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Monday, January 13, 2025

Parting Gift To Trump, Biden Surges Oil Prices With Russian Sanctions Days Before Inauguration

 For the duration of his fake, first and only presidential term, Joe Biden did everything in his power to avoid a rise in oil prices, knowing nothing would seal his fate as America's worst president than a gas price spike in the twilight days of his life and career. He would court dictators (from a persona non grata, Venezuela's Nicolas Maduro quietly became one of Biden's BFFs), he would prevent sanctions against Iran from being fully enforced (allowing China to buy up Iranian oil at pennies on the dollar and keep overall oil prices subdued), and most importantly, he would water down sanctions against Russian oil for the past two years, realizing that crippling Russian oil exports would be a mutually assured destruction move, crushing both Putin and his own administration by sharply reducing oil output and sending oil prices sharply higher, even as it was those oil exports that kept Russia war machine humming and enabling the Kremlin to play cat and mouse with Zelensky, now that the Russian army is in full advance across Ukraine.

But now that Biden is out of the White House (having easily won the "worst US president" designation many times over), the Democrats are in disarray, and the world looking with some semblance of hope toward Trump's second term, Biden has decided that it is finally time to do the "right thing" and send oil prices surging by announcing  the most sweeping and aggressive sanctions yet on Russia’s oil trade, making life for his successor hell as gas prices are about to soar following closely the spike in oil.

Indeed, it was last Friday, with less than 2 weeks to go until Biden is kicked to the curb, when we got the shocking news that the US Treasury would enforce sanctions against Russian oil giants, Surgutneftgas and Gazprom Neft, while also dramatically expanding a highly effective program of targeting individual oil tankers expanding the list to some 270 total tankers sanctioned for carrying Russian oil, listing traders organizing hundreds of illicit shipments, naming pivotal insurance companies, and telling two US oil service providers to exit.

In short, an unprecedented crackdown on Russian oil exports, one which should have taken place the day after the Ukraine war, but didn't because Biden knew it would send oil prices surging.

Biden's surprise move, could reduce what the International Energy Agency predicts will be a supply surplus of almost 1 million barrels a day this year to zero (between them, Surgutneftgas and Gazprom Neft shipped about 970,000 barrels a day of oil by sea in 2024 and they are main source of commodity product for refiners in China and India) if not push it negative for another year, only this time Cushing is at "tank bottoms" meaning commercial inventory levels are at record low and the US Strategic Petroleum Reserve is... well, everyone knows where that is.

And lo and behold, with everyone on Wall Street beared up on oil to unprecedented levels - not just the cartoonish analysts at Citi who think $0 would be too high a price for a barrel of Brent but literally everyone - oil has surged to a four-month high with Brent oil futures, which ended 2024 below $75 a barrel, rising above $81, and WTI trading at $78, up $10 in a month and the highest price since August.

The news of Biden's farewell gift to Trump spread like a shockwave around the world, as crude oil futures on the Shanghai International Energy Exchange surged by their daily limit, and helped send India’s rupee to a record low against the dollar.

The Biden sanctions prompted a cascade of frenzied headline reports, such as these...

... which did nothing to ease the market's sudden panic that everyone - literally everyone - is positioned incorrectly (short) in oil, and as a result of the coming squeeze we may see triple digit oil again. Wall Street analysts, who also had been remarkably bearish on oil, are now scrambling to undo their positioning

But has Biden truly succeeded in laying the biggest Easter Egg possible for Trump? That is the topic of a note published overnight by Goldman's commodity analyst Daan Struyen titled "Risks from Russia Sanctions" (available to pro subscribers), in which he writes that while the uncertainty from the Russia sanctions is very high, Godlman has not changed its base case for Russia production and oil prices for three reasons:

  • First, Russian oil can discount to incentivize continued shipping by a dynamic shadow fleet and continued purchases by price-sensitive buyers.
  • Second, Goldman assumes that the incoming US administration will likely want to avoid large and persistent drops in Russian volumes given its goal of lower US energy prices and its commentary signaling a greater focus on reducing oil revenues from Iran than from Russia.
  • Third, higher Russian refinery runs and higher refined products exports can help ease constraints on crude oil exports.

That said, Friday’s announcement strengthens Goldman's view that "the risks to our $70-85 Brent range forecast are skewed to the upside in the short term" and the bank now estimates that Brent could rise just above the top of our range if Russian production briefly falls by 1mb/d and to $90/bbl in a combined scenario where Iran supply also falls 1mb/d but in a persistent way.

Furthermore, Struyven writes that while a close call as sanctions may push up prices significantly further, Goldman is closing its ‘Well-Timed’ trade recommendation (long May-June 2025 vs. short May-June 2026 Brent timespreads) "because it has achieved its goal to capture US policy-driven short-term gains. We recommend oil producers take advantage of the increase in prices and in call skew to hedge downside risks with producer three-ways."

