17 July 2018

Washington University’s new ALS therapy in clinical trial stage 

Washington University School of Medicine’s investigational therapy for an inherited form of amyotrophic lateral sclerosis (ALS), which it had tested on genetically modified mice and rats, is now being studied in a phase 1/2 clinical trial.

The inherited form of ALS being focused on in the trial is caused by mutations in a gene called SOD1. These mutations cause the SOD1 protein to be over-active, thus reducing levels of the protein, which may help ALS patients. This form of the disease affects approximately 2% of patients with ALS.

ALS kills nerve cells that control walking, eating and breathing, with few people surviving more than three years after diagnosis.

Washington University researchers collaborated with US-based Ionis Pharmaceuticals to test DNA-based compounds known as antisense oligonucleotides (oligos) that block the production of SOD1 protein in mice and rats that had been genetically modified to carry a mutated form of the human SOD1 gene.

The first dose of either anti-SOD1 oligo or a placebo was administered at day 50, followed by a second dose six weeks later. The mice that received the drug maintained their weight 26 days longer and lived 37 days longer than those given placebo; this represents a 22% increase in life span. The rats that received the drug maintained their weight more than nine weeks longer and survived between eight and nine weeks longer than the placebo group.

Since at nine weeks mice showed signs of deteriorating neuromuscular function, the mice were treated with anti-SOD1 or a placebo nine weeks into the trial. The muscle function of those receiving the oligo steadily improved over the next eight weeks and continued to decline for the placebo group. Neurological damage increased in both groups, but it was twice as fast to develop in the placebo group.

Washington University professor of neurology and study lead Timothy Miller said: “This drug had an impressive effect in mice and rats with just one or two doses. We don’t know yet if this works in people, but we’re very hopeful. We’ve completed the first phase of safety testing, and now we’re working on finding the right dose.”

The clinical trial is being led by Miller’s colleague Robert Bucelli and it aims to evaluate the safety of using oligos in people. Different doses and regimes will be studied to determine the most effective way to reduce SOD1 without unacceptable side effects.

Miller said: “The phase 1/2 trial is really still a safety trial. There are not enough patients in it to really be able to accurately see an effect on disease. But we’re on the cusp of testing the hypothesis that people with ALS caused by mutations in SOD1 can benefit from this treatment. We predict the effect will be good, but we can’t know until we test it.”

16 July 2018

J&J collaborates with Merck to launch diabetes drug in China

Johnson & Johnson (J&J) subsidiary Xian Janssen Pharmaceuticals has signed a deal with Germany-based Merck to introduce Janssen’s diabetes drug Invokana to the Chinese market.

Invokana was approved in China in September 2017 for the treatment of type 2 diabetes in conjunction with metformin or a combination of metformin plus sulfonylurea in adults with inadequate glycaemic control with other oral therapies.

The two companies will partner on the future development, distribution and commercialisation of Invokana, but Merck will have exclusive promotion rights for the drug in China. The financial details of the agreement have not been disclosed.

Invokana is a sodium-glucose co-transporter 2. Instead of having a mechanism of action related to insulin secretion and sensitivity, the drug works independently, reducing the reabsorption of filtered glucose in the kidneys and lowering the renal threshold for glucose. The drug has been shown to also reduce body weight, lower blood pressure and slow the progression in albuminuria.

Merck has experience working in China; the company already has a division in the country, which works across seven major therapeutic areas, but with a particular focus on cardiovascular conditions, endocrinology and oncology. Recently, Merck signed an agreement with internet company Alibaba Healthcare to improve access to healthcare using digital technology.

Merck Healthcare China managing director and general manager Rogier Janssens said: “Our mission is to transform 40 million patients’ lives in China by 2025. We are very pleased to be collaborating with Xian Janssen, who shares our goal of helping improve the lives of people living with or at risk of type 2 diabetes.

“Merck has been making continued efforts to expand its portfolio with the aim of providing more high-quality medicines and better treatment options for millions of diabetic patients in China. The introduction of INVOKANA® to China reinforces our long-term commitment to China.”

