Bayer files first application of menopause drug elinzanetant

 Bayer has filed for approval in the US for elinzanetant as a non-hormonal treatment for menopausal symptoms such as hot flushes, with a rival therapy from Astellas in its sights.

The FDA submission is for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause, based on three phase 3 studies showing that elinzanetant significantly reduced their frequency and severity over 12 weeks compared to placebo.

The oral neurokinin (NK) 1 and 3 antagonist – if approved – will represent the first direct competition to Astellas' NK 3 antagonist Veozah (fezolinetant) which was cleared by the FDA in May last year and is now available in 14 countries worldwide.

Both drugs are being positioned as alternatives to conventional hormone replacement therapy (HRT) for menopausal VMS, which can be highly effective but isn't recommended in some women, such as those who have an elevated risk of stroke, heart attack, or some forms of cancer.

Financial results posted today by Astellas showed sales of JPY 6.6 billion ($44 million) in the first three months of its current fiscal year, a more than tenfold increase on the same period of fiscal 2023, with the US contributing the lion's share of that total.

That is a welcome sign of growing momentum for Veozah, which made less than $50 million in the entire year to 31st March, and a relief for Astellas, which has stuck with its annual sales estimate of between $2.2 billion and $3.6 billion for the drug at peak.

Analysts have suggested that having a second NK-acting drug in the marketplace could raise awareness and help drive the uptake of both products, which are expected to appeal to women unwilling to go down the HRT route and seeking a non-hormonal alternative.

The potential market is massive, with around 27 million women in the US currently going through menopause, and the number worldwide is expected to reach 1.2 billion by 2030. VMS is reported by up to 80% of women at some point during menopause, and around a third report severe VMS, which can last 10 years or more after the last menstrual period.

"Despite the impact menopausal symptoms may have on women's health and quality of life, many go without treatment due to gaps in awareness, education, and limitations of treatment options available," said Christine Roth, head of global product strategy and commercialisation at Bayer.

HRT – which remains the main obstacle to growth for the NK antagonist drugs – is generally widely available (despite some recent supply chain issues) and cheap, and after falling out of favour 20 years ago due to safety concerns, has seen an increase in popularity in recent years.

That is in part due to other potential benefits – like improved mental and potentially cognitive health – as well as research suggesting the risk of side effects like breast cancer is lower than previously thought, particularly with newer formulations.

Bayer meanwhile recently started a fourth phase 3 trial of elinzanetant that will test the drug's ability to treat VMS associated with endocrine therapy of breast cancer.

GlobalData recently predicted Astellas' therapy will make $1.8 billion in 2030, thanks to its first-to-market advantage, with elinzanetant making $1 billion in the same year.

https://pharmaphorum.com/news/bayer-files-first-application-menopause-drug-elinzanetant

Central Banks Purchase Gold To Offset Their Own Monetary Destruction

 by Daniel Lacalle via The Mises Institute,

Why is the price of gold rising if the global economy is not in recession and inflation is allegedly under control? This is a question often heard in investment circles, and I will try to answer it.

We must begin by clarifying the question. It is true that inflation is slowly decreasing, but we cannot say that it is under control. Let us remember that the latest CPI data in the United States was 3% annualized and that in the eurozone it is 2.6%, with eight countries publishing data above 3%, including Spain.

This is why central banks need to give the impression of hawkishness and maintain rates or lower them very cautiously. However, monetary policy is far from being restrictive. Money supply growth is picking up, the ECB maintains its “anti-fragmentation mechanism,” and the Federal Reserve continues to inject money through the liquidity window. We can say, without a doubt, that monetary policy is beyond accommodative.

At the end of this article, the price of gold is above $2,400 an ounce, up 16.5% between January and July 19, 2024. In the same period, gold has performed better than the S&P 500, the Stoxx 600 in Europe, and the MSCI Global. In fact, over the past five years, gold has outperformed not only the European and global stock markets, but also the S&P 500, with only the Nasdaq surpassing the precious metal. This is a period of alleged recovery and strong expansion of the stock markets. On the one hand, the market is discounting the central banks’ continued accommodative and expansionary policies, even possible high debt monetization, given the unsustainable deficits in the United States and developed countries. That is, the market assumes that the Federal Reserve and the ECB will not be able to maintain the reduction of their balance sheets in the face of rising debt and public spending in many economies. As a result, gold protects many investors against the erosion of the currency’s purchasing power, i.e., inflation, without the extreme volatility of Bitcoin. If the market discounts further monetary expansion to cover the accumulated deficits, it is normal for the investor to seek protection with gold, which has centuries of history as an alternative to fiduciary money and offers a low-volatility hedge against currency debasement.

