Boehringer, Lilly’s Jardiance ties to match AZ’s Farxiga with heart failure label

Boehringer and Eli Lilly have moved closer to a heart failure indication for their SGLT2 inhibitor Jardiance, as the FDA starts a fast-track review of the drug in its first use beyond diabetes.

The US regulator is looking at data from the EMPEROR-Reduced trial of Jardiance (empagliflozin), which found that the drug achieved a 25% reduction in the combined primary endpoint of cardiovascular death or hospitalisation compared to placebo.

Lilly and Boehringer claim almost 60% market share for Jardiance among SGLT2 drugs used to treat type 2 diabetes, driving blockbuster sales for the brand.

It was the top-selling drug in the SGLT2 inhibitor class in 2019, with sales of almost $3 billion, helped by side-effect problems that have afflicted first-to-market rival Invokana (canagliflozin) from Johnson & Johnson.

However its rivals – which also include AstraZeneca’s Farxiga (dapagliflozin)  – have moved more swiftly into areas like heart failure and chronic kidney disease (CKD) which have made large numbers of new patients eligible for treatment with the class.

The new FDA review – covering Jardiance as a treatment for adults with heart failure with reduced ejection fraction (HFrEF) in patients with and without diabetes – is Lilly and Boehringer’s first chance to fight back.

Farxiga won FDA approval for adults with HFrEF in May 2020, which helped to drive its third-quarter sales up by a third to $525 million. AZ picked up EU approval for the same indication the following November.

Lilly and Boehringer will be hoping for a swift FDA review so that Jardiance will not fall too far behind its competitor in the heart failure category, and that looks likely as the benefit in HFrEF increasingly appears to be an SGLT2 class effect.

GlobalData has said that heart failure could add billions to the sales of the two SGLT2 inhibitors, particularly if they also claim approvals in heart failure with preserved ejection fraction (HFpEF), a larger patient population.

It says Farxiga will reach peak sales of $9 billion in 2028, with Jardiance forecast to reach $4.6 billion, assuming a launch for HFrEF this year. The bulk of those sales will come from HFpEF, however,  as in this form of heart failure there is a huge unmet need and no approved therapies.

Boehringer and Lilly are waiting for the results of the EMPEROR-Preserved later in 2021, while AZ should also Farxiga in the DELIVER trial in HFpEF, with additional data on both HFrEF and HFpEF due from the DETERMINE study, before year-end.

Meanwhile, EMPEROR-Reduced also showed a slowdown in the rate of decline in kidney function among patients with HFrEF, an effect that Lilly and Boehringer are exploring in the CKD patient population in the EMPA-KIDNEY trial due to generate results in 2022.

Invokana was the first mover among the SGLT2 drugs in the kidney area, winning FDA approval towards the end of 2019 for diabetic kidney disease. After a couple of years of declining sales due to concern about a risk of lower limb amputation, Invokana managed a 25% gain to $224 million in third-quarter 2020.

Farxiga meanwhile has already been filed for CKD on the back of the DAPA-CKD trial, with a verdict due in the second quarter.

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NICE backs AZ’s Forxiga for heart failure

Just a few weeks after its EU approval for heart failure, AstraZeneca’s Forxiga has been backed by NICE for this use by the NHS in England and Wales.

Forxiga (dapagliflozin) – originally developed as a type 2 diabetes drug – is the first SGLT2 inhibitor to be approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) in adults with and without diabetes.

It got a green light for this use in the EU in early November and in the US in May, with the new indication helping to drive third-quarter sales up by a third to $525 million.

Approval for Farxiga was based on positive results from the phase 3 DAPA-HF trial, which showed Farxiga achieved a statistically significant and clinically meaningful 26% reduction of death or hospitalisation for heart failure compared with placebo.

Today, NICE issued draft guidance which recommends Forxiga as an option for treating symptomatic HFrEF in adults if used as an add-on to standard drugs, which would make around 260,000 additional people eligible for treatment with the drug.

Novartis’ Entresto (sacubitril/valsartan) is also used to treat HFrEF, an indication which propelled it to sales of almost $2 billion last year.