Across scenarios, the long-term price impact of lower sanctioned supply is limited because Goldman also assumes that OPEC+ would stabilize the market by deploying its high spare capacity and by raising production for longer than in our base case.

Below we excerpt from the Goldman Q&A in the note to clients (the full report is available to professional subscribers in the usual place).

Q1. What drove the oil price rally through Thursday ahead of the latest sanctions announcement?

In addition to algorithmic buying, we think three factors have driven the rally to $77/bbl through Thursday.

  • First, cold winter weather is modestly tightening the oil balance and could tighten it further. On the demand side, we estimate a 0.1mb/d boost to global oil heating demand from cold US weather (Exhibit 1, left panel). Cold weather in Europe or Asia can also indirectly and more persistently boost oil demand via gas-to-oil switching by boosting natural gas prices more than oil prices.1 On the supply side, freeze-offs may reduce oil production.
  • Second, market perception around the 2025 balance has changed as salient US crude inventories have declined for 7 weeks. Effective OPEC+ market stabilization, and rising compliance drove a 0.6mb/d deficit in 2024Q4, and we continue to disagree with the consensus narrative that a large 2025 surplus is a done deal given the uncertainty around non-OPEC and sanctioned supply.
  • Third, the market now appears to price in some premium compensating for the risk of a decline in Iran exports, where we see some signs of early frictions and an increase in the relative price of medium sour barrels (e.g. Dubai) similar to those that Iran produces (Exhibit 1, right panel).

Q2. What sanctions did the US Treasury announce on Friday?

The US imposed its broadest and strictest package of sanctions on Russia oil production and exports yet. The UK joined the US Treasury in sanctioning two Russia oil majors, which together accounted for nearly 1mb/d of oil seaborne exports in 2024. The US has also sanctioned 183 Russian vessels (mostly oil tankers) to increase pressure on Russia’s “shadow fleet”. Following the announcement, the number of Russian oil tankers sanctioned by the US, UK, and EU has doubled to 270 vessels.

We estimate that the vessels targeted by the new sanctions transported 1.7mb/d of crude and products in 2024 or 25% of Russia’s export volumes (Exhibit 3), with the vast majority being crude oil.

The latest measure also targets “opaque traders willing to ship and sell” Russia’s oil and the two largest Russian insurance providers for oil tankers, pushing Russia’s fleet further outside of credible insurance markets. The White House highlighted three key reasons for imposing sanctions only now, 10 days before inauguration: 1) higher spare capacity, 2) forecasts of a 2025 surplus, and 3) currently lower prices.

Q3. Have you changed your oil price forecast?

While the uncertainty is elevated, we have not changed our base case for Russian production (total liquids 2025 average of 10.6mb/d) and oil prices (Brent in the $70-85 range, averaging $76/bbl in 2025) for three reasons.

First, Russian oil can discount to incentivize continued shipping by a dynamic shadow fleet and continued purchases by price-sensitive buyers in new or existing destination countries, with both the ships and buyers being less sensitive to Western sanctions. We recently showed that sanctioned vessels often keep shipping Iranian oil in some  capacity, that new entrants tend to join the shadow fleet, and that most Iranian exports head to independent Chinese refiners that are less exposed to sanctions.3 Turning to the price-sensitive buyers, Exhibit 5 shows that India, China, and Turkey became the largest importers of Russian crude since the West imposed sanctions since 2022.

Second, we assume that the incoming US administration will likely want to avoid large and persistent drops in Russian oil volumes given its policy goal of lower US energy prices and commentary from several key incoming energy and foreign policy US officials signaling a greater focus on reducing oil revenues from Iran than from Russia. That said, President-elect Trump may not ease sanctions once he takes office but could tie their removal to the negotiation and/or successful implementation of a potential Ukraine-Russia peace deal. Third, higher Russian refinery runs and higher refined products exports can help ease constraints on crude oil exports.

Q4. How do you now see the risks to your oil forecast?

Friday’s announcement strengthens our view that the risks  to our $70-85 Brent range forecast are skewed to the upside in the short term, although we still see the medium-term risks to our range as skewed to the downside given high spare capacity. Exhibit 6 plots Brent oil prices in our base case and in four disruption scenarios. Our base case assumes that OPEC8+ raises production for four months starting in July with a cumulative contribution from reversing the extra voluntary cuts to production of +450kb/d. Across scenarios, the long-term price impact of lower sanctioned supply is limited because we assume that OPEC8+ would stabilize the market by deploying its high spare capacity and by raising production for longer than in our base case. The first scenario (dark blue) assumes that Russian production falls by 1mb/d in February and then recovers in April and May, and that OPEC8+ starts raising production in April, consistent with its data-dependent announcement, but only for four months (as in our base case). In this scenario, we estimate that Brent peaks at $86/bbl in March before gradually normalizing.

