Almost A Third Of New FDA-Approved Pharmaceuticals Have Post-Trial Safety Events

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Almost a third of new therapeutic drugs released onto the US market with Food and Drug Administration (FDA) approval subsequently have what are called “safety events”.

Most often, these lead to warnings on packets or to doctors indicating the drug should not be taken by people with certain rare conditions or under particular circumstances. In only a tiny minority are the events serious enough to require withdrawal of the product.

Drug approval is a never-ending balancing act. Make trials too comprehensive and people are left waiting for a product that might save, or at least greatly improve, lives. Yet if you don’t test widely enough, you risk another thalidomide – a drug with great benefits for many people, but devastating during pregnancy.

Dr Joseph Ross of Yale University explored one aspect of how our current efforts are working by looking at what happened after the release of 222 products  granted approval by the FDA between 2001 and 2010. The findings have been published in the Journal of the American Medical Association.

How you view Ross’s findings depends on whether you are a glass half-empty or glass half-full type of person. For those inclined to negativity, problems emerged with 32 percent of the therapeutics, leading to changes in the terms of their approval. Since some of these had more than one issue arise, there were a total of 123 safety events recorded. The number is likely to grow for the pharmaceuticals and biologics (approved therapeutics that are biologically derived rather than synthesized) released towards the end of the period.

More positively, in only three cases (1.4 percent) was the issue so serious or widespread that the product had to be withdrawn. Another 61 warnings were added to the products’ boxes, while 59 involved safety communications to prescribers. The average gap between approval and the first post-market safety event was 4.2 years.

Drug trials can only involve so many people without becoming prohibitively expensive. Most involve fewer than 1,000 participants. Unless there are grounds to suspect the drug will be a problem for people with a rare condition, it’s unlikely many people with that condition will participate in the trial. So if the drug has negative side effects for just that group, this probably won’t be detected during clinical trials. Once a product is on the market however, and given to hundreds of thousands or millions of people, patterns can start to emerge in which groups experience side effects.

Consequently, it is unsurprising many boxes will need warnings added to them, or doctors instructed that the drug is contra-indicated for certain people. Ross’s findings can help feed a debate on whether the current rate is acceptable or if we should be spending more to make trials larger.


Lilly allays Ireland’s fears and moves forward with biologics plant expansion that will add 130 jobs

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The on-again, off-again $215 million expansion of an Eli Lilly biologics plant in Ireland is on again.

The Indianapolis, Indiana-based company said Monday it will move forward with plans to add a manufacturing line at its site in Kindsdale, County Cork. It said construction should begin in coming months and commissioning will begin in 2019. The expansion is expected to add about 130 workers to the site by 2020.

Spokesperson Tamara Ann Hull said in an email that because negotiations are underway, specifics of the investment were not being released. Earlier reports put the cost at about €200 million.

Tremors of concern spread through Ireland in February when Lilly said it halted preparations for the project. That ignited speculation among some politicians that Lilly might divert funds to the U.S. after President Trump held a meeting with pharma execs in which he urged them to invest in U.S. manufacturing. Lilly’s new CEO David Ricks was at that meeting.

Weeks later, Ricks announced an $85 million expansion at an insulin device plant in Indianapolis and pointed to $850 million in capital outlays this year in the U.S. as an indicator of its commitment to investing there.

Lilly has been expanding its biopharma operations in Cork for some years. In 2012, it began construction of a 22,000-square-meter bioprocessing plant. It also has a 158,000-square-meter monoclonal antibody plant there that was completed in 2010.

The site also does API production for a host of small molecule drugs. Last year, the company said it would invest nearly $40 million (€35 million) to build a continuous manufacturing facility there. At the time it said it had invested about $740 million (€650 million) in the site in 8 years, hiring 350 employees.


Cheap blood test may help tailor prostate cancer treatment

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A blood test that costs less than £50 to perform could prevent men from undergoing treatment with two drugs that cost thousands of pounds per month.

The test works by identifying men whose particular form of prostate cancer is resistant to the drugs enzalutamide and abiraterone, making treatment with the drugs unnecessary.

