Bacterial therapy shows early promise in patients with advanced solid tumours

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Researchers have presented results of a Phase I clinical trial using bacterial Clostridium novyi-NT spores to target advanced solid tumours.

A Phase I clinical trial that investigated the use of bacterial Clostridium novyi-NT spores as an injectable monotherapy showed toxicities that were manageable and early clinical efficacy in patients with treatment-refractory solid tumour malignancies.

“Even after a single injection of this bacterial therapy, we see biological and, in some patients, clinically meaningful activity,” said Dr Filip Janku, Associate Professor at the Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Centre, Houston.

“This strategy is feasible, has manageable adverse effects, and could be clinically meaningful in patients with few therapeutic options.”

Previous therapies have tested the use of bacteria, but have often caused infection. In this study, the use of C. novyi-NT spores in the open-label, first-in-human study, the researchers explained how a hypoxic environemnt is necessary for the bacterium. It requires a feature of cancerous lesions to survive and proliferate, and thus does not affect healthy cells.

“By exploiting the inherent differences between healthy and cancerous tissue, C. novyi-NT represents a very precise anticancer therapeutic that can specifically attack a patient’s cancer,” Prof Janku said.

Between 2013 and 2017, 24 patients were enrolled with treatment-refractory solid tumors, with 15 patients having sarcoma, seven patients having diverse carcinoma and two with melanoma.

Tumours were injected with a single dose of C. novyi-NT, from 10,000 to 3 million spores. Patients administered with 3 million spores experienced dose-limiting toxicities of grade 4 sepsis, and as such the highest tolerated dose was determined to be 1 million spores.

Tumour shrinkage of greater than 10 percent was identified in 23 percent of the patients, and 21 had stable disease, measured by RECIST. Prof Janku mentioned that RECIST may not accurately capture results of the trial.

“Despite the absence of clinical signs of germination in some patients, we saw improved tumor-specific immune responses through the increased secretion of T-cell cytokines and increased presence of tumor infiltrating lymphocytes in injected tumors,” said Prof Janku.

“From these preliminary results, it appears that C. novyi-NT is able to activate the immune response besides causing tumor destruction.”

C. novyi-NT elicits an immune response, and as such Prof Janku believes this therapy will be synergistic with checkpoint inhibition.

“We were extremely encouraged by the results of this trial, especially in patients with advanced sarcomas, where immunotherapy hasn’t proven very efficacious,” Prof Janku concluded. “This bacteriolytic strategy has the potential to be clinically meaningful, especially in combination with checkpoint inhibitors, for patients with advanced solid tumors.”

The data was presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival.

SOURCE: www.europeanpharmaceuticalreview.com/news/79682

Ipsen appoints two leading R&D experts in bid to strengthen oncology arm

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French pharma firm Ipsen has announced the appointment of Dr. Yan Moore as Senior Vice President, Head of Oncology Therapeutic Area and Dr. Alexander “Sandy” McEwan, as Vice President, Head of Radiopharmaceuticals.

It is hoped that the move, which has seen the company take on two leading oncology specialists within a month of each other, will strengthen the company’s oncology arm.

Alexandre Lebeaut, Executive Vice President R&D and Chief Scientific Officer, Ipsen, commented: “I am thrilled to welcome Yan and Sandy as talented leaders who will assume pivotal roles in the next phase of our R&D transformation, and whose unique goal is to accelerate the development and deliver innovative therapeutic solutions to cancer patients.”

While Tel Aviv University graduate Dr Moore’s appointment with the Paris-headquartered company is effective immediately, Dr McEwan will join Ipsen on November 1st. Both R&D leaders will report to Dr. Alexandre Lebeaut, Executive Vice-President R&D and Chief Scientific Officer.

Dr Moore brings with him a wealth of experience from large multinationals including Bristol-Myers Squibb. Sanofi-Aventis and GlaxoSmithKline. Commenting Lebeaut said: “Yan is an outstanding biopharmaceutical executive who brings over 18 years of industry experience in oncology development across solid tumors, hematology‐oncology, gene and immune‐therapy. In his new role, Yan will lead and further strengthen our global oncology development powerhouse.”

