The Asheville, NC-based healthcare and wellness company sells topical products aimed at improving immune health, neuromuscular health and skin barrier health targeted to institutional and self-care markets.
Friday, January 17, 2020
Cheap drug may alleviate treatment-resistance in leukemia
A common and inexpensive drug may be used to counteract treatment resistance in patients with acute myeloid leukemia (AML), one of the most common forms of blood cancer. This is the conclusion of a study in mice and human blood cells performed at Karolinska Institutet and SciLifeLab and published in the medical journal EMBO Molecular Medicine. The researchers will now launch a clinical study to test the new combination treatment in patients.
Leukemia is a group of blood cancers that results in excess amounts of white blood cells. There are both chronic forms of leukemia that progress slowly over many years and acute types of leukemia that evolve rapidly. AML affects more than 20,000 people in the United States each year, and the mortality rate is high especially in older patients.
One of the most common drugs to treat AML is cytarabine (ara-C), a cytotoxic drug that interferes with DNA replication. However, many patients do not respond to the treatment because their leukemic cells express high levels of the enzyme SAMHD1, which breaks down the active metabolite of cytarabine, ara-CTP. These patients have a significantly worse survival rate than patients with low leukemic levels of SAMHD1. Therefore, one promising strategy to improve the treatment of AML is to inhibit the effects of this enzyme on cytarabine.
In this study, the researchers tested the impact of more than 33,000 different substances on SAMHD1’s ability to break down ara-CTP in leukemia cells treated with cytarabine. The experiment led to the identification of three different substances, so-called ribonucleotide reductase inhibitors (RNRi), that all reduced SAMHD1’s ability to deactivate ara-CTP: hydroxyurea, gemcitabine and triapine.
“Adding any of these three substances significantly improved the effect of the cytarabine-treatment in cell samples with high levels of SAMHD1,” says Nikolas Herold, researcher at the Department of Women’s and Children’s Health at Karolinska Institutet in Sweden. “This was true for AML samples from both adults and children. In AML-mice, we also saw that the median survival was significantly prolonged when cytarabine was combined with an RNR-inhibitor.”
Hydroxyurea is an inexpensive drug that is used to treat blood diseases such as AML. However, it has not systematically been used in combination with cytarabine. Gemcitabine is a potent drug that is used to treat many different types of cancers, but it can be toxic if given repeatedly. Triapine is a drug currently undergoing clinical studies for cancer treatment. In animal studies, the combination therapies did not exhibit any excess side-effects beyond those already established in cytarabine-treatments.
The research group is now planning to move forward with a clinical study that will evaluate the effect of combining standard AML-treatment with hydroxyurea in recently diagnosed patients. The study will be conducted in collaboration with the Swedish AML-group and will begin recruiting patients within a few weeks.
“Hydroxyurea is an approved drug that is already used to treat AML, so we think it has great potential,” says Nikolas Herold. “If our research results can be confirmed in clinical trials, the treatment of AML could be significantly improved also in developing countries with limited resources since hydroxyurea is patent-free and doesn’t cost more than ibuprofen.”
The researchers were also able to show how the RNR-inhibitors affected the SAMHD1-levels mechanistically. These drugs change the intracellular composition of deoxynucleoside triphosphates (dNTP), which are building blocks for molecules. Since SAMHD1 needs dNTPs to activate its enzymatic activity, this effectively abrogates its ability to break down ara-CTP.
Story Source:
Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.
Journal Reference:
- Sean G Rudd, Nikolaos Tsesmetzis, Kumar Sanjiv, Cynthia BJ Paulin, Lakshmi Sandhow, Juliane Kutzner, Ida Hed Myrberg, Sarah S Bunten, Hanna Axelsson, Si Min Zhang, Azita Rasti, Petri Mäkelä, Si’Ana A Coggins, Sijia Tao, Sharda Suman, Rui M Branca, Georgios Mermelekas, Elisée Wiita, Sun Lee, Julian Walfridsson, Raymond F Schinazi, Baek Kim, Janne Lehtiö, Georgios Z Rassidakis, Katja Pokrovskaja Tamm, Ulrika Warpman‐Berglund, Mats Heyman, Dan Grandér, Sören Lehmann, Thomas Lundbäck, Hong Qian, Jan‐Inge Henter, Torsten Schaller, Thomas Helleday, Nikolas Herold. Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy. EMBO Molecular Medicine, 2020; DOI: 10.15252/emmm.201910419
Analysts tip Biogen to file for aducanumab approval within weeks
Analysts at Jefferies expect Biogen to file for approval of aducanumab in Alzheimer’s disease within weeks. Biogen, for its part, is keeping mum about its plans, stating only that it is preparing modules of the common technical document for submission to the FDA.