The two drugs, enzalutamide and abiraterone, are used in cases where prostate cancer no longer responds to standard hormone therapy and has begun to spread further. The treatment is currently administered for 12 weeks before doctors are able to examine whether it is having a positive effect.

However, the new test is able to determine whether genetic mutations mean that the treatment will be effective or not. It works by analysing blood samples, taken through a simple blood test, to identify changes to the Androgen Receptor. This particular protein is part of the process that causes cancer cells to grow, which allows certain drugs, such as enzalutamide and abiraterone, to target it. In certain cases, further mutations in the protein mean that it is not impacted by such treatment.

“A man with incurable prostate cancer does not have time to waste taking drugs that will not work for him,” says Dr Iain Frame, Director of Research at Prostate Cancer UK. “To stop prostate cancer from being a killer, we need to move away from a one-size-fits-all approach to treatment. This test could be a significant step towards that and we’ll be watching its development very closely. Thanks to our supporters, we are ramping up investment in prostate cancer research to get the right drug for the right man at the right time.”

Prostate Cancer UK has provided funding for the development of the test, which is now progressing into further clinical trials. The prospect is that the test could be used by doctors to cheaply identify those patients who would not respond to treatment. With a monthly supply of abiraterone alone costing £2,000, this could lead to savings in treatment cost at a time when the NHS is under pressure over funding.


Regeneron and Inovio to aim immunotherapy at hard-to-treat brain tumour

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Regeneron is to collaborate with Inovio to investigate a three-way immunotherapy combination against glioblastoma multiforme (GBM), an aggressive and hard-to-treat brain tumour.

Regeneron’s drug is bringing its PD-1 inhibitor, REGN2810 to the partnership, and will combine this with two of Inovio’s candidates: INO-5401 T cell activating immunotherapy encoding multiple antigens and INO-9012, an immune activator encoding IL-12.

For Regeneron, it needs to find a niche for its drug amid intense competition from established PD-1 drug such as BMS’s Opdivo and Merck Inc’s Keytruda, and no drug in the class has yet shown efficacy against GBM.

Last month, BMS announced that Opdivo had failed its phase 3 trial in patients with first recurrent of the brain tumour, finding it did not improve overall survival compared to Avastin monotherapy.

Meanwhile Merck & Co unveiled a partnership in January which will see it combine Keytruda with Agenus’ cancer vaccine Prophage in GBM.

Regeneron already has a partnership with Sanofi to develop REGN2810 alone and in combinations, but is also free to forge new partnerships.

Inovio and Regeneron will recruit people with newly-diagnosed GBM, with the hope that the three-way combination can help lengthen survival for these patients. Currently the prognosis for patients receiving standard of care is 15 months, and the average five year survival rate is less than 3 per cent.

“The unmet need for effective therapies in GBM remains extremely high. Certain immune checkpoint inhibitors have shown efficacy in certain cancers, but evidence increasingly suggests that the benefit of checkpoint inhibitors can be enhanced when used in combination with therapies that generate T cells,” said David Reardon, MD, Clinical Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School.

Inovio has an innovative immunotherapy platform which has shown the ability to generate antigen-specific T cells in disease areas including cancer. We look forward to exploring the potential of combining a T cell generating immunotherapy encoding multiple antigens with REGN2810, a PD-1 checkpoint inhibitor.”

Inovio will be in sole charge of the trial, and Regeneron will supply REGN2810. Inovio and Regeneron will jointly conduct immunological analyses in support of the study.

“I am a strong believer in this combination regimen approach in immuno-oncology: use Inovio immunotherapies to generate killer T-cells to turn ‘cold’ tumours into ‘hot’ tumours, then block T cell suppression via checkpoint inhibition,” said J. Joseph Kim, PhD, Inovio’s president and chief executive.

The company suffered a setback in October when the FDA placed a clinical hold on its proposed phase 3 trial of its VGX-3100 for HPV-related high grade cervical dysplasia.  The US regulator was apparently concerned with the shelf-life of the disposable parts of the Cellectra 5PSP device used to deliver the immunotherapy.