Meanwhile McEwan, the author of more than 900 articles in peer reviewed journals and past President of the Society of Nuclear Medicine and Molecular Imaging, joins the organisation from the University of Alberta in which he held positions as Professor in the Department of Oncology and Adjunct Professor for the Department of Radiology and Diagnostic Imaging.

Lebeaut noted: “Sandy is a world-renowned expert in oncology and nuclear medicine who brings to Ipsen unique experience in this field. He will play a defining role in the acceleration of the development of Ipsen’s radiotherapeutics pipeline, providing strategic direction and managing the execution of the global clinical development of both satoreotide tetraxetan (IPN01072) and Satoreotide Trizoxetan (IPN01070) and also IPN01087 programs. Sandy will build and maintain trustworthy relationships with external oncology and nuclear medicine experts, academic networks, and professional organizations.”

SOURCE: www.pharmafile.com/appointment/518915

Pfizer CEO Ian Read set to step down from head position

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Ian Read is set to step down from his position as Chief Executive Officer (CEO) of American pharma firm Pfizer, having led the company for the past eight years.

In handing the reins to Pfizer veteran Albert Bourla, who was elected unanimously by the pharma giant’s board of directors, the Scottish-born CEO suggested that “now is the right time for a leadership change.”

“It’s been an honour to serve as Pfizer’s CEO for the past eight years,” Read said. “However, now is the right time for a leadership change, and Albert is the right person to guide Pfizer through the coming era. Albert is an energizing leader who has an unwavering commitment to serving patients. With 25 years at Pfizer, he has developed an extensive knowledge of the industry and demonstrated an ability to build and grow businesses. With Albert at the helm, our dedicated colleagues across the globe are poised to deliver the next stage of growth. I look forward to working with Albert and the Board to continue serving patients and delivering value for shareholders.”

The position will be taken over by current Chief Operating Officer (COO) Bourla, who will assume his new role on January 1st 2019. Meanwhile Read will transition into his new position as Executive Chairman of Pizer’s board of directors.

“I am humbled and privileged to be the next CEO of Pfizer, and I appreciate the confidence that both Ian and the Board of Directors have placed in me. I also want to thank Ian for his constant support, and am fortunate to have him as both a mentor and friend. I welcome Ian’s continuing contributions as Executive Chairman.”

Since joining the company in 2010 the Imperial College London graduate has overseen 30 FDA approvals, a 70% increase in annual dividends, and total shareholder return of 250%.

However, having joined Pfizer as the firm was hit by the expiry of the patents on both Viagra, and the world’s best-selling drug Lipitor; Read persevered through a turbulent period for the US drugmaker, during which the company experienced $27 billion in lost sales.

Nevertheless the Pfizer chief received a 61% pay rise last year in agreement for staying on at the company until March. The boost saw his total pay package come in at $27.9 million, making him one of the highest paid execs in the whole of the pharmaceutical industry.

Shantanu Narayen, Lead Independent Director of Pfizer’s Board of Directors, commented: “On behalf of the Board of the Directors, I want to thank Ian for his remarkable leadership as CEO. During an extraordinary period for the company, he successfully managed through $23 billion of lost revenue due to product losses of exclusivity, while at the same time driving strong and consistent financial performance and investing for the future. Consequently, Pfizer now has a pipeline that we believe is as deep and strong as ever. In addition, Ian has built a unique ownership culture that increased accountability and encouraged collaboration. As such, the company is now better positioned for success”

He added that “Today’s leadership announcement is part of a thoughtful, multi-year succession planning process”

Pfizer shares were up 0.4% in pre-market trade in New York on Monday morning after closing on a 17 year high.

SOURCE: www.pharmafile.com/news/518936

Cancer immunotherapy pioneers awarded Nobel medicine prize

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Cancer immunotherapy pioneers James Allison and Tasuku Honjo have been awarded this year’s Nobel Prize in Physiology or Medicine.

The Karolinska Institutet’s Nobel Assembly awarded the prize for their discovery of cancer therapy “by inhibition of negative immune regulation.”

