Inovio's endpoint switcheroo backfires as phase 3 misses on new measure, hits on old

 Inovio’s attempt to make its phase 3 trial better ended up making it worse. Eleven months after changing the primary endpoint of its late-phase cervical dysplasia study, the DNA medicine specialist has revealed the study failed against the new measure—but hit the mark on the old endpoint.

Here’s how things went down. In April, Inovio responded to the results of its first phase 3 clinical trial of VGX-3100—a DNA vaccine encoding human papilloma virus genes—and talks with the FDA by changing the primary endpoint of a second study, REVEAL2. The change narrowed the analysis to a biomarker-based subpopulation of women Inovio thought were more likely to respond to therapy, rather than all comers. 

Under the new design, the FDA no longer considered REVEAL2 to be pivotal, shutting down Inovio’s plans of filing for approval based on the data this year. Instead, the biotech would need to run one or two additional trials in the biomarker population. The REVEAL2 data suggest Inovio may have been wrong about the biomarker. 

VGX-3100 was no better than placebo at improving lesion regression and viral clearance in the biomarker-based subpopulation of women with high-grade squamous intraepithelial lesions, abnormal cells that form on the cervix and can turn cancerous. However, VGX-3100 did significantly improve lesion regression and viral clearance in the original all-participants primary endpoint population.

In the all-comers population, 27.6% of recipients of VGX-3100 met the primary endpoint, versus 8.7% of their counterparts in the placebo arm. The biomarker-selected population was much smaller—25 people versus 203 in the wider trial—and, while VGX-3100 beat placebo by 28.6% to 0%, it fell short of statistical significance with a p-value of 0.115. 

“We did expect a higher number of subjects to have the biomarker based on what we saw in REVEAL 1, Michael Sumner, Inovio’s chief medical officer, said on an analyst call. “But really, it wasn't a powering issue with the study. We genuinely saw a lower efficacy rate from the biomarker selective population. So that's what really makes us want to dig into the data and understand what went on. We're just not at the stage to do that at the moment.” 

After pooling the data with the results of the earlier phase 3 trial, Inovio reached statistical significance in both the biomarker-based and the all-comer populations. The biotech is now reviewing all of the data. Inovio CEO Jacqueline Shea, Ph.D., said the goal is to “really narrow down” and focus on the best opportunities. It is unclear whether VGX-3100 will make the cut. Inovio said the results “will be used as supportive data in any future regulatory interactions involving VGX-3100.”

The biotech ended last year with $253 million in the bank, a sum it expects to support its operations into the first quarter of 2025. Inovio’s pipeline also features a potential treatment for recurrent respiratory papillomatosis, another HPV-related disease, and a brain cancer candidate.

https://www.fiercebiotech.com/biotech/inovios-endpoint-switcheroo-backfires-phase-3-misses-new-measure-hits-old

Cross-Border 'Terror Attack' On Russia Involved Dozens Of Armed Saboteurs Attacking Villages

 The Kremlin has condemned what it called a new terrorist attack on its soil Thursday carried out by Ukrainian saboteurs who allegedly breached a border region. 

Russian presidency spokesman Spokesman Dmitry Peskov said militants entered the Bryansk Oblast in Western Russia and attacked villages there, resulting in the death of one civilian and another wounded. "This is an attack by terrorists," Peskov said.

Conflicting initial reports indicated Russia’s Federal Security Service engaged in a gun battle with  the infiltrators, with the Kremlin saying "Measures are currently underway to eliminate these terrorists."

The Associated Press describes based on national media that "Tass, citing Russian law enforcement, reported earlier that the saboteurs were holding up to six people hostage."

"The local governor said the group had fired on a vehicle there, killing one man and wounding a 10-year-old," AP continues. The report details further:

Thursday's apparent incursion was also embarrassing for Russian President Vladimir Putin, coming days after he ordered the Federal Security Service to tighten controls on Russia’s border with Ukraine.

Tass reported, citing an unnamed security official, that two villages in the Bryansk region — Sushany and Lyubechane — were under attack by "several dozen armed fighters."

