Category Archives: Pulmonology

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.”


Eczema drug effective against severe asthma

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Two new studies of patients with difficult-to-control asthma show that the eczema drug dupilumab alleviates asthma symptoms and improves patients’ ability to breathe better than standard therapies.

Two new studies of patients with difficult-to-control asthma show that the eczema drug dupilumab alleviates asthma symptoms and improves patients’ ability to breathe better than standard therapies. Dupilumab, an injectable anti-inflammatory drug, was approved in 2017 by the Food and Drug Administration as a treatment for eczema, a chronic skin disease.

The more than 2,000 patients enrolled in the studies suffered from moderate to severe asthma. All used standard asthma inhalers, and some also took oral steroids to control their severe asthma symptoms.

In one study, the rate of asthma exacerbations was almost cut in half for those taking dupilumab compared with those taking a placebo. On average, patients taking a placebo had close to one exacerbation per day during the year of the study. Exacerbations are periods of sudden worsening of asthma symptoms such as wheezing, coughing, shortness of breath and tightness in the chest.

Although the drug significantly reduced asthma symptoms for all patients, dupilumab worked particularly well in patients with high numbers of a specific type of white blood cell, called eosinophils, circulating in the bloodstream. For those patients, asthma exacerbations were cut by two-thirds.

“This drug not only reduced severe symptoms of asthma, it improved the ability to breathe,” said Dr Mario Castro, the Alan A. and Edith L. Wolff Distinguished Professor of Pulmonology and Critical Care Medicine. “That’s important because these patients have a chronic disabling disease that worsens over time with the loss of lung function. So far, we do not have a drug for asthma that changes the course of the disease. Current drugs for severe asthma help reduce trips to the emergency room, for example, but they don’t improve lung function.”

The first study included about 1,900 patients of at least 12 years of age and with moderate to severe asthma requiring they use at least three different inhalers to control their symptoms. One inhaler contained a corticosteroid that reduces inflammation, another contained a long-acting bronchodilator that relaxes airway muscles, and the third was a “rescue” inhaler filled with albuterol, a short-acting bronchodilator that quickly opens up the airway in the event of a more severe asthma attack.

Patients taking these inhaled medications then were randomly assigned to receive either dupilumab or a placebo for one year. Patients receiving dupilumab — an injectable antibody — also were randomly assigned to a higher or lower dose of the drug. Neither patients nor their doctors knew whether they were receiving the drug or the placebo.

In addition to reduced symptoms, the patients receiving dupilumab showed improved lung function in a test of “forced expiratory volume.” This test measures the amount of air a person can force from the lungs during a deep exhale. Patients receiving dupilumab, regardless of dose, improved their lung function by approximately 130-200 millilitres greater than those receiving the placebo. In general, there were no significant differences between the patients receiving high and low doses of dupilumab.

Rates of emergency room (ER) visits and hospitalisations also were improved for patients receiving the drug. In the placebo group (with 638 patients), on average, 6.5 percent of the patients required an emergency room visit or hospitalisation due to asthma during the study. In the dupilumab group (with 1,264 patients), on average, 3.5 percent of patients needed emergency care or hospitalisation due to asthma.

Based on the second study, Dr Castro said another benefit of the drug could be the ability to wean severe asthma patients off of chronic oral steroids, which can cause debilitating long-term side effects, including stunted growth, diabetes, cataracts and osteoporosis. The second study included about 200 patients using the same inhaled asthma medications as patients in the larger trial, plus additional oral steroids — usually prednisone — to control their more severe symptoms. Half of the patients receiving dupilumab in this study were able to completely eliminate prednisone use. And 80 percent of dupilumab-treated patients were able to at least cut their doses in half. Patients on placebo also reduced prednisone use but to a lesser degree, likely because the protocols of participating in a clinical trial help asthma control generally.

Dr Castro said doctors would like to help patients rely less on steroids for asthma control because those with severe asthma can be forced to take these drugs for decades to enable them to breathe.

“I have patients who have had to stop working and go on disability because their asthma symptoms are so severe they can no longer function in the workplace,” Dr Castro said. “I’m excited about the potential of dupilumab because I have so many patients who have maxed out on available therapies and they still can’t breathe. It can become a very disabling disease.”

Patients receiving dupilumab did experience known side effects of the drug, including pain and swelling at the injection site and a short-term bump in the number of eosinophil cells in the blood. Five patients who received dupilumab and three patients who received placebo died during the study period. According to the investigators and descriptions of these patients’ medical histories, all suffered from multiple severe medical conditions, and none of the deaths was deemed related to the study protocol.

