SPECULATORS' NET SHORT BETS ON 2-YEAR TREASURIES ROSE TO RECORD HIGH DEC. 5 -CFTC DATA
Saturday, December 9, 2023
Autolus Data Updates at the American Society of Hematology
- Pooled analysis of the FELIX Phase Ib/II study demonstrated prolonged event free survival and low overall immunotoxicity across all cohorts in r/r B-ALL, and particularly in patients with low leukemic burden at lymphodepletion
- Longer-term data from a pooled analysis from the ALLCAR19 study and FELIX Phase Ib in r/r B-ALL showed durable remissions with obe-cel as a stand-alone therapy in a subset of patients after a median follow up of >3 years
- Additionally, ALLCAR19 extension cohorts demonstrated long-term responses with low immunotoxicity and prolonged persistence in patients with aggressive and indolent r/r NHL and r/r CLL
- Initial data from the MCARTY Phase I study in multiple myeloma showed AUTO8 was well tolerated, with responses observed in all patients
Autolus will host an in-person and webcast Analyst/Investor event to discuss the data onSunday, December 10, 2023 at8:00 AM PT /4.00 PM GMT
Webcast Registration: A live webcast will be held alongside the event. To register for the webcast please follow this link.
A recording of the event together with the presentation materials will be available on the Company’s website after the event.
Palestinians report Israeli battles in Khan Younis after US blocks Gaza ceasefire call
Israel ordered residents out of the centre of Gaza's main southern city Khan Younis and pounded the length of the enclave overnight, after the United States wielded its U.N. Security Council veto to shield its ally from a demand for a ceasefire.
Since a truce with Hamas in the two-month-old war collapsed on Dec. 1, Israel has expanded its ground assault into the southern half of the Gaza Strip, pushing into Khan Younis, where residents reported fierce battles. Both sides reported a surge in fighting in the north.
Israel said its campaign was making progress. National Security Adviser Tzachi Hanegbi said Israeli forces had killed at least 7,000 Hamas militants, without saying how that estimate was reached, and military chief Lieutenant-General Herzi Halevi told soldiers "we need to press harder".
An official toll of deaths in Gaza from the Palestinian health ministry in the Hamas-run enclave exceeded 17,700 on Saturday, with many thousands missing and presumed dead under the rubble. The ministry has said about 40% of deaths were of children under 18.
Israel launched its campaign to annihilate Gaza's Hamas rulers after their fighters burst into Israeli towns on Oct. 7, killing 1,200 people and taking 240 hostage, according to Israeli tallies.
Some 137 hostages remain in captivity, and thousands of Israelis rallied in Tel Aviv on Saturday to demand their release. A soldier who fought on Oct. 7 died from his wounds, the Israeli army said early on Sunday, adding four other soldiers died fighting in southern Gaza.
Most of Gaza's 2.3 million residents have been forced from their homes, often several times. As fighting rages across the territory, residents and U.N. agencies say there is effectively nowhere safe to go, though Israel disputes this.
Six French teenagers convicted in connection with 2020 beheading of teacher Paty
A French court on Friday convicted six teenagers in connection with the 2020 beheading of history teacher Samuel Paty, whose murder shocked the country.
The teacher had shown his pupils caricatures of the Prophet Mohammad in a class on freedom of expression, angering some Muslim parents. Most Muslims avoid depictions of prophets, considering them to be blasphemous.
Among those on trial was a teenage girl who had allegedly told her parents that Paty had asked Muslim pupils to leave the room before showing the caricatures.
The court found her guilty of having made false accusation charges and slanderous comments, as it was established that she was not in the class at the time.
The other adolescents were found guilty of charges related to taking part in a pre-meditated criminal conspiracy and helping to prepare an ambush.
Paty, 47, was killed outside his school in a Paris suburb by an 18-year-old assailant of Chechen origin, who was shot dead by police soon after the attack.
The court found those adolescents as guilty of having pointed out Paty to the murderer.
Louis Cailliez, lawyer for Paty's sister Mickaelle, told reporters his client was "satisfied with the full conviction", but less so with the sentences, that she found "too lenient".