According to NICE, while there are no head-to-head trials comparing Entresto and Forxiga, AZ’s drug “is likely to be as effective as [Entresto] at reducing the risk of death from heart disease

AZ’s rivals Eli Lilly and Boehringer Ingelheim meanwhile are also attempting to develop their SGLT2 inhibitor Jardiance (empagliflozin) for heart failure. They suffered a setback a year ago when the drug failed to improve exercise ability in two phase 3 studies, but bounced back with the results of the EMPEROR-Reduced study in July.

GlobalData has said that heart failure could add billions to the sales of the two SGLT2 inhibitors, particularly if they also claim approvals in heart failure with preserved ejection fraction (HFpEF), a larger patient population. It says Farxiga will reach peak sales of $9 billion in 2028, with Jardiance forecast to reach $4.6 billion, assuming a launch for HFrEF in 2021.

AZ is also putting Forxiga through its paces in heart failure in combination with other drugs, including its mineralocorticoid receptor modulator AZD9977 and selective endothelin A antagonist zibotentan (also known as AZD4054), with mid-stage trials on the go.

Meanwhile, heart failure is just one area into which AZ is hoping to expand Forxiga before its patents start to expire in the coming years. It’s also looking at chronic kidney disease (CKD), and has picked up a breakthrough designation from the FDA for this indication.

Forxiga was the first medicine to significantly prolong survival in patients with CKD, either with or without diabetes, in the DAPA-CKD trial.

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Entresto set for big sales hike after FDA panel endorsement

Novartis’ Entresto is on course to become the first drug to be approved in the US for a form of heart failure that is notoriously hard to treat effectively, despite missing the mark in a phase 3 trial.

An FDA advisory committee 12 to 1 in favour of approving Entresto (sacubitril/valsartan) for heart failure with preserved ejection fraction (HFpEF), which accounts for around half of all heart failure cases but proves highly resistant to drug treatment. In HFpEF, the heart muscles pump normally but the organ is too stiff to fill properly.

Entresto is already approved to treat heart failure with reduced ejection fraction (HFrEF), caused by the heart muscles not pumping effectively, and has revitalised the treatment of patients with this form since its launch in 2015.

After a slow start, it has grown to become a $1.7 billion product last year, and that represented a surge from around $1 billion in 2018 revenues.

Analysts have predicted that approval in HFpEF – which affects around 3 million people in the US alone – could more than double Entresto’s sales, perhaps driving them as a high as $5 billion a year. There’s also plenty of upside in HFrEF as three out of four eligible patients are still not being treated with the drug, according to Novartis.

The prospect of adding HFpEF to Entresto’s label looked shaky last year however, when the drug missed its primary objective in the phase 3 PARAGON-HF trial.

The 4,822-patient study missed statistical significance for a composite primary endpoint of reducing cardiovascular death and total heart failure hospitalisations by 13% compared with valsartan alone, but only by a whisker, and Novartis has been upbeat since about the chances of approval.

The published data from the study suggested that the drug performed better in women, people with structural abnormalities in the left ventricles of their hearts, and those with very low ejection fractions – the amount of blood pushed out of the heart each beat.

The positive vote by FDA advisors came after the FDA reviewer acknowledged the narrow miss for statistical significance and pointed to the pressing need for a drug treatment for HFpEF.

The agency’s own expert said that “various pre-specified and post-hoc analyses suggest that sacubitril/valsartan compared to valsartan reduces HF events” in HFpEF, and of course Entresto’s long track record of safety stands in its favour.

While the FDA doesn’t have to follow its advisory committee’s advice it generally does, and Novartis is now eyeing approval of Entresto in HFpEF in the first quarter of 2021.

The main question now is exactly how the FDA will word the label if it approves the drug, with panellists debating the use of ejection fractions percentages to guide treatment with little agreement.

PARAGON-HF in included patients with left ventricular ejection fraction (LVEF) of 45% or more, but earlier studies have suggested the drug can have a benefit in people with scores below 40%.