The work by Allison and Honjo paved the way for drugs such as Bristol-Myers Squibb’s Yervoy (ipilimumab), which work by turning off the safety mechanisms in the immune system that prevents it from attacking the patient’s own body.

This allows the immune system to launch an attack against cancer – a mechanism that is fast becoming the basis for standard therapy in diseases such as melanoma and lung cancer.

Allison, currently professor and chair of Immunology and executive director, immunotherapy platform at the M. D. Anderson Cancer Center, studied a known protein, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), that functions as a brake on the immune system.

He realised the potential of releasing the brake and thereby unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients.

Inhibition of CTLA-4 is the mechanism exploited by Bristol-Myers Squibb’s Yervoy (ipilimumab), the first checkpoint inhibitor approved by the FDA in 2011, to treat melanoma.

Honjo, now deputy director-general at the Kyoto University Institute for Advanced Study (KUIAS), discovered the programmed cell death protein (PD-1)  protein on immune cells.

After careful exploration of its function, he eventually revealed that it also operates as a brake, but with a different mechanism of action.

In inhibition of PD-1, or its ligand, PD-L1, it forms the basis for all the other checkpoint inhibitors approved so far, including Merck’s blockbuster Keytruda (pembrolizumab).

In its statement the Nobel assembly noted that although PD-1 had proved to be more effective overall, combining the two forms of therapy could be even more effective, as demonstrated in patients with melanoma.

(c) Nobel Media

James Allison

The committee concluded in its statement: “Allison and Honjo have inspired efforts to combine different strategies to release the brakes on the immune system with the aim of eliminating tumour cells even more efficiently.

(c) Nobel Media

Tasuku Honjo

“A large number of checkpoint therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as targets. For more than 100 years scientists attempted to engage the immune system in the fight against cancer. Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionised cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

In a statement, Shigefumi More, director general and distinguished professor at KUIAS, said: “It is wonderful that the efficacy of cancer immunotherapy by PD-1 blockade has now been demonstrated worldwide, and that this therapy is actually saving the lives of many people. I would like to express my respect for his important work for human beings, and wish Distinguished Professor Honjo continued success in the future.”

SOURCE: www.pharmaphorum.com/news

Roche buys Tusk, plus cancer immunotherapy drug, for £62m

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Roche has bought immuno-oncology biotech firm Tusk Therapeutics for an upfront payment of £62 million.

Tusk’s shareholders will receive the upfront cash payment, plus additional contingent payments of up to £521 million, if and when certain milestones are achieved.

Tusk, which is based in Stevenage, has developed a first-in-class antibody, CD25, for the depletion of regulatory T-cells (TRegs), which suppress the body’s immune reaction to cancer cells.

This novel antibody enables the body’s other immune cells to fight tumours while leaving healthy tissue unharmed. Clinical trials are expected to start next year.

Luc Dochez, CEO of Tusk Therapeutics, said: “We are delighted that Roche will further develop this novel antibody and drive the development ahead.

“The remaining portfolio of our immune-oncology targets will be further developed by Black Belt Therapeutics, a newly formed company spun out of Tusk Therapeutics.”

Droia Oncology Ventures, Tusk’s majority shareholder, founded the company in 2014. Droia is a specialist investor, which focuses on fighting cancer.

It invests in promising new cancer therapies and accelerates their progress by actively supporting young drug development companies to achieve clinical proof of concept with their lead programmes. The deal will expand Roche’s oncology pipeline.

Also, Roche today announced a new collaboration with Novo Nordisk, which specialises in the treatment and management of diabetes and obesity.

The plan is to integrate insulin dosage information from Novo Nordisk’s connected pen technology into Roche’s open ecosystem, whereby it will communicate with its digital diabetes management solutions including mySugr, which allows people to monitor their glucose levels.

Marcel Gmuender, global head of Roche Diabetes Care, said: “The integration of insulin pen data in our digital health solutions such as mySugr will make it much easier for people with diabetes and their caregivers to track the effect of insulin on blood glucose levels.

“This enables more efficient and targeted decision support, as they can act on near real-time insights to optimise the personalised diabetes management, thereby reducing the risk of costly secondary complications and contributing to improved therapy outcomes and better quality of life.”