J&J has also announced the US Food and Drug Administration has extended the review timeline for its supplemental new drug application for Invokana to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have a cardiovascular disease or at are risk of one.

16 July 2018

EMA’s safety committee advises limiting use of Xofigo

The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended restricting the use of prostate cancer drug Xofigo (radium-223 dicholoride) at its July 2018 plenary meeting.

The safety committee advised that the drug should only be taken by patients who had undergone two previous treatments for metastatic prostate cancer, when tumours have spread to the bones, or by those who cannot tolerate other treatments.

PRAC also noted that Xofigo should not be used in combination with other systemic therapies with the exception of hormone therapy or for patients with low numbers of bone metastases, as well as confirming its previous recommendation that it must not be used for patients with no symptoms or in combination with Zytiga and prednisone/prednisolone.

This decision followed PRAC’s review of data from study ERA223, which was requested by the European Commission (EC) in November 2017. The trial was investigating the safety and efficacy of combining Xofigo with Zytiga and prednisone/prednisolone in patients with no or mild symptoms. Currently Xofigo is only approved for those with symptomatic bone metastases.

ERA223 showed that patients taking the Xofigo combination had a higher risk of dying earlier and witnessed more fractures than those taking a placebo. On average participants in the Xofigo group died 2.6 months earlier than those taking the placebo combination and 29% of Xofigo combination patients had fractures compared with 11% for the placebo group.

The safety committee called on Bayer, the pharmaceutical company marketing the drug, to conduct further studies to explore the reasons for earlier death and increased risk of fractures reported in the study.

PRAC’s recommendations will be sent to the EMA’s Committee for Medicinal Products for Human Use (CHMP), which will decide the EMA’s stance. This verdict will then be sent to the EC, which will formulate a legally binding ruling that will be applicable in all European Union member states.

Xofigo is classed as a radiopharmaceutical, since it contains an active radioactive substance. Radium-223 combats metastatic prostate cancer because it accumulates in bone tissues where the cancer spreads and the alpha particles it emits destroy the nearby cancer cells and help to manage related symptoms.

The drug was approved in Europe in November 2013 to treat castration-resistant prostate cancer in patients with symptomatic bone metastases.

13 July 2018

Janssen reports negative results from PHOENIX trial

Janssen Pharmaceutical Companies of Johnson & Johnson has reported negative results from the PHOENIX trial after the study failed to meet its primary endpoint.

PHOENIX is a Phase lll, randomised, double-blind, placebo-controlled, multicentre trial designed to analyse the investigational use of Imbruvica (ibrutinib) for the treatment of newly diagnosed non-Germinal Center B cell (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

The trial also compared Imbruvica with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) against R-CHOP, the existing standard of care in DLBCL.

Its primary endpoint included event-free survival in patients with a non-GCB subtype of DLBCL, including an activated B-cell-like (ABC) subtype of DLBCL.

DLBCL is an aggressive form of non-Hodgkin lymphoma (NHL) that affects a type of white blood cell called B-cell lymphocytes.

Janssen Research and Development Clinical Development and Global Medical Affairs vice president Craig Tendler said: “While we are disappointed that the overall study did not result in the outcome that we had hoped for in patients living with DLBCL, we are conducting additional analyses to further understand potential benefits we have observed in a sub-population of patients.

“These analyses will be informative in preparation for upcoming consultations with health authorities.

“We look forward to these regulatory discussions and to submitting the PHOENIX data for presentation at a major medical conference later this year.”

Janssen Biotech, along with Pharmacyclics, has developed Imbruvica, an inhibitor of Bruton’s tyrosine kinase (BTK) protein, which transmits signals that cause B-cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.

12 July 2018

FDA orders safety label changes for fluoroquinolone antibiotics

The US Food and Drug Administration (FDA) has ordered changes to safety labelling of the fluoroquinolone antibiotics class to include associated mental health side effects and serious blood sugar disturbances.