With Biogen having shared the analyses it thinks will support approval of aducanumab last year, the focus has shifted to the timing of the filing and a search for clues about the FDA’s position. The annual J.P. Morgan Healthcare Conference in San Francisco provided analysts and investors with an opportunity to probe Biogen, but the company gave little away.
Asked about the filing, Biogen Chief Medical Officer Al Sandrock said: “We’ve been constructively engaged with FDA, basically since last June. It’s a matter of preparing all the different modules of the common technical document and submitting them to FDA as rapidly as possible.”
The lack of concrete information from Biogen has left analysts to speculate. Michael Yee and his colleagues at Jefferies said their “best estimate and interpretation” is that Biogen will make the filing “within weeks,” although even that tentative prediction came with the caveat that details “are very much unclear.” Given the tightrope Biogen is walking, its secrecy is explicable.
“[Biogen] is clearly taking a strategic (and perhaps smart) approach to not say anything to jeopardize discussions,” the analysts wrote in a note to investors.
Sandrock and his colleagues are being similarly tight-lipped about other aspects of the effort to get aducanumab to market. Biogen is now in talks with regulators in Europe and Japan but declined to be drawn in on how their views on the data compare to those of the FDA, saying only that the discussions have been “positive.”
The next potential pointer toward regulatory attitudes about the data will come when the FDA decides to put aducanumab in its standard or priority review pathway. Yee expects investors to interpret acceptance of aducanumab for priority review as a positive for the drug’s prospects, making it a stock-moving event.
Asked about how the complexity of the data set may affect the chances of a getting priority review, Sandrock said: “We’re in a very unique situation. I’ve never been in one quite like this. To go from futility to a filing is unique. The level of constructive engagement we’ve had, essentially since the first type C meeting in June, is pretty unusual. I would leave it at that.”
JPM: Pfizer, GSK execs talk contradictory scenarios for hiving off consumer JV
GlaxoSmithKline and Pfizer seem to have contradictory plans for their consumer health joint venture.
During a Tuesday presentation at the J.P. Morgan Healthcare Conference, Pfizer chief Albert Bourla said he believes the JV is heading toward an IPO within three to four years in a move that provides the New York pharma a “clear exit strategy.”
Maybe not, GSK’s chief strategy officer David Redfern said in an interview with Bloomberg the following day.
“Actually we haven’t decided anything,” Redfern was quoted as saying. “When we announced the deal, we said we expect it to separate within three years, but actually up to five years. And it’s entirely our decision.”
In December 2018, when the two companies unveiled the deal to merge their consumer health businesses into one huge JV with 2017 sales of $12.7 billion, GSK said it intended “to separate the joint venture from GSK via a demerger of its equity interest to GSK shareholders” and list it on the U.K. equity market. But it also said it “retained the right” for a straightforward IPO.
As for timing, the agreement specifies that within the first five years, GSK, which owns 68% of the JV, will “have the sole right to decide” a separation path for the JV. But after the fifth anniversary of deal closing, both GSK and Pfizer will have a say.
“We have the control of the timing, for up to five years […] but our intent is to demerge within three,” GSK CEO Emma Wamsley said on a conference call back then.
For the business now, GSK is trying to keep its mind focused on integration and sales growth, Redfern told Bloomberg.
“We don’t want it too distracted right now thinking about capital markets,” he reportedly said. “Whether it’s an IPO or just a straight spin, all options are on the table.”
The ultimate destination is still a separation; that part hasn’t changed. Both Glaxo and Pfizer are looking to focus their energies on higher-margin innovative medicines.