Anders Toft, corporate vice president of commercial innovation at Novo Nordisk, echoed this, adding: “Digital health solutions like mySugr are already helping thousands of patients. By integrating Novo Nordisk connected technology with mySugr, we can further ease the day-to-day burden of disease management and provide data-based insights to improve the dialogue between patients and caregivers.”

SOURCE: www.pharmaphorum.com/news

Instagram has a drug problem. Its algorithms make it worse.

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As it tries to crack down on ads for illegal drugs, the company is struggling to keep up with its own algorithms and systems, which serve up personalized drug-related content for people interested in buying substances illicitly.

Instagram is known for its celebrity posts and photos of enviable vacations. But it has also become a sizable open marketplace for advertising illegal drugs. The company has pledged a crackdown in recent weeks, but it is struggling to keep pace with its own algorithms and systems, which serve up an array of personalized drug-related content aimed directly at people who show an interest in buying substances illicitly.

Recent searches on Instagram, which is owned by Facebook, for hashtags of the names of drugs – such as #oxy, #percocet, #painkillers, #painpills, #oxycontin, #adderall and #painrelief – revealed thousands of posts by a mash-up of people grappling with addiction, bragging about their partygoing lifestyle and enticements from drug dealers.

Following the dealer accounts, or even liking one of the dealer posts, prompted Instagram’s algorithms to work as designed – in this case, by filling up a person’s feed with posts for drugs, suggesting other sellers to follow and introducing new hashtags, such as #xansforsale. Ads from some of the country’s largest brands, including Target, Chase and Procter & Gamble, as well as Facebook’s own video streaming service, appeared next to posts illegally selling pills.

Even as top executives from Facebook and Twitter, which has also long struggled with posts offering drugs illegally, promised earlier this month during a congressional hearing that they were cracking down on sales of opioids and other drugs, their services appeared to be open marketplaces for advertising such content. Facebook’s chief operating officer, Sheryl Sandberg, said her company was “firmly against” such activity. Twitter chief executive Jack Dorsey said he was “looking deeply” at how drug-selling spreads on the site.

But activists and other groups have warned tech companies about illegal drug sales on their platforms for years. In recent months, lawmakers, the Food and Drug Administration and some advertisers have stepped into the fray. In April, FDA Commissioner Scott Gottlieb charged Internet companies with not “taking practical steps to find and remove opioid listings.” Sen. Joe Manchin III, D-W.Va., called social media companies “reckless,” saying, “It is past time they put human life above profit and finally institute measures that crack down on these harmful practices, preventing the sale of illegal narcotics on or through their platforms. “

The prevalence of drug posts on social media – which the FDA says has helped fuel the opioid epidemic that claimed more than 40,000 lives in the United States last year – shows how tech companies are often outsmarted by the software they created. The algorithms that power social media spread illicit content – from illegal drug ads to misinformation and hate speech – faster than the companies know how to take it down. The most common features of social platforms, such as hashtags and algorithms that deliver personalized feeds, drive drug-sale posts directly to users who have expressed interest in them – potentially exposing the most vulnerable people to addictive drugs.

“Just as drug use rewires the brain to crave more of the substance, social media platforms have designed their sites in such a way that after a single search for an illicit drug, the algorithm gets rewired to advertise drugs to the already vulnerable user,” said Rick Lane, a longtime technology policy adviser who helped push legislation known as FOSTA-SESTA through Congress this year. That law holds technology companies liable for prostitution and sex-trafficking ads on their platforms. He is now pushing for similar legislation for drug ads.

Facebook’s vice president of global marketing solutions, Carolyn Everson, said Instagram was paying more attention to illegal sales of drugs because of a growing focus on safety and on preventing abuses of the company’s platform, from Russian meddling to fake news. “We’re not yet sophisticated enough to tease apart every post to see if it’s trying to sell someone illegal drugs or they are taking Xanax cause they are stressed out,” said Everson, referring to the company’s artificial intelligence technology. “Obviously, there is some stuff that gets through that is totally against our policy, and we’re getting better at it.”