The studies will be published online in The New England Journal of Medicine.


AZ’s Fasenra stumbles in P3 for COPD

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AstraZeneca’s Fasenra arrived later on the scene than GSK rival med, Nucala, and so it needed to quickly rack up indications to mount a serious challenge – in COPD, at least, that looks more unlikely after the treatment wasn’t able to meet its primary endpoints in a Phase 3 trial.

Fasenra is already approved to treat severe eosinophilic asthma in major markets around the world but was hoping to add to this with an expansion into treating exacerbations in those with moderate to very severe COPD.

Had it succeeded to hit its endpoints, it would have joined GSK in submitting for regulatory approval but now looks set to fall behind, should its rival receive approval.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: “COPD is a debilitating disease with significant unmet need among patients whose disease remains uncontrolled despite treatment with existing inhaled therapies. We will now await the results of Terranova and a full evaluation of both trials to determine next steps for Fasenra in COPD.”

GSK did not have a smooth path to acquire the data needed it to submit for approval; in its Metreo study, the drug demonstrated a reduction in exacerbations but not to a level that were statistically significant.

However, it managed to scrape successful results in another trial that was on-going concurrently (Metrex) in reducing exacerbations. It shows that these types of monoclonal antibody treatments can be hit-and-miss in trials for COPD.

Full details were not revealed by AstraZeneca about how far its drug missed the mark but, as mentioned by Bohen, the company has another trial running. If this trial succeeds and the drug only just missed the mark, it could still be emboldened to attempt to file for approval – in a similar manner to GSK.

Fasenra entered the market two years after Nucala but has some advantages that could see it leech GSK’s sales in the area; the product is administered by subcutaneous injection but is delivered every eight weeks (compared to four weeks for Nucala), after a lead-in dosing schedule and is priced at a lower level.


Vertex says ‘some way’ to CF drug price deal after NHS meeting

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Representatives of Vertex Pharmaceuticals and NHS England met last week in an attempt to end a two-year long stand-off over the price of cystic fibrosis drugs – but there is still a long way to go before the matter is resolved.

Pressure from patient groups forced a parliamentary debate on access to Vertex’s CF drugs, after NICE rejected the company’s Orkambi combination therapy in 2016.

An online petition attracted more than 100,000 signatures, the threshold for a discussion in Parliament, and ministers have written to Vertex asking for the matter to be resolved.

Vertex is asking the NHS for a deal covering the price of its portfolio of CF drugs, including those that are yet to be approved, and will expand the proportion of the disease population who will be eligible for treatment.

The company confirmed in a statement that Vertex met with representatives of NHS England last Wednesday.

But a spokesperson added: “Both parties recognise there is still some way to go to reach an agreement and Vertex is committed to working together to achieve this. We share the cystic fibrosis community’s sense of urgency and have agreed to meet again in the coming weeks. There’s lots of work to do on both sides ahead of this to progress discussions as quickly as possible.”

However there is hope that there will be further progress in meetings over the coming weeks.

pharmaphorum understands that the biggest stumbling block is that NHS England wants to pay the same price as Vertex’s already-approved and NICE-backed Kalydeco (ivacaftor) for the company’s drugs.

Kalydeco’s list price is around £182,600 per year, although the company has agreed a confidential discount.

Cystic Fibrosis Trust public affairs manager Lynsey Beswick said: “We welcome the news that Vertex and NHS England have had further talks on the company’s medicines. This appears to be positive progress in our goal to gain access to the most advanced new medicines for people with cystic fibrosis at the earliest possible opportunity.”


GlaxoSmithKline and Innoviva publish positive new IMPACT data

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GlaxoSmithKline, alongside Nasdaq-listed partner Innoviva, announced the publication of the landmark IMPACT study – one of the biggest ever conducted in patients with chronic obstructive pulmonary disease with a history of exacerbation – in the New England Journal of Medicine on Thursday.

The FTSE 100 pharmaceutical giant said that in the study, ‘Trelegy Ellipta’ (fluticasone furoate/umeclidinium/vilanterol) achieved superiority to members of two different classes of dual combination therapy, Relvar/Breo and Anoro, on the primary endpoint of reduction in the annual rate of on-treatment moderate/severe exacerbations and a range of other clinically important outcomes, including lung function and health-related quality of life.