In a second scenario (red) where Russia supply falls persistently by 0.5mb/d, reflecting for instance that the Trump administration maintains Russia sanctions during the bargaining and/or the implementation of a potential Ukraine-Russia peace deal, we estimate that Brent rises to $83/bbl by mid-2025. We also assume OPEC8+ production increases in April-December at the announced pace (vs. July-October in our base case). In a third scenario (green) where only Iran supply drops by 1mb/d, reflecting tighter sanctions enforcement in a ‘maximum pressure’ campaign, we estimate that Brent rises to $83/bbl by mid-2025. We assume OPEC8+ production increases in
April-February 2026.

In a fourth combined scenario (grey) where Russian production briefly falls by 1mb/d (as in scenario 1) and Iran supply also falls 1mb/d but in a persistent way (as in scenario 3), we estimate that Brent rises to a peak of $90/bbl in March. We again assume OPEC8+ production increases in April-February 2026.

Q5. What Russia supply risks is the market pricing? Are you changing your recommendations to investors and oil producers?

Brent (1/36m) timespreads strengthened by $3/bbl from Friday’s open to close. Leveraging our pricing model, we estimate this is equivalent to a 0.5mb/d downgrade to Russian supply over the next six months, or a 25pp increase in the chance of a large 2mb/d disruption over this time period. Actual timespreads have now essentially caught up with our fair value estimate (which uses our baseline path for inventories assuming no Russia disruptions), implying a significantly faster closure in the undervaluation gap than we had assumed.

Ultimately, given our assumption that the US administration likely does not want to meaningfully disrupt the oil market, we view this as a significant repricing of supply risks. While a close call, we thus close our ‘Well-Timed’ trade recommendation (long May-June 2025 vs. short May-June 2026 Brent timespreads), which has, in our view, achieved its goal of capturing exposure to US policy-driven short-term gains.

Closing this recommendation is a close call because Russia or Iran sanctions may push up prices significantly further. After all, after Russia’s invasion of Ukraine, prices sharply overshot the impact implied by actual Russia disruptions. Because this rally was large relative to the actual 0.7mb/d peak drop in liquids supply, the Brent 1M/36M timespread remained 10-15pp above its fair value for the rest of 2022, consistent with a persistent risk premium of around $10/bbl

We also reiterate our recommendation that oil producers take advantage of the increase in prices and call skew to hedge downside risks with producer three-ways (e.g. sell 80 WTI call, buy WTI 65/55 put spread).

https://www.zerohedge.com/markets/parting-gift-trump-biden-sends-oil-prices-soaring

Sunday, January 12, 2025

German Chancellor Scholz Blocks €3 Billion Arms Package To Ukraine Ahead Of Election

 by Thomas Brooke via Remix news,

Germany’s federal government is reportedly embroiled in a behind-the-scenes dispute over plans to deliver an additional €3 billion in arms to Ukraine, according to German news outlet Der Spiegel.

It reported late on Thursday that Foreign Minister Annalena Baerbock and Defense Minister Boris Pistorius are pushing for the emergency funding ahead of the Feb. 23 federal election, but Chancellor Olaf Scholz has opposed the proposal over fears of further alienating disillusioned voters ahead of the vote.

Baerbock and Pistorius began assembling the aid package in November 2024, after the coalition government dissolved. Their proposal includes three Iris-T anti-aircraft batteries with ammunition, Patriot guided missiles, wheeled howitzers, and artillery shells, in response to Ukraine’s escalating military needs amid Russia’s intensified offensive and key territorial losses.

While Baerbock and Pistorius are understood to be eager to push through the funding, particularly ahead of U.S. President-elect Donald Trump’s inauguration amid concerns over the U.S.’ appetite to continue its support, the Chancellery believes there is no immediate need for additional aid.

According to Der Spiegel, Scholz noted that Germany’s 2025 provisional budget already allocated €4 billion for Ukraine’s military aid and Kyiv has access to a $50 billion loan pool provided by G7 nations, backed by frozen Russian state assets.

Scholz’s Social Democratic Party (SPD) has plummeted in the polls and is currently on course to attain 14 percent in the federal elections next month — down from 26 percent at the last vote. While his resistance may be an attempt to mitigate the losses, a frustrated Green Party — to which Foreign Minister Annalena Baerbock belongs — is attempting to push through the funding to shore up its own core voters by demonstrating its unwavering commitment to Ukraine.

The political landscape is further complicated by the breakup of the ruling coalition which triggered the snap election. The SPD and the Greens are now governing with a parliamentary majority, meaning efforts are needed to garner support from the Christian Democratic Union (CDU) and the Free Democratic Party (FDP). The former is currently predicted to become the largest party in the Bundestag next month and is unlikely to throw the current government a bone, while the latter recently resigned from the government and is also lacking the political appetite to cooperate.

In October last year, Remix News reported that a majority of German voters want an end to the conflict that has plagued Europe and led to economic hardship through inflated energy prices and significant Western financial and military assistance to Kyiv.