Instagram co-founders Kevin Systrom and Mike Krieger said late Monday that they were exiting the company. Adam Mossieri, a longtime deputy to Facebook chief executive Mark Zuckerberg, is likely to become the photo-sharing app’s next leader, according to a person familiar with the matter.

“Some of the emergent behaviors we’ve seen have presented a new challenge, and we’re focused on tackling them alongside law enforcement, our peers and the FDA,” said Twitter spokesman Ian Plunkett said.

Pharmaceutical companies are allowed to promote their brands on social media, but the process is highly regulated by the FDA, and companies and individuals are not allowed to sell actual drugs through social media.

Technology companies, which are lightly regulated compared with other industries, face the prospect of stricter rules if they cannot control the problems. During this month’s technology hearings, Manchin told the executives that his state had been hard-hit by opioid addiction and that he was interested in launching a bill modeled after the sex-trafficking law that would hold companies liable for drug dealing taking place on their services.

John Montgomery, executive vice president for global brand safety for the ad-buying giant GroupM, whose agencies work with companies such as Procter & Gamble and Target, said Instagram was moving too slowly. “With illegal pharma content, there is little nuance. So it should be possible to identify and block faster than we’ve seen,” he said.

Instagram has become one of the most potent platforms for drug marketing, said Libby Baney, senior adviser for the advocacy group Alliance for Safe Online Pharmacies. Its growing use among teenagers as well as the service’s emphasis on visuals, its sophistication at personalizing content and its allowance of anonymous accounts have turned it into a hotbed of illegal promotion of drugs, she said.

Eric Feinberg, a researcher and the chief executive of GiPEC, a New York City-based cyberintelligence start-up that tracks illegal activity such as counterfeit goods and terrorist content on technology platforms, began hunting for drug posts in June by searching for obvious hashtags. He found hundreds of Instagram posts appearing alongside content from 60 different advertisers. Some of the Instagram dealers touted corresponding Twitter accounts, and Feinberg began tracking those accounts, too. Some of the Twitter accounts were even more brazen and had been up for years.

Once he followed the sellers’ accounts, Instagram’s algorithms began delivering posts marketing drugs directly into his feed, suggesting other drug sellers for him to follow and introducing him to additional hashtags that he used as clues. At one point, posts from sellers constituted about 40 percent of his feed, he said. Feinberg said he plans to sell his monitoring software, but his company doesn’t yet earn any revenue.

Facebook said Feinberg’s feed was not a real representation of what the vast majority of people see in their feeds, because he exclusively followed bad actors and some brands, prompting the company’s algorithm to cluster the two types of content together. “That being said, even a single piece of bad content on our platforms is one too many, and we’re working hard to improve our detection and enforcement,” Facebook spokesman Joe Benarroch said.

Most of the posts that appeared to be from dealers had a similar format: Photos of different types of drugs captioned with a string of hashtags and instructions to contact the account holder through a channel outside Instagram, such as email or messaging platforms Wickr, Facebook-owned WhatsApp and Kik. (Most drug posts included explicit instructions to avoid “DMs,” or direct messages, on Instagram itself. Such messages could be more easily traced.)

In recent months, Instagram took what it described as an extreme step by blocking search results for certain hashtags, such as #fentanyl, #cocaine and #heroin, even though that had the unwanted side effect of limiting people’s ability to seek support for substance abuse issues, Facebook’s Everson said. The hashtags can still be used and the posts can still be found through a person’s network, even though they are unavailable through a public search.

To get around blocked hashtags, sellers now market opioids under Xanax- and Adderall-related hashtags, many of which are searchable, Feinberg said. They also slightly tweak the spelling of drug names and include their contact details in the photos themselves, such as writing them on a piece of paper and then photographing it, to avoid software tools that can identify problematic keywords in a caption. Instagram appeared to suspend some hashtags when asked about them by The Washington Post.

Dealers appear to employ a “spray and pray” strategy designed to get around Instagram’s monitoring, Feinberg said. They post frequently, with individual posts getting a small number of likes before many were taken down by Instagram’s systems within 48 to 72 hours, often because users flagged them as problematic. As soon as one account was taken down, dealers created multiple Instagram accounts with similar names, such as a cluster including FoxPharm, FoxPharm12, FoxPharm69 and FoxPharm90, all featuring the same contact information.

