Glaxo bets on lift from new lung drugs ahead of Advair’s last gasp

GlaxoSmithKline is putting more marketing muscle behind its new lung drugs and is looking for a sales boost as top respiratory experts gather to analyse clinical trials data at a meeting in San Diego this weekend.

The British drugmaker has dominated the lung drug market for decades, but its pre-eminence is no longer guaranteed, given declining sales of the ageing Advair inhaler, which could soon face generic competition in the United States.

The market is also seeing intensified pricing pressure, raising doubts over the long-term profitability of newer drugs.

That makes this year’s meeting of the American Thoracic Society (ATS) from May 18 to 23 a critical venue for GSK.

Luke Miels, GSK’s head of pharmaceuticals, told Reuters the good sales trajectory seen in the first quarter with its novel three-in-one inhaler Trelegy and the injectable Nucala had continued since March, with ATS offering further upside.

A recent expanded U.S. label for Trelegy, to include chronic obstructive pulmonary disease (COPD) patients who need long-term therapy, means GSK can aim its product at millions more patients. Doctors will be presented with clinical data from a pivotal study in this patient group at ATS.

The so-called IMPACT study showed GSK’s once-daily Trelegy was superior to other approaches at reducing severe attacks and improving lung function.

“I think the IMPACT data is going to generate lot of interest and out of that we will see a heightened interest in Trelegy,” Miels said.

Still, pricing pressure in respiratory medicine remains a black cloud, especially with U.S. generic Advair looming.

Although Advair copycats failed to launch in 2017 as U.S. regulators knocked back applications, they are very possible this year, with Mylan due to hear next month whether the U.S. Food and Drug Administration will approve its version.

TIME WILL TELL

The price squeeze in the U.S. inhaler market is proving more severe than GSK had anticipated at the start of the year, particularly in the ICS/LABA area, which includes Advair. Another class known as LAMA medicine is faring better.

Since Trelegy includes all three products in a single inhaler, it is potentially caught in the cross-fire.

GSK has priced Trelegy at a 20 percent discount to its components and the company has not reduced the price since its launch, but Miels acknowledged this might change once Advair generics arrive.

“We are not experiencing direct pressure on Trelegy at this point in time. I think it’s reasonable to think there will be some pressure with the introduction of Advair generics but we’re confident we can manage that,” he said.

Outside the United States, which is likely to account for around 60 percent of sales, Trelegy has already launched in Britain and is now being rolled out in Germany and Canada.

Consensus analyst forecasts compiled by Thomson Reuters don’t predict it becoming a $1 billion-a-year blockbuster before 2023 but Miels said such estimates looked conservative.

“We are more confident,” he said. “Time will tell but I hope that over time the analysts will move their numbers up.”

Miels, who was hired by new CEO Emma Walmsley last year from AstraZeneca, has redeployed resources to focus on such priority products and nearly all of GSK’s more than 2,000 respiratory reps in the United States are now selling Trelegy and Nucala, plus two other relatively new lung drugs Breo and Anoro.

That leaves only a small contract team working on Advair.

GSK will also present long-term data on Nucala – a new kind of biotech drug for severe asthma – at ATS. The medicine has enjoyed a head-start over rivals but now faces competition from AstraZeneca’s Fasenra.

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Appaloosa gets permission for activist stance with Allergan stake

David Tepper’s Appaloosa Management and two of his funds received Federal Trade Commission clearance earlier this week that could clear the way for the billionaire to become an activist investor in drugmaker Allergan Plc.

Tepper received the Hart-Scott-Rodino anti-trust clearances on Wednesday, according to the FTC’s website.

Wells Fargo analyst David Maris said in a research note that Allergan “indicated this clearance provides flexibility to the filer as to whether they want take an activist approach to the investment or not.”

Tepper’s Appaloosa LP increased its stake in Allergan to 3.7 million shares from around 3.5 million shares over the last quarter, the firm said in a filing with the Securities and Exchange Commission on Tuesday.

“Allergan welcomes all investments in our company,” spokeswoman Amy Rose said, when asked about the clearances. Appaloosa was not immediately available for comment.

The company’s shares roe $5.70, or 3.7 percent, to $160.23 on Thursday.

