptors, including age-related macular degeneration and retinitis pigmentosa. During the progression of degenerative photoreceptor diseases, light-sensitive and light-insensitive photoreceptor regions in the retina coexist. For example, macular degeneration patients lose vision in the central portion of their retina but retain peripheral eyesight.
Scientists have now succeeded in developing a new therapeutic approach to restore light sensitivity in degenerating retina without negatively affecting remaining vision. They were inspired by species found in nature, such as bats and snakes, that can localize near-infrared light emitted by the bodies of their preys. This is done by using heat-sensitive ion channels which are able to detect the heat of the near-infrared light. This enables the bats and snakes to superimpose thermal and visual images in the brain and thus react to their environment with greater precision. To equip retinal photoreceptors with near-infrared sensitivity, the researchers devised a three-component system. The first component contains engineered DNA that ensures that the gene coding for the heat-sensitive channel is only expressed in photoreceptors. The second component is a gold nanorod, a small particle, that efficiently absorbs near-infrared light. The third component is an antibody that ensures strong binding between the heat-sensitive channel expressed in photoreceptors and the gold nanorods that locally capture near-infrared light and locally release heat.
The researchers first tested their system in engineered mice with retinal degeneration, confirming that near-infrared light effectively excites photoreceptors and that this signal is transmitted to retinal ganglion cells, the latter representing the output of the retina towards higher visual centers in the brain. Next, they showed that stimulating the mouse eye with near-infrared light is also picked up by neurons in a brain area that is important for conscious vision, the primary visual cortex. They also designed a behavioral test in which untreated blind mice were not able to use near-infrared stimulation to learn a simple task whereas blind mice treated with the three-component system could perform the task related to near-infrared stimulus.
In collaboration with Arnold Szabo, a co-author of the paper and Assistant Professor at the Semmelweis University in Hungary, the researchers could test their new approach on human retinas that can be kept alive in culture medium for months, though blindness sets in a day or so after death by photoreceptors losing their ability to detect light. Experimental results showed that following treatment with the three-component gene therapy method, near-infrared light exposures reactivated the human retina’s visual circuitry.
“We believe that near-infrared stimulation is an important step towards providing useful vision to blind patients so that they can regain their ability to read or see faces,” says Daniel Hillier, head of the junior research group Visual Circuits and Repair at DPZ, and adds: “We want to give hope to blind people with these findings and will further intensify our research activities in this area here at DPZ within our main project, which focuses on the restoration of vision.”

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Story Source:
Materials provided by Deutsches Primatenzentrum (DPZ)/German Primate Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Dasha Nelidova, Rei K. Morikawa, Cameron S. Cowan, Zoltan Raics, David Goldblum, Hendrik P. N. Scholl, Tamas Szikra, Arnold Szabo, Daniel Hillier, Botond Roska. Restoring light sensitivity using tunable near-infrared sensors. Science, 2020; 368 (6495): 1108 DOI: 10.1126/science.aaz5887

https://www.sciencedaily.com/releases/2020/06/200604152048.htm

Applying symptom tracking to COVID-19 outpatient care using famotidine [Pepcid]

A patient-reported symptom tracking method used for patients with cancer has now been adapted for patients with COVID-19. Investigating the effect of famotidine, a potential treatment for COVID-19, on non-hospitalized patients with COVID-19, clinicians at Northwell Health and cancer researchers at Cold Spring Harbor Laboratory (CSHL) developed the method to use in addition to laboratory tests. This outpatient approach addresses the need to care for the majority of COVID-19 patients who do not require hospitalization. The first clinical case series showed that famotidine may help patients with mild to moderately severe symptoms from COVID-19. Next, the team will test the drug in a randomized clinical trial.