It said results from additional secondary and other endpoints included a “statistically significant” 34% reduction in COPD hospitalisations for Trelegy compared to Anoro, and a reduction of 13% compared to Relvar/Breo, which was not statistically significant.

They also included a “significant” reduction in the risk of on-treatment all-cause mortality, observed for both inhaled corticosteroid containing arms compared to Anoro.

A 42.1% reduction in the risk of on-treatment all-cause mortality was observed for Trelegy compared to Anoro as well.

To fully understand the implications of the all-cause mortality observation, off-treatment data also needed to be considered, GSK explained.

Work was ongoing to investigate that further, and would be presented at future scientific meetings.

“Reducing exacerbations to keep patients out of hospital is a key goal of COPD management alongside improving lung function and quality of life,” said Dave Allen, GSK’s head of respiratory therapy area research and development.

“The IMPACT study shows how Trelegy Ellipta can help patients with a history of exacerbation achieve these goals.

“We believe its publication in NEJM is an important addition to the evidence base that informs the management of this progressive and debilitating disease.”

Dr Fernando Martinez, chief of the division of pulmonary and critical care medicine at the New York-Presbyterian Hospital/Weill Cornell Medical Center, said IMPACT “significantly advances” medicine’s understanding of COPD management by addressing a number of key evidence gaps.

“By comparing various combinations of effective medications in the same device the study clarifies which type of patient gains greatest benefit from each class of medicine,” Dr Martinez explained.

“As many patients experience frequent exacerbations or ‘flare ups’, which can often result in hospitalisation, these data will be highly relevant to patients and clinicians as they consider the optimal treatment.”

GSK and Innoviva said the safety profile of single inhaler triple therapy was consistent with the safety profile of the individual components.

The most common adverse events across the treatment groups were viral upper respiratory tract infection, worsening of COPD, upper respiratory tract infection, pneumonia and headache.

Consistent with previous studies, the incidence of pneumonia as a serious adverse event was 4%, 4%, and 3% for FF/UMEC/VI, FF/VI and UMEC/VI, respectively.

“The role of inhaled corticosteroids in COPD have long been debated, and this landmark trial provides further evidence of their benefit in the population studied and compelling data towards clarifying the role of ICS containing regimens in the COPD treatment paradigm,” said Dr Ted Witek, Innoviva’s senior vice president and chief scientific officer.

“We congratulate our partners at GSK for this vital contribution to the field of respiratory medicine.”

Results from IMPACT were submitted to the regulatory authorities in the US and EU in November 2017 and February this year, respectively.

Further regulatory submissions in other countries were expected during 2018.


The future’s bright, the future’s digital in drug delivery

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As a new era of digital drug delivery is making headway, Dr Steven Wick, vice president, Product Development & Commercialisation, 3M Drug Delivery Systems, gives his thoughts on this digital future.

Across the drug delivery industry, there is currently a big movement toward digital enhancement of inhalation devices used by patients with asthma and COPD. With fewer step-change improvements in drug therapies, the pharmaceutical industry is now focusing its attention on drug delivery technologies as a means to improve compliance and therefore patient outcomes. The concept of digital health will allow us to properly equip patients to manage their condition and ultimately take control of their health.

A patient-centred model

A focal point of my career in pharmaceutical research and product development has been to drive innovation with a priority placed on improving patient outcomes. The technological advances that have made digital health possible are changing the landscape of device design to a more patient-centric model. Traditionally, drug delivery methods were designed without much consideration for the patient experience. Now, product developers and engineers are considering the challenges facing patients first. They use these insights to improve drug delivery device design, and by addressing patient challenges directly, they improve patient outcomes in the process.

A 2008 research report showed that up to 94% of patients make mistakes when using their inhalers, and these were the dry powder inhalers that were intended to be easier to use. None of the current devices are perfect, with up to 76% of patients struggling to use metered dose inhalers as well. Also, patients struggle to adhere to their medication schedule. When patients forget to dose themselves or inadvertently use their inhalation devices incorrectly, it doesn’t matter how great the drug is — it will be less effective.

Digital health is helping to solve these usability and adherence issues. For example, the 3M Intelligent Control Inhaler (ICI) is breath-actuated so that patients do not have to coordinate their in-breath with triggering of the device, and actuation is triggered at a low flow-rate and at the optimal point within the patient’s inspiration cycle, so that even patients with a severe condition and poor lung function can use the device.

Proprietary flow-sensing technology optimises the inhalation cycle and can detect whether a patient is inhaling the drug properly to ensure a full dose is received.

