Category Archives: Nephrology

AZ’s potassium drug Lokelma finally approved in US

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AstraZeneca badly needs new drugs on the market as several former blockbusters have been hit by generic competition – and finally its high potassium treatment Lokelma has been approved by US regulators.

The drug, a highly selective potassium-removing agent, has been approved at the third time of asking by the FDA, which had been concerned about issues at its manufacturing plant in Texas.

European regulators approved the drug formerly known as ZS-9 in March after their concerns over the issues were resolved, and after two previous rejections the US regulator is also satisfied with the technical arrangements at the facility.

AZ gained rights to the drug after buying ZS Pharma in 2015 for $2.7 billion and is designed to treat hyperkalaemia, where high potassium levels threaten kidney and heart function.

Lokelma (sodium zirconium cyclosilicate) will compete with Vifor Pharma group member Relypsa’s rival Veltassa (patiromer), which has been on the market for a few years in the US and Europe.

The Anglo-Swedish pharma has predicted sales in excess of $1 billion annually for ZS-9, although some analysts say this is a conservative estimate.

The risk of hyperkalaemia increases significantly for patients with chronic kidney disease (CKD) and for those who take common medications for heart failure (HF), such as renin-angiotensin-aldosterone system (RAAS) inhibitors, which can increase potassium in the blood.

To help prevent the recurrence of hyperkalaemia, RAAS-inhibitor therapy is often modified or discontinued, which can compromise cardio-renal outcomes and increase the risk of death.

Sean Bohen, chief medical officer at AstraZeneca, said: “The consequences of hyperkalaemia can be very serious and it’s reassuring for treating physicians that Lokelma has demonstrated lowering of potassium levels in patients with chronic kidney disease, heart failure, diabetes and those taking RAAS inhibitors.”

AZ badly needs the new sales – sales of its Crestor (rosuvastatin), a former blockbuster were down 38% in Q1, to $338 million, and overall revenues fell 4% to just under $5.2 billion.

The company is selling off its old and unwanted drugs to prop up revenues and reduce costs – but this can only be seen as a short-term measure before new revenues come on stream.

CEO Pascal Soriot also faces a shareholder revolt, after more than 37% of shareholders voted against or abstained at the firm’s annual meeting when asked to approve a £9.4m pay package for Soriot, down from £14.3 million last year.

Soriot has set a sales target of above $40 billion by 2023, despite the struggles getting new drugs to the market.


Oral antibiotics may raise risk of kidney stones

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Paediatric researchers have found that children and adults treated with some oral antibiotics have a significantly higher risk of developing kidney stones.

This is the first time that these medicines have been linked to this condition. The strongest risks appeared at younger ages and among patients most recently exposed to antibiotics.

“The overall prevalence of kidney stones has risen by 70 percent over the past 30 years, with particularly sharp increases among adolescents and young women,” said study leader Dr Gregory E. Tasian, a paediatric urologist at Children’s Hospital of Philadelphia (CHOP). Dr Tasian noted that kidney stones were previously rare in children.

Study co-author Dr Michelle Denburg, a paediatric nephrologist at CHOP, added, “The reasons for the increase are unknown, but our findings suggest that oral antibiotics play a role, especially given that children are prescribed antibiotics at higher rates than adults.”

The study team drew on electronic health records from the United Kingdom, covering 13 million adults and children seen by general practitioners in the Health Improvement Network between 1994 and 2015. The team analysed prior antibiotic exposure for nearly 26,000 patients with kidney stones, compared to nearly 260,000 control subjects.

They found that five classes of oral antibiotics were associated with a diagnosis of kidney stone disease. The five classes were oral sulfas, cephalosporins, fluoroquinolones, nitrofurantoin, and broad-spectrum penicillins. After adjustments for age, sex, race, urinary tract infection, other medications and other medical conditions, patients who received sulfa drugs were more than twice as likely as those not exposed to antibiotics to have kidney stones; for broad-spectrum penicillins, the increased risk was 27 percent higher.

The strongest risks for kidney stones were in children and adolescents. The risk of kidney stones decreased over time but remained elevated several years after antibiotic use.

Scientists already knew that antibiotics alter the composition of the human microbiome–the community of microorganisms in the body. Disruptions in the intestinal and urinary microbiome have been linked to the occurrence of kidney stones, but no previous studies revealed an association between antibiotic usage and stones.

Dr Tasian pointed out that other researchers have found that roughly 30 percent of antibiotics prescribed in office visits are inappropriate, and children receive more antibiotics than any other age group, so the new findings reinforce the need for clinicians to be careful in prescribing correct antibiotics. He added, “Our findings suggest that antibiotic prescription practices represent a modifiable risk factor–a change in prescribing patterns might decrease the current epidemic of kidney stones in children.”

One co-author of the current paper Dr Jeffrey Gerber, is an infectious diseases specialist at CHOP who leads programs in antibiotic stewardship–an approach that guides health care providers in prescribing the most appropriate antibiotic for each patient’s specific infection, with the aims of improving individual outcomes and reducing the overall risk of antibiotic resistance.