A YouGov poll from the time showed that 59 percent of Germans supported resuming direct communication between Chancellor Scholz and Russian President Vladimir Putin, hoping to advance peace negotiations.

The German view is reflected across much of Europe, and even among citizens in Ukraine’s most fervent allies. Last month, a new survey out of the Polish CBOS showed that some 55 percent of the Polish population now supports ending the war in Ukraine, even if it means Kyiv loses territory to Moscow.

https://www.zerohedge.com/geopolitical/german-chancellor-scholz-blocks-eu3-billion-arms-package-ukraine-ahead-election

HPE wins US$1 billion AI server deal for Elon Musk's X

 Hewlett Packard Enterprise Co. (HPE) won a deal worth more than US$1 billion to provide Elon Musk's X social network with servers optimized for artificial intelligence (AI) work.

https://www.digitimes.com/news/a20250113VL201/hpe-ai-server-elon-musk-dell-supermicro.html

US probe finds China unfairly dominates shipbuilding, paving way for penalties, sources say

 U.S. President Joe Biden's administration has concluded that China uses unfair policies and practices to dominate the global maritime, logistics and shipbuilding sectors, three sources familiar with the results of a months-long trade investigation told Reuters.

U.S. Trade Representative (USTR) Katherine Tai launched the probe in April 2024 at the request of the United Steelworkers and four other U.S. unions under Section 301 of the Trade Act of 1974, which allows the U.S. to penalize foreign countries that engage in acts that are "unjustifiable" or "unreasonable," or burden U.S. commerce.

Investigators concluded that China targeted the shipbuilding and maritime industry for dominance, using financial support, barriers for foreign firms, forced technology transfer and intellectual property theft and procurement policies to give its shipbuilding and maritime industry an advantage, said one of the sources, who was not authorized to speak publicly.

Beijing also "severely and artificially suppressed China's labor costs in the maritime, shipbuilding and logistics sectors," that person added, citing excerpts of the report.

No immediate comment was available from USTR, the White House or the transition team of President-elect Donald Trump. Chinese officials were not immediately available for comment.

The probe cites data showing that China's share of the $150 billion global shipbuilding industry has expanded to over 50% in 2023 from around 5% in 2000, largely aided by government subsidies, while once dominant U.S. shipbuilders have seen their share dwindle below 1%. South Korea and Japan are the next biggest shipbuilders.

The report provides a fresh cudgel for the incoming administration to hammer China, and could pave the way for tariffs or port fees on Chinese-built vessels, as proposed by the unions. Such a move would likely come after a public comment period, they said.

Trump used the same Section 301 statute to impose tariffs on hundreds of billions of dollars of Chinese imports during his first term after a USTR investigation found China was misappropriating U.S intellectual property and coercing the transfer of U.S. technology to Chinese firms.

USTR will release its findings later this week, days before Biden, a Democrat, leaves office on Jan. 20, said the sources.

The report comes on the heels of sharp criticism from the U.S. and other Western powers of China's aggressive industrial policies and over-production of commodities like steel, and reflects rare bipartisan agreement about the need to fix U.S. shipbuilding. China denies any wrongdoing.

The report follows four years of efforts by the Biden administration to reduce China's dominance by continuing Trump-era tariffs, adding new ones, including on electric vehicles, and imposing a range of export controls.

Tai's office last month announced a last-minute trade investigation into older Chinese-made "legacy" semiconductors that could heap more U.S. tariffs on chips from China that power everyday goods from autos to washing machines to telecoms gear.

Experts agree that rebuilding the once vibrant U.S. shipbuilding and maritime industry will take decades and cost tens of billions of dollars. Tariffs alone will not suffice, they said.

"China's targeting of the maritime, logistics and shipbuilding sectors for dominance is the greatest barrier to the revitalization of U.S. industries in these sectors," the report concludes, according to an excerpt shared with Reuters.

Scott Paul, president of the American Alliance for Manufacturing, a nonprofit labor-business partnership, said he understood that the findings were compelling.

"My understanding is that ... a process will be laid out to try to stop the erosion of our shipbuilding industrial base and to start it growing again," he said.

Trump, who has said he will increase tariffs on Chinese goods to 60%, last week blasted its moves to dominate commercial and military shipbuilding, telling radio host Hugh Hewitt that the U.S. had "suffered tremendously" and needed to shift course.

He also suggested that the U.S. might have to turn to allies to build needed naval vessels for the U.S. military.

Trump's incoming national security adviser Mike Waltz has also been deeply engaged on the issue, drafting a bipartisan bill with Democratic Senator Mark Kelly to revitalize the U.S. shipbuilding industry before he resigned from Congress.

"We're way too dependent on China in particular. We do not have surge capacity. We have very little shipbuilding capacity, and for a superpower that's completely unacceptable," Paul said.