Inovio said recently that it is generating the necessary data to reassure the FDA, and aims to begin the trial in the first half of 2017.

Other trials underway against GBM include a promising CAR-T trial published in the NEJM in late 2016, which showed a dramatic shrinking of tumours in the brain and spine, an effect which lasted for seven and a half months.


Johnson Matthey reveals refreshed identity

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200-year company brand refresh reflects Johnson Matthey’s position as a science-led company for cleaner and healthier life.

This week, Johnson Matthey, a global leader in science that provides cleaner air, improved health and more efficient use of natural resources, reveals a refreshed brand identity: “Inspiring science, enhancing life.”

Johnson Matthey is involved in an array of science, from catalysts that enable cleaner air to pharmaceutical ingredients. Its work is unified by a common theme: to enhance quality of life.

Work by the company includes reshaping battery technology for the automotive industry with new materials; and optimising efficiency of world scale processes used to produce important chemical intermediates.

Company progress

200 years after Percival Norton Johnson founded the company, it is celebrating global operations on all continents and annual sales of more than £3bn.

More than 90% of the company’s sales come from technologies that have an explicit environmental, health or sustainability benefit.

Today, the company employs 13,000 people in 30 countries worldwide. One pound in every twenty generated is reinvested in research and development. Last year alone, Johnson Matthey invested £188m in research and development projects around the globe.


£6 million statin study to determine potential therapeutic use in MS

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A large study will take place in the UK to determine whether statins, commonly prescribed to combat “bad cholesterol”, are able to be used in the treatment of multiple sclerosis.

The research comes after a smaller study, of 140 people, found that patients taking high doses of simvastatin showed slower rates of brain shrinkage compared with those receiving placebo.

The new Phase 3 study will contain 1,180 people and will take place over six years. If the research yields similar findings to the previous Phase 2 trial, it could lead to a quick regulatory approval for statins to be used in MS treatment.

Statins are already commonly prescribed and safety data on the medication is already abundant, which could be used as part of any regulatory filing.

There are approximately 100,000 sufferers of MS in the UK currently. Women are disproportionately affected with the condition, where the immune system attacks the central nervous system. The condition can cause problems with movement and thought processes, such as emotions and memory.

Dr Jeremy Chataway, of the UCL Institute of Neurology, who is leading the research, commented: “This drug holds incredible promise for the thousands of people living with secondary progressive MS in the UK, and around the world, who currently have few options for treatments that have an effect on disability. This study will establish definitively whether simvastatin is able to slow the rate of disability progression over a three year period, and we are very hopeful it will.”

Dr Chataway led the initial study into the impact of statins on disease management. In the previous study, half of the participants took statins while the other half received placebos; the results found that those on statins displayed brain shrinkage of 0.3% compared with 0.6% in those that received placebo. Patients receiving statins also displayed an improvement in their disability scores.

The research is being funded by the National Institute for Health Research, as well as by the charities MS Society UK and National MS Society (based in the US).


Sanofi, Exscientia link to develop bispecific small molecule drugs

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Dundee, Scotland-based artificial intelligence group Exscientia has signed a research collaboration and licence option agreement with Sanofi focusing on the “high-interest area of metabolic disease”.

Under the alliance, Exscientia will use its platform to seek out and validate combinations of drug targets that could work synergistically and be amenable to its bispecific-small-molecule design strategy – by which a small molecule is designed to be compatible with two distinct drug targets.

Exscientia is responsible for all compound design, whilst chemistry synthesis will be delivered by Sanofi. Further assays, preclinical experiments and subsequent trials for compounds progressing to the clinic will be managed by Sanofi, where the French drugmaker exercises its licence option.

As per the terms of the deal, Exscientia will receive research funding in order to identify target pairs with the best combination of chemical compatibility and strong biological relevance plus further funding for prioritised candidate delivery opportunities.

The firm could also bag non-clinical and clinical milestones for compounds reaching agreed delivery criteria, as well as sales milestones for any products reaching the market, with the total amount potentially payable by Sanofi to Exscientia on achieving these milestones 250 million euros.