The regulatory agency requires these warnings to be consistent across all fluoroquinolones administered either orally or by injection.

Fluoroquinolones are used to treat serious bacterial infections. However, a comprehensive review of adverse event and case reports showed instances of fluoroquinolone users experiencing hypoglycaemic coma.

Based on these findings, the FDA has called for inclusion of the potential risk of coma with hypoglycaemia in the blood glucose disturbances subsection of the labels on systemic fluoroquinolones.

Currently, various mental health side effects are described in the warnings and precautions section of the labelling of all fluoroquinolone antibiotics.

As per the new changes, the mental health side effects will be listed independently from other central nervous system side effects.

FDA Office of Antimicrobial Products director Edward Cox said: “The use of fluoroquinolones has a place in the treatment of serious bacterial infections – such as certain types of bacterial pneumonia – where the benefits of these drugs outweigh the risks, and they should remain available as a therapeutic option.

“The FDA remains committed to keeping the risk information about these products current and comprehensive to ensure that health care providers and patients consider the risks and benefits of fluoroquinolones and make an informed decision about their use.”

The first boxed warning on fluoroquinolone antibiotics was added in July 2008 to inform users of the increased risk of tendinitis and tendon rupture, followed by various other additions in 2011, 2013 and 2016.

The fluoroquinolones currently approved by the FDA comprise evofloxacin (Levaquin), ofloxacin, ciprofloxacin (Cipro), gemifloxacin (Factive), ciprofloxacin extended-release tablets, moxifloxacin (Avelox) and delafloxacin (Baxdela). These antibiotics have more than 60 generic versions.

9 July 2018

Glasgow University uncovers molecular structure of herpes virus

Researchers from the University of Glasgow have used Nobel prize-winning cryo-electron microscopy (cryo-EM) to reveal the molecular structure of the common herpes virus in high definition.

The capsid, which stores the virus’ DNA, has been difficult for scientists to analyse because of its microscopic size: it measures 1/10,000th of a millimetre in diameter.

Cryo-EM has enabled researchers to visualise and understand the structure and mechanism of a motor-like molecule, which they named the portal. It is used to pump the herpes virus’ DNA into the capsid for storage and to eject the DNA from the capsid when infecting the host’s cells. The technique also illustrated how the herpes virus packs DNA inside the capsid.

Dr David Bhella, lead author of the study from the MRC-University of Glasgow Centre for Virus Research, said: “Cryo-electron microscopy, combined with new computational image processing methods allowed us to reveal the detailed structure of the unique machinery by which the virus packs DNA into the capsid. The DNA is packed very tightly, reaching a pressure similar to that inside a bottle of Champagne.

“We hope that this study will eventually lead to the development of new medicines to treat acute herpes virus infections, through the design of drugs that will block the action of the portal motor.”

Cryo-EM was developed by the Medical Research Council (MRC) Laboratory of Molecular Biology. It works on a frozen sample, which is studied by a beam of electrons. These electrons interact with the molecules and map the structure, movement and functions of biomolecules. The resulting image is more detailed and clear than those produced by alternative microscopy techniques.

MRC head of infections and immunity Dr Jonathan Pearce said: “Dr Bhella and his team have now used this technique to elucidate the structure of the herpes virus, revealing a ‘molecular machine’ that is involved in virus replication. The findings provide scientists with a better understanding of the virus and its anatomy, and, in turn, an insight into potential new therapeutic targets.

“These elegant experiments exemplify the potential of the Scottish Centre for Macromolecular Imaging due to be launched later this year at the CVR, led by Dr Bhella, which will support vital research into diseases posing the greatest threat to human health.”

Members of the herpes virus family can cause cold sores and chicken pox, as well as cancers and severe illness in unborn children. The University of Glasgow research team hope this breakthrough will aid the development of drugs to treat the disorder.