The U.S. now has just 20 public and private shipyards down from over 300 American shipyards in the early 1980s. Experts say demand is strong and growing for civilian and military vessels.

https://www.aol.com/exclusive-us-probe-finds-china-060609350.html

Keytruda and Opdivo Scrutiny Highlights FDA’s Evolving Biomarker Focus

 

An FDA committee’s September 2024 vote to limit the use of Merck’s Keytruda and BMS’ Opdivo in stomach and esophageal cancers based on PD-L1 expression levels reflects an emerging trend that leverages ever-maturing datasets.

In the last decade, cancer treatment has pivoted to a precision medicine approach, with immunotherapies providing the backbone for many regimens. With this shift, patient biomarker data has become a crucial aspect of clinical trials, and recently, the FDA has been reassessing labels based on maturing datasets after approval.

Often, therapies for diseases with high mortality rates such as cancer are greenlit under the FDA’s accelerated approval pathway before all the data are evident. This has been the case for PD-1 inhibitors, including Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo, both of which are approved for treating several types of cancer.

“When [PD-1 inhibitors] first came out, we were like ‘everyone gets pembro,’ no matter the PD-L1 expression level because there was literally nothing else,” Harpreet Singh, former FDA division director of oncology and current chief medical officer at Precision Medicine, told BioSpace.

Now, treatment options have expanded, and the FDA is setting limits on when certain inhibitors should be used. In September 2024, the FDA’s Oncology Drugs Advisory Committee (ODAC) voted 10-2 against the use of Keytruda and Opdivo as first-line treatments for advanced HER2-negative stomach cancer in patients with PD-L1 expression scores less than 1, and 11-1 against the use of Keytruda and Opdivo in first-line unresectable or metastatic esophageal squamous cell carcinoma with low or no PD-L1 expression. The therapies are currently approved for use in all patients regardless of PD-L1 expression.

Despite the overwhelmingly negative ODAC votes in September, the FDA has yet to release a verdict, and Singh said “it’s not clear whether they will.” But there is precedent.

In 2022, the FDA limited the use of PARP inhibitors from Clovis Oncology and GSK to ovarian cancer patient populations with certain BRCA mutations. Prior to that, in 2018 the agency incorporated PD-L1 status into the labels of Keytruda and Tecentriq for existing frontline approvals for patients with urothelial cancers. The change came after a study revealed that patients with PD-L1 low status had decreased overall survival in the single-agent immunotherapy arms compared to chemotherapy.

“FDA is a data-driven scientific agency,” Singh said. “As the data grows and evolves, they’re adjusting their behavior to go where the data takes them.”

Following the Data

At the crux of the September ODAC votes was the risk-benefit profile of the PD-1 inhibitors in patients with low levels of the biomarker. Ultimately, the panelists concluded that if the PD-1 inhibitors do not appear to have substantial benefit for patients with PD-L1 scores lower than 1, their use is more likely to harm than to help.

PD-L1 is a measure of how involved the immune system is in a cancer, explained Elad Sharon, a medical oncologist at the Dana-Farber Cancer Institute. If an immune response is evident by the presence of PD-L1 on the cell surfaces, then PD-1 inhibition has a chance to work and benefit the patient, he told BioSpace. But if the immune system doesn’t interact with the tumor microenvironment to begin with, this type of inhibition is unlikely to provide any benefit.

“If you’re not providing benefit to a patient, then you probably are only providing harm,” Sharon said, noting that immuno-oncology agents thwart a normal regulatory pathway of the immune system. “You essentially take that tool out of the toolbox for the immune system, and that’s how you end up with these toxicities like inflammation or other areas of concern.”

These instances of regulatory reassessment follow the collection of further evidence, Singh said. The initial approval of Keytruda in 2014 was based on single-arm trials, which showed sufficient evidence of benefit to warrant approval, she explained. However, as a broader range of treatments became available, more biomarker data began to emerge. As these data matured for gastric and esophageal tumors, the hazard ratio uncovered wasn’t so favorable for patients without PD-L1 expression.

The FDA is the only regulatory body in the world that receives a company’s raw data, Singh explained. In the case of Keytruda and Opdivo in stomach and esophageal cancer, the agency utilized the subject-level datasets from each company to aggregate and interrogate the massive amounts of data, including biomarker status.

“They’re looking for trends across therapeutic classes . . . to see critical patterns that companies can’t identify alone because they don’t have each other’s subject level data,” Singh said.

The question comes down to the FDA’s role in these situations, she continued. Should the agency aggregate and publish the data to inform providers or take it a step further and restrict the label? A Merck spokesperson told BioSpace that the company “cannot speculate on the future actions of the FDA” and is “committed to continuing discussions” with the agency.

It’s a balance between leading with the data and patient access, Singh said, indicating her preference to publish the data and allow practitioners to ultimately make the call for their patients. However, if the label is restricted, she clarified that very few patients will be affected as gastroesophageal junction tumors are rarely negative for this biomarker.

