Synthetic stress hormone dexamethasone could reduce certain breast cancer metastases

The drug dexamethasone supplements cancer treatments to alleviate side effects of chemotherapy such as nausea or inflammation. Researchers at the University of Basel, Switzerland, have now discovered that it also fights metastases in certain types of breast cancer.

The active substance dexamethasone is a synthetic signaling substance with a similar effect to the body's own stress hormone cortisol. A research group at the University of Basel has found evidence that this drug, which has been in use for a long time, could have a new, additional effect on certain treatment-resistant breast cancers.

Breast cancer of the "estrogen receptor-positive" (ER+ for short) subtype can usually be treated with anti-hormonal therapy. The target of this therapy is the estrogen receptor, which is hyperactive in these tumors and drives abnormal cell division. Hormone therapy uses drugs that deactivate or break down the estrogen receptor, thereby slowing the growth of cancer cells. However, this type of tumor sometimes forms metastases that no longer respond to hormone therapy.

Fewer metastases

A research team led by Professor Mohamed Bentires-Alj from the Department of Biomedicine at the University of Basel and the University Hospital Basel reports in the journal EMBO Molecular Medicine that dexamethasone can combat precisely these therapy-resistant metastases. In trials with mice with therapy-resistant ER+ tumors, dexamethasone reduced liver metastases and prolonged the animals' survival.

Further analyses provided more detailed insights into how the drug achieves this effect: dexamethasone activates the glucocorticoid receptor. This, in turn, suppresses the production of the estrogen receptor. "As a result, the cancer cells lose the main driver of tumor growth," explains Dr. Madhuri Manivannan, lead author of the study.

In addition to the trials with mice, the researchers also used patient-derived tumor tissue grown in the laboratory known as organoids. Here, they also observed that the amount of estrogen receptor decreased with the addition of dexamethasone

https://en.wikipedia.org/wiki/Dexamethasone

Synthetic stress hormone dexamethasone could reduce certain breast cancer metastases

Praxis Precision Medicines Announces FDA Acceptance and Priority Review of New Drug Application for Relutrigine in Patients with SCN2A and SCN8A DEEs

Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a fully integrated, leading central nervous system (CNS) precision neuroscience biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has accepted for priority review its New Drug Application (NDA) for relutrigine, for the treatment of SCN2A and SCN8A developmental and epileptic encephalopathies (DEEs). The FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) of September 27, 2026.

• FDA assigned PDUFA target action date of September 27, 2026

“Our first FDA acceptance of an NDA submission marks a significant milestone in our evolution to a commercial-stage company and an important step toward delivering innovative, precision neuroscience therapies to patients in need. SCN2A/8A DEEs have no currently approved targeted therapies and relutrigine, if approved, would be the first disease-modifying therapy for children suffering from these devastating and fatal conditions. We look forward to working closely with the FDA during the review process while continuing to advance our launch preparations,” said Marcio Souza, president and chief executive officer.

Relutrigine for treatment of SCN2A/8A DEEs

The NDA is supported by positive results from the EMBOLD study, which was stopped early for efficacy following a successful interim analysis and recommendation from the Data Monitoring Committee. Relutrigine has an Orphan Drug Designation, as well as a Rare Pediatric Disease Designation and a Breakthrough Therapy Designation. If granted approval, relutrigine will be the first FDA-approved therapy for SCN2A/8A DEE as well as be eligible for a Pediatric Review Voucher.

Relutrigine is also being investigated in broad DEEs through the EMERALD trial, which is expected to be completed by the end of 2026.

About Relutrigine

Relutrigine is a first-in-class small molecule in development for the treatment of developmental and epileptic encephalopathies (DEEs) as a preferential inhibitor of persistent sodium current, shown to be a key driver of seizure symptoms in severe DEEs. Relutrigine’s mechanism of precision sodium channel (NaV) modulation is consistent with superior selectivity for disease-state NaV channel hyperexcitability. In vivo studies of relutrigine have demonstrated dose-dependent inhibition of seizures up to complete control of seizure activity in SCN2A, SCN8A and other DEE mouse models. Relutrigine has been generally well-tolerated in three Phase 1 studies and has demonstrated biomarker changes indicative of NaV channel modulation. Data from cohort 1 of the Phase 2 EMBOLD study demonstrated a well-tolerated, robust, short- and long-term improvement in motor seizures in a heavily pre-treated population, alongside maintained seizure freedom in some patients with SCN2A- and SCN8A-DEE. Relutrigine has received Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation from the FDA for the treatment of SCN2A-DEE, SCN8A-DEE and Dravet syndrome; as well as Breakthrough Therapy Designation (BTD), and ODD from the European Medicines Agency for the treatment of SCN2A-DEE and SCN8A-DEE.

Praxis Precision Medicines Announces FDA Acceptance and Priority Review of New Drug Application for Relutrigine in Patients with SCN2A and SCN8A DEEs

Elevar Therapeutics Announces FDA Acceptance for Review of New Drug Application for Lirafugratinib as Second-line Cholangiocarcinoma Treatment

Elevar Therapeutics, Inc., a majority-owned subsidiary of HLB Co., Ltd. and a fully integrated biopharmaceutical company dedicated to elevating treatment experiences and outcomes for patients who have limited or inadequate therapeutic options, today announced that the U.S. Food and Drug Administration (FDA) has completed its filing review of the New Drug Application (NDA) for lirafugratinib, an investigational therapy, for the treatment of patients with cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements who have received prior therapy. The FDA determined that the NDA is sufficiently complete to permit a substantive review and granted Priority Review, with a Prescription Drug User Fee Act (PDUFA) target action date of September 27, 2026.