Published in the journal GUT, the Northwell-CSHL case series is unique in its adaptation of quantitative tracking of patient-reported outcome measures. The methodology is suitable for testing drugs in patients well enough to be managed at home and allows the recruitment of diverse subjects via community-based health organizations and individual practitioners.
The lead author of the study, CSHL Assistant Professor Tobias Janowitz, is a Medical Oncologist and a Cancer Researcher, who investigates the whole-body causes and effects of diseases. “The experience of a patient at one point in time is very valuable, but learning about the change in their experience over time is even more important,” says Janowitz. “Change indicates if the patients’ condition is getting better or worse. A graded symptom score enables the physician and the patient to track symptoms using numbers.”
Observing that for COVID-19, most symptomatic people do not require hospitalization, Janowitz and colleagues developed a 4-point scale for six common COVID-19 associated symptoms that patients score every day. Janowitz simplifies how the scale can help track the course of a patient’s disease:
“You may call up your doctor and say, I have headaches and shortness of breath, and am only able to do the basics for self-care, which would be grade 3 symptoms. If you still had the symptoms two days later, but are now able to do light work, these symptoms would now be scored at grade 2. This approach makes it very easy for you and your doctor to document that your symptoms are improving. The value of this approach from a research perspective is that experiences from many patients become comparable and can be pooled for analysis.”
If a drug speeds recovery, then most patients will report more rapid improvement of symptoms.
The innovations in this study are the product of scientists and physicians who never expected to work on a pandemic infection. But the collaborative, multidisciplinary approach is a hallmark of the strategic research affiliation between CSHL and the academic physicians at Northwell Health. Chief, General Internal Medicine, Northwell Health and Professor at the Feinstein Institutes, and a co-author on the study, Joseph Conigliaro says:
“There are a lot of things that we were doing that worked well in how we address this pandemic. I’m a health services addiction researcher. I didn’t think I’d ever be the person who would be studying this pandemic and this virus. And Tobias does cancer research. What we did is we used our existing tools and talents that were not specifically geared towards studying a viral pandemic, but we used it and modified it in ways that were very, very helpful.”
CSHL Professor David Tuveson, Director of the CSHL Cancer Center and another co-author, is interested in the broader implications of the patient-oriented research approach as a way to better connect science and healthcare. CSHL’s commitment to bridging the gap between research and the clinic is evident in an initiative championed by Janowitz to study how disease impacts the entire body. Tuveson says:
“You’re trying to scientifically assess a symptom, is what you’re really doing. Tobias and his colleagues can look at the whole body while they study cancer. And so Tobias is someone who thinks about the big picture of health. He’s basically shifting his approach to solving complex problems to COVID-19 and he started by saying ‘how can we describe one patient relative to the next?'”
Janowitz agrees, “It seems reasonable to me to make that extension to this healthcare crisis and to acknowledge that we can learn a lot from the individual who has the disease as long as we find a way to make it quantifiable.”
Once validated, the patient-reported symptom tracking method will be a key component in a clinical trial that is “double-blind,” meaning that neither patient nor doctor know whether the patient is getting the test drug or a placebo until the trial is completed. Without a double-blind clinical trial and a careful scientific examination of the mechanism of action of a drug and its side effects, it is impossible to rule out that the preliminary findings were due to factors other than the drug. The early findings of this case series were communicated to co-author Dr. Timothy Wang at Columbia University Medical Center. Interestingly, Dr. Wang and colleagues were also able to find an association between famotidine usage and the improved outcomes of patients hospitalized for COVID-19. Based on the findings in the case series, a double-blind clinical trial of famotidine is the next step in the joint plan of the Northwell-CSHL team. Other treatments may also be explored.
Conigliaro explains why he is hopeful that the study will work as designed to find drugs that will be effective against COVID-19:
“We had about a thousand patients that we tracked in our practices, just in my couple of academic practices, that never made it to the hospital. And my Doc’s were calling them every day and asking all those questions: ‘Do you have aches and pains? Do you have fever today? How’s your breathing today?’ We didn’t know what their blood levels were. We didn’t know what their oxygen levels, because we didn’t have access to that. So these surrogate measures are very common and the best way to assess what’s going on in the outpatient. I’m actually pretty confident. I think there’ll be another surge but I think we’ll be much better prepared and I think that hopefully lives will be saved.”

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Story Source:
Materials provided by Cold Spring Harbor Laboratory. Original written by Eliene Augenbraun. Note: Content may be edited for style and length.

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Journal Reference:

1. Tobias Janowitz, Eva Gablenz, David Pattinson, Timothy C Wang, Joseph Conigliaro, Kevin Tracey, David Tuveson. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series. Gut, 2020; gutjnl-2020-321852 DOI: 10.1136/gutjnl-2020-321852

https://www.sciencedaily.com/releases/2020/06/200605004329.htm