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Kidney Toxins Created by Meat Consumption

As I discuss in my video How to Treat Heart Failure and Kidney Failure with Diet, one way a diet rich in animal-sourced foods like meat, eggs, and cheese may contribute to heart disease, stroke, and death is through the production of an atherosclerosis-inducing substance called TMAO. With the help of certain gut bacteria, the choline and carnitine found concentrated in animal products can get converted into TMAO. But, wait a second. I thought atherosclerosis, or hardening of the arteries, was about the buildup of cholesterol. Is that not the case?

“Cholesterol is still king,” but TMAO appears to accelerate the process. It seems that TMAO appears to increase the ability of inflammatory cells within the atherosclerotic plaque in the artery walls to bind to bad LDL cholesterol, “which makes the cells more prone to gobble up cholesterol.” So TMAO is just “another piece to the puzzle of how cholesterol causes heart disease.”

What’s more, TMAO doesn’t just appear to worsen atherosclerosis, contributing to strokes and heart attacks. It also contributes to heart and kidney failure. If you look at diabetics after a heart attack, a really high-risk group, nearly all who started out with the most TMAO in their bloodstream went on to develop heart failure within 2,000 days, or about five years. In comparison, only about 20 percent of those starting out with medium TMAO levels in the blood went into heart failure and none at all in the low TMAO group, as you can see at 1:21 in my video.

So, those with heart failure have higher levels of TMAO than controls, and those with worse heart failure have higher levels than those with lesser stage heart disease. If you follow people with heart failure over time, within six years, half of those who started out with the highest TMAO levels were dead. This finding has since been replicated in two other independent populations of heart failure patients.

The question is, why? It’s probably unlikely to just be additional atherosclerosis, since that takes years. For most who die of heart failure, their heart muscle just conks out or there’s a fatal heart rhythm. Maybe TMAO has toxic effects beyond just the accelerated buildup of cholesterol.

What about kidney failure? People with chronic kidney disease are at a particularly “increased risk for the development of cardiovascular disease,” thought to be because of a diverse array of uremic toxins. These are toxins that would normally be filtered out by the kidneys into the urine but may build up in the bloodstream as kidney function declines. When we think of uremic toxins, we usually think of the toxic byproducts of protein putrefying in our gut, which is why specially formulated plant-based diets have been used for decades to treat chronic kidney failure. Indeed, those who eat vegetarian diets form less than half of these uremic toxins.

Those aren’t the only uremic toxins, though. TMAO, which, as we’ve discussed, comes from the breakdown of choline and carnitine found mostly in meat and eggs, may be increasing heart disease risk in kidney patients as well. How? “The cardiovascular implication of TMAO seems to be due to the downregulation of reverse cholesterol transport,” meaning it subverts our own body’s attempts at pulling cholesterol out of our arteries.

And, indeed, the worse our kidney function gets, the higher our TMAO levels rise, and those elevated levels correlate with the amount of plaque clogging up their arteries in their heart. But once the kidney is working again with a transplant, your TMAO levels can drop right back down. So, TMAO was thought to be a kind of biomarker for declining kidney function—until a paper was published from the Framingham Heart Study, which found that “elevated choline and TMAO levels among individuals with normal renal [kidney] function predicted increased risk for incident development of CKD,” chronic kidney disease. This suggests that TMAO is both a biomarker and itself a kidney toxin.

Indeed, when you follow kidney patients over time and assess their freedom from death, those with higher TMAO, even controlling for kidney function, lived significantly shorter lives, as you can see at 4:44 in my video. This indicates this is a diet-induced mechanism for progressive kidney scarring and dysfunction, “strongly implying the need to focus preventive efforts on dietary modulation,” but what might that look like? Well, maybe we should reduce “dietary sources of TMAO generation, such as some species of deep-sea fish, eggs, and meat.”

It also depends on what kind of gut bacteria you have. You can feed a vegan a steak, and they still don’t really make any TMAO because they haven’t been fostering the carnitine-eating bacteria. Researchers are hoping, though, that one day, they’ll find a way to replicate “the effects of the vegetarian diet…by selective prebiotic, probiotic, or pharmacologic therapies.”


For more on this revolutionary TMAO story, see:

For more on kidney failure, see Preventing Kidney Failure Through Diet and Treating Kidney Failure Through Diet.

In health,

Michael Greger, M.D.