Botox maker Allergan launched a strategic review of its business earlier this year. CEO Brent Saunders said in March the declining stock price required the company to look at all options “with a sense of urgency.”

Still, Saunders indicated on the company’s earnings conference call last month that he did not feel a fundamental change to the company’s strategy was necessary.

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ED med, flu vax may help immune system fight cancer post surgery

A new study suggests that a common treatment for erectile dysfunction combined with the flu vaccine may be able to help the immune system mop up cancer cells left behind after surgery. The study, published in OncoImmunology, shows that this unconventional strategy can reduce the spread of cancer by more than 90 percent in a mouse model. It is now being evaluated in a world-first clinical trial.

“Surgery is very effective in removing solid tumours,” said senior author Dr. Rebecca Auer, surgical oncologist and head of cancer research at The Ottawa Hospital and associate professor at the University of Ottawa. “However, we’re now realizing that, tragically, surgery can also suppress the immune system in a way that makes it easier for any remaining cancer cells to persist and spread to other organs. Our research suggests that combining erectile dysfunction drugs with the flu vaccine may be able to block this phenomenon and help prevent cancer from coming back after surgery.”

The current study investigated sildenafil (Viagra), tadalafil (Cialis) and an inactivated influenza vaccine (Agriflu) in a mouse model that mimics the spread of cancer (metastasis) after surgery. The researchers evaluated these treatments by counting the number of metastases in mouse lungs. They found an average of:

• 37 metastases with cancer cells alone
• 129 metastases with cancer cells and surgery
• 24 metastases with cancer cells, surgery and one of the erectile dysfunction drugs
• 11 metastases with cancer cells, surgery, one of the erectile dysfunction drugs and the flu vaccine

Surgery is very effective in removing solid tumors, but researchers now know that it also changes the immune system in a way that allows tiny cancers (metastases) to grow and spread. Credit: Rebecca Auer, Lisa MacKenzie

Dr. Auer is now leading the first clinical trial in the world of an erectile dysfunction drug (tadalafil) and the flu vaccine in people with cancer. It will involve 24 patients at The Ottawa Hospital undergoing abdominal cancer surgery. This trial is designed to evaluate safety and look for changes in the immune system. If successful, larger trials could look at possible benefits to patients.

“We’re really excited about this research because it suggests that two safe and relatively inexpensive therapies may be able to solve a big problem in cancer,” said Dr. Auer. “If confirmed in clinical trials, this could become the first therapy to address the immune problems caused by cancer surgery.”

Using a variety of mouse and human models, Dr. Auer’s team has also made progress in understanding how erectile dysfunction drugs and the flu vaccine affect cancer after surgery. Normally, immune cells called natural killer (NK) cells play a major role in killing metastatic cancer cells. But surgery causes another kind of immune cell, called a myeloid derived suppressor cell (MDSC), to block the NK cells. Dr. Auer’s team has found that erectile dysfunction drugs block these MDSCs, which allows the NK cells to do their job fighting cancer. The flu vaccine further stimulates the NK cells.

“Cancer immunotherapy is a huge area of research right now, but we’re still learning how best to use it in the time around surgery,” said first author Dr. Lee-Hwa Tai, former postdoctoral fellow in Dr. Auer’s lab and now assistant professor at the Université de Sherbrooke. “This research is an important step forward that opens up many possibilities.”

Dr. Auer noted that although erectile dysfunction drugs and the flu vaccine are widely available, people with cancer should not self-medicate. Any changes in medication should be discussed with an oncologist.

More information: Lee-Hwa Tai et al, Phosphodiesterase-5 inhibition reduces postoperative metastatic disease by targeting surgery-induced myeloid derived suppressor cell-dependent inhibition of Natural Killer cell cytotoxicity, OncoImmunology(2018). DOI: 10.1080/2162402X.2018.1431082

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Antibacterial in your toothpaste may combat severe lung disease

A common antibacterial substance found in toothpaste may combat life-threatening diseases such as cystic fibrosis, or CF, when combined with an already FDA-approved drug.

Michigan State University researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, is combined with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because they are protected by a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics.

“The problem that we’re really tackling is finding ways to kill these biofilms,” said Chris Waters, lead author of the study and a microbiology professor.