Biomarker-Driven Drug Development

Perhaps the biggest lesson to be learned from the increased biomarker scrutiny after approval is for drug developers, Sharon said. He recommended the FDA require pre-specified analyses of relevant biomarkers in early-stage clinical trials.

“Identifying appropriate patient populations and developing statistically valid conclusions from clinical trials is an essential role that sponsors have to play,” he said.

Early-stage trials are crucial for determining if a drug works the way it’s expected to. Often, therapeutics have a compensatory mechanism or accessory pathway that can be affected, making it unwise to begin a trial with the assumption that a drug will be ineffective for a particular population, Sharon explained. Ideally, companies should track biomarkers but not exclude patients. These data can then be used to target the drug to the population expected to see the greatest benefit as well as develop an accompanying biomarker test for selection purposes.

“You can’t really separate the two,” Sharon said. Selectivity is only as good as the tests available, he explained, and “every time you end up with a new diagnostic technology, you have the ability to retest your assumptions and see if you can more precisely treat patients according to their specific needs.”

Ultimately, it’s the responsibility of both the FDA and the sponsors to determine which patients will actually benefit from a treatment, Sharon concluded—and what is really needed is more rigorous data.

“We have the technology to lead us to the right patient with the right therapy at the right time more now than ever,” he said. “We just have to make sure that when we’re developing new agents, we rigorously test and co-develop these biomarkers so that we can achieve that significant level of precision and benefit for our patients.”

https://www.biospace.com/drug-development/keytruda-and-opdivo-scrutiny-highlights-fdas-evolving-biomarker-focus

5 Cardio Gene Therapies on the Near Horizon

 

Benefiting from technological and conceptual groundwork and positive early data, gene therapies are advancing in the clinic for cardiovascular diseases including congestive heart failure, chronic refractory angina and cardiomyopathy.

Precision medicines—and particularly gene therapies—are coming for heart disease. That’s according to Faraz Ali, CEO of Tenaya Therapeutics, a California-based biotech focused on developing practice-changing cardiovascular therapies.

Cardiovascular diseases are the leading cause of death worldwide, claiming nearly 18 million lives annually, according to the World Health Organization. The disease category itself refers to a diverse set of conditions that afflict the heart and blood vessels, ranging from highly prevalent disorders such as heart failure and coronary artery disease to the rarer cases of cardiomyopathy associated with Duchenne muscular dystrophy or transthyretin amyloidosis.

In most cases, the first intervention option for cardiovascular disease is a change in lifestyle, including diet and exercise patterns. Medications are prescribed on a symptomatic basis—aspirin, for instance, thins the blood and combats clotting, while beta blockers slow down the heartbeat and help lower blood pressure.

But another therapeutic class, gene therapies, is starting to gain traction in this space. “We now have some early successes,” Ali told BioSpace, noting Rocket Pharmaceuticals’ work in Danon disease and Lexeo Therapeutics’ progress in Friedreich’s ataxia cardiomyopathy. “Now you have two examples of an AAV gene therapy for genetic cardiomyopathy where there’s early clinical benefit.”

The concept of gene therapy—using a healthy gene to improve or restore the expression of a certain protein—has at this point been validated as an effective treatment approach, Ali continued. Additionally, the techniques and tools that scientists use to identify and isolate genes of interest and package them into therapeutic particles have been highly refined, he said.

Here, BioSpace reviews five promising gene therapies being investigated for cardiovascular indications.

Renova Therapeutics’ RT-100

Indication: Congestive heart failure

The most mature asset on this list is Renova’s RT-100, which the California–based biotech is developing for congestive heart failure (CHF).

Afflicting more than 6 million Americans, CHF is linked to a variety of causes, including infections, blood clots or other cardiovascular conditions such as high blood pressure, heart inflammation or coronary artery disease.

According to Renova’s website, RT-100 works by delivering a copy of the AC6 gene, which encodes a protein found in heart muscles and plays a central role in regulating heart function. RT-100’s mechanism of action allows it to boost the content of the AC6 protein in the heart, improving the organ’s function.

In 2016, Renova published Phase II findings for RT-100 in JAMA Cardiology, touting a significant increase in left ventricular peak versus placebo at 4 weeks. Left ventricular peak is a key measure of left ventricular diastolic function that is typically compromised in heart failure patients. The gene therapy also significantly improved left ventricular ejection fraction at the same time point.

RT-100 was found to be safe for CHF patients, with no increase in arrhythmias, according to Renova. Two patients died, one in the active treatment group and another in the placebo arm. The rate of hospitalization for heart failure was likewise comparable between the RT-100 and placebo groups.

The study was small, however, enrolling only 56 patients, of whom 42 were dosed with RT-100. Renova was preparing to submit its plan for a pivotal Phase IIb/III study to the FDA as of May 2024. If successful in the Phase IIb part, RT-100 would then move on to the Phase III portion of the trial, setting the gene therapy up for a regulatory filing.

