Hezbollah Chief: US "Directly Responsible" For Gaza Atrocities, Will Soon Pay "Heavy Price"

 Summary recap: Hezbollah Secretary-General Hassan Nasrallah's speech went for just under one-and-a-half hours, and while full of threats and ultra-provocative heated words aimed at Israel and the United States, this was not a declaration of war speech. But he emphasized that Hezbollah's full entry into war with Israel will be determined based on developing events in Gaza, and whether Israel halts its attacks on the Palestinian people. Shelling on the Israel-Lebanese border was reportedly ongoing through and by the end of the speech in Beirut (Nasrallah addressed his top officers via remote feed from a secure location). Some highlights from Nasrallah's speech...

All "Options" on the table

"I assure you all options are open on the southern front. They can be adopted anytime," he said. "I assure you it will not be the end, this is not sufficient."

"If you wish to steer away from a regional war, you must end the war on Gaza. This front will develop according to developments in Gaza."

"If Israel strikes Lebanon it will be the most foolish act in all of Israel's existence."

US sent message to Hezbollah, warning its ships & planes will attack

Nasrallah related that Hezbollah was warned soon after Oct.7 that US ships and war planes positioned in the Mediterranean would bombard southern Lebanon if Hezbollah fighters escalate attacks on Israel. 

But Nasrallah said, "We will continue to infiltrate" and that Hezbollah's calculus will be "a civilian for a civilian" - meaning that attacks from southern Lebanon will be determined based on the intensity of Israel's attacks on Palestinians. 

On prospect of major regional war

"To the Americans I say, focusing your threats on Hezbollah and the region are pointless," Nasrallah said. The US said it "would not only attack Lebanon but will attack Iran."

"Your fleets in the Mediterranean do not and will not cause us to fear. We have prepared for your fleet what it takes. You Americans remember your defeats from Lebanon (early 80s), Iraq, and Afghanistan... your humiliating retreat from Afghanistan. He praised the recent attacks by Iraqi Shia militias against US based in the region.

"If an all out war erupts your fleet will be no good, your warplanes will be pointless, you will pay a heavy price."

America oversees aggression on Gaza, and can stop it

“Only you Americans can end what is happening now in Gaza, since you started it. The only factor that will affect our position is the progression of the war.” US is "directly responsible".

"I tell Israel: Do not go any further. Many civilians have already died. I promise you: A civilian for a civilian."

Hezbollah attacks have forced Israel to pull military assets

At one point in the speech he laid out that Hezbollah's daily missiles and shelling of northern Israel (which have remained limited) have served to force Israel to deploy up to one-third of its military hardware and assets to its northern border.

Nasrallah explained that in doing so, Israel is not prevented from focusing its full firepower on attacking "resistance factions" (Hamas and PIJ) in Gaza.

Via AP

And more notes from the speech via Bloomberg:

• “We have to be ready and present for all future probabilities”
• Says attacks on Israel near Lebanon borders “is very big from our side and very important and it won’t be enough for us anyway”
• Says the group is aware it’s taking a risk in the daily border attacks against Israel
• He says Israel forced to deploy heavily on the border with Lebanon, taking away from its fight in Gaza
• Says Oct. 7 attack on Israel was purely Palestinian decision and execution and “no one knew” about Hamas plan
• Says the US is “directly responsible” for Israel attacks on Gaza
• Says Israel will fail in wiping out Hamas as it failed in 2006 with its aim to wipe out Hezbollah
• Praises “martyrs” in Lebanon and elsewhere who were killed in fighting against Israel since the conflict began
  • Says dying in fight against Israel is “greatest of all”
  • “Just watch how a fighter advances and places rocket on an Israeli tank. How can they defeat this land and these type of fighters?”
  • Says previous and future sacrifices in Gaza, West Bank and all fronts are worth it
• Says Hamas attack showed Israel’s vulnerability and weakness strategically and militarily to the point that the US sent its ships to the Mediterranean at the onset of the attack

* * *

At 3 p.m. Lebanon time (9am ET), the leader of Hezbollah Hassan Nasrallah will give his first speech since the war between Israel and Hamas began, at a moment Israel is on a very high state of alert along its northern border.