Outrage over Duchenne drug price reinflamed by PTC’s $35,000 price tag

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Families affected by the rare muscle wasting disease Duchenne muscular dystrophy will still have to pay a huge premium for Emflaza, a newly-approved drug based on an old steroid that helps alleviate symptoms.

Emflaza’s active ingredient is deflazacort, an old steroid that families were using off-label to treat symptoms of DMD in boys affected by the genetic disease.

The drug was being procured by US families by importing it from abroad for around $1,600 a year.

Marathon gained FDA approval for its use in Duchenne muscular dystrophy earlier this year, but abandoned its launch following the backlash over its $89,000 a year price from patient groups and politicians.

Following the public relations disaster, Marathon decided to sell off the rights to Emflaza to PTC Therapeutics for $140 million.

So families affected by DMD are unlikely to welcome news that PTC’s price for Emflaza will work out at around $35,000 per year for a 25 kilogramme patient – and probably much more than this for many others.

Because of the US approval families can no longer import the drug, so they will have to pay the higher price demanded by PTC, which some suggest may even exceed that charged by Marathon in some patients.

PTC Therapeutics’ CEO Stuart Peltz said in a first quarter conference call: “We believe this represents sustainable pricing which balances providing access to all eligible patients in the United States in an ultra orphan population while maintaining sufficient infrastructure and programme including continued investment in Duchenne.”

Peltz said PTC had been “actively engaged” with the DMD community when deciding the new price – but the company’s share price fell as commentators on twitter dismissed the announcement as a PR stunt.

PTC has so far failed to get its Translarna (ataluren) DMD gene therapy approved in the US, although it is approved in the EU.

The FDA in February last year refused to accept PTC’s filing for Translarna, but in March filed the drug over protest, forcing the regulator to make a decision by October 24.

Last year the FDA controversially decided to approve Sarepta’s Exondys 51 (eteplirsen) in DMD, even though its advisers had recommended rejecting it because of concerns that data did not demonstrate efficacy.


Study: Systemic therapy preserves vision of uveitis patients better than intraocular implant

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Systemic therapy consisting of corticosteroids and immunosuppressants preserved vision of uveitis patients better – and had fewer adverse outcomes – than a long-lasting corticosteroid intraocular implant, according to a clinical trial funded by the National Eye Institute (NEI).

After seven years, visual acuity on average remained stable among participants on systemic therapy but declined by an average of six letters (about one line on an eye chart) among participants who had the implant. NEI is part of the National Institutes of Health.

“This trial provides good evidence that for the average patient with uveitis, systemic therapy would be the first choice of treatment,” said John Kempen, M.D, Ph.D., of Massachusetts Eye and Ear/Harvard Medical School, Boston, chair of the writing committee for the report. “The visual outcome over the long run was better, on average, there were fewer adverse outcomes, and the cost is less.” The findings were published today in the Journal of the American Medical Association.

Uveitis is an inflammatory disease of the eye and the fifth leading cause of vision loss in the United States. Concerns about potential adverse effects of systemic corticosteroid and immunosuppressive therapy drove the development of an intraocular implant to treat uveitis locally. The fluocinolone intraocular implant, developed by Bausch & Lomb, was approved by the U.S. Food and Drug Administration in 2005. Early data suggested the implant was effective at controlling inflammation but had local ocular side effects. The Multicenter Uveitis Steroid Treatment Trial (MUST) was undertaken to evaluate whether the implant treatment was an improvement over systemic therapy for management of uveitis.

Researchers recruited 255 uveitis patients at 23 sites (21 in the U.S., one in the U.K., and one in Australia) and randomly assigned them to receive the fluocinolone implant or systemic treatment with corticosteroids (prednisone) and immunosuppressants (such as methotrexate or mycophenolate mofetil). Systemic corticosteroids, which are FDA-approved for treatment of uveitis, reduce acute inflammation effectively but have potential systemic adverse effects when used at a high dose for a long time. The immunosuppressants, which are not FDA-approved for uveitis, inhibit pathological immune responses, thus reducing the amount of corticosteroids needed over the long-term, mitigating such side effects.

