Codiak Engineered Exosome Candidates Show Early Antitumor Activity

 

• Codiak BioSciences Inc 
  CDAK-10.4%+ Free Alerts
   announced platform-validating clinical data from Phase 1 trials of exoSTING and exoIL-12, and it plans to advance both candidates into Phase 2 trials. 
• In an open-label Phase 1 trial, exoIL-12 demonstrated a differentiating favorable safety and tolerability profile, with no detectable systemic exposure of IL-12 and no treatment-related adverse events. 
• The two patients with cutaneous T cell lymphoma who have been treated each received multiple injections of exoIL-12 and experienced tumor regressions in both injected and non-injected lesions, including a partial response in one patient. 
• In the Phase 1/2 trial of exoSTING in late-stage refractory solid tumors, data across all five dose cohorts showed that repeat doses of exoSTING were well-tolerated and demonstrated tumor retention with no systemic exposure of the STING agonist.
• In a subset of patients, tumor shrinkage was observed in injected and uninjected lesions. 

https://www.benzinga.com/general/biotech/22/06/27916340/codiak-biosciences-engineered-exosome-candidates-show-early-antitumor-activity

Takeda's Hereditary Angioedema Treatment Prevents Attacks In Kids Under 12

 

• Takeda Pharmaceutical Co Ltd 
  TAK+0.43%+ Free Alerts
   announced late-breaking data from the Phase 3 SPRING study presented at the European Academy of Allergy and Clinical Immunology Hybrid Congress 2022.
• The data demonstrated positive results of Takhzyro (lanadelumab) for preventing hereditary angioedema (HAE) attacks in patients 2 to <12 years of age, which were consistent with earlier studies in adult and adolescent patients.
• HAE attacks, which can involve serious and severely debilitating swelling in the abdomen, face, feet, genitals, hands, and throat, may occur very early in childhood. 
• Takhzyro reduced the rate of HAE attacks in children by a mean of 94.8% compared to baseline, from 1.84 attacks per month to 0.08 attacks during treatment.
• Most patients (76.2%) were attack-free during the 52-week treatment period, with an average of 99.5% attack-free days.
• No deaths or serious treatment-emergent adverse events (TEAEs) were reported during the study, and no patients withdrew from the study due to TEAEs.

https://www.benzinga.com/general/biotech/22/07/27932268/takedas-hereditary-angioedema-treatment-prevents-attacks-in-kids-below-12-years

CDC says ice cream is implicated in deadly outbreak of Listeria infections

 State and federal officials say ice cream is behind a deadly outbreak of Listeria monocytogenes infections that has affected people in 10 states.

“As a result of this investigation, Big Olaf Creamery in Sarasota, FL, is voluntarily contacting retail locations to recommend against selling their ice cream products. Consumers who have Big Olaf Creamery brand ice cream at home should throw away any remaining product,” according to a notice posted tonight by the federal Centers for Disease Control and Prevention.

As of June 30 there were 23 confirmed patients, one of whom died. Another patient was a pregnant woman who lost her baby because of the infection, the CDC reported earlier this week. Twenty-two of the patients were so sick they had to be hospitalized.

Of the 17 people interviewed as of today, 14 reported eating ice cream. Among 13 people who remembered details about the type of ice cream they ate, six reported eating Big Olaf Creamery brand ice cream or eating ice cream at locations that might have been supplied by Big Olaf Creamery.

The investigation is ongoing. The company has not initiated a recall.

“Of the 22 people with information, 20 sick people reported living in or traveling to Florida in the month before they got sick, although the significance of this is still under investigation. Illnesses started on dates ranging from Jan. 24, 2021, through June 12, 2022,” the CDC reported.

Whole genome sequencing showed that bacteria from sick people’s samples are closely related genetically. This means that people in this outbreak likely got sick from the same food.

Sick people range in age from less than 1 to 92 years, with a median age of 72, and 52 percent are male. Five people got sick during their pregnancies, and one illness resulted in a fetal loss.

The true number of sick people in an outbreak is likely higher than the number reported, and the outbreak may not be limited to the states with known illnesses, according to the CDC. In addition, recent illnesses may not yet be reported as it usually takes 3 to 4 weeks to determine if a sick person is part of an outbreak.

Seattle food safety attorney Bill Marler represented victims in recent years who were infected with Listeria monocytogenes found in Blue Bell ice cream. He said it is unfortunate to see the scope of the current outbreak in the wake of the Blue Bell outbreak.