Some appeared to have been created automatically, Feinberg said, suggesting the sellers are using bots. The different iterations of the name reminded him of Islamic State terrorist accounts and disinformation groups, which use a similar tactic.

“They are playing whack-a-mole here. They take them down, and then they come back again,” Feinberg said. “If [the tech companies] were really doing a full-court press, we wouldn’t keep finding what we are finding.”

Everson said Facebook and Instagram were in the early stages of developing artificial-intelligence tools that could flag drug content. She compared it to Facebook’s efforts, starting two years ago, to building AI software that it says can detect the majority of Islamic State accounts before people can see them. Now they are building visual classifiers that can recognize photographs of particular pills and detect common patterns, such as the inclusion of a phone number to move the transaction onto an encrypted messaging platform.

Facebook also gives advertisers tools to block their messages from appearing alongside certain publishers or categories of content, including tragedy or controversial social issues.

This month, Instagram also launched a pop-up notification that appears when someone searches hashtags for opioids, prescription medications or illegal drugs. The pop-up offers to connect people with free and confidential treatment referrals and information about substance use, prevention and recovery.

SOURCE: www.seattletimes.com/business

Urine exRNA may be source of biomarkers for muscular dystrophy

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Massachusetts General Hospital (MGH) researchers have found that extracellular RNA (exRNA) in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

The report published in online journal Nature Communications, is the first to show that urine exRNA can be used to monitor systemic diseases that do not directly affect the urinary tract.

“Our findings could facilitate drug development by offering a convenient, painless and relatively low-cost assay that may reduce and perhaps eventually eliminate the need for multiple invasive muscle biopsies to track disease activity and therapeutic response,” says Thurman Wheeler, MD, MGH Department of Neurology, senior author of the report. “Urine exRNA monitoring could determine whether a drug is reaching its target long before clinical effects on muscle function could be detected and may enable early identification of whether dosage adjustments may be required, something that would be impossible with invasive muscle biopsies.”

There are several types of muscular dystrophy, all of which lead to progressive muscle weakness and loss of muscle mass. Duchenne muscular dystrophy (DMD) is the most common form, with symptoms that usually begin in children under the age of 5. Myotonic muscular dystrophy (DM) is the most common adult-onset form and has two subtypes – DM1 and DM2. Each form is caused by a different gene mutation. In DMD, the mutation affects the gene for dystrophin, a protein essential to the strength of muscle fibers. DM-associated mutations – in the DMPK gene for DM1 and in the CNBP gene for DM2 – involve excessive repeats of nucleotides, leading to abnormal processing of RNA molecules.

The mutation associated with DM1 affects RNA splicing, the process that removes non-coding segments from an RNA molecule. A single gene can normally give rise to several different proteins, with the differences being determined by alternative RNA splicing patterns. The DM1 mutation interferes with appropriate splicing of RNAs encoding several other proteins, and analysis of RNA splice variants in muscle biopsies has been used to determine disease severity in patients. In animal models, splice variants in muscle tissue have been used to indicate whether potential therapies are reaching their molecular target. A less invasive way of assessing disease severity and therapeutic response could expand the number of patients who could receive therapeutic drugs or participate in clinical trials. For example, a recent clinical trial for a DM1 drug was restricted to adult patients partially because of the need for repeat muscle biopsies.

Carried through bodily fluids like blood and urine in membrane bubbles called vesicles, exRNA encompasses messenger, non-coding, and microRNA molecules and can reflect mutations, deletions and other molecular variants. A few muscular-dystrophy-associated RNA or protein biomarkers have been identified in the blood of patients. Even though it seemed unlikely that exRNA from the skeletal and cardiac muscle tissues affected by DM1 could pass through the kidney’s filtration system into the urine, urine is such an easily accessible fluid that Wheeler’s team analyzed vesicles from both blood and urine for exRNAs that could reflect results of the DM1 mutation.