Alexander Bogomaz, the governor of the Bryansk region, which borders Ukraine, said the group fired on a vehicle in Lyubechane, killing one man and wounding a child. He also said that a Ukrainian drone struck a house in the Sushany, setting it ablaze.

Multiple war monitoring accounts have picked up on the below video which is widely being flagged as showing one of the alleged attackers:

Peskov said in response to a question over what action Moscow could take in the international arena, "On the international arena, [we] have drawn and continue drawing the attention of the world public to those terror attacks that these people [Ukrainian terrorists] carry out."

Putin also directly addressed the cross-border terror attack in a video address after convening his national security council to be briefed on the matter...

"They opened fire on civilians,... they saw that there were children in the car," Putin said.

The incident comes after Monday into Tuesday a series of drone attacks on Russian facilities, believed launched by the Ukrainians, triggered air alert sirens in various locations across the country. One or more even reached to within 100km of Moscow. 

Concerning the drone attacks, Russia's Deputy Minister of Foreign Affairs has charged that the Ukrainians had covert help from the United States in carrying out the sophisticated drone operations, one of which damaged an oil facility some 500km inside Russian territory. "Attack of drones on aviation facilities in Saratov and Ryazan could not have been carried out without the active assistance of the United States," Ryabkov said in a press statement.

https://www.zerohedge.com/geopolitical/cross-border-terror-attack-russia-involved-dozens-armed-saboteurs-attacking-villages

Beer drinkers cut back as Bud Brewer AB InBev raises prices

 The world’s largest brewer reported a fall in sales volume at the end of the year as steep price increases prompted a drop in demand for beer in the U.S., but American beer drinkers are now getting over their sticker shock, Anheuser-Busch InBev SA Chief Executive Michel Doukeris said.

AB InBev’s drop in volume during the fourth quarter came as companies across the consumer-products industry have grappled with how much they can raise prices to offset rising costs without deterring shoppers. For much of last year, AB InBev said drinkers were not giving up their brews despite inflation’s bite, though that trend appeared to end in the last few months of the year.

In the 12 weeks before Christmas, prices for American lagers such as Bud Light and Coors Light climbed an average of 10% higher than the year-earlier period, according to an analysis of Nielsen data by the Bump Williams Consulting Co., an industry consulting firm. AB InBev said its revenue per hectoliter in the U.S. rose 12.2% in the quarter, primarily driven by price increases.

AB InBev on Thursday said its global sales volume declined 0.6% in the final three months of 2022, missing analysts’ expectations of a 2.1% increase. Shares of the company fell more than 3% in early trading in Brussels.

The steepest fall in quarterly volumes came in North America, down 8.3%. In the U.S., AB InBev reported weaker sales to wholesalers and retailers, which it attributed to a drop in orders after retailers stocked up ahead of an October price increase and poor weather in December. Still, it said revenue rose in the U.S. thanks to higher selling prices and its strategy to push into more premium brews.

The company’s price increases have lagged inflation, Doukeris said Thursday. He said U.S. beer prices last year rose far less than prices for soft drinks or food. In the first six weeks of this year, U.S. beer sales volumes stabilized, falling 1%, he said, citing IRI data. Additionally, people are eating and drinking more at home, a setting that tends to favor beer over cocktails or other drinks, he said.

"Beer remains resilient," Doukeris said. "I’ll never say that beer is immune to the inflation and everything that is happening out there, but [it] remains a very resilient category."

For years, the brewer has seen its mainstream brands Budweiser and Bud Light decline, partly amid a broader shift by American drinkers from beer toward wine and spirits. In response, it has worked to increase its exposure to premium offerings such as Michelob Ultra and Stella Artois. The company said those brands outperformed the industry last year.

As inflation-pinched consumers drink more at home, AB InBev has been shifting the imagery in some of its advertising from traditional settings—such as a bar or sports game—to the home. For example, in a Bud Light ad that ran during last month’s Super Bowl, actor Miles Teller and his wife, Keleigh Sperry Teller, grabbed a couple of beers for an impromptu dance party in their living room to pass the time while one of them waited on hold on the phone.