Secretrary-General Nasrallah's speech could prove a turning point in the whole conflict depending on whether he tells his many tens of thousands of hardline Shia troops that a full war front will be opened against Israel. Will broader regional war kick off? Watch the speech live from Beirut: 

The US, Israel, and various Lebanese political factions have warned and urged Iran-backed Hezbollah not to escalate the conflict with Israel. Further Israeli officials have warned of military strikes on Hezbollah's key backers in Damascus and Iran should it escalate the war along Israel's northern border.

https://www.zerohedge.com/geopolitical/watch-live-hezbollah-leader-gives-first-speech-israel-high-state-alert

Scholar Rock Data from Phase 1 DRAGON Trial Showing Promising Anti-Tumor Activity

 

• Promising anti-tumor activity in heavily pretreated clear cell renal cell carcinoma (ccRCC) patients
• Objective response rate (ORR) of 21.4% and disease control rate of 57%
• Biomarker data supports proof of mechanism across multiple tumor types
• Combination therapy of SRK-181 and pembrolizumab was generally well tolerated
• Company to discuss SRK-181 program during conference call on third quarter 2023 financial results and business updates, Tuesday, November 7^th at 8 a.m. EST

https://www.biospace.com/article/releases/scholar-rock-presents-new-data-from-phase-1-dragon-trial-showing-promising-anti-tumor-activity-in-anti-pd-1-resistant-metastatic-ccrcc-patients-and-supporting-srk-181-continued-tolerability/

Confidence and Caution as AI Predicts Drug Safety

 When Alex Zhavoronkov launched Insilico Medicine in 2014, the company’s main focus was on using artificial intelligence as an alternative to animal testing for pharmaceutical research and development. Using deep learning, an advanced form of machine learning, the company aimed to predict how drug compounds would affect cells and what the side effects might be.

Fast forward to 2023, and Insilico has evolved into an end-to-end AI-driven biotech company, deploying AI from lead and target discovery through clinical trials. Insilico’s Pharma.AI platform, backed by $2 trillion in machine-readable research data, contains over 40 generative algorithms. The firm uncovered the intracellular “Target X” for idiopathic pulmonary fibrosis (IPF) using AI analysis, and subsequently developed a novel small molecule inhibitor, INS018_055, which has shown potential in preclinical studies for improved fibrotic disease treatment with fewer side effects. In August, it became the first drug fully generated by AI to enter a Phase II trial.

Making up the Pharma.AI platform, Insilico’s PandaOmics for target discovery, Chemistry42 for drug design and InClinico for clinical trial prediction “work together in an end-to-end feedback loop,” Zhavoronkov explained.

“However, safety of the target is accounted for at two different stages,” said Alex Aliper, president of Insilico. First, PandaOmics uses relevant existing information to find the safest and most promising therapeutic targets, while Chemsitry42 enables multi-parametric optimization of the molecules.

The latter includes ADMET predictors, a machine learning (ML) software tool, to assess how the body processes the generated molecule, covering aspects like absorption, distribution, metabolism, elimination and toxicity, as well as enzyme inhibition like cytochrome P450, which is involved in drug side effects. “Chemistry42 also has around 500 medicinal chemistry filters that filter out compounds with structural motifs known to be toxic,” Aliper told BioSpace.

“Our initial studies have indicated that INS018_055 has the potential to address some of the limitations of current IPF therapies—including unpleasant side effects—and we are hopeful that the data from our current and future clinical trials will confirm this belief,” Zhavoronkov said.

Schrödinger’s Selectivity

New York- and Germany–based Schrödinger focuses on the safety of small-molecule drugs. Its platform blends AI/ML efficiency with physics-based accuracy, enabling its specialists to design and synthesize desired molecules, thus reducing time and costs.

“In some cases, the clinical candidate has been selected after synthesizing just 100 molecules instead of the thousands made using traditional design approaches,” said Robert Abel, the company’s chief computational scientist.

In order to minimize drug side effects, Schrödinger uses its platform to design molecules that bind potently and selectively to the intended protein target versus related proteins, explained Karen Akinsanya, president of R&D, therapeutics at Schrödinger. “This approach allows us to find molecules that might provide a therapeutic benefit without binding to hERG, CYPs, PXR and other well-known off-target proteins that are well known to cause side effects,” she told BioSpace.