Another important factor is the central bank’s purchase of gold. JP Morgan is credited with the phrase “gold is money and everything else is credit.” All the world’s central banks include treasury bonds from countries that serve as global reserve currencies in their asset base. This allows central banks around the world to try to stabilize their currencies. When we read that a central bank buys or sells dollars or euros, it is not making transactions with physical currency but with government bonds. Hence, as the market price of government bonds has fallen 7% between 2019 and 2024, many of these central banks are facing latent losses from a slump in the value of their assets. What is the best way to strengthen a central bank’s balance sheet, thereby diversifying and reducing exposure to fiat currencies? Purchase gold.

The rising purchases of gold by central banks are an essential factor justifying the recent increase in demand for the precious metal. Central banks, especially in China and India, are trying to reduce their dependence on the dollar or the euro to diversify their reserves. However, this does not mean full de-dollarization. Far from it.

According to the World Gold Council, central banks have accelerated their gold purchases to more than 1,000 tonnes per year in 2022 and 2023. This means that monetary authorities account for almost a quarter of the annual demand for gold during a period when supply and production have not grown significantly. The ratio of output to demand stands at 0.9 in June 2024, according to Morgan Stanley.

Global official gold reserves have increased by 290 net tonnes in the first quarter of 2024, the highest since 2000, according to the World Gold Council, 69% higher than the five-year quarterly average (171 metric tonnes).

The People’s Bank of China and the Central Bank of India are the biggest buyers as they aim to balance their reserves, adding more gold to reduce loss-making exposure to government securities. According to Metals Focus, Refinitiv GFMS, and the World Gold Council, China has been increasing its gold purchases for seventeen months, and since 2022, it has shot up its reserves by 16%, coinciding with the increase in global polarization and the trade wars.

That does not mean full de-dollarization, as the People’s Bank of China has 4.6% of its total reserves in gold. US Treasury bonds are the most important asset, accounting for more than 50% of the Chinese central bank’s assets. However, its goal is to raise gold reserves to at least 14%, according to local media. Thus, it would imply a significant annual purchase of gold for years.

India’s central bank increased its gold reserves by 19 metric tonnes during the first quarter. Other central banks that are diversifying and buying more gold than ever are the National Bank of Kazakhstan, the Monetary Authority of Singapore, the Central Bank of Qatar, the Central Bank of Turkey, and the Central Bank of Oman, according to the sources cited above. During this period, both the Czech National Bank and the National Bank of Poland increased their gold reserves in Europe, reaching the highest level since 2021. In these cases, the aim is to balance the exposure in the asset base with more gold and less eurozone government bonds.

The goal of this central bank trend is to increase the weight of an asset that does not fluctuate with the price of government bonds. It is not about de-dollarization but about balancing the balance sheet from the volatility created by their own misguided expansionary policies. For years, the policy of central banks has been to reduce their gold holdings, and now they must come back to logic and rebalance after suffering years of latent losses on their government bond holdings. In fact, one could say that the world’s central banks anticipate their own widespread erosion of the purchasing power of reserve currencies due to the saturation of fiscal and monetary policies, and for that reason, they need more gold.

After years of thinking that money can be printed without limits and without creating inflation, monetary authorities are trying to return to logic and have more gold on their balance sheets. At the same time, many expected that the trade war between China and the United States and global polarisation would be reversed in the Biden years, and the opposite has happened. It has accelerated. Now, the latent losses in the sovereign bond asset portfolio are leading all these central banks to buy more gold and try to protect themselves from new bursts of inflationary pressures.

In an era of high correlation between assets and perpetual monetary destruction, gold serves as a low volatility, low correlation, and strong long-term return addition to any prudent portfolio.

https://www.zerohedge.com/markets/central-banks-purchase-gold-offset-their-own-monetary-destruction

US Embassy Implores Americans To Leave Lebanon On 'Any Ticket Available'

 The US embassy in Lebanon has issued an alert warning American citizens to exit Lebanon on "any ticket available" as the likelihood of a major war between Israel and Hezbollah as well as Iran grows.

A series of international and Western airlines have suspended service to the region as a the specter of all-out war looms. The embassy said that though there have been service stoppages and cancellations, "commercial transportation options to leave Lebanon remain available."

We encourage those who wish to depart Lebanon to book any ticket available to them, even if that flight does not depart immediately or does not follow their first-choice route," the embassy stated.