PS: If you haven’t yet, you can subscribe to my free videos here and watch my live presentations:

AZ’s Q3 results disappoint – but COVID19 vaccine trial is still on track

AstraZeneca has posted an uninspiring set of quarterly results as it gears up for results from its closely watched coronavirus vaccine trial.

AZ said in its third quarter results statement that it is on track to meet its guidance for the year, with total revenue expected to grow by 8%-12% and core earnings per share increasing by 15%-19%.

In the three months to the end of September AZ’s revenue increased by 3% to $6.6 billion, with products sales up 6%.

Earnings per share fell to $0.94, missing analysts’ estimates of $1, as some patients held off treatments for ailments unrelated to COVID-19.

AZ has pursued a strategy of selling off its older or unwanted drugs and has been benefiting from “collaboration revenue” from these deals as development partners reach certain milestones.

This revenue fell by 79% to $58 million compared with the same quarter last year, although the company said that this was down to a strong performance in last year’s Q3.

The company suggested that collaboration revenue may be higher in the next quarter as this income tends to come in chunks as various research projects reach fruition or sales targets are met.

At the same time the company also grabbed two new European approvals – for Lynparza in castration-resistant prostate cancer and for Forxiga for a form chronic heart failure.

The company’s coronavirus vaccine is perhaps the company’s most eagerly-watched pipeline asset, although AZ is unlikely to make much money from it – at least until the worst of the pandemic is over.

As reported by pharmaphorum earlier this week, AZ expects results from its late-stage trial by the end of the year despite a safety scare in September, setting up approval by regulators early in 2021.

AZ has pledged to sell the vaccine at cost price until a cut-off point expected midway through next year.

But as the UK heads for another economically damaging month-long lockdown the company confirmed that it could have crucial phase 3 data from the vaccine by the end of the year.

If approved the vaccine will do little for the company’s figures but will create huge goodwill as governments across the world seek an end to the spiral of death caused by the coronavirus.

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Boehringer, Yale trial digital tech in heart failure

Patients with heart failure often have a dismal prognosis as the condition usually worsens over time, but a new study aims to see if digital health technologies can improve their prospects.

The trial – run by Boehringer Ingelheim and Yale University – will test a smart bathroom scale device that has cardiac monitoring built in, as well as an app to help patients improve their diet and lose weight and a digital assistant designed to motivate them to actively manage their health.

The investigators hope the digital tools will encourage people with heart failure to make and adhere to changes in their lifestyle that will improve “patient outcomes, clinical efficiencies and…quality of life.”

If it works, the approach could have a significant impact on the care of people with heart failure, which is a massive problem worldwide. In the US alone there are six million people with failing hearts, leading to a million hospitalisations each year.

The 200-patient study will look at each of the three digital technologies separately, added to standard care for heart failure, and see how they perform compared to standard care alone over a six-month period.

The primary endpoint of the study is improvement in quality of life assessed by a scale known as the KCCQ survey, with secondary measures including the number of hospitalisations, treatment prescribing rates and mortality.

Crucially, given the ongoing pandemic, all the digital technologies can be used in the home, so there will be no need for anything more than the regular follow-ups in clinic for the enrolled subjects.

Perry Wilson

“Our digital health study…will move beyond evaluating if these tools work and establish if they actually help make patients’ lives better, which is how these technologies should be judged,” said Yale professor of medicine Perry Wilson, one of the study investigators.

“The health of heart failure patients can change quickly, and these tools can help healthcare providers intervene before serious complications lead to hospitalisations, alleviating our overburdened healthcare system,” he added.

Boehringer is already an investor in the smart scale – called Bodyport – as the pharma company led the start-up’s $11 million first-round financing in August. The device is designed to detect cardiac signals and biomarkers through a user’s feet, rather than relying on wearables.

The live coaching app, Noom, provides personalised diet and weight management advice and its developers have also previously partnered with Novo Nordisk on a programme designed to help people struggling with obesity.

Finally, the motivational tool – Conversa – is an automated conversational platform that its developers say uses artificial intelligence and behavioural science methodology to encourage patient engagement.

The tool is already being used by hundreds of hospitals in the US to help manage chronic care, acute discharge, perioperative, cancer treatment and COVID-19, according to the company.