The former president of Blue Bell, Paul Krouse, is set to go on trial beginning Aug. 1. The sanitary record of Blue Bell has become a pretrial issue that could spill over into any pre-outbreak record.

The CDC did not specifically report where the Big Olaf ice cream implicated in the current outbreak was manufactured.

About Listeria infections
Food contaminated with Listeria monocytogenes may not look or smell spoiled but can still cause serious and sometimes life-threatening infections. Anyone who has eaten any of the implicated Big Olaf ice cream and developed symptoms of Listeria infection should seek medical treatment and tell their doctors about the possible Listeria exposure.

Also, anyone who has eaten any of the recalled products should monitor themselves for symptoms during the coming weeks because it can take up to 70 days after exposure to Listeria for symptoms of listeriosis to develop. 

Symptoms of Listeria infection can include vomiting, nausea, persistent fever, muscle aches, severe headache, and neck stiffness. Specific laboratory tests are required to diagnose Listeria infections, which can mimic other illnesses. 

Pregnant women, the elderly, young children, and people such as cancer patients who have weakened immune systems are particularly at risk of serious illnesses, life-threatening infections, and other complications. Although infected pregnant women may experience only mild, flu-like symptoms, their infections can lead to premature delivery, infection of the newborn, or even stillbirth.

https://www.foodsafetynews.com/2022/07/cdc-says-ice-cream-is-implicated-in-deadly-outbreak-of-listeria-infections/

Most Dangerous Time To Drive Is Independence Day Weekend

 A record 42 million Americans are expected to hit the highways this Independence Day weekend. A new report warned roads across the country will be the most dangerous in years. 

The National Safety Council (NSC), a 501 nonprofit that promotes health and safety, estimated that 462 people might lose their lives on roadways this holiday weekend in preventable crashes. 

"On a typical day, more than 100 people die on our roads, and that number is climbing," Mark Chung, executive vice president of roadway practice at NSC, said in a statement. 

In a separate report, the National Highway Traffic Safety Administration expects roads will be the most dangerous in 16 years. Independence Day weekend appears to be the riskiest time to drive of the year. 

NSC didn't explain why the Fourth of July holiday celebrating the Declaration of Independence, ratified on July 4, 1776, is the most dangerous period of the year to drive, beating out New Year's Eve.

Independence Day is associated with fireworks, barbecues, carnivals, fairs, parties, and vacations. However, if we must opine, what else is there to do on a federal holiday when everything is closed? ... drink, of course. 

Law enforcement agencies are boosting patrols starting tonight and will through Monday night. Their biggest concern is drunk drivers. This also means authorities will operate overnight sobriety checkpoints throughout the weekend, a move to curb drinking and driving.

The average cost of a DUI is upwards of $20,000 – and that doesn't include property damage or anyone harmed. It's cheaper to Uber or Lyft this holiday weekend than risk a DUI.  

https://www.zerohedge.com/personal-finance/most-dangerous-time-drive-independence-day-weekend

Abortion and the FDA

 

• BY DEREK LOWE

I am not going to go into the politics of Friday's Supreme Court decision on abortion, and I need to start out by saying that I will reserve the right to delete comments to this post that are only politics-based flaming on the subject. But there is a drug regulation part of this story that could become increasingly important. This is of course the practice of "medication abortion", which is most commonly done through taking mifepristone (also known as RU-486) and misoprostol. Mifepristone became available in the US in 2000, and has over the years become the route for about half the abortions in the country, on a steadily rising trend that will surely continue. 

First the biology, then the regulatory affairs. Mifepristone is a competitive antagonist at the progesterone steroid receptor, a very potent one indeed (IC50 of about 25 picomolar) and it thus blocks progesterone's effects. It's an antagonist at some other steroid receptors as well (antiglucocorticoid and antiandrogen), but at potencies 100x to 1000x lower. Since we're talking nuclear receptors here, the terms "agonist" and "antagonist" (which were imported from G-protein coupled receptors) don't really fit all that well, though: mifepristone is an antagonist if it's competing with progesterone, but by itself (no progesterone around) it might be better described as a partial agonist, which is a pretty roomy category with the steroid receptors and the nuclear hormone receptors in general. But in the case of pregnancy, there is most definitely progesterone around (it's essential), and mifepristone shuts down its effects. That stops the maintenance of the uterine lining and starts its shedding process, detaching the embryo. After mifepristone treatment, misoprostol (a prostaglandin analog) dilates the cervix and induces muscle contractions, clearing the uterus. (Misoprostol itself can also induce an abortion, but it's more effective in combination with mifepristone). This whole process is basically what happens naturally in case of a miscarriage, so this is in fact a voluntary, chemically induced miscarriage. The usual regiment is 200mg of mifepristone, followed by 800 micrograms of misoprostol 24 to 48 hours later, and this combination has a very high success rate.