The device can connect to a smartphone or tablet for reminders and further instructions, and it can record data for sharing with a healthcare provider, to influence and inform healthcare decisions.

The focus of our efforts is to identify areas where drug delivery device technologies could add significant benefits to the patient and help manage costs for the provider and payer. In that vein, 3M has also developed a respiratory tracker to help patients identify and monitor triggers that result in breathing difficulty. The 3M Respiratory Tracker is not a drug delivery device but a consumer wearable designed to give the wearer a greater understanding of how their breathing patterns are related to environmental or weather-related considerations. It provides personalised forecasts tailored to an individual’s potential triggers in their local environment, while delivering dynamic tips and insights relating to breathing and activity.

Bringing the vision to life

One major factor that stands in the way of future advancements in the digital drug delivery space is cost. Billions of dollars per year are invested in digital health start-ups, and creative solutions are always on the horizon. However, these innovative inventions are struggling to move from the development lab to the pharmacy counter because we have yet to generate the pharmaco-economic models and the associated business cases required to create the necessity for these new digital drug delivery technologies.

To move forward, it is important for all parties involved: pharmaceutical companies, payers, providers, and patients, to understand how total healthcare costs will benefit from these new technologies. If a patient is receiving the right dose of medication at the right time on a consistent basis, one could surmise that the patient’s symptoms would be better managed and the patient would make fewer trips to the doctor’s office or emergency room. In the end, this will drive down overall patient costs and significantly reduce the financial burden on the healthcare system.

We must also consider the investment of time. For healthcare providers, helping patients is the ultimate goal. However, it’s typically the provider’s responsibility to teach his or her patient how to properly use the device, which means the provider must first be trained in how to use it. At 3M, we are sensitive to these factors and keep input from patients and providers at the forefront of all development stages. Our goal is a product that is as straightforward and beneficial as possible for both parties. Despite the bells and whistles that new technology allows, an inhalation device must be intuitive to use — plain and simple.

Moving forward

To stay aligned with this new era of drug delivery, organisations across the board have had to adapt. Here at 3M, we must now be more strategic in our R&D efforts than ever before. Because of the unique financial framework outlined above, we can no longer afford to innovate simply for the sake of innovation. Instead, we start by identifying a problem and then search for a feasible solution.

It is an exciting time to be involved in the drug delivery industry. I believe going digital will improve consistency in drug delivery, increase the efficacy of drug products, and reduce the opportunity for patient errors. I also believe it will offer providers and payers valuable new data to help them identify patients who need extra intervention, thus preventing a potentially catastrophic and costly event. Everything you can imagine doing, there is a possibility with digital health, which is why it will continue to be an unstoppable transition in the inhalation therapy for years to come.


MSD cuts 1,800 jobs in US operations restructure

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MSD has revealed its intention to cut 1,800 sales positions from its workforce in the US.

Across the total number, the cuts include the elimination of US sales teams in primary care, endocrinology and hospital chronic care. In their place, the company will add 960 positions with the formation of a new chronic care sales force.

This new force will focus on key products in the company’s pipeline including its diabetes treatment Januvia (sitagliptin) and insomnia therapy Belsomra (suvorexant) in addition to women’s health and respiratory disease products.

It should be noted however that this still leaves 840 positions which will not be replaced, and the company has confirmed it will not be shifting the roles to outside the US.

The move follows MSD’s decision not to seek regulatory approval for its cholesterol therapy anacetrapib after it failed to achieve adequate results during clinical trials, as well as the discontinuation of its development of a drug combination to treat chronic hepatitis C last month.

“This is part of ongoing prioritisation efforts and the ebb and flow of our business means that at the same time we’re eliminating certain US jobs, we’re also adding new US jobs in growth areas,” the spokeswoman explained, continuing “these changes are part of ongoing company-wide efforts to sharpen Merck’s focus on innovative R&D that addresses significant unmet medical needs and on our best opportunities for growth, while reducing overall costs.”


Polyphor launches the development of an inhaled antibiotic murepavadin

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Polyphor Ltd has announced €5m funding, in order to support and accelerate the develop­ment of an inhaled dosage form of murepavadin.

Polyphor Ltd has announced the development of an inhaled dosage form of its break­through antibiotic Murepavadin.