Starting in late June, Biden's special envoy Amos Hochstein warned the Lebanese government, "The US won’t be able to hold Israel back if the situation on the border continues to escalate and that Hezbollah needs to indirectly negotiate with Israel instead of ratcheting up tensions."

Hezbollah Secretary General Hasan Nasrallah has warned of a "new phase" in the war following an Israeli airstrike targeting and killing his top military chief Fuad Shukr this week.

Iran has already signaled what this will look like, with its Permanent Mission to the United Nations on Saturday saying in a statement to CBS that the group is expected to strike deeper inside Israel and that it will no longer confine itself to military targets.

The Iranian statement outlined that so far Hezbollah has limited itself according to an "unwritten understanding" or status quo engagement with Israel "confining their actions to border areas and shallow zones, targeting primarily military objectives."

"However, the [Israeli] regime’s attack on the Dahieh [neighborhood] in Beirut and the targeting of a residential building marked a deviation from these boundaries," the statement added. 

"We anticipate that, in its response, Hezbollah will choose both broader and deeper targets, and will not restrict itself solely to military targets and means," the spokesperson emphasized.

If the situation begins to spiral, it is likely the US military will use its significant naval assets in the Mediterranean to begin evacuating American nationals from Lebanon. Often the first place Israel bombs is Beirut's lone international airport.

On Friday night US Defense Secretary Lloyd Austin ordered additional navy cruisers, destroyers and a fighter squadron to deploy to the Middle East.

https://www.zerohedge.com/geopolitical/us-embassy-implores-americans-leave-lebanon-any-ticket-available

Dangerous Ozempic scams on the rise

 You want to lose weight — but you could lose money or end up in the hospital with one of these risky Ozempic scams.

New research warns of illegal online pharmacies peddling faux or substandard Ozempic, or in some cases, taking money for nothing in return.

“It’s hard to say how widespread these scams are,” Tim Mackey, a professor in the Global Health Program at the University of California, San Diego, told The Post in an email. “It changes based on availability of raw materials, and there are different levels of counterfeiters (some that produce product with no active ingredient, wrong ingredient, some ingredient, and online scams that don’t deliver anything).”

The counterfeit market will likely grow as Ozempic becomes even more popular.Wild Awake – stock.adobe.com

Last summer, Mackey and his colleagues searched for websites advertising semaglutide without a prescription. Semaglutide is the active ingredient in the diabetes drug Ozempic and the weight loss drug Wegovy. Both require prescriptions.

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The team purchased six products for quality control testing but only received three.

“Three vendors selling Ozempic injections engaged in nondelivery scams requesting extra payments (range, US $650-$1200) to purportedly clear customs, confirmed as fraudulent by customs agencies,” the researchers wrote in their findings, published Friday in JAMA Network Open.

The study authors reported that semaglutide was present in the three samples sent to them but the purity varied (7% to 14% versus the advertised 99%) and the amount of semaglutide exceeded what was on the label by 29% to 39%.

Some of the patients who accidentally overdosed on semaglutide had to be hospitalized. Symptoms often include nausea, vomiting, abdominal pain, fainting, headache, migraine, dehydration, acute pancreatitis and gallstones.metamorworks – stock.adobe.com
Semaglutide overdoses have become commonplace. US poison centers fielded nearly 3,000 semaglutide calls from January to November 2023 — 15 times the amount in 2019.

The US Food and Drug Administration (FDA) issued an alert last week about semaglutide overdoses.

Most reports stemmed from patients drawing up more than the prescribed dose — sometimes five to 20 times more — from a multi-dose vial for injection.

Some of the patients had to be hospitalized, with symptoms ranging from nausea, vomiting and abdominal pain to fainting, headache, migraine, dehydration, to acute pancreatitis and gallstones.

Illnesses will likely become more widespread as the counterfeit market expands along with Ozempic’s growing popularity.

Mackey pointed out there are about 30,000 to 40,000 active illegal online pharmacies, which could get in on the action. People who try to buy unauthorized Ozempic online risk getting a product without semaglutide, the wrong amount of semaglutide, a dangerous ingredient instead, a contaminated product or no product at all.

“Consumers really need to partner with their health care provider to ensure that semaglutide is even appropriate for them in the first place, and then only source it from a legitimate licensed pharmacy in order to ensure their treatment is not compromised,” Mackey told The Post.

https://nypost.com/2024/08/02/lifestyle/dangerous-ozempic-scams-can-cost-you-money-your-good-health/

'Midlife Blood Biomarkers Predict Late-Life Dementia'

 Blood biomarkers specific to Alzheimer's disease -- specifically, amyloid-beta 42/40 ratios and measures of phosphorylated tau 181 (p-tau181) -- had a relationship with subsequent dementia that started in midlife, a retrospective analysis showed.