For Pfizer, after striking the consumer deal with GSK, it agreed to offload its off-patent drugs franchise, Upjohn, in a merger with Mylan, leaving only the R&D-heavy pharma portfolio and pipeline.
Meanwhile, GSK is gearing up in oncology under Walmsley. With its $5.1 billion takeover of Tesaro, it snared PARP inhibitor Zejula and “highly skilled employees with deep expertise in oncology,” Walmsley said in her Tuesday JPM presentation.
Those talents, spanning R&D, regulatory, medical affairs and sales, will help with GSK’s three oncology launches expected in 2020. These include Zejula’s potential use in first-line ovarian cancer maintenance, belantamab mafodotin in relapsed/refractory multiple myeloma and dostarlimab in second-line endometrial cancer.
After CES, Twitter exec highlights gadgets, gossip and buzz for pharma
The annual Consumer Electronics Show in Las Vegas hasn’t been a traditional gathering place for pharma. But Twitter’s Lisa Bookwalker thinks that’s changing—and should.
Bookwalker joined Twitter in September as director of client services for health and went to CES for the first time this year. There, she met up with forward-looking pharma marketers scouting new ideas to help them engage patients. And at CES that means technology.
“Social platforms like Twitter are the very intersection of human connectivity powered by technology. All of my discussions with marketers centered around this premise,” Bookwalker said via email. “Instead of shying away from social due to industry regulations, many pharma marketers want to explore the idea first and then figure out how to make it compliant, versus the other way around.”
While Bookwalker spent time at the convention in meetings, she also traversed the vast show floor. On her radar of up-and-coming health tech that might work for pharma were a watch that calculates calories by reading body signals, pajamas that monitor vital signs and gaming technology that helps people rehabilitate after a stroke. The theme underlying all those devices is empowering consumers—something pharma needs to embrace.
And while technology has been important to pharma for some time, Bookwalker pointed out that “the level and speed with which it is driving innovation as it relates to care is unprecedented.”
People across the healthcare value chain, from patients to caregivers to payers to physicians to pharma companies, are adopting technologies that let them access information, foster connections and deliver messaging faster than ever, she noted.
As for Twitter’s role in pharma’s tech evolution? “I think the critical piece here is data—and how can data drive better results for pharma brands,” Bookwalker said. “For example, at Twitter we have incredible data/insights from the hundreds of billions of Tweets on our service. Because of this, pharma marketers look to us to identify trends to inform their marketing and look into how they can better move patients through their patient journey.”
Seneca Biopharma rockets 129% on cell therapy promise
Thinly traded nano cap Seneca Biopharma (SNCA +129%) (formerly Neuralstem) has annihilated short sellers on a whopping 90x surge in volume.
Investors are reacting to its presentation at the Biotech Showcase and Sachs Associates Neuroscience Innovation Forum, both held in San Francisco this week.
The presentation focused on three potential indications of lead candidate NSI-566, a spinal cord-derived stem cell therapy, for amyotrophic lateral sclerosis (ALS), chronic stroke and chronic spinal cord injury.
ALS: Phase 1&2 results showed preliminary clinical benefit versus historical data. A pivotal trial is next up.
Stroke: Phase 1 data showed improvement in motor function from baseline.
Spinal cord injury: Phase 1 results showed some gain in voluntary muscle movement below the injury site.
Genetically engineered mosquitoes halt Dengue spread
A new study published in the journal PLOS Pathogens in January 2020 reports the development of mosquitoes that have been genetically modified to resist infection by several types of the dengue virus. This is the first time ever that all types of the virus have been targeted by the engineering of the mosquito DNA. Covering all virus types is essential to achieve proper disease control.
What is Dengue?
Dengue is a viral disease spread by mosquitoes that is becoming a global problem due to its numerous complications and the fatality rate. It is chiefly transmitted by Aedes aegypti mosquitoes. According to World Health Organization (WHO) statistics, millions of people in subtropical and tropical climate zones fall victim to this often deadly viral infection, which readily attacks those with weakened immunity. Especially poignant is the number of severe illnesses and deaths due to dengue in children in Asia and Latin America.