XyloCor’s XC001

Indication: Chronic refractory angina

Close behind Renova is XyloCor Therapeutics, which is targeting chronic refractory angina with XC001. In particular, the biotech is focusing on patients who are ineligible for coronary artery bypass and percutaneous coronary intervention, and who have tried and failed all other available pharmacologic options.

Affecting some 10 million people in the U.S., angina is a cardiovascular symptom that refers to chest pain or discomfort, typically due to plaques that obstruct the flow of oxygenated blood into the heart, forcing the organ to pump harder and faster. Angina is eased by addressing the underlying cardiovascular disease causing it, usually through the use of anticoagulants, blood pressure medication and cholesterol-lowering drugs.

Patients who continue to suffer from angina despite receiving optimal medical therapy develop chronic refractory angina.

XC001 addresses angina by delivering a copy of the VEGF gene into the heart, which promotes the development of new blood vessels that bypass existing obstructions and restore healthy levels of oxygen in heart muscles, according to XyloCor’s website.

In May 2024, XyloCor released final findings from the Phase II portion of its Phase I/II EXACT clinical trial, demonstrating that the gene therapy was safe and had “transformative disease-modifying potential” in patients with chronic refractory angina, the company said at the time. The data, published simultaneously in Circulation: Cardiovascular Interventions, showed that XC001 could significantly improve exercise duration, angina frequency and chest pain in patients.

XyloCor president and CEO Al Gianchetti said at the time that the biotech was preparing its next clinical trial to advance the development of XC001. According to a July 2024 press release, XyloCor will start a Phase IIb study for XC001 in chronic refractory angina, though the company has yet to provide a detailed timeline.

Regenexbio’s RGX-202

Indication: Cardiomyopathy in Duchenne muscular dystrophy

One of the hottest targets in biopharma, Duchenne muscular dystrophy (DMD) is a rare neurodegenerative disease marked by weakness and wasting in patients, who are typically diagnosed between the ages of three and six years. The disease mostly affects boys, at a frequency of 1 in 3,500 live births worldwide.

DMD is caused by mutations in the DMD gene on the X chromosome, which encodes the dystrophin protein, a crucial component of muscle cells. Alterations in the DMD gene lead to faulty dystrophin, in turn progressively compromising muscles across the body, including the trunk and limbs. Ultimately, DMD can also affect the heart muscles, leading to life-threatening complications.

Regenxbio is proposing RGX-202 as a one-time treatment for DMD. The investigational gene therapy works by delivering the microdystrophin transgene that codes for a dystrophin protein bearing an amino acid chain called a C-terminal domain. According to the biotech, this add-on domain has been shown in preclinical assessments to help make heart muscles more robust, in turn helping to preserve the healthy function of the organ.

In August 2024, Regenxbio reported interim data from the Phase I/II AFFINITY DUCHENNE trial, touting 77.2% and 46.5% microdystrophin expression in patients 5.8 and 8.5 years of age, respectively. The biotech at the time called these findings “robust,” adding that they “support plans for accelerated approval.” In November, the company announced that it has aligned with the FDA on the pivotal phase of AFFINITY DUCHENNE, for which the first patient had been dosed.

AFFINITY DUCHENNE is expected to be completed in December 2025, with a Biologics License Application scheduled for 2026.

AskBio’s AB-1002

Indication: Congestive heart failure

Joining Renova against CHF is Bayer subsidiary Asklepios BioPharmaceutical, or AskBio. The North Carolina–based biotech is advancing AB-1002, a one-time gene therapy designed to boost the expression of a specific protein inhibitor in the heart.

According to AskBio’s website, one potential cause of CHF is the downregulation of the inhibitor of protein phosphatase 1 (PP1) in the heart. PP1 is an important regulator of cellular pathways, and in the heart, it plays a central role in restoring the contractility of muscles to basal levels. Precise control over the action of PP1 is critical in maintaining the healthy function of the heart, and its excessive enzymatic activity has been linked to heart failure. AskBio’s AB-1002 seeks to address this particular cause of CHF by delivering a gene into the heart muscles, promoting their production of an inhibitory protein to PP1.

In November 2023, the biotech presented early Phase I data for AB-1002, showing that at the 12-month follow-up, a single dose of the gene therapy led to “clinically meaningful improvements” in left ventricular ejection fraction and symptoms in three patients, who also saw better exercise function. AB-1002 is currently being studied in the Phase II GenePHIT study, for which the first patient was randomized in February. The study’s primary completion date is October 2026.

Tenaya Therapeutics’ TN-201

Indication: Hypertrophic cardiomyopathy

Tenaya is taking a precision medicine approach to cardiovascular diseases, disaggregating patients into smaller subgroups according to biomarkers and targeting specific disease-causing genes.

“We’re taking a page out of the playbook of oncology,” Ali said of the company’s drug development philosophy. “We don’t just talk about breast cancer, right? We talk about breast cancer with a specific mutation that allows for more precise development and a more enriched study and potentially larger effect sizes.”