According to Waters, there are many common biofilm-related infections that people get such as ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

The research is published in the journal Antimicrobial Agents and Chemotherapy.

Waters and his co-authors, Michael Maiden and Alessandra Hunt, grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

“It’s well known that triclosan, when used by itself, isn’t effective at killing Pseudomonas aeruginosa,” Hunt said, a post-doctoral associate of microbiology and molecular genetics. “But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time.”

Triclosan has been used for more than 40 years in soaps, makeup and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern that it was being overused. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

“Limiting its use is the right thing to do,” Maiden said, a graduate student in medicine. “The key is to avoid creating resistance to a substance so when it’s found in numerous products, the chances of that happening increase.”

Tobramycin is currently the most widely used treatment for CF, but it typically doesn’t clear the lungs of infection, Waters said. Patients typically inhale the drug, yet find themselves chronically infected their whole lives, eventually needing a lung transplant.

“Most transplants aren’t a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years,” he said. “The other issue is that tobramycin can be toxic itself.”

Known side effects from the drug include kidney toxicity and hearing loss.

Michigan State University microbiology professor Chris Waters (pictured left), with research associates Micheal Maiden and Alessandra Hunt, have found that a common antibacterial substance found in toothpaste may combat life-threatening …more

“Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times,” Hunt said.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won’t help to treat lung infections though, Maiden said.

“We’re working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives.”

 Explore further: Ban on triclosan shows need for new chemicals to demonstrate efficacy and safety

Journal reference: Antimicrobial Agents and Chemotherapy

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How social isolation transforms the brain

Chronic social isolation has debilitating effects on mental health in mammals—for example, it is often associated with depression and post-traumatic stress disorder in humans. Now, a team of Caltech researchers has discovered that social isolation causes the build-up of a particular chemical in the brain, and that blocking this chemical eliminates the negative effects of isolation. The work has potential applications for treating mental health disorders in humans.

The work, led by postdoctoral scholar Moriel Zelikowsky, was done in the laboratory of David J. Anderson, Seymour Benzer Professor of Biology, Tianqiao and Chrissy Chen Leadership Chair, Howard Hughes Medical Institute Investigator, and director of the Tianqiao and Chrissy Chen Institute for Neuroscience. A paper describing the research appears in the May 17 issue of the journal Cell.

Confirming and extending previous observations, the researchers showed that prolonged social isolation leads to a broad array of behavioral changes in mice. These include increased aggressiveness towards unfamiliar mice, persistent fear, and hypersensitivity to threatening stimuli. For example, when encountering a threatening stimulus, mice that have been socially isolated remain frozen in place long after the threat has passed, whereas normal mice stop freezing soon after the threat is removed. These effects are seen when mice are subjected to two weeks of social isolation, but not to short-term social isolation—24 hours—suggesting that the observed changes in aggression and fear responses require chronic isolation.

In a previous study of the Drosophila fly, the Anderson laboratory had discovered that a particular neurochemical called tachykinin plays a role in promoting aggression in socially isolated flies. Tachykinin is a neuropeptide, a short protein molecule that is released from certain neurons when they are activated. Neuropeptides bind to specific receptors on other neurons, altering their physiological properties and thereby influencing neural circuit function.

To investigate whether the role of tachykinin in controlling social isolation-induced aggression might be evolutionarily conserved from insects to mammals, Anderson’s team turned to laboratory mice. In mice, the tachykinin gene Tac2 encodes a neuropeptide called neurokinin B (NkB). Tac2/NkB is produced by neurons in specific regions of the mouse brain such as the amygdala and hypothalamus, which are involved in emotional and social behavior.

The researchers found that chronic isolation leads to an increase in Tac2 gene expression and the production of NkB throughout the brain. However, administration of a drug that chemically blocks NkB-specific receptors enabled the stressed mice to behave normally, eliminating the negative effects of social isolation. Conversely, artificially increasing Tac2 levels and activating the corresponding neurons in normal, unstressed animals led them to behave like the stressed, isolated animals.

The researchers also inhibited the function of Tac2 and its receptors in multiple specific brain regions. They found that suppressing the Tac2 gene in the amygdala eliminated the increased fear behaviors, but not aggression, while conversely suppressing the gene in the hypothalamus eliminated increased aggression but not persistent fear. The results imply that Tac2 must increase in different brain regions to produce the various effects of social isolation.