Aedes aegypti mosquito on human skin. Image Credit: Khlungcenter / Shutterstock
Just a short while ago, the highest ever prevalence of dengue in the American continents was reported by the Pan American Health Organization (PAHO). Beginning with high fever and headache, the illness progresses with other flu-like symptoms including rashes. If not controlled in time by the natural immune response, it may cause critical bleeds within the body’s various organs by lowering the platelet count through different mechanisms. Since there is no way to eradicate the virus, prevention requires virus control measures.
The solution
Genetic engineering has made it possible today to generate mosquitoes that cannot play the role of a host to the virus – this is called reducing the vector competence. This modification makes it difficult for mosquitoes to pick up the virus and to transmit it to other hosts.
The study describes the result of changing around certain genes in the Aedes aegypti mosquito in order to render them resistant to many types of the dengue virus. These engineered mosquitoes have a gene that codes for a single-chain bit of a human monoclonal antibody that has a broadly neutralizing effect against the dengue virus. Such an antibody is able to bind all types of dengue virus and not just a particular subtype.
This fragment, called the single-chain variable fragment (scFv) codes for the antibody region which determines which antigen it will bind. The new antibody prevents the infection with or transmission of any of the four dengue virus types in a mosquito that expresses it. This means they can no longer spread the virus to humans. This is the first time an engineered mosquito has been developed to resist all dengue strains.
After identifying the antibody, they inserted it as a payload into the female Aedes mosquitoes. When this engineered mosquito takes in a blood meal, the antigens activate the antibody which is then expressed in the mosquito cells. This is how the mosquito’s immune reaction against the virus is set off. This prevents viral replication and keeps the virus from being able to spread throughout mosquito tissues. By this means, humans can no longer be infected by the virus through a bite from this mosquito.
Advantages
The study thus presents a highly attractive route by which dengue virus control can be achieved with great effectiveness, using a gene-based technique. This may be useful to deactivate the transmission of other viruses related to this organism. The authors also suggest that if this gene strategy is coupled with a gene-drive system, which uses gene editing technologies like CRISPR-Cas9 to insert the desired gene into other mosquitoes, it could enable a dissemination mechanism whereby wild-type mosquitoes, or the type found in nature, can be quickly infected with the modified gene, to completely prevent the dengue virus from being transmitted by mosquitoes.
The best part of this finding is, according to the researchers, the fact that the newly developed mosquito strain cannot act as host to any of the four known types of dengue viruses, allowing it to be a genetic tool to control the spread of dengue through mosquitoes in nature.
Implications
Commenting on the work, researcher James Crowe says, “It is fascinating that we now can transfer genes from the human immune system to confer immunity to mosquitoes. This work opens up a whole new field of biotechnology possibilities to interrupt mosquito-borne diseases of man.” Co-researcher Omar S. Akbari says that in the not-so-distant future dengue could be controlled by field-based methods, reducing the toll of this infection on human health and life. His laboratory has been involved in validating and testing different techniques to prevent mosquito-mediated dengue transmission as well as the spread of many other viruses like the Zika, yellow fever and Chikungunya viruses all at the same time.
Mosquitoes are involved in the spread of multiple serious and even killer diseases including the above illnesses and of malaria. In this way the existence of infectious mosquitoes puts the health of 6.5 billion people around the world at risk. With such a bad reputation, there is little wonder that most research to date has concentrated on eliminating the mosquito vector rather than disarming it. Says global director of the Tata Institute for Genetics and Society (TIGS), Suresh Subramani, “Work from the Akbari lab and at TIGS is aimed at disarming the mosquito instead by preventing it from transmitting diseases, without killing the messenger. This paper shows that it is possible to immunize mosquitoes and prevent their ability to transmit dengue virus, and potentially other mosquito-borne pathogens.”
Journal reference:
Broad dengue neutralization in mosquitoes expressing an engineered antibody Buchman A, Gamez S, Li M, Antoshechkin I, Li HH, et al. (2020) Broad dengue neutralization in mosquitoes expressing an engineered antibody. PLOS Pathogens 16(1): e1008103. https://doi.org/10.1371/journal.ppat.1008103, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008103
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