Category Archives: FDA

FDA gives go-ahead for CRISPR-based sickle cell disease trial

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Development of a stem cell therapy for sickle cell disease from Vertex and development partner CRISPR therapeutics can go ahead, after the FDA lifted a hold on a review.

The companies had applied to begin an early stage trial of CTX001, a gene therapy derived from a patient’s own stem cells, for beta-thalassemia and sickle cell disease.

Although it’s a long way from the market, the drug could be one of the first to use the revolutionary CRISPR/Cas9 gene editing technology to correct a genetic defect causing a disease.

After an application in April for a phase 1/2 trial in the UNS for adults with sickle cell disease, the FDA had further questions that needed to be resolved.

Without revealing further details, the companies said the trial had been put on hold until they could provide the information the FDA required.

The FDA has now lifted the clinical hold and allowed development to go ahead, although the companies gave no further information about the information required by the regulator.

CRISPR and Vertex have obtained approval for clinical trial applications for several countries outside the US for beta-thalassemia and SCD.

They said they are on track to begin a phase 1/2 study in SCD by the end of 2018 and are enrolling patients transfusion dependent beta-thalassemia in a phase 1/2 trial in Europe.

CTX001 uses the CRISPR gene editing technique to make a patient’s haematopoietic stem cells produce high levels of foetal haemoglobin (HbF) in red blood cells.

HbF is a form of the oxygen carrying molecule haemoglobin naturally present at birth, which is replaced by the adult form of haemoglobin.

The elevation of HbF by CTX001 could alleviate transfusion requirements for beta-thalassemia patients and painful and debilitating sickle crises for sickle cell patients.

CRISPR and Vertex began a strategic research collaboration in 2015 to discover and develop gene editing treatments using the CRISPR/Cas9 technology to correct defects in genes known to cause or contribute to certain diseases.

Vertex has exclusive rights to license up to six new CRISPR/Cas9-based treatments that emerge from the collaboration, and CTX001 represents the first treatment to emerge from the joint research program.

For CTX001, CRISPR and Vertex will equally share all research and development costs and profits worldwide.

Novartis yesterday unveiled data showing its crizanlizumab reduced occurrence of the painful and potentially fatal vaso-occlusive crises that occur when blood cells become stacked in patients with SCD, blocking arteries and cutting the oxygen supply to vital organs.

SOURCE: www.pharmaphorum.com/news/fda

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

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

Teva wins FDA OK for crucial migraine drug

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Vital to Teva’s turnaround, Ajovy will challenge Novartis/Amgen’s Aimovig.

Teva has secured US approval for migraine drug Ajovy, a key part of new chief execeutive Kåre Schultz’s turnaround plan for the company.

The FDA approved the CGRP inhibitor for the prevention of migraine in adults with either monthly or quarterly dosing, based on two phase 3 studies showing that it could reduce the number of migraine days over a 12 -week period compared to placebo.

Ajovy (fremanezumab) is the second CGRP inhibitor to be approved for marketing after Novartis and Amgen’s Aimovig (erenumab), which got the green light in May and is dosed monthly, and ahead of late-stage rivals from Eli Lilly (galcanezumab) and Alder Biopharma (eptinezumab).

Teva would have been earlier to market but the FDA review for its products was delayed by three months while it sorted out some manufacturing issues. With Lilly due to hear from the FDA any day now, potentially setting up a three-way marketing battle, the Israeli drugmaker will be hoping the three-monthly dosing option will be popular with doctors and patients – particularly as there seems to be little to separate the antibodies when it comes to efficacy.

In a statement, Teva said that it had set a list price of $575 for the monthly dose and $1,725 for the quarterly dose, giving an annual cost of $6,900 before rebates and discounts – exactly the same level as Novartis and Amgen positioned Aimovig, and in line with stablished therapies like Allergan’s Botox.

It is estimated that with discounts the annual cost of the drugs could be around the $5,000 mark. However, the US-based Institute for Clinical and Economic Review (ICER) said recently that – even at that lower price – the new drugs should only be used with prior authorisation and after other preventive options such as Botox and anti-epilepsy drugs like topiramate because their long-tern safety is still unclear.

It is estimated that more than 36 million people in the US suffer from migraines, with around 40% of these would be suitable for preventive treatment, and that has led some analysts to predict buoyant sales of the CGRP inhibitors.