AB InBev also said quarterly volumes fell in China, down 6.9%, where beer sales were hit as COVID-19 infections surged after the country scrapped most of its "zero-COVID" restrictions.

Consumption is now rebounding quickly, said Doukeris, who recently returned from a trip to the country.

Despite big challenges in two of the company’s largest markets, AB InBev reported a 10.2% rise in quarterly revenue to $14.67 billion boosted by higher selling prices. Net profit for the quarter also rose, coming in at $2.84 billion, up from $1.96 billion in the same period a year earlier. Doukeris also noted that the company’s sales volumes for the full year reached a record high.

AB InBev is still negotiating an exit from its joint venture in Russia with Turkish brewer Anadolu Efes, nearly a year after beginning discussions, Doukeris said. Budweiser remains on sale in Russia, despite AB InBev’s request to Efes, the controlling partner, to halt the brand’s sales there.

"We’ve been making good progress," Doukeris said. "We have to get this done with the partner. We can’t do this unilaterally."

He declined to say when he expected the divestment to be complete. Efes has said that it remains in talks with AB InBev.

Anheuser-Busch Inbev

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Ticker	Security	Last	Change	Change %
BUD	ANHEUSER-BUSCH INBEV	60.25	-0.45	-0.74%
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Looking ahead, AB InBev said it expected earnings before interest, taxes, depreciation and amortization to grow in line with its medium-term outlook of between 4% and 8%, and for revenue to grow ahead of Ebitda, supported by a combination of volume and price.

https://www.foxbusiness.com/economy/beer-drinkers-cut-back-bud-brewer-ab-inbev-raises-prices

Mobius warns over China’s ‘crazy’ business tactic: Be 'very careful'

 Mark Mobius, who allocates capital all over the world, has raised a red flag about doing business – or trying to bow out of your business – with China.

"I'm personally affected because I have an account with HSBC in Shanghai. I can't get my money out. The government is restricting the flow of money out of the country," Mobius told FOX Business host Maria Bartiromo. "So I would be very, very careful investing in China."

On "Mornings with Maria" Thursday, the Mobius Capital Partners founder noted that China’s bottom line is moving "in a completely different direction" than its former open-minded-market revolutionary leader Deng Xiaoping.

"Now you have a government which is taking gold in shares in companies all over China. That means they're going to try to control all these companies," Mobius explained. "So I don't think it's a very good picture when you see the government becoming more and more control oriented in the economy."

China has made a "very significant" effort to allegedly prevent Mobius from removing capital from Chinese-based stocks.

"I can't get an explanation of why they're doing this. It's just amazing. They're putting all kinds of barriers," the investor said. "They don't say, 'No, you can't get your money out,' but they say, 'Give us all the records from 20 years of how you've made this money,' and so forth. It's crazy."

Mobius’ comments come as a recent survey on Chinese business sentiment from the American Chamber of Commerce revealed a majority of U.S. companies say China is no longer seen as a "top three investment priority."

The best investment alternative with the most economic opportunity, Mobius advised, is India.

"You've got a billion people, they can do the same thing that the Chinese do. They can do the same kind of manufacturing and so forth," he said. "I'm now in Brazil, and Brazil, you've got 250 million-plus people, very good people, open society. Hey, why not come here? It's another alternative."

In terms of America’s economy, Mobius said he doesn’t believe things will get worse amid rising tension with China.

"I think the U.S. is in pretty good shape. And the reason why is that, let's face it, the U.S. is at war. They're at war in Ukraine and more and more at war with China indirectly. And when you have a war situation, spending goes up," Mobius said.

"That's the reason why you see the labor market being relatively tight in America. So I'm relatively bullish despite the interest rates. If you look at the history of interest rates, high interest rates don't necessarily mean a poor market," the investor added. "So I think the U.S. looks pretty good."

https://www.foxbusiness.com/markets/billionaire-investor-issues-warning-china-crazy-business-tactic

State-Dept-Funded Censorship-Group Punished Conservative Websites For Circulating Lab-Leak Theory

 by Paul Joseph Watson via Summit News,

The US State Department-funded Global Disinformation Index punished conservative websites by throttling their advertising revenue if they gave credence to the COVID-19 lab leak theory, despite it subsequently proving likely true.