The hERG gene is crucial for heart rhythm regulation; CYPs, or cytochromes, are liver enzymes that metabolize drugs, potentially causing interactions; PXR, a cellular protein, helps process drugs and foreign substances by influencing enzyme production. These factors are vital in drug development and medication safety, Akinsanya said. “Protein structures, including binding sites, are crucial for our computational platform, but starting a drug discovery project often lacks enough experimental data for naive AI approaches due to the vast chemical space, which exceeds available data,” she explained. “Schrödinger addresses this by using advanced physics-based calculations to efficiently generate the needed binding affinity datasets.”

Both Insilico and Schrödinger use AI to discover drugs that they claim would be safer than those hunted down using non-AI methods. Big pharma players also entered this space a few years ago, either directly or by partnering with tech companies or incubating smaller AI-based startups. AstraZeneca collaborated with BenevolentAI to discover new targets and predict potential drug side effects by analyzing scientific literature, clinical trial data and biomedical databases.

Novartis employs AI for intelligent molecular design to develop safe molecules for patients. By analyzing various data sources, including chemical properties and biological interactions, the company aims to identify compounds with lower risk profiles. Meanwhile, Merck KGaA has been busy inking AI deals aimed at making safer medicines. In 2018, Merck struck an alliance with Canadian company Cyclica that uses the latter’s cloud-based technology to uncover new drug targets and identify off-target adverse effects. Then, in February 2022, the company announced a partnership to leverage Quris’ BioAI safety prediction platform, which uses miniaturized human tissues on a chip, nano-sensing and machine learning to predict the safety of drug candidates in humans.

Confidence and Caution

AI’s potential in drug development is often recognized with respect to saving time and money. However, its increasing deployment in drug safety studies elicits both confidence and caution from industry and researchers, according to experts such as Andreas Bender, a chemoinformatics researcher at the University of Cambridge, U.K.

Bender, who has been working with AstraZeneca on computational drug safety studies, said there is often a “tech push and a science pull” about AI. Although data collection becomes easier, understanding the data’s signal is more critical, he told BioSpace. “We have quite a lot of data, but we don’t understand much of that pile, like how certain biological mechanisms relate to a phenotype,” he said. Using AI to identify potential side effects is “like [finding] a needle in a haystack.”

Drug safety lies not just in how the molecule has been designed but also in other factors. For example, Bender explained, the use of excipients—the inert or slightly active substances used in formulating a drug compound into a drug product—and other additives can affect a drug’s safety profile, as can patient biology and environmental stimuli.

“There are mechanistic side effects that you know where they come from and what to do about, but there are also idiosyncratic side effects that you don’t know where they come from, so you cannot predict such adverse reactions using AI,” he said. Hence, along with machine learning, his group’s research also integrates chemical biology and human physiology to predict drug toxicity.

There are multiple other challenges, Bender continued, such as how different countries define specific side effects. “How do we translate, then, the [computational predictions] into decision-making?” he asked. “That integration is often where the real problems come from, and that’s why you always need to integrate computers with experiments—[to] follow up on predictions.”

Still, he said, AI-based predictions of drug safety could improve the drug development process. “It is, rather, about making better decisions. I’m not saying nothing works, but also not that everything works; just . . . that finding meaningful signals in drug safety prediction is statistically more difficult and depends on several [kinds of] data, so promises must be cautious and realistic.”

https://www.biospace.com/article/confidence-and-caution-as-ai-predicts-drug-safety/

Regeneron’s Eylea Sales Decline in Q3, Battle with Roche’s Vabysmo Heats Up

 Regeneron was hit with a sales decrease for its lead drug Eylea (aflibercept) in the third quarter due to a lower net selling price as a result of increased competition with Roche’s Vabysmo (faricimab-svoa).

On Thursday, Regeneron revealed that Eylea pulled in over $1.4 billion in U.S. sales, an 11% drop from $1.6 billion in the third quarter of 2022. The company blamed the decline on “a lower net selling price driven by changing market dynamics, including increased competition.” 