“The approach used here allowed us both to compare the effects of different manipulations of Tac2 signaling in the same brain region, as well as to compare the effects of the same manipulation across different brain regions,” says Anderson. “The rich data set generated by these experiments revealed how this neuropeptide acts globally across the brain to coordinate diverse behavioral responses to social isolation stress.”

Though the work was done in mice, it has potential implications for understanding how chronic stress affects humans.

“Humans have an analogous Tac2 signaling system, implying possible clinical translations of this work,” says Zelikowsky. “When looking at the treatment of mental health disorders, we traditionally focus on targeting broad neurotransmitter systems like serotonin and dopamine that circulate widely throughout the brain. Manipulating these systems broadly can lead to unwanted side effects. So, being able to precisely and locally modify a neuropeptide like Tac2 is a promising approach to mental health treatments.”

More information: “The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress”Cell (2018). DOI: 10.1016/j.cell.2018.03.037

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FDA Approves Amgen’s Migraine Drug

The U.S. Food and Drug Administration has approvedAmgen AMGN +0.47%’s erenumab (which it’s calling Aimovig) to prevent migraines.

“We feel pretty strongly this is a huge opportunity to help patients with a targeted, migraine specific medication that’s broadly efficacious, and can be administered in a patient-friendly way,” said Rob Lenz, VP, development at Amgen who lead the development of Aimovig. The drug’s list price is $6,900 per year, or $575 per monthly injected dose, lower than many market-watchers expected. Amgen is commercializing Aimovig with Novartis in the U.S.

That Aimovig is the first drug approved in a new class of migraine drugs targeting a protein called CGRP class is “key,” Cowen analyst Steve Scala wrote in a note to clients earlier this week, “as there will likely be several competitors and differentiation does not appear substantial.”

The competition: Alder Biopharmaceuticals’ eptinezumab (an infusion patients get every three months), Lilly’s galcanezumab (a monthly injection) and Teva’s fremanezumab (a monthly or quarterly injection). Lenz emphasized Aimovig’s convenience for patients as a once-a-month injection, and that the drug proved effective in people who have migraines at least four days a month, people who have migraines at least half the days out of a month, and people who tried at least two migraine-prevention drugs before to no avail.

“Aimovig provides patients with a novel option for reducing the number of days with migraine,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We need new treatments for this painful and often debilitating condition.”

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Inappropriate, Omitted Rx Common at Discharge for Older Adults

Potentially unsafe prescriptions are common at the time of discharge for older patients, according to a new study, with 83.8% of patients receiving at least one potentially inappropriate medication (PIM) or having a potential prescribing omission (PPO).

Patients with at least one PIM were significantly more likely to experience three or more readmissions, and those with at least one PPO were significantly more likely to die during the study follow-up.

“The study provides good evidence that older patients are often prescribed potentially harmful medications, and there are missed opportunities for prescribing medications that would be beneficial,” said Andrew Dunn, MD, MPH, FACP, SFHM, who was not involved in the study. Dunn is chair of the American College of Physicians Board of Regents and professor of medicine, chief, Division of Hospital Medicine, Department of Medicine, Mount Sinai Health System, New York City.

David Counter, MBChB, from the NHS Grampian Aberdeen Royal Infirmary in, Aberdeen, United Kingdom, and colleagues report their findings online May 10 in the British Journal of Clinical Pharmacology.

The Screening Tool of Older Person’s Prescriptions/Screening Tool to Alert Doctors to the Right Treatment (STOPP/START) criteria were published in 2008 and are widely used in Europe. They were updated in 2014 to include 80 STOPP criteria and 34 START criteria. Additions to the STOPP criteria cover antiplatelet/anticoagulant medications, medications that affect or are affected by renal function, and medications that raise anticholinergic burden. Added START categories include urogenital system medications, analgesic drugs, and vaccines.

“PIMs and PPOs identified using this tool have been associated with increased frequency of adverse drug reactions, increased morbidity and mortality and reduced quality of life,” Counter and colleagues explain. “Interventional studies applying these criteria to reduce PIMs and PPOs have reported reduced incidence of [adverse drug events], falls, and delirium with reduced duration of hospitalisation and healthcare costs.”