The Global Disinformation Index is a British-based non-profit group that previously received $665,000 from the Global Engagement Center and National Endowment for Democracy (NED), a State Department-backed group, while it was overseeing censorship of “conspiracy theories” about COVID-19.

One of these conspiracy theories was the notion that COVID-19 originated from a lab leak in Wuhan, which GDI claimed had “been fact-checked and proven untrue.”

GDI abused its influence to pressure Big Tech firms like Google to cut advertising from conservative websites that pushed the lab leak theory, placing them on a secret blacklist called a “dynamic exclusion list” in an effort to put them out of business.

The group targeted firms that were “providing ad revenue streams to known disinformation sites peddling coronavirus conspiracies.”

Microsoft later had to suspend its partnership with the group after the GDI had been using the company’s Xandr advertising and analytics subsidiary to freeze out conservative sites.

From 2021 onwards, the lab leak theory was no longer being treated as a “conspiracy theory,” and both the Department of Energy and the FBI recently came out and asserted it was likely true.

“GDI is part of [a] disturbing constellation of pop-up censorship organizations that all descended on stifling COVID origins discourse online simultaneously,” Mike Benz, a former State Department official told the Washington Examiner.

This once again underscores how hysteria over ‘fake news’ and ‘disinformation’ has been weaponized to justify the censorship of awkward stories and even facilitate actual cover-ups.

As we highlighted yesterday, the Chinese Communist Party threatened Elon Musk to stop sharing stories about the Wuhan lab leak, suggesting Tesla’s business interests in China would be at risk if he kept amplifying the issue.

https://www.zerohedge.com/political/state-department-funded-censorship-group-punished-conservative-websites-circulating-lab

NBC Reporter Goes To Crimea, Shocks Viewers By Telling The Truth

 Mainstream media correspondents for major US networks rarely, if ever, report from inside Crimea and certainly are nowhere near Russian-held territory in eastern Ukraine. However, this week NBC News chief international correspondent Keir Simmons went to Sevastopol, surrounded by a significant Russian military presence given it is home to the Russian Navy's Black Sea Fleet, and in a live segment admitted that it's not at all realistic Zelensky and Ukrainian forces can ever hope to take Crimea. 

This is especially as the "the people there... view themselves as Russian." Simmons noted that "This is the closest that any US news crew has got to the Russian Black Sea Fleet in many many years." He explained that "Vladimir Putin will be determined to defend that port - to not have it take it away from him - he may well do pretty much anything to try to achieve that."

"It is a very, very dangerous standoff.. it's hard to see how you reach a negotiation over that. There's military absolutely everywhere, it is a military town," he continued, before saying...

"When for example Victoria Nuland talks about that at the very least we [the US] want Crimea to be demilitarized, I find myself standing there and wondering, how on earth does that happen?"

Ukrainian officials and pro-Kyiv media pundits are said to be outraged at the segment, given it repeatedly and bluntly referenced that Crimeans see themselves as Russians. Even a separate write-up filed days earlier from inside Crimea and posted to NBC's website included the following: 

This is not Russia, according to Kyiv, its Western allies and the United Nations. It was annexed by the Kremlin in 2014, with the U.N. calling on Russia to return to its "internationally recognized borders." And following Moscow’s broader invasion launched a year ago, President Volodymyr Zelenskyy has vowed Ukraine will take Crimea back.

But Praskovya Baranova, 73, speaks Russian, feels Russian and lives here.

But it appears that the NBC correspondent, once he was on the ground in a place that few Western reporters ever venture, couldn't deny the plain truth he was seeing all around him.

David Sacks comments of the refreshingly truthful segment, "Not long ago, these were denounced as Putin talking points." 

Sacks also says regarding NBC clearly conceding that Zelensky’s goal of retaking Crimea remains unrealistic and dangerous...