In the battle of wet age-related macular degeneration (wAMD) drugs, Vabysmo remained a formidable competitor in the quarter. In its third-quarter results announced last month, Roche reported that Vabysmo sales were 1.6 billion Swiss franc (CHF), or $1.7 billion, around the globe. In contrast, U.S. sales were reported at 1.3 billion CHF, or $1.4 billion, in the third quarter.

Despite its decline in sales, Regeneron is touting the FDA approval for an 8-mg dose of Eylea in August 2023, allowing dosing to occur in wider intervals.  The third quarter was the first quarter that the company started recording U.S. sales for Eylea HD, which was approved for wAMD, diabetic macular edema (DME) and diabetic retinopathy.

Under the new high-dose regimen, Eylea injections can be given every four weeks for the first three months across all indications. In diabetic retinopathy, the treatment can be administered every eight to 12 weeks thereafter, while the dosing interval can stretch up to 16 weeks in patients with wAMD and DME.

On the positive side of the ledger, sales of Regeneron’s eczema treatment Dupixent in the third quarter increased 33% to $3.1 billion, while Libtayo brought in $232 million, a 62% jump from the third quarter of last year.

“We have continued our momentum in the third quarter of 2023 with double-digit year-over-year revenue growth, driven by strong Dupixent and Libtayo performance, as well as strong initial uptake of Eylea HD following its late August launch,” Regeneron CEO Leonard Schleifer said in a statement. 

Overall, Regeneron pulled in good overall sales numbers for the third quarter, recording over $3.36 billion in revenues, a 15% increase from the same period in 2022. At the same time, Roche hit stumbling blocks  in the third quarter with a decline in sales stemming from a decrease in COVID-19 products. 

“Our third quarter financial results reflect robust execution across the enterprise, including notable pipeline advances and strong commercial performance,” Regeneron CFO Robert Landry said in a statement. 

The company on Thursday also touted its lymphoma treatment, odronextamab, which was accepted by the FDA for priority review. The drug has a target action date of March 31, 2024. 

https://www.biospace.com/article/regeneron-shows-eylea-sales-decline-in-battle-with-roche-s-vabysmo/

House GOP opens probe into FDA response to drug shortages

 House Republicans are launching a probe into how the Food and Drug Administration (FDA) is responding to a growing number of prescription drug shortages in the country. 

In a letter sent to FDA Commissioner Robert Califf, Republicans on the House Committee on Oversight and Accountability requested documents and a staff-level briefing to understand the agency’s role in monitoring drug shortages and mitigation strategies. 

The letter was signed by committee Chairman James Comer (R-Ky.) and health subcommittee Chairwoman Lisa McClain (R-Mich.). 

The FDA’s drug tracker lists nearly 130 drugs currently in short supply, including generic cancer drugs, amoxicillin, albuterol and Adderall. Earlier this year, there was a shortage of children’s acetaminophen and ibuprofen.  

Earlier this year, the FDA temporary authorized the importation of cancer drugs produced by non-FDA approved Chinese manufacturers to help ease the shortages. 

“The FDA is failing to ensure vitally important pharmaceuticals remain on pharmacy shelves,” the lawmakers wrote, adding that the agency’s problem with shortages predates the COVID-19 pandemic.  

“There are a variety of reasons for the current state of drug shortages apart from pandemic supply chain delays, including an over-reliance on offshore manufacturing facilities, surging demand for pharmaceuticals, and diminishing manufacturing of generics,” the lawmakers wrote.

The FDA said it had received the letter and will respond directly to the committee.

“While the agency does not manufacture drugs and cannot require a pharmaceutical company to make a drug, make more of a drug, or change the distribution of a drug, the public should rest assured the FDA is working closely with numerous manufacturers and others in the supply chain to understand, mitigate and prevent or reduce the impact of intermittent or reduced availability of certain products,” an agency spokesperson said in a statement to The Hill.

Comer and McClain asked for a staff-level briefing by Nov. 9 and documents by Nov. 16.  

https://thehill.com/policy/healthcare/4292104-house-gop-opens-probe-fda-response-drug-shortages/

Adderall makers agree to increase production: DEA

 Drug manufacturers have agreed to increase their production of stimulant medications like Adderall to help address the ongoing shortage in the U.S., with the Drug Enforcement Administration (DEA) making changes to its quota process.