GlobalData said recently that it expects the market for migraine drugs to grow at more than 10% a year to reach almost $9bn by 2026, with the prevention category driven by the injectable CGRP inhibitors.

”Market share is going to come down to…variables such as frequency of administration, position to market, and market access strategy,” according to GlobalData analyst Rahael Maladwala.

“Each drug has its own set of advantages; Aimovig will be the first to market, Eli Lilly’s has significant experience in marketing drugs, and an extensive sales force, while both of the other drugs have a quarterly dosing regimen compared to monthly.”

On balance, GlobalData is putting Aimovig out in front in 2026 given its first-mover advantage generating nearly $1.4bn in sales in the seven major pharma markets (US, France, Germany, Italy, Spain, UK, and Japan).  Teva filed Ajovy in Europe earlier this year, but here it will also lag behind Aimovig as Novartis and Amgen picked up EMA approval for their drug in July.

Analysts at Jefferies have suggested Ajovy could become a $500m product in 2022, which will go some way towards counteracting the decline in sales of Teva’s blockbuster multiple sclerosis therapy Copaxone (glatiramer acetate), its rapidly ageing cash-cow product.

Since Schultz took the helm last year, Teva has been shedding staff and restructuring the business to cut costs, selling off its women’s health business for almost $2.5bn in order to pay down a very high level of debt stemming from its $39bn acquisition of Allergan’s generics business Actavis in 2015.

Ajovy is one of 23 New Drug Application (NDA) approvals Teva is targeting between fiscal 2019 and fiscal 2023 to help replace Copaxone and drive top-line growth, along with other new products such as movement disorder therapy Austedo (deutetrabenazine).

SOURCE: www.pmlive.com/pharma_news

AZ, Amgen’s first-in-class asthma drug gets breakthrough status

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AstraZeneca and partner Amgen have picked up a breakthrough designation from the FDA for tezepelumab, a drug that AZ claims could be a “best in disease” therapy for severe asthma.

Tezepelumab is a thymic stromal lymphopoietin (TSLP) targeting antibody that would slot into AZ’s key respiratory portfolio alongside Fasenra(benralizumab), the company’s interleukin-5 inhibitor antibody which was approved for severe asthma in Europe in January but just failed a test in chronic obstructive pulmonary disease (COPD).

The new candidate is in a phase III programme called PATHFINDER – due to report results from 2020 – and according to AZ chief executive Pascal Soriot has shown remarkable activity in mid-stage testing, reducing several key asthma biomarkers including blood eosinophils, fractional exhaled nitric oxide (FENO) and immunoglobulin levels as well as cutting asthma attacks.

Drugs like Fasenra and GlaxoSmithKline’s rival IL-5 inhibitor Nucala(mepolizumab) have emerged as an important treatment option for people with severe asthma characterised by high levels of eosinophils. However, the FDA’s BTD for tezepelumab is for patients “without an eosinophilic phenotype, who are receiving inhaled corticosteroids/long-acting beta2-agonists with or without oral corticosteroids and additional asthma controllers,” says AZ.

Because it acts further upstream in the inflammatory cascade responsible for asthma, tezepelumab could be suitable for a broader range of patients than Fasenra and Nucala, and also potentially Sanofi and Regeneron’s new candidate Dupixent (dupilumab), an IL-4 and IL-13 inhibitor that is already approved for atopic dermatitis. Dupixent was filed for asthma in the US in March and is due for an FDA verdict by 20 October, but some analysts have said they also expect Dupixent to be used mainly in patients with eosinophilic asthma.

Tezepelumab new status comes on the back of the phase IIb PATHWAY study which showed a significant reduction in the annual asthma exacerbation rate compared with placebo in a broad population of severe asthma patients irrespective of patients’ characteristics at enrolment. Around 10% of all asthma patients are thought to have severe symptoms making them eligible for antibody therapies.

“Tezepelumab is exciting because it has the potential to treat a broad population of severe asthma patients, including those ineligible for currently-approved biologic therapies,” said Sean Bohen, AZ’s chief medical officer.  The BTD “will help us bring tezepelumab to patients as quickly as possible,” he added.

Biologic drugs for asthma are predicted to make several billions of dollars in sales at peak, and there are already signs of string growth for some new products. Nucala made £245m ($317m) in the first six months of the year, with later entrant Fasenra bringing in $86m. Analysts have suggested tezepelumab could be a blockbuster in its own right.