As of 2016, this combination is approved for use 70 days (or fewer) since a woman's last menstrual period. And now we get to the legal and regulatory aspects. FDA approval is of course a Federal decision - a drug (or a drug's use) that is approved by the FDA is approved in all fifty states and US territories. Here we have an example of the Supremecy Clause, more specifically the doctrine of "pre-emption", that Federal laws override state ones. If you really want to dive into that idea, it can be divided into "impossibility pre-emption", where it would just be impossible to follow both a state and a Federal law that conflict with each other, and "obstacle pre-emption", where a state law places undue obstacles to following the Federal one. But that is in constant tension with the Tenth Amendment, which says that the Federal government's powers are not unlimited, that these are only the powers delegated to it by the Constitution, and that all other rights, etc. are reserved for the states themselves. There have been a number of battles over the years about where the line is drawn between these two. A particular battleground has been one of those enumerated powers of the Federal government known as the Commerce Clause. This is the power to regulate commerce "among the several states", and for many years Federal authority had expanded in many areas under this heading. But in 1995, the Supreme Court in United States v Lopez held that Congress had managed to exceed its authority under the Commerce Clause (the first time in decades that any ruling like that had happened), and this came up again in United States v Morrison in 2000. You can come up with a lot of rationales for how some particular policy would affect interstate commerce, but you can't go on doing that forever in all directions.

I am most definitely not going to dive into the complications of the Commerce Clause or pre-emption, but I did want to illustrate the basic principles and to show that these are very much fields for argument. Because that's what we're about to see. After Friday's Supreme Court ruling in Dobbs, Attorney General Merrick Garland issued a statement that said (among other things) "we stand ready to work with other arms of the Federal government that seek to use their lawful authorities to protect and preserve access to reproductive care. In particular, the FDA has approved the use of the medication Mifepristone. States may not ban Mifepristone based on disagreement with the FDA’s expert judgment about its safety and efficacy." Xavier Becerra of HHS had similar words. Here's a Perspective piece earlier this year in the NEJM on pre-emption and mifepristone, which is a good look at the history of various state attempts to regulate it. Many of these are designed to avoid conflict with the safety-and-efficacy territory of FDA regulation, and instead come under the state-by-state regulation of medical practice - such as requiring an in-person doctor's visit (rather than telehealth), addition of waiting periods, or even provisions that the drug has to be taken in the presence of a physician. But it has to be noted that some of these are part of the federal Risk Evaluation and Management Strategy (REMS) that applies to mifepristone anyway.

So there's going to be plenty of sparring. This article from the New York Times is an early look at the landcape, and Steve Usdin has another at BioCentury. A key ruling is the 2014 attempt by the state of Massachusetts to ban the sale of Zohydro (a hydrocodone formulation), which was struck down in court because it could not stand up to FDA's regulatory pre-emption. But this issue will be revisited with particular attention to the FDA's ruling in April of 2021 that it would not enforce the mifepristone REMS requirement for in-person dispensing (which prohibited telehealth appointments and ordering through mail-order pharmacies). One side will argue that these have nothing to do with the agency's purview of regulating safety and efficacy, while the other will counter that because the drug has been shown to be safe and efficacious that these modifications are appropriate and need to be stated to prevent unlawful attempts to narrow them. Personally, I have never liked "decline to enforce" as a regulatory principle. I think it's a weak platform to stand on (are you trying to have things both ways?), and it just invites challenges that could be avoided by a more comprehensive change in the regulations. The FDA seems to be thinking this way as well - in December it announced that it was going to formally remove the in-person dispensing requirement from the REMS. You can expect lawsuits that will challenge this, probably from several states, and corresponding fights about whether the new rule should stay in effect while the court cases develop, etc.

Remember, the Dobbs ruling does not make abortion illegal. It reverses the Roe v Wade principle that it cannot be declared illegal, though, and thus returns the whole issue to a state-by-state battle. There's a lot of confusion on this point, as well as a lot of confusion about "returning to the time before Roe v Wade", since many people don't realize that that time was one of loosening abortion restrictions in general (with wider access state-by-state than we're going to see now, judging from the legislation already existing or underway in many states). Things have changed. But another one of those changes is the availibility of safe, effective abortion medication under federal regulatory law, and we're about to see how that mixes with "let the states decide". 

https://www.science.org/content/blog-post/abortion-and-fda