The U.S. is experiencing a shortage of several stimulant drugs, including Adderall, Ritalin and Vyvanse. The Adderall shortage has gone on for more than a year now, impacting the thousands who rely on it for school or work.

Outside of work or school, stimulant drugs also help children regulate their mood and sleep, both of which can be affected if they suddenly stop taking their medication.

In a Friday letter addressed to the public, DEA Administrator Anne Milgram stated her agency and the Food and Drug Administration (FDA) recognize the “important role that prescription stimulants play in the treatment of conditions such as attention-deficit/hyperactivity disorder (ADHD), binge eating disorder, and narcolepsy.”

She emphasized that the DEA does not itself manufacture drugs and cannot compel a pharmaceutical company to make a drug, make more of a drug or change its distribution.

She further noted that manufacturers in 2022 did not produce the complete amount of stimulants they were permitted to produce, leading to a shortfall of 1 billion doses not made. Data from this year has indicated a similar trend.

After communicating with 18 relevant manufacturers, Milgram said 17 had agreed to use their given quota amounts and increase the production of stimulants. A time frame of when these substances will become available at pharmacies is still being determined.

Along with this action, Milgram shared steps the DEA was taking to increase transparency among drugmakers including requiring them to submit anticipated production timelines to the DEA before they receive their quota allotments; requiring manufacturers to apply for such allotments on a quarterly basis as opposed to annually; requiring digital reporting on how much of a drug is being produced and shipped; specifying whether a company’s quota allotment is for domestic production or export.

“These changes are designed to help us see shortages coming and adjust more quickly over the long run,” Milgram wrote. “We are also taking steps to reduce the burden on patients.”

“DEA is committed to ensuring that patients who need stimulant medications have access to them and to ensuring that these drugs are being prescribed thoughtfully and responsibly, and we will continue working with our partners inside and outside of government to do so.”

https://thehill.com/policy/healthcare/4292394-adderall-makers-agree-to-increase-production-dea/

Zinke proposes bill to ban Palestinians from entering US

 Rep. Ryan Zinke (R-Mont.) introduced a bill Thursday that could ban Palestinians from entering the U.S. and possibly expel those who are already here. 

Zinke, who served as secretary of the Interior Department under former President Trump, introduced legislation called the Safeguarding Americans from Extremism Act.

The legislation would require the Department of Homeland Security (DHS) to halt granting visas, asylum and refuge for people who have a Palestinian Authority-issued passport. The bill would revoke the entrance or visa for individuals who came to the U.S. after Oct. 1.

“This legislation keeps America safe,” Zinke said. “I don’t trust the Biden Administration any more than I do the Palestinian Authority to screen who is allowed to come into the United States. This is the most anti-Hamas immigration legislation I have seen and it’s well deserved. Given the circumstances, the threats to our immigration system and the history of terrorists abusing refugee, asylum and visa processes all over the world, the requirements in this bill are necessary to keep Americans safe. This bill does exactly that.”

Zinke’s bill would bar DHS Secretary Alejandro Mayorkas from granting Temporary Protected Status to people with the passport, along with refugee status and asylum. It would direct DHS to work with Customs Enforcement and United States Citizenship and Immigration Services to “identify” and remove individuals “without lawful status, including newly revoked status.” 

The legislation comes after GOP lawmakers issued a letter earlier in October to Mayorkas and Secretary of State Anthony Blinken to revoke and deport students on temporary student visas who “have expressed support for Hamas” in the aftermath of the deadly Oct. 7 attack on Israel that left more than 1,400 people dead. 

Zinke’s bill has 10 co-sponsors — Reps. Andy Harris (R-Md.), Aaron Bean (R-Fla.), Ralph Norman (R-S.C.), Scott DesJarlais (R-Tenn.), Clay Higgins (R-La.), Ronny Jackson (R-Texas), Bill Posey (R-Fla.), Barry Moore (R-Ala.), Marjorie Taylor Greene (R-Ga.) and Andy Biggs (R-Ariz.).

https://thehill.com/homenews/house/4292692-gop-rep-zinke-proposes-bill-to-ban-palestinians-from-entering-us/