To determine the association between PIMs and PPOs and hospital readmission and mortality rates among older adults, the researchers conducted a retrospective study using the updated criteria. They examined data on consecutive emergency admissions of 259 patients (mean age, 77 years; range, 65 – 97 years; 51% women) to a hospital medical ward during an 8-month period, with a mean follow-up duration of 41.5 months (standard deviation [SD], 2.0; range, 38 – 46 months).

At discharge, patients had a mean of 5.4 comorbidities (SD, 2.1; range, 0 – 14 comorbidities). Patients were prescribed a mean of 9.3 distinct medications at discharge (SD, 4.0; range, 1 – 31 medications), with 88.8% (n = 230) receiving five or more distinct medications and 44% (n = 114) receiving 10 or more distinct medications.

Patients had a median number of two readmissions (interquartile range, 1 – 4), and just more than half (50.2%; n = 130) died during follow-up.

After adjusting for demographic and outcome variables, patients who had more than five medications prescribed were more than twice as likely to have PIMs (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.34 – 5.62), and more than threefold as likely to have PPOs (OR, 3.20; 95% CI, 1.57 – 6.54), compared with patients who had fewer than five medications.

PIMs and PPOs were tied to worse patient outcomes. Specifically, those who had a PIM were twice as likely to have three or more hospital readmissions (OR, 2.43; 95% CI, 1.19 – 4.98; P < .05), and those with PPOs were also significantly more likely to die (OR, 1.88; 95% CI, 1.09 – 3.27; P < .05) overall.

After adjustment, patients who received prescriptions for more than five medications at discharge were five times more likely to experience at least one potentially inappropriate prescription (PIP; OR, 5.86; 95% CI, 2.56 – 13.39; P < .001). Those who had one or more PIP were also significantly more likely to die during the follow-up period (OR, 2.51; 1.20 – 5.28; P = .015).

The reasons for the increased mortality are unclear. “[H]owever it is possible that the failure to commence evidence based therapies may result in increased morbidity and mortality or that in a population with high inherent mortality and poor prognosis prescribers are less willing to add to their medication burden,” the researchers explain.

“[S]ometimes it is hard to disentangle if it’s medications that are causing the problem, the kind of access to higher-quality primary care that’s the problem, or the underlying issues around psychiatric illness or pain which cause these problems. [T]hose are all very tightly interrelated and hard to disentangle in the observational study,” Andrew Auerbach, MD, MPH, editor-in-chief, Journal of Hospital Medicine, and professor of medicine, University of California, San Francisco, School of Medicine, told Medscape Medical News.

Clinical Judgement Critical, Experts Say

Most physicians use their clinical judgment, rather than strict criteria alone. “The Beers criteria are helpful and can be used for older adults; however, they may not apply well to all patients. For example, an older adult with no comorbidities and excellent functional status may tolerate a medication on the list better than a patient with multiple severe comorbidities,” Dunn explained.

“Many clinicians pay close attention to the medications they prescribe to older adults, but there is a lack of a standardized process to reduce the risks of overprescribing and underprescribing,” he added.

Auerbach concurred. It is true that there is no standard algorithm, “because there’s probably multiple algorithms based on whether it’s a patient with chronic pain or patients with difficult-to-control thought disorders or refractory depression. A lot the medications that you use for all those are on the list of potentially inappropriate medications from Beers and STOPP/START. That’s where you have to start using clinical judgment,” he said.

Auerbach said in some cases, a patient’s primary physician may have put them on a “third- or fourth-line medication” after trying others that were ineffective or had intolerable adverse effects, and the patient may have taken that medication for a long time with good results.

That said, the authors emphasize that their findings are clinically important. “Applying version 2 of the STOPP/START criteria to a population of older adults before discharge from hospital identifies those at high risk of readmission and death who may benefit from interventions to reduce PIMs and PPOs,” the researchers conclude.

“We now need studies that rigorously assess whether applying these criteria prior to discharge can help physicians provide better care and improve patient outcomes,” Dunn said.

The authors have disclosed no relevant financial relationships. Dunn and Auerbach have disclosed no relevant financial relationships.

Br J Clin Pharmacol. Published online May 10, 2018. Abstract

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