Their experiments comparing urine exRNAs from DM1 patients, patients with two other forms of muscular dystrophy and unaffected control volunteers identified 10 transcripts that are alternatively spliced in a pattern unique to DM1 patients, most of which had been previously found in patient muscle biopsies. A composite biomarker incorporating these 10 transcripts was 100 percent accurate in distinguishing DM1 patients from unaffected controls in a different group of participants. Samples taken from untreated DM1 patients over several months indicated consistency of splicing patterns within an individual, suggesting that repeat sampling could accurately reflect disease state and treatment response.

Along with developing a more precise assay for rapid measurement of alternative RNA splicing in urine and other bodily fluids, the team showed that splicing patterns in total RNA from the cells in the urine were different from and less useful as biomarkers than those from exRNAs and found that exRNAs in blood could not distinguish between DM1 patients and controls. They also found that the splicing patterns of some urine exRNA transcripts reflected the severity of DM1 symptoms, and that a small group of asymptomatic patients with the DM1 mutation had urine exRNA splicing patterns midway between those of symptomatic patients and unaffected controls.

A group of drugs being evaluated for the treatment of DMD manipulate splicing of the dystrophin gene in order to remove a specific exon – a protein-coding segment of RNA – producing a shortened but partially functional version of the dystrophin protein. The MGH team showed that urine exRNAs from six untreated DMD patients accurately reflected the specific gene mutation in each patient. In two DMD patients being treated with eteplirsen – an FDA-approved DMD drug that induces skipping of the target exon – analysis of urine exRNA was able to confirm the drug was reaching its molecular target, the first such confirmation not provided by muscle biopsy.

“Our demonstration of disease-specific splice variants in urine exRNA suggests the value of biofluids as a means of identifying novel splice variants that may help correlate gene variants with symptoms for several diseases for which noninvasive biomarkers are unavailable,” says Wheeler, an assistant professor of Neurology at Harvard Medical School. “These findings support studies of exRNA from urine, blood or cerebrospinal fluid as biomarker replacements for tissue biopsies in other conditions with altered RNA splicing – including other types of muscular dystrophy, spinal muscular atrophy and amyotrophic lateral sclerosis.”

SOURCE: www.news-medical.net/news

Patients call for end to CF drug price row at key meeting

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Representatives of NHS England and cystic fibrosis drug company Vertex are to meet on Thursday to try and resolve a two-year impasse over access to life-changing medications.

Charities and patients called for a resolution to the ongoing pricing row, which began two years ago when NICE said Vertex’s combination therapy Orkambi (lumacaftor+ivacaftor) is too expensive for the NHS.

Orkambi is the first medicine to treat the underlying cause of cystic fibrosis in people with two copies of the F508del mutation, aged six or over, and Vertex has other drugs in its pipeline that will mean a wider group of patients will get treated.

NHS England and Vertex have been locked in an increasingly bitter argument over pricing, with the manufacturer accusing the NHS of undervaluing cystic fibrosis patients.

Vertex is trying to get the NHS to fund all its approved CF drugs, and any future medications in its pipeline in a long-term deal.

In July Vertex said it received an offer worth about £500 million over five years, and more than £1 billion over 10 years for Orkambi.

This was rejected and Vertex has made veiled threats that it will consider spending its R&D budget elsewhere because of the row.

It has also refused to engage with NICE until the cost-effectiveness body changes its assessment methods.

David Ramsden, chief executive of the Cystic Fibrosis Trust has written to Vertex’s chief executive Jeffrey Leiden, and NHS England’s chief executive Simon Stevens calling for the matter to be resolved.

Ramsden urged Leiden to do “everything in [his] power” to reach an agreement, while calling on Stevens to find a way to “value and reward” the innovative drugs from Vertex.

The UK has the second largest population of patients with CF in the world, with around 10,000 people affected.

Christina Walker, from the patient group UKneedsorkambi, said the drug should be made available as soon as possible so that patients such as her son Luis can receive it.

Walker said: “It’s been a devastating summer for the campaign group while this impasse has persisted. We’ve watched our loved ones’ health decline with exacerbations, made many hospital visits and have mourned CF angels who’ve lost their final battle.

“Whether or not this situation continues unchecked is in the hands of the people from Vertex and the NHS around the table on Thursday.