This is a huge admission because it means that Biden’s policy of "only the Ukrainians can decide" the objectives of the war makes no sense. We’re effectively delegating our foreign policy to Zelensky, who is pursuing objectives that we don’t agree with.

"At the same time that MSNBC is suddenly airing the truth about Crimea, its chief Ukraine pundit is lobbying for an all-out attack," Sacks also observes of the timing of the mid-week report.

"It’s getting easier to see who are the real fanatics in this war," Sacks concluded.

https://www.zerohedge.com/geopolitical/msnbc-reporter-goes-crimea-shocks-viewers-telling-truth

Bond Vigilantes Awaken As Inflation Becomes Embedded

 by Simon White, Bloomberg macro strategist,

The risk of a structural rise in yields has heightened as bondholders begin to demand more compensation for inflation that is increasingly ingrained.

For all the opprobrium heaped on markets for being unruly and disobedient, they’ve been remarkably pliant in believing central banks will soon return inflation to 2%. The bond vigilantes (apart from a brief appearance during the UK’s LDI crisis) have been extraordinary only by their absence.

But that looks as if it is about to change. Term premium, essentially the extra yield long-term bond holders require for inflation risks, has been rising as data show the disinflation trend in the US running out of steam, helping push 10-year yields back over 4%.

In fact, over the last six months we have seen more extreme daily rises (i.e. those in the top 0.5% of all daily moves going back to 1960) in term premium than we have since the early 1980s, when Fed Governor Volcker was in the last throes of his conclusive battle with inflation.

Term premium captures several risks for holders of long-term bonds, but key is inflation.

The 10-year ACM term premium spent most of the 1970s above 1%, and peaked at 5% in 1984. Since then it has trended consistently lower, and has remained surprisingly contained over the last few years despite inflation hitting multi-decade highs.

The disconnect can be seen most clearly by looking at the precipitous rise in the volatility of inflation – which captures the extra uncertainty bond holders are facing – and still-subdued term premium.

The implications are considerable if bond holders are worrying inflation is becoming embedded. Most immediately, yields would be biased structurally higher, and would decline less when the Fed cuts rates, lowering the control the central bank has over longer-term borrowing costs.

This was the invidious position in which Volcker found himself in the early 1980s. The Fed at that point had “imperfect credibility”: when it hiked rates, the market did not believe it would keep them there. Instead, it was forced to cut them again when the ensuing recession hit. This meant inflation persisting, term premium rising, and the yield curve steepening – even as the Fed was hiking rates aggressively.

It was only when Volcker raised rates to 20% in 1981 - despite a deep recession - that the deadlock was finally broken and inflation began to fall. Nonetheless, term premium did not peak until three years later as the market remained wary the inflation beast had not been decisively floored. Once bond markets scent inflation, it takes years before they become desensitized to it.

Rising term premium also risks a self-reinforcing feedback loop. When it is increasing, the yield curve has a steepening bias, and steeper yield curves go hand-in-hand with higher rate volatility.

This is because longer-term forward yields must converge to shorter-term yields. The steeper the yield curve, the more paths yields can take to converge, which means higher yield volatility. Higher volatility means bond holders demand a higher yield to compensate, i.e. term premium rises.

Avoiding a rise in term premium is thus highly desirable. But the cat may already be out of the bag. Term premium looks to be catching up to the much higher level currently implied by forecasters.

There is no binding constraint that the forecasters’ view need be correct, but inflation is a social and behavioral phenomenon as much as an economic one. At some point, inflation expectations become self-fulfilling and drive inflation itself. An emerging narrative that inflation is becoming persistent adds to the likelihood that that is what we will soon see.

And inflation expectations are already rising at the fastest rate in decades. As the chart below shows, this adds further confidence to the notion that term premium will keep rising.

A structural, term-premium driven rise in yields could take years to reverse as hitherto dormant bond vigilantes become conditioned to a world where inflation is persistently elevated and prone to sudden flare-ups.

It would also mean an end to the uneasy alliance between central banks and markets fostered over the last four decades. Term premium thus bears watching very closely.

https://www.zerohedge.com/markets/bond-vigilantes-awaken-inflation-becomes-embedded