Through the first two years, the visual acuity remained about the same in the two groups (results published in 2011). At seven years, visual acuity on average remained stable in the systemic group but declined about six letters in the implant group. The researchers found that implant-treated eyes had reactivations of uveitis after about five years, which coincided with a decline in visual acuity. The loss of vision in the implant group appears to have been due to increased damage in the retina and choroid (a tissue rich in blood vessels lying underneath the retina).

“These results emphasize the importance of longer follow-up for studies of treatments for chronic diseases that are likely to require years of treatment,” said Elizabeth Sugar, Ph.D., of Johns Hopkins University, Baltimore, chair of the statistical analysis committee for the MUST research group and lead statistician for the manuscript.

With respect to side effects, patients in the implant group were more likely to develop ocular side effects like cataracts, intraocular pressure elevation that required treatment with medicine and often surgery, and glaucoma. Patients receiving systemic therapy had increased risk of needing treatment with antibiotics, possibly due to immunosuppression, but otherwise did not have large increases in the risk of adverse effects typically associated with systemic corticosteroids such as high blood pressure or diabetes.

“We were able to avoid most of the systemic adverse outcomes that people worry about with systemic corticosteroid and immunosuppressive therapy by following expert panel guidelines. The result is meaningful not just in ophthalmology but in other disease areas, because many different fields use this strategy to treat the inflammatory diseases of many different organs,” said Kempen.

The results of this trial suggest that oral corticosteroids and immunosuppression may be a preferable initial choice for therapy of more severe uveitis, said Douglas A. Jabs, M.D., of the Icahn School of Medicine at Mount Sinai, New York City, and chair of the MUST Research Group. However, the implant may have a role in treating patients where systemic therapy fails to control inflammation or patients cannot tolerate the oral medications, he added.

“MUST results provide guidance to clinicians and their patients in making informed decisions about veitis treatment,” said Sangeeta Bhargava, Ph.D., program director at the National Eye Institute.


Pfizer launches antibiotic resistance surveillance website

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Pfizer has made an online move into the fight against antimicrobial resistance with the launch of a new online and mobile information resource.

Its Antimicrobial Testing Leadership and Surveillance, or ATLAS, site will provide the health community with country-specific data on the efficacy from, and resistance to, antibiotic treatments.

It’s available online as a stand-alone website and also as a mobile app – albeit so far only in an iPhone version – and covers more than 60 countries.

Dr Freda Lewis-Hall, Pfizer’s chief medical officer, said: “An important aspect for physicians when treating patients is knowledge; knowledge of where certain resistant bacterial infections tend to occur and knowledge of which antibiotics remain effective against them.

“ATLAS underscores our continued commitment to providing patients and physicians with meaningful resources that can help ensure appropriate utilisation of antibiotics and improve infection prevention and control.”

The pharma firm hopes ATLAS will help doctors select appropriate antibiotics for their patients and inform global health strategies against the rising threat of antimicrobial resistance.

Around the world some 700,000 deaths per year are attributed to antimicrobial resistance, a figure that’s predicted to rise to 10 million by 2050 if action is not taken.

To that end Pfizer and more than 100 other firms and 13 trade associations last year signed up to the Declaration on Combating Antimicrobial Resistance, calling for greater industry and government collaboration to address AMR.

This was followed later in 2016 by the Industry Roadmap to Combat Antimicrobial Resistance. It was supported by Pfizer and 13 other pharma companies, who committed to reducing the environmental impact of antibiotic production, helping ensure appropriate use, improving access to current and future antibiotics and pursuing public-private collaborations.

Through its new website Pfizer will provide doctors and data around parameters such as pathogen, region, specimen source and in vitro susceptibility data. The ATLAS database will be updated every six months with new resistance data from healthcare institutions in more than 60 countries.

Meanwhile, Pfizer’s new antibiotic for multidrug resistant (MDR) infections, Zavicefta, was launched in its first European markets earlier this year after the pharma firm paid its developer AstraZeneca $1.58bn for it.