These midlife biomarkers demonstrated long-term associations with late-life amyloid positivity and dementia diagnoses, reported Priya Palta, PhD, MHS, of the UNC School of Medicine in Chapel Hill, in a session presented at the Alzheimer's Association International Conferenceopens in a new tab or window.

Dementia risk rose with each standard deviation (SD) change in midlife plasma amyloid-beta 42/40 ratio (HR 1.11, 95% CI 1.02-1.21) and in midlife plasma p-tau181 (HR 1.15, 95% CI 1.06-1.25), Palta and co-authors reported in a corresponding paper published in JAMAopens in a new tab or window.

Late-life levels of amyloid, tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) also were associated with dementia. NfL is a measure of neuronal injury; GFAP reflects astrogliosis.

"This is a very important data set where they followed individuals, including a large proportion of African American individuals, over a number of decades," noted Stephen Salloway, MD, MS, of Brown University in Providence, Rhode Island, who led an editorialopens in a new tab or window accompanying the JAMA paper.

The findings mean that "as we move earlier in detection and earlier in preventive and risk reduction strategy, I see us eventually being able to detect who's at risk for Alzheimer's disease many years -- decades really, in midlife -- before the onset of symptoms, and then being able to institute either risk reduction and or biological treatments that modify that risk," Salloway said in a JAMA podcastopens in a new tab or window.

"We can't take these results directly now into testing people at midlife with large-scale screening," Salloway pointed out.

But the study "gives us a clue that we will be able to, as our precision increases and the sensitivity of our measures improves, so we can tell who's on the pathway to developing Alzheimer's disease many years before there's any impairment," he said. "That's really exciting. It's a little bit futuristic, but really exciting."

Palta and co-authors used data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCSopens in a new tab or window), a study that recruited a diverse group of middle-aged adults in the late 1980s.

They analyzed data from 1,525 ARIC-NCS participants retrospectively. Blood biomarker data were collected at both midlife (mean age 58) and late-life (mean age 76) periods. Links between blood biomarkers and incident all-cause dementia were evaluated in a subpopulation of 1,339 participants who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013.

Overall, women made up 59.9% of the study population; Black participants made up 25.8%. Dementia was ascertained through neuropsychological assessments, participant or informant contacts, and medical record surveillance. Overall, 252 participants (16.5%) developed dementia in late life.

Decreasing amyloid-beta 42/40 ratios and increasing p-tau181, NfL, and GFAP were seen from midlife to late life, all indicating greater Alzheimer's pathology with aging. Biomarker changes occurred more rapidly in people who carried an APOE4 allele.

Midlife hypertension was associated with a 0.15-SD faster increase in NfL and a 0.08-SD faster increase in GFAP per decade. Midlife diabetes was tied to a 0.11-SD faster NfL increase and a 0.15-SD faster GFAP increase.

Only amyloid and tau biomarkers in midlife demonstrated long-term relationships with dementia. All biomarkers in late life, however, had statistically significant associations with late-life dementia. Plasma NfL had the strongest association (HR 1.92, 95% CI 1.72-2.14).

"There is a shortage of research on blood biomarker changes in individuals in their mid- to late-life, especially in diverse community-based cohorts, and on the relationships between biomarker changes and midlife cardiometabolic disorders," Palta said.

"Understanding these biomarker relationships could provide us further insights into how we can help maintain brain function in people at risk for dementia, monitor disease progression, or identify individuals who may benefit from treatment," she added.

The study had several limitations, the researchers noted. Plasma biomarkers were measured at three time points at most. Only modest associations between p-tau181 and incident dementia were observed in this study; other p-tau assays, like p-tau217, may produce better results.

Disclosures

The Atherosclerosis Risk in Communities (ARIC) study is carried out by NIH grants. The blood biomarker measurements were in part supported by grants by the National Institute on Aging (NIA).

Palta was supported in part by NIA grants.

Salloway reported multiple relationships with industry.

Primary Source

JAMA

Source Reference: opens in a new tab or windowLu Y, et al "Changes in Alzheimer disease blood biomarkers and associations with incident all-cause dementia." JAMA 2024; DOI: 10.1001/jama.2024.6619.