Dylan Slama, a lawyer for one of the teenagers, said that though it was hard to talk about satisfaction in such tragic circumstances, there was a sense of relief for his client.
The heaviest sentence was given to an adolescent who was formally given a 6-month prison sentence, although he should be able to serve this at home while under electronic surveillance.
The girl who was found guilty of making false accusations and slanderous comments was given an 18-month suspended sentence and put on probation measures for two years.
All six teenagers' suspended sentences are tied to them following a strict set of probation measures for two to three years.
Another trial in connection with Paty's killing, involving adults this time, is set to take place at the end of next year.
https://news.yahoo.com/six-teenagers-convicted-connection-2020-194123280.html
Back in Court: The Inflation Reduction Act's Drug Pricing Ideas
BY DEREK LOWE
I wrote here in September about Merck's lawsuit fighting the Medicare-drug-price-negotiation mechanism in new Inflation Reduction Act, but they're not the only drug company in court about this, nor are their arguments the only ones being deployed. AstraZeneca also filed suit back in August, and there have been more filings in this case since then. In November, the US government answered in their own filing by saying that the company lacks standing to bring any such complaint and that their legal argument is flawed from the start anyway.
That argument is on a different basis than Merck's suit (which is largely based on constitutional provisions against "illegal takings" by government action). Instead, AZ says that the drug-price provisions of the new law violate the Administrative Procedures Act. The law says that ten "qualifying single-source drugs" a year (starting in 2026) will be subject Medicare (CMS) price negotiations - that is, only ones that have no generic or biosimilar competition (and were approved a sufficient number of years beforehand). And for the first round of such price restrictions, the agency needs to see proof of such generic competition by August of 2024 (which is when the negotiation period for the 2026 price changes ends, apparently). The deadline to make the call for the 2027 price changes is April of 2026. The law says that there has to be "bona fide" marketing for such a generic competitor, and they have a number of criteria for determining that.
And that's where AZ says the law is written in an illegal fashion. Their diabetes drug Farxiga (dapaglifozin) is on the list, but a generic competitor won't be on the market until after the August 2024 date (but will be in place before the actual price restrictions hit). So they will be subject to generic competition, but will have to negotiate their price down with CMS as if they didn't have any such competition at all, and will thus feel both effects at the same time. The company also says that the rules for determining whether something is a single-source drug will discourage it (and any othe drug company) for researching further uses of such a drug, since any new indication for it or new formulations for it will be automatically subject to the negotiated price. They note that Farxiga itself has had its FDA approval label extended to things like prevention of cardiovascular events in diabetes patients due to the company running further trials on it, but that this sort of work will be actively discouraged by the IRA provisions:
CMS’s definition of Qualifying Single Source Drugs dramatically alters manufacturers’ incentives to invest in such follow-on therapies using a previously approved active moiety. Under the agency’s approach, a product approved under a different NDA with the same active moiety as a selected drug product will now be treated as the same drug, and immediately become subject to the Maximum Fair Price. Under the agency’s definition, AstraZeneca would have no incentive to spend years and a steep financial investment researching alternative treatment uses for the active moiety of a selected product.
The company claims that both overriding the existing definiton of a single-source drug and the "sweeping" of later iterations under its provisions violate the Administrative Procedures Act. I myself am not enough of a lawyer to say if this argument has any force. I doubt that the government's claim that the company has no standing to sue will hold up ("You don't even have standing" is a standard legal tactic, just as asking for summary judgment is), but I can't guess intelligently how the two sides will fare in front of a judge. But we'll be finding out in the next few months, and finding out if all these legal challenges will delay the CMS timetable in general.
https://www.science.org/content/blog-post/back-court-inflation-reduction-act-s-drug-pricing-ideas
Trouble from CAR-T Treatment?
BY DEREK LOWE
The FDA took everyone by surprise recently by announcing that they were looking into 19 cases of lymphoma that they believe were actually brought on by the use of CAR-T cell therapy to treat other blood cancers. CAR-T is pretty much the last technological resort for resistant forms of leukemia, lymphoma, and myeloma; you turn to this method after all others have failed.