In order to support and accelerate the develop­ment, Polyphor will leverage a European program dedicated to the development of in­haled anti­biotics, iABC – a consortium of leading lung specialists in 18 hospitals and research insti­tutions in eight Euro­pean countries. These institutions will receive up to EUR 5 million funding for this project from the Innovative Medicines Initiative (IMI), a public-private partnership of European Federation of Pharmaceutical Industries and Associations (EFPIA) and the EU, while Polyphor will invest up to EUR 5 million.

Respiratory infections, especially those caused by drug-resistant bacteria, are the main cause of dis­ease and death in people with cystic fibrosis and bronchiectasis. Thanks to inhaled anti­biotics, patients now live longer than ever before and enjoy a better quality of life. However, ad­ditional treatment options are needed to reduce the bacterial load and fight resistant patho­gens – and especially resistant Pseu­do­monasstrains.

The iABC project is a Europe-wide program funded by the IMI to develop new, life-saving anti­biotic treat­ments to manage chronic lung infection. The two industry partners are Polyphor and Novartis.

Murepavadin (POL7080) is the first representative of the Outer Membrane Protein Targeting Antibiotics (OMPTA), a class of antibiotics against Gram-negative bacteria with a novel mode of action discovered by Polyphor. It is a precision antibiotic specifically targeting Pseudo­mo­nas aeruginosa, one of the most difficult to treat pathogens, and is highly potent and active also against multi-drug resistant strains.

Pivotal studies of Murepavadin’s intravenous formulation will be initiated in the first months of 2018 for the treatment of patients with nosocomial pneumonia (Ventilator-associated and hospital-acquired pneumonia; VAP/HAP) caused by Pseudomonas aeruginosa, including its resistant strains.

The inhaled formulation of Murepavadin could extend the therapy to the treat­ment of chronic infections by Pseudomonas aeruginosa– affecting for example over 60% of the adult patients with cystic fibrosis and many of those with non-CF bronchiectasis and other rare lung diseases.

Professor Stuart Elborn, Professor of respiratory medicine at the Royal Brompton Hospital in London and Principal Investigator, said: “Just a few decades ago, most cystic fibrosis patients died in early childhood. Thanks to antibiotics, patients born today can expect to reach early middle age. However, this progress is threatened by the fact that current medicines do not fully eradicate the infections.” He continued: “The iABC project represents an important contri­bution to efforts to counter this threat. Our work has the potential to deliver new inhaled anti­biotics that will improve the quality of life and survival of patients with cystic fibrosis and bron­chi­ectasis by reducing the number of lung infections, improving lung function, and overcoming antibacterial resistance.”

Giacomo Di Nepi, Chief Executive Officer of Polyphor, said: “Cystic fibrosis and bronchiectasis patients are a vulnerable group. They are at particular risk of chronic infection. We are pleased and honoured to be selected as one of two industry partners of the iABC consortium to develop an inhaled formulation of Murepavadin as a new treatment option. Our investigational anti­bio­tic reaches a high concentration in the lung and shows a high efficacy against Pseudomonas aeru­­­ginosa, the main cause of chronic lung infections in cystic fibrosis, affecting the majority of patients. In addition, by targeting only Pseudomonas aeruginosa, Murepavadin does not in­duce further resistance in other pathogens, which could infect these patients. Murepavadin may, therefore, provide a new important treatment option for patients with cystic fibrosis and bron­chiectasis.”

Murepavadin (POL7080) is the first representative of the Outer Membrane Protein Targeting Antibiotics (OMPTA) class, a class of antibiotics against Gram-negative bacteria with a novel mode of action discovered by Polyphor. Murepavadin is highly potent and unlikely to nega­­tively impact the patient’s native bacterial flora. No cross-resistance with a current standard of care antibiotics has been observed.

Earlier this summer, Polyphor received positive guidance from the US Food and Drug Admini­stra­tion (FDA) and the European Medicines Agency for phase III development of Murepavadin for the treatment of patients with nosocomial pneumonia (ventilator-associated and hospital-ac­quired pneumonia; VAP/HAP) caused by infections through Pseudomonas aeruginosa, including its resistant strains. The Company is currently finalizing the study protocol in collabo­ration with its investigators and is initiating the pivotal development program. First patient en­rolling is expected by Q1/2018.

In addition, the FDA has granted the QIDP (Qualified Infectious Disease Product) status to Murepavadin, which makes the compound eligible for priority review and statutory exclusivity for an additional five years upon approval. Such status is exclusively reserved for break­through medicines in life-threatening indications. Polyphor also develops other members of this new class of antibiotics which show excellent activity towards a broad range of Gram-negative pathogens, including isolates resistant to all other antibiotic classes.