“They must both compromise heavily – more than they want to – because lives are at stake and what’s the alternative? Too many people have died already. These transformational treatments can reduce the considerable suffering of this cruel condition, and patients must have them now. Time is up, and any further delay will be unforgivable.”

SOURCE: www.pharmaphorum.com/news

Novartis to shut Grimsby site amid manufacturing overhaul

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Novartis has announced plans to close its manufacturing site in Grimsby, UK, by the end of 2020, among a wider job cull likely to affect more than 2,200 positions in the country and Switzerland.

According to the Swiss drug giant, the proposal to shut the site is part of a “global transformation of the manufacturing network and product portfolio, reflecting today’s changing healthcare needs”.

It comes as the firm moves away from high volume products – such as those produced in Grimsby – and towards more specialised and personalised innovative medicines, such as CAR-T cell therapy, which are more complex to produce.

The move will directly affect 395 employees in Grimsby, but additional contactors employed through third parties may also be impacted, the firm said.

“Novartis has been a part of the Grimsby community for many years so this has been a very difficult decision,” said Haseeb Ahmad, Novartis UK country president.

“This decision has been made alongside broader changes to our business globally, and as a result of the changes in our product portfolio which now focuses on more specialised medicines, reflective of today’s changing healthcare needs.”

He went on to stress that the company “remains committed to the UK and believes that the UK is a world-leader in life sciences,” and stressed the move is not linked to Brexit.

Novartis also revealed that around 1,700 job cuts would be made in Switzerland under the plans, which fall under a wider global manufacturing strategy initiated by the firm back in 2016.

SOURCE: www.pharmatimes.com/news

JM to offer a new process to synthesise CBD

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Johnson Matthey to offer a new process to synthesise ultra-pure cannabidiol, expanding on existing cannabinoid offerings.

Johnson Matthey, a global leader in science that enables a cleaner and healthier world has announced an expansion to its API and controlled substances portfolio by establishing a new synthetic method for ultra-pure cannabidiol, a medicinal component of the cannabis plant.

This synthesis will help Johnson Matthey (JM) support companies in developing novel treatments and medicines to help patients across a range of disease areas.

Cannabidiol (CBD) is one of the many chemical compounds in the cannabis plant and is known to possess medicinal and therapeutic properties. Unlike tetrahydrocannabinol (THC), another molecule in the cannabis plant, CBD does not cause intoxication or euphoria, two unwanted side-effects for medicines.

In light of CBD’s medicinal applications and the absence of psychoactive side-effects, demand for GMP-grade CBD from pharmaceutical companies has increased extensively in recent years.

It is now being investigated as a potential therapeutic treatment for various illnesses and diseases, including multiple cancers, seizures, dermatological conditions and anxiety.

JM has established more than 15 years’ experience in developing and commercialising a portfolio of ultra-pure synthetic cannabinoids and other controlled substances. By adding cannabidiol into this portfolio and filing a US drug master file (DMF) with a validated synthetic process, JM is excited to support companies looking to explore CBD’s medicinal applications further.

With manufacturing sites based in the US, JM is able to apply its knowledge of synthetic chemistry and purification techniques to CBD synthesis. In particular, JM’s solid form chemistry expertise has enabled the development of a free flowing crystalline powder, which is able to be particle size adjusted for a variety of formulation requirements.

Furthermore, JM has established a full suite of references of standards and impurities to facilitate CBD product development, which helps to ensure molecules are synthesised to an ultra-pure standard.

As well as synthetic chemistry expertise in controlled substances, JM also offers API manufacturing capabilities for botanical extraction and purification of cannabinoids. Based on the growing popularity of medicinal cannabinoids, JM is actively investigating the development of other cannabinoid compounds.

“As a leader in API development, we are delighted to add the high-value synthesis of cannabidiol to our expanding portfolio of Pharma solutions,” said Paul Evans, VP Generic Products and Solutions at JM.

“This will enable companies to easily explore the medicinal properties of cannabinoids, and combined with our development and manufacturing capabilities, deliver novel treatments and medicines to patients.”

SOURCE: www.manufacturingchemist.com/news