Dr Tasian and colleagues are continuing to investigate the microbiomes of children and adolescents with kidney stones in a single-centre study at CHOP. Their goal is to expand this research into broader, population-based studies to better understand how variations in microbiome composition may influence the development of kidney stones.


Merck, Eisai sign deal to further develop, sell Eisai cancer drug

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Merck & Co and Japan’s Eisai Co Ltd on Wednesday announced a potential multibillion-dollar collaboration to develop and sell Eisai’s cancer drug Lenvima, which is already approved in many countries for two uses.

The deal, under which Lenvima will be developed for several types of cancer alone and in combination with Merck’s immunotherapy Keytruda, could be worth up to $5.76 billion to Eisai, but most of that would be contingent on eventual sales.

Meanwhile, Merck will be entitled to half of all global Lenvima sales, even for its already-approved uses for thyroid cancer and in combination with another drug for kidney cancer.

The deal is similar to a multibillion-dollar oncology collaboration Merck struck with AstraZeneca Plc last July.


Improving healthcare has led to a higher salt requirement

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The number of dialysis treatments is increasing across the globe, mainly due to an increasing number of patients and improved healthcare in many developing countries.

The main market for pharmaceutical grade salt lies in dialysis solutions. Supply has struggled to keep up with demand, which led to AkzoNobel expanding its production site in Denmark.

AkzoNobel’s Specialty Chemicals business completed the expansion of its production site, which supplies pharmaceutical grade salt to the healthcare industry, increasing capacity by 60%.

Located in Mariager, the products supplied by the facility are used as an active pharmaceutical ingredient in various applications, including intravenous solutions, insulin and baby food.

“Our facility produces the purest salt in the world,” said Nils van der Plas, General Manager of AkzoNobel’s Salt business, “this expansion will now enable us to serve a strong growing market worldwide.

“Following a year of detailed engineering, construction and testing, the Mariager site is now well positioned to continue capturing the organic dialysis market developments. This specific market is growing globally by 7 to 8% per year and is expected to continue growing at this pace for at least another generation.”

In addition to dialysis, pharmaceutical grade salt is also used as a base material for liquid medications and dietary formulations.


J&J seeks US OK to add cardiovascular claim to Invokana label

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Johnson & Johnson has moved swiftly ahead with a filing for its diabetes drug Invokana that would include a claim that it can reduce major adverse cardiovascular events (MACE).

The filing is based on the results of the CANVAS trial, which showed that its SGLT2 inhibitor Invokana (canagliflozin) was able to reduce the combined risk of cardiovascular death, myocardial infarction and stroke by 14% compared to placebo in at-risk patients with type 2 diabetes, and also cut the risk of hospitalisation for heart failure by a third.

J&J’s pharma division Janssen is trying to get the cardiovascular outcome claim added to Invokana and its combination products Invokamet and Invokamet XR (canagliflozin and metformin), and if it succeeds will be able to make a strong case for its product to prescribers and payers. Adults with type 2 diabetes are four times more likely to develop cardiovascular disease, and this is the leading cause of death in these patients.

If the FDA approves the label, Invokana could be able to match rival SGLT2 inhibitor Jardiance (empagliflozin) from Eli Lilly and Boehringer Ingelheim, which had cardiovascular outcomes data added to its label in the wake of the EMPA-REG study, as well as Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) which was given a cardiovascular disease reduction indication in August.

“People with type 2 diabetes have a substantially increased risk of developing cardiovascular disease, and it’s encouraging that we now have data to show Invokana may help address this challenge,” said Janssen’s head of cardiovascular and metabolism James List. “Invokana has shown a clear benefit in reducing cardiovascular risk in adults with type 2 diabetes and we look forward to working with FDA as it reviews our filing.”

One issue that could hold back J&J’s Invokana franchise is that of a higher risk of leg and foot amputations, with the FDA requiring a black box warning – its most prominent – on the products’ label earlier this year. The US regulator’s current thinking is that this has only been confirmed with canagliflozin, although the EMA recently suggested that while this has not been seen with other SGLT2 inhibitors, doctors and patients should be vigilant with all drugs in the class.

Analysts have suggested that cardiovascular outcomes data could boost peak sales of Jardiance by up to $1.7bn, and that the amputation issue with Invokana could mean that Lilly and Boehringer’s drug has the most to gain from cardiovascular labelling, threatening Invokana’s current market-leading position. J&J counters that it was only because CANVAS was such a big programme that the safety signal was able to be observed

J&J is hoping to tilt the balance in its favour with a large-scale trial called CREDENCE that will try to show a benefit for Invokana on renal damage in type 2 diabetes – something that was shown in the CANVAS-R companion trial – but Lilly and Boehringer have designs in that area too with an outcomes trial planned for Jardiance in chronic kidney disease patients both with and without diabetes.

AstraZeneca and Pfizer/Merck & Co are the laggards in the category, with AZ not expecting prospective cardiovascular outcomes data for Farxiga(dapagliflozin) until 2019 and Pfizer and Merck still waiting for approval of their ertugliflozin-based products.