This approach has produced Tenaya’s lead asset TN-201, an investigational gene therapy delivered using an adeno-associated virus vector and targeting mutations in the MYBPC3 gene.

According to the biotech, approximately 20% of hypertrophic cardiomyopathy patients in the U.S.—corresponding to around 120,000 people—harbor mutations in the MYBPC3 gene, which in turn leads to an insufficiency in a key protein involved in regulating heart contraction. As a result, patients with this genetic anomaly have abnormally thick heart walls, which could give rise to several life-threatening complications such as heart failure and cardiac dysfunction.

Last month, Tenaya released early Phase Ib/II data for TN-201, demonstrating that after receiving a 3E13-vg/kg dose of the gene therapy, patients showed detectable levels of the vector DNA in their heart tissues, as well as signs of transgene RNA expression. Over time, levels of the TN-201 mRNA and the myosin-binding protein C also increased. Clinical markers of the disease also stabilized or gradually improved in two patients who had received TN-201.

At the time, CMO Whit Tingley said these data “provide important de-risking” of the TN-201 program and will allow the company to enroll patients into a higher-dose cohort. Still, investors were underwhelmed, sending Tenaya’s stocks tanking 50% following the readout.

William Blair analysts attributed the selloff to the RNA expression data, which was “significantly lower than what was observed in preclinical models.” More data from this study are expected this year, according to Tenaya.

https://www.biospace.com/drug-development/5-cardio-gene-therapies-on-the-near-horizon

Coalition Of Women's Sports Groups Urge Trump To Help Reform NCAA Rules

 by Steven Kovac via The Epoch Times,

A coalition of female athletes and women’s advocacy groups has asked President-elect Donald Trump for his help in demanding that the NCAA “restore fairness and opportunity to collegiate sports.”

In a letter to Trump dated Jan. 9, the coalition requests the soon-to-be inaugurated president to use his “powerful voice to urge the NCAA to take action and clarify participation rules to protect the rights and opportunities of female athletes.”

The coalition alleged that the NCAA has “failed” to respond to female athletes “who have been forced to choose between forfeiting games or participating in competitions that are fundamentally unfair and even dangerous.”

The group said it is appealing to the NCAA “in the name of fairness and commonsense.”

The letter was sent on the day the U.S. District Court in the Eastern District of Kentucky struck down the proposed Title IX regulations created by the outgoing Biden Department of Education.

The proposed rules would have added the terms “sexual orientation” and “gender identity” to the existing categories of male and female when defining sex discrimination.

The court decision applies to all educational institutions that receive federal funding.

Adopting the name “Our Bodies, Our Sports (OBOS),” the coalition is demanding that the NCAA establish and enforce the right of female athletes to participate in sports based on biological sex.

The coalition wants the NCAA to repeal all policies and rules that allow male athletes to take roster spots on women’s teams and compete in women’s events.

Beyond the Ruling

OBOS is demanding the NCAA revoke all records set by male athletes competing in female sports and restore the female NCAA sports archives by erasing championship wins by teams with male players and those of individual male competitors.

Single-sex locker rooms for female athletes are also among the OBOS demands, as is restoring the Title IX guarantee of equal opportunity for the sexes—a concept they say was “gutted” by the Biden administration.

Adriana McLamb is a former collegiate women’s volleyball player who is now coaching and serving as a recruiting coordinator in Florida.

McLamb, an activist with the Independent Women’s Forum, told The Epoch Times that the timing of the court ruling was good for her movement and that the election of Trump was “pivotal.”

“The two events mark the beginning of the change back to commonsense. A male is a male and a female is a female,” she said.

“Though the fight is not over, we can see the end of men playing in women’s sports and women getting their locker rooms back. Protecting women’s spaces is not anti-trans. It is pro-woman,” McLamb said.

McLamb stated that banning males from women’s sports, revoking the records men set, and stripping championships from trans-identifying individuals or teams with trans-identifying players, was all about “protecting future female athletes and righting the wrongs of the past.”

Rachel Crandall-Crocker, executive director of TransMichigan, an LGBT advocacy group, told The Epoch Times that the proposed actions would be “absolutely discriminatory.”

Crandall-Crocker expects there will be protests and hopes that the court’s decision will be overturned on appeal.

At the close of the letter to Trump, the coalition writes, “We the undersigned represent thousands of female athletes and women’s advocacy groups from across the political spectrum.

“We stand together in honor of the generations of women who came before us and in defense of all the women and girls who will come next.

“We ask for your help in demanding that the NCAA finally act to restore fairness and opportunity in collegiate sports,” the letter said.

Some of the eleven signatories to the letter include the Independent Women’s Forum, Young Women for America, and the Women’s Liberation Front.

The NCAA and the office of the president-elect did not provide comment by publication time.

https://www.zerohedge.com/political/coalition-womens-sports-groups-urge-trump-help-reform-ncaa-rules