“We launched this study with Yale to help identify how digital health technology may address some of the key pain points for adults with heart failure, like the need for more frequent communication with healthcare providers in between visits and coaching to help with the daily management of the condition,” said Christine Marsh, Boehringer’s senior vice president, market access.

Results from the study are due next year, according to the investigators.

Heart failure has become a hot topic for study of digital interventions, in part because of the slow progression of the condition also because adherence to treatment and lifestyle interventions is closely linked to how well patients fare.

Johnson & Johnson for example is deploying wearables and smartphone apps in the CHIEF-HF trial of its Invokana (canagliflozin) in heart failure patients.

Amgen meanwhile is sponsoring a study in the US to investigate whether wearables can help physicians monitor changes in heart failure patients’ conditions so they can get the optimal doses of medications.

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Amgen Report Mixed Results of Omecamtiv Mecarbil in P-lll GALACTIC-HF Study for Heart Failure

Shots:

  • The P-lll GALACTIC-HF study involves the assessing of Omecamtiv mecarbil (25mg, bid with the maintenance dose of 50 mg, 37.5mg, or 25mg, bid) vs PBO in 8,256 patients with HFrEF
  • Result: The study met its 1EPs of reduction in CV death or HF events (HF hospitalization and other urgent treatment for HF) while the study did not meet its 2EPs of reduction in time to CV death, presented at AHA 2020
  • Omecamtiv mecarbil is a cardiac myosin activator, targeting the contractile mechanisms of the heart, being developed under a collaboration between Amgen and Cytokinetics, with funding and strategic support from Servier

    Click here ­to­ read full press release/ article | Ref: Amgen | Image: The Times

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Amgen shares down as heart failure drug disappoints in phase 3 trial

Shares in Amgen were down nearly 7% after close of trading yesterday after the company’s heart failure drug omecamtiv mecarbil disappointed in a large phase 3 trial.

Take a look at Amgen’s portfolio and it becomes apparent how important this potential new drug is: the company is relying on its ageing inflammatory diseases drug Enbrel for a large chunk of its revenue.

It is also hoping to steal market share from rivals with biosimilars, which are comparatively cheaper versions of biologic drugs.

Psoriasis drug Otezla is also bringing in the bucks – but Amgen paid $13.4 billion for this after Celgene was forced to sell it as a condition of its merger with Bristol-Myers Squibb.

Amgen looks in need of fresh home-grown revenues, but investors don’t think these will come from omecamtiv mecarbil, based on the findings of the phase 3 GALACTIC-HF trial.

The trial met its primary endpoint by demonstrating a statistically significant effect to reduce cardiovascular death or heart failure events compared with placebo in patients treated with standard care.

But there was no reduction in the secondary endpoint measuring only cardiovascular death in the trial, which with 8,256 patients with reduced ejection fraction in 35 countries is one of the largest phase 3 cardiovascular outcomes studies in heart failure ever conducted.

Adverse events, including major ischemic cardiac events, were balanced between treatment arms, Amgen said.

With such a large cohort of subjects, Amgen and partners Cytokinetics and Servier have nowhere to hide – they cannot claim the trial was not powered to produce a result against this important secondary endpoint measuring the impact on mortality.

Merck & Co and Bayer are trying to develop a rival heart failure drug in patients with reduced ejection fraction, vericiguat, but that has also produced similar results, scoring against a composite measure of deaths and hospitalisation but failing to outperform placebo at reducing deaths.

Developed by Cytokinetics, omecamtiv mecarbil is a cardiac myosin activator that works by increasing interactions between filaments in the heart muscle to improve its pumping.

Amgen has been working on the drug with Cytokinetics since 2006, and Servier bought European rights in 2013.

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Study puts Jardiance in hot pursuit of AZ’s Farxiga in heart failure

The FDA’s approval of AstraZeneca’s SGLT2 inhibitor Farxiga in heart failure was a first for the class, but Boehringer Ingelheim and Eli Lilly are closing the gap with a positive pivotal trial for their rival drug Jardiance.

Top-line data from the phase 3 EMPEROR-Reduced study have shown that Jardiance (empagliflozin) beat out placebo on the primary objective of reducing death and hospitalisation rates in heart failure patients with and without diabetes.