But that’s not because it doesn’t work, of course. Chimeric antigen receptor T cell therapy is often dramatically effective, but it’s a very expensive and laborious way to go. That’s because the treatment has to be customized for each individual patient. T cells from a patient are genetically modified to express receptors that target specific antigens (like CD19 and BMCA) that are not found in wild-type cells. These modified cells are expanded to large numbers and gradually infused back into the patient, where they start attacking their targets. That attack is a stressful process that can involve cytokine release syndrome and other side effects, but it can do a spectacular job of clearing the overabundant blood cell types that are the hallmark of those malignancies. The CAR-T cells multiply after infusion, and the effects can last for years. (In childhood syndromes like ALL, this is often used to buy time for eventual stem-cell transplants into the bone marrow, which can be curative).
The FDA says it’s aware of 19 cases of T-cell lymphoma, however, that may have been brought on by the modified T cells themselves. One way that could happen would be during the engineering to get the chimeric antigen receptors into their genomes - if these land in some specific (and specifically wrong!) places in the DNA sequence, it could set off carcinogenesis. At first, that might even manifest itself as a strong response to therapy - the CAR-T cells are multiplying away and killing off the B-cells (or other target) of the cancer to be treated. But what if they don’t stop, because they are experiencing cancerous growth themselves?
Interestingly, from news reports (here’s Stat and FiercePharma) the companies involved in making these therapies say that they have not received enough reports to add up to the FDA figure, and practitioners are expressing surprise as well. It’s certainly possible, though, that the agency has reports of its own. The total number of patients treated with CAR-T therapy so far would appear to be in the low tens of thousands. So that’s where you start working on the risk assessment. Are there particular antigens that are more likely to lead to T-cell malignancy? Particular ways of inserting them into the T-cell genomes? How many of the affected patients have had these cells sequenced to see if they really are a result of the CAR-T engineering, versus wild-type malignancies? These questions will all have to be sorted out to understand what we’re looking at.
The calculation would be easier if they patient population stayed in the “last resort” category, because those patients are going to die anyway, unfortunately, and do so rather quickly if something like CAR-T isn’t applied. But there are reports that CAR-T when administered earlier can spare patients years of chemotherapy - which is good, but now a possible risk of T-cell trouble may have to be factored in. If it turns out that chimeric antigen receptor therapy (as currently practiced) can lead to rare cases of T-cell lymphoma, the answer may be to change the way we do it - the technology for cell engineering is getting better all the time, and we should be able to lower the incidence of inadvertently producing a cancer cell line in the process, if that’s what’s going on.
https://www.science.org/content/blog-post/trouble-car-t-treatment
New cause of diabetes discovered, offering potential target for new classes of drugs to treat
Researchers at Case Western Reserve University and University Hospitals have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes.
Their study, published Dec. 5 in the journal Cell, focuses on nitric oxide, a compound that dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions.
How nitric oxide performs these activities had long been a mystery.
The researchers discovered a novel "carrier" enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action.
They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes.
Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases.
"We show that blocking this enzyme protects from diabetes, but the implications extend to many diseases likely caused by novel enzymes that add nitric oxide," said the study's lead researcher Jonathan Stamler, the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation at the Case Western Reserve School of Medicine and president of Harrington Discovery Institute at University Hospitals.
"Blocking this enzyme may offer a new treatment."
Given the discovery, next steps could be to develop medications against the enzyme, he said.
The research team included Hualin Zhou and Richard Premont, both from Case Western Reserve School of Medicine and University Hospitals, and students Zack Grimmett and Nicholas Venetos from the university's Medical Science Training Program.
Many human diseases, including Alzheimer's, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide binding excessively to key proteins.
With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus.
With diabetes, the body often stops responding normally to insulin.
The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems.
Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease.
But the reason that insulin stops working isn't well understood.
Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can't be targeted specifically, Stamler said.
"This paper shows that dedicated enzymes mediate the many effects of nitric oxide," he said. "Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases."
Journal Reference:
- Hua-Lin Zhou, Zachary W. Grimmett, Nicholas M. Venetos, Colin T. Stomberski, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, Rongli Zhang, James D. Reynolds, Richard T. Premont, Jonathan S. Stamler. An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling. Cell, 2023; DOI: 10.1016/j.cell.2023.11.009
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