SOURCE: www.pmlive.com/pharma_news

Ionis/Akcea’s ultra-rare disease drug rejected by FDA

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The FDA has opted to refuse approval to Akcea and Ionis’ Waylivra (volanesorsen) for the treatment of the ultra-rare hereditary condition familial chylomicronemia syndrome (FCS), despite the submission of Phase 3 data from the largest-ever study of the disease.

The US regulator alerted the manufacturers via a complete response letter (CRL), originating from its Division of Metabolism and Endocrinology Products, but the reason for the rejection was not given. Submitted data had shown that Waylivra reduced triglycerides by 94% in patients compared to placebo, which raised levels by 18%

FCS is characterised by extremely elevated triglyceride levels in the blood – levels which can’t be adequately metabolised due to a deficiency off lipoprotein lipase; it severely impacts daily life and can cause a range of damaging conditions including unpredictable and potentially fatal acute pancreatitis, chronic complications due to permanent organ damage.

“We are extremely disappointed with the FDA’s decision. FCS is an ultra-rare and debilitating disease. Our disappointment extends to the patient and physician community who currently do not have a treatment available to them,” commented Paula Soteropoulos, Chief Executive Officer of Akcea Therapeutics. “We continue to feel strongly that Waylivra demonstrates a favourable benefit/risk profile in people with FCS as was reflected in the positive outcome from our Advisory Committee hearing in May. We will continue to work with the FDA to confirm the path forward.”

Dr Brett P Monia, Chief Operating Officer of Ionis Pharmaceuticals, added: “We are fully supportive of WAYLIVRA and the many patients, physicians and researchers who are working to provide the first therapeutic option for FCS, a truly life-altering disease that deserves a treatment.”

SOURCE: www.pharmafile.com/news/518434

Researchers develop anti-nicotine addiction drugs

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Washington State University researchers have developed an array of drug candidates which they believe may help tackle addiction to nicotine.

The drugs, outlined in the Journal of Medicinal Chemistry, target CYP2A6, a liver enzyme which metabolises nicotine. The researchers aim to slow the process through which nicotine is metabolised by inhibiting CYP2A6. As such nicotine would last longer in the body and thus people would experience fewer cravings and withdrawal symptoms.

One of the researchers Dr Philip Lazurus explained that “Nicotine in the body will get metabolized and excreted and it can be a fast turnover in some people. What we are trying to do is prevent the turnover and metabolism of it.”

However blocking the enzyme CYP2A6 is in many ways the easy part. Making sure the inhibitor doesn’t interfere with other processes is much harder. As such with over 600 possible inhibitors the process became one of trial and error as candidates which affected other processes were gradually excluded. Nevertheless the researchers were able to narrow the list of potential candidates to just 18 different compounds.

Travis Denton, a former tobacco chewer who led the study commented: “I quit cold turkey and I know how hard it is. Would this have helped? I believe so, because again, the people who want to quit, really want to quit,” he said. “They just can’t because it’s too doggone hard. Imagine if you could take this pill and your jitters don’t come on as fast — it’s just super reinforcing to help you quit”

Once the drug candidates are verified as safe by the FDA, clinical trials can begin.

SOURCE: www.pharmafile.com/news/518432

AstraZeneca spinout Entasis files for $86M IPO to fund antibiotic phase 3

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Entasis Therapeutics has filed to raise up to $86 million through an IPO.

The AstraZeneca spinout is seeking the money to fund a phase 3 trial of a drug to overcome bacterial resistance to beta-lactams.

Massachusetts-based Entasis spun out of AstraZeneca with an antibiotic drug discovery platform and funding in 2015. Since then, Entasis has raised $82 million from backers including Clarus Lifesciences, Novo Holdings and Frazier Life Sciences, enabling it to take its lead candidate to the cusp of phase 3.

The phase 3 will assess the effect of an intravenous fixed-dose combination of beta-lactam antibiotic sulbactam and Entasis’ experimental beta-lactamase inhibitor, ETX2514. Entasis aims to link ETX2514 to reduced 28-day all-cause mortality in patients infected with carbapenem-resistant Acinetobacter, thereby validating its belief the drug stops resistance by inhibiting class A, C and D beta-lactamases.

With the phase 3 trial due to start in the first quarter of next year, Entasis is seeking $86 million from public investors. The funding will see Entasis through to the delivery of data in 2020. Entasis plans to file for FDA approval on the strength of data from that single phase 3 trial.