The study was carried out in heart failure patients with reduced ejection fraction (HFrEF), the same group for which AZ claimed an FDA approval for Farxiga (dapagliflozin) in May.

Boehringer and Lilly now plan to present the data from EMPEROR-Reduced at the European Society of Cardiology (ESC) congress next month, and start filing for approval of Jardiance for HFrEF before the end of the year.

Jardiance was the top-selling drug in the SGLT2 inhibitor class with sales of almost $3 billion last year helped by side-effect problems that have afflicted Johnson & Johnson’s first-to-market Invokana (canagliflozin).

Farxiga has been gaining ground quickly however, with sales topping $1.5 billion in 2019 and growing another 20% in the first half of 2020, despite the impact of the coronavirus pandemic.

“The results of the EMPEROR-Reduced trial indicate that SGLT2 inhibitors have the potential to become a new standard of care for this disease, which will be a meaningful addition to currently established treatments,” said lead investigator Milton Packer of Baylor University Medical Center in Dallas.

Analysts at GlobalData have suggested that heart failure could add billions to the sales of the two SGLT2 inhibitors, particularly if they also claim approvals in heart failure with preserved ejection fraction (HFpEF), a larger patient population.

GlobalData has predicted that Farxiga will reach peak sales of $9 billion in 2028, while Jardiance is forecast to reach $4.6 billion, assuming a launch for HFrEF in 2021.

The bulk of those sales will come from HFpEF, which has “a huge unmet need and no specific standard of care,” it says.

AZ will however start losing patent protection for its drug in the coming years, depending on the outcome of patent litigation, so the launch of generics could rein in the SGLT2 market.

There have been numerous trial failures in HFpEF in recent years, including Novartis’ big selling heart failure therapy Entresto (sacubitril/valsartan), and Farxiga, Jardiance, and Merck & Co/Bayer’s vericiguat are the only drugs with positive data in this form of heart failure.

Boehringer and Lilly are waiting for the results of the EMPEROR-Preserved next year, while AZ is testing Farxiga in the DELIVER trial in HFpEF, with additional data on both HFrEF and HFpEF due from the DETERMINE study. Both of those Farxiga trials are also due to read out in 2021.

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FDA grants fast review for Bayer/Merck & Co’s heart failure drug

The FDA has granted a faster Priority Review for Bayer and Merck & Co’s filing for vericiguat, which is being developed for chronic heart failure with reduced ejection fraction, following a previous heart failure event. 

US-based Merck, known as MSD outside North America, has been developing vericiguat with ejection fraction less than 45% following a worsening heart failure event. 

Filing was based on data from the phase 3 VICTORIA study and the Priority Review tees up a potential approval within six months instead of the standard 10-month timeframe. 

The FDA has set a decision date of January 20, 2021. 

Merck & Co paid Bayer $1 billion in 2016 for US rights to the drug, which if approved could be a competitor to Novartis’ blockbuster Entresto (sacubitril+valsartan). 

The companies are jointly developing the soluble guanylate cyclase (sGC) stimulator, and in 2016 took a gamble by pushing it into phase 3 development despite mixed results at phase 2. 

VICTORIA met its composite primary endpoint when vericiguat reduced risk of heart failure hospitalisation or cardiovascular death in patients with worsening chronic heart failure with reduced ejection fraction, when added to available heart failure therapies and compared with placebo. 

However it emerged when detailed data were revealed from the 5,050-patient trial a few months later that the composite endpoint was met mainly thanks to a statistically significant reduction in risk of hospitalisations of 10%. 

There were 7% fewer deaths in the trial treated with the drug, but that result was not statistically significant. 

Secondary endpoints include time to occurrence of cardiovascular death, time to first occurrence of heart failure hospitalisation, time to total heart failure hospitalisations (including first and recurrent events), time to the composite of all-cause mortality or heart failure hospitalisation, and time to all-cause mortality. 

Merck and Bayer are also trialling vericiguat in heart failure with ejection fraction at phase 2 – an indication where Novartis’ Entresto surprisingly flopped in a phase 3 trial.

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