5 July 2018

Anti-coagulants study shows lower risk of major bleeds

The University of Nottingham’s Division of Primary Care has investigated the risks and benefits of the three most common types of direct anti-coagulants (DOACs), apixaban, dabigatran and rivaroxaban, compared with the current main treatment warfarin for patients with or without atrial fibrillation (AF).

The study concluded that, after taking into account risk factors, apixaban was associated with a lower risk of major bleeding, compared with warfarin in those with and without AF. Researchers said this conclusion appears ‘to show apixaban to be the safest drug’.

This investigation also demonstrated that those with AF taking apixaban and dabigatran had a lower risk of an intracranial bleed and those without AF had a lower risk of an intracranial bleed if they took rivaroxaban and a lower risk of a gastrointestinal bleed if they took apixaban.

However, the study, which was supported by the UK’s National Institute of Health Research, found that rivaroxaban and low doses of apixaban had a higher risk of death than warfarin.

The lowest number of each DOAC needed to avoid one extra major bleed, which is commonly referred to as treat, or harm, compared with warfarin supported this trend. For all patients, over six months, the lowest needed to treat was for apixaban and the lowest needed to harm was rivaroxaban.

The University of Nottingham’s research project utilised data from two large UK primary care databases and identified 196,061 patients who had started or restarted anti-coagulants between 2011 and 2016. Of the total, 53% had AF, 132,231 took warfarin, 7,741 took dabigatran, 37,863 took rivaroxaban and 18,223 took apixaban. The results were published in the British Medical Journal.

The major benefit of DOACs over warfarin is that patients do not need regular tests to check they have the correct amount of the drug in their blood stream.

Previous clinical trials had only compared DOACs and warfarin in carefully selected patients so bleeding rates may not be the same in everyday clinical practice. Prior observational studies had only included those with AF, meaning there was a gap in information about those without the condition.

It was an observational study, which means that conclusions cannot be drawn about cause and effect regarding anti-coagulants and major bleeds.

However, the research concluded: “Our results give an initial, reassuring, indication of the risk patterns for all patients taking anti-coagulants, in particular with respect to those prescribed apixaban.”

3 July 2018

Amazon set to acquire PillPack and disrupt healthcare

Amazon continues to disrupt and challenge conventional businesses with its recent acquisition of an online pharmacy, PillPack.

The deal is expected to close in the second half of 2018 and is reportedly worth close to $1bn. This deal not only solidifies Amazon as a key player within the healthcare industry, but also allows it to directly and commercially compete with key players within the healthcare setting.

PillPack is an innovative company with a simple idea: to minimise confusion for patients by providing small packs of their medications that are pre-sorted by dosage, time, and day, and delivered to their door. Moreover, there is client support with a 24/7 online and telehealth pharmacy team available.

Jeff Wilke, CEO of Amazon Worldwide Consumer, commented during a press release that “PillPack’s visionary team has a combination of deep pharmacy experience and a focus on technology. PillPack is meaningfully improving its customers’ lives, and we want to help them continue making it easy for people to save time, simplify their lives, and feel healthier. We’re excited to see what we can do together on behalf of customers over time.”

PillPack was last valued at $361m after a round of funding in 2016. The fact the deal is being reported at around $1bn demonstrates the increased competition and increased opportunity within the electronic health market. In addition, the infrastructure and resources that Amazon already has in place for directly delivering goods to consumers will allow PillPack to scale much more easily.

Not only does the deal give Amazon PillPack’s ecommerce pharmaceutical business, it also includes added value in the operating system PillPack uses to aggregate patient data. In an age where healthcare companies are moving towards data-driven business decisions, this will allow Amazon to venture into other healthcare settings: the ability to set up proprietary healthcare databases and manage them is directly translatable to other sectors of the healthcare industry.

The announced merger has already created trouble for conventional brick and mortar pharmacies, as share prices for CVS, Walgreens, and Rite Aid plummeted. The three companies combined lost more than $11bn in market value.

Conversely, CEOs and analysts are not particularly worried by the acquisition, noting that the pharmacy business is more intricate than simply delivering drugs to patients.

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