Secondary Source

JAMA

Source Reference: opens in a new tab or windowSalloway S, et al "Are blood tests for Alzheimer disease ready for prime time?" JAMA 2024; DOI: 10.1001/jama.2024.12814.

https://www.medpagetoday.com/meetingcoverage/aaic/111356

Berkshire Quietly Dumps Half Its Apple Shares Amid Unprecedented Selling Spree

When yesterday we said, when discussing Buffett's ongoing liquidation of his Bank of America stake, that "Berkshire's rising cash stockpiles merely reflect the firm's inability to find deals in today's overvalued and weak economic environment", little did we know just how accurate that would be, because fast-forwarding just one day later we find that far from only dumping Bank of America, the 93-year-old Omaha billionaire had been busy quietly dumping his most iconic holding in an unprecedented selling spree that sent Berkshire's cash pile soaring by a record $88 billion to an all time high $277 billion at the end of Q2.

As shown in the chart below, in the second quarter (which ended June 30, and thus just two weeks after the Apple's Developer Conference which took place on June 10 and which was - at least on the day of - a total bust), Berkshire sold a net $75.5 billion worth of stock, the bulk of which we now know, came from Buffett's liquidation of half his Apple shares.

While there was no 13F filed yet to go with the Berkshire's 10Q, the company did provide a snapshot of its top holdings, revealing that as of June 30 it held only $84.2 billion in Apple stock, down sharply from $135.4 billion as of March 31 and $174.3 billion as of Dec 31, 2023. This translates into just 400 million shares of AAPL held as of June 30, down almost 50% from 789.4 million as of March 31 and 905.6 million as the end of 2023.

The rest of Berkshire's top 5 holdings (Bank of America, American Express, Coca Cola and Chevron) was left untouched in Q2, meaning that Buffett clearly decided that it was time for Apple to go (we have since learned that subsequent to the end of Q2, Buffett also started to dump a large portion of his Bank of America shares where he is the single largest shareholder).

While Berkshire's cash balance rose by a record $88 billion - where proceeds from the sale of Apple were the bulk of the new cash - the company also generated substantial cash from its own operations, and in Q2 Berkshire reported operating earnings of $11.6 billion, up from $10 billion for the same period a year ago.

Berkshire has for years struggled to find ways to deploy its mountain of cash in a sluggish deal environment, lamenting the lack of cheap opportunities. At the firm’s annual shareholder meeting in May, Buffett said he wasn’t in a rush to spend “unless we think we’re doing something that has very little risk and can make us a lot of money.” It now appears that not only was Buffett not in a rush to spend, but taking advantage of the AI bubble, he has been aggressively liquidating his biggest holding.

What is perhaps most remarkable is when and how Buffett dumped half his Apple holdings: Berkshire managed to offload a stunning $84 billion, or some 390 million shares, in AAPL at a time when the stock was appreciating rapidly, and especially after the meltup following the WWDC24 developer conference. In other words, the smart money was furiously dumping to retail, because as we noted at the time, hedge funds were certainly not buying tech at this time, as we reported on July 1 in "Getting Out Of Dodge: Hedge Funds Are Selling And Shorting Stocks At The Fastest Pace In Two Years", almost as if they had notice that Buffett was dumping...

It also makes one wonder if Buffett may not have had something to do with Apple's bizarre performance after the WWDC24 conference. As a reminder, the kneejerk response to Tim Cook's "earthshattering" reveal of a chatGPT Siri was a huge dud, with the stock dumping on the day of WWDC24.

It wasn't until the next day when, thanks to a relentless barrage of bullish sellside reports and kickstarted by a furious buyback order from the company itself, the stock proceeded to surge and regain the world's most valuable slot from Microsoft. Almost makes one wonder if Buffett didn't call in a few favors from his banker friends on this one...

Finally, it's not just AAPL that Buffett believes is overvalued and is aggressively dumping: the billionaire clearly believes the entire market is way expensive, and Berkshire bought back only $345 million of its own shares during the quarter, the lowest amount since the company changed its buyback policy in 2018. It's hardly a surprise why:  as we noted in "Berkshire's Growing Cash Pile Has A Hidden Message On Stocks" the Buffett Indicator has rarely signaled a more expensive market.

Bottom line: unlike October 2008, when Buffett led the clarion call to "Buy American", this time he is selling American at a never before seen pace.

Are you?

One thing we know, Buffett is fearful.

https://www.zerohedge.com/markets/buffett-calls-top-berkshire-quietly-dumps-half-its-apple-shares-amid-record-liquidation