The development strategy gives Entasis a shot at bringing ETX2514 to market in extremely unwell patients with Acinetobacter infections, before potentially expanding its use into other groups. Entasis is gathering data on ETX2514 on carbapenem-resistant Enterobacteriaceae and Pseudomonas in its Acinetobacter-focused clinical trials.

Entasis has a second program, gyrase-inhibitor zoliflodacin, that is also set to enter phase 3 next year. The Drugs for Neglected Diseases initiative is fully funding the gonorrhea trial, freeing Entasis to put the rest of its anticipated IPO haul into earlier-stage candidates.

A second beta-lactamase inhibitor, ETX0282, is in development as part of a combination treatment for complicated urinary tract infections. The trial has hit some early problems. In the single-ascending dose phase, four out of 36 subjects suffered mild-to-moderate vomiting. Entasis is now exploring ways to mitigate the effect, including modified-release formulations and administration with food.

The IPO is expected to give Entasis money to support early-phase work on ETX0282 and leave it with enough left to move a candidate from its non-beta-lactam inhibitors of the penicillin-binding proteins (NBP) program into the clinic. Entasis thinks NBPs are a new class of Gram-negative antibiotics.

SOURCE: www.fiercebiotech.com/biotech

Demographic shifts create biotechnology opportunities

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Ageing populations which are increasingly wealthy means opportunities for biotech and healthcare investors.

Globally, populations are rapidly growing, ageing and becoming richer. It is estimated that within 25 years, the number of over 65s in Asia will exceed the total populations of the eurozone and US combined.

This progression, accompanied by declining birth rates in the developed world, is creating a growing demographic imbalance. Simultaneously, incomes are rising in developing economies, so emerging market consumers are increasingly entering the global middle class.

When populations become wealthier, healthcare spending infallibly increases and pockets of new healthcare needs (in response to lifestyle changes) often emerge. The consequences of these demographic shifts – both current and emerging – include far greater pressures on healthcare and a greater reliance on the private sector to provide care solutions.

Against this backdrop, biotechnology (or biotech) businesses can minimise the strain of (and theoretically profit from) global demographic adjustment. The biotech sector is broad-based, but primarily seeks to improve healthcare and treat disease through clinical research and drug development. Crucially for long-term investors, the sector also benefits from the relatively non-discretionary nature of demand for its products and services.

We have been taking advantage of these opportunities since 2016, when we began investing in an actively managed healthcare and biotech investment trust. We see high growth potential and strong structural tailwinds in the industry, and have since added to our exposure by investing in a passive exchange-traded fund (ETF) tracking the Nasdaq Biotechnology Index.

Having fallen sharply between late 2014 and 2016, the Nasdaq Biotechnology Index has been tracking steadily upward ever since. Despite its considerable growth potential and solid performance since 2017, the sector continues to trade at relatively attractive valuations; since the 2014-2016 sell-off, the sector’s price-to-earnings ratio has languished below that of the broader market for the first time in history.

As any excess capital is generally reinvested into further research and development, the majority of returns from the biotech sector are driven by mergers and acquisition activity and – crucially – the number of new drug approvals in a given year. The latter is positive news for investors, as approvals are on track for near-record levels in 2018, backing up strong years in 2015 and 2017.

For the sector’s world leaders in the US, biotech activities are tightly regulated by the Food and Drugs Agency (FDA). However, in a characteristically controversial manoeuvre, President Trump recently found himself on the biotech frontline when signing the ‘Right-to-try’ law – legislation permitting terminally ill patients to bypass the FDA to gain faster, unhindered access to experimental treatments. While not universally supported, and not without ethical constraints, the act should widen the pipeline of information on the effectiveness of potential new treatments. In turn, this could accelerate decision making over the fate of these new drugs. 

As with all sectors, biotech has its weaknesses. The most commonly highlighted risks are the binary nature of research results and the subsequent price movements in individual companies. More recently, political pressure to address fears around drug pricing is also mounting.

Mindful of these risks, but also seeking to harness biotech’s many compelling opportunities, our diversified positioning aims to limit the portfolios’ exposure to stock-specific risk, while allowing access to the benefits of powerful demographic shifts.

SOURCE: www.moneyobserver.com/demographic-shifts-create-biotechnology-opportunities