• With Priority Review designation, FDA set a Sept. 27 PDUFA date for approval decision
• Lirafugratinib achieved a 46.5% ORR, in CCA patients with FGFR2 fusion and rearrangement

Priority Review designations are given to applications for medicines that, if approved, would lead to “significant improvements in the safety or effectiveness of the treatment” of a serious condition, according to the FDA. The Priority Review designation of the lirafugratinib NDA was supported by positive clinical data from the Phase 1/2 ReFocus trial (NCT04526106), which demonstrated a confirmed objective response rate (ORR) of 46.5% in the patients with the proposed indication. Its safety profile in the clinical data has been shown to be predictable and manageable through dose adjustments.

“Lirafugratinib has established a compelling clinical profile that differentiates it from existing treatment options,” said Dong-Gun Kim, chief executive officer of Elevar. “We are very pleased with the FDA’s priority review designation and focused on advancing the review process efficiently to bring this therapy to patients as quickly as possible.”

CCA, also known as bile duct cancer, is rare, with about 8,000 people in the U.S. diagnosed each year, according to the American Cancer Society.

Elevar Therapeutics continues to evaluate lirafugratinib in ongoing clinical development programs, including studies in other FGFR2-altered solid tumors. Any future indications will be subject to regulatory review and approval.

For more information about lirafugratinib, visit ElevarTX.com.

About Lirafugratinib

Lirafugratinib (RLY-4008) is a potent, selective, and oral small molecule inhibitor of FGFR2, a receptor tyrosine kinase that is frequently altered in certain cancers. FGFR2 is one of four members of the FGFR family, a set of closely related proteins with highly similar protein sequences and properties. Preclinically, lirafugratinib demonstrated FGFR2-dependent killing in cancer cell lines and induced regression in in vivo models with minimal inhibition of other targets, including other members of the FGFR family. In addition, lirafugratinib demonstrated strong activity against known clinical on-target resistance mutations in vitro and in vivo preclinical models. Lirafugratinib is currently being evaluated in a clinical trial to enroll additional patients with previously treated, advanced or metastatic solid tumors other than CCA harboring FGFR2 fusion or rearrangement, who have not been treated with prior FGFR inhibitors.

Elevar Therapeutics Announces FDA Acceptance for Review of New Drug Application for Lirafugratinib as Second-line Cholangiocarcinoma Treatment

How statins harm muscles—and how to stop it

In continuation of my update  on statin 

Statins have transformed heart health, saving millions of lives by lowering cholesterol and reducing the risk of heart attacks and strokes. But for many patients, these drugs come with a troubling downside: muscle pain, weakness and, in rare cases, severe muscle breakdown that can lead to kidney failure.

University of British Columbia researchers and their collaborators at the University of Wisconsin-Madison have now pinpointed the cause. Their findings, published last week in Nature Communications, could pave the way for a new generation of statins without these side effects.

How statins affect muscle cells

The team used cryo-electron microscopy, a powerful imaging technique that reveals proteins at near-atomic detail, to capture how statins interact with a critical muscle protein called the ryanodine receptor (RyR1). This protein acts like a gatekeeper for calcium inside muscle cells, opening only when muscles need to contract. When statins bind to it, they force the gate open, causing calcium to leak continuously—a toxic effect that can damage muscle tissue.

"We were able to see, almost atom by atom, how statins latch onto this channel," said lead author Dr. Steven Molinarolo, a postdoctoral researcher in UBC's department of biochemistry and molecular biology. "That leak of calcium explains why some patients experience muscle pain or, in extreme cases, life-threatening complications."

Implications for future statin development

The study focused on atorvastatin, one of the most widely prescribed statins, but the findings suggest the effect may be common across the drug class. The researchers discovered that statins bind in a highly unusual way: Three molecules cluster together inside a pocket of the protein. The first molecule attaches when the channel is closed, priming it to open. Two more molecules then wedge in, forcing the channel wide open.

"This is the first time we've had a clear picture of how statins activate this channel," said Dr. Filip Van Petegem, senior author and professor at UBC's Life Sciences Institute. "It's a big step forward because it gives us a roadmap for designing statins that don't interact with muscle tissue."

By adjusting only those parts of the statin molecule that are responsible for the negative effects, scientists could preserve the part that lowers cholesterol while reducing the risk.

https://en.wikipedia.org/wiki/Statin

How statins harm muscles—and how to stop it

Methamphetamine impairs dopamine uptake by targeting a protein modification

In continuation of my update on Methamphetamine

Dopamine brings on a surge of pleasure, but too much dopamine in a synapse can ultimately lead to mood disorders and addiction. A recent preclinical study published in The FASEB Journal suggests that methamphetamine boosts dopamine levels by reversibly reducing the amount of a modification on the dopamine transporter. Loss of the modification decreases the transporter's ability to remove the neurotransmitter from synapses.

The findings shed new light on how the transporter works and could help researchers develop new treatments for addiction and neurological disorders, such as depression and schizophrenia.

The neurotransmitter dopamine is involved in many processes, such as movement, reward, motivation, learning, and memory. When triggered, special neurons in the brain release dopamine into the gaps between neurons, called synapses, making a person experience happiness and euphoria. Low levels, however, can make a person feel depressed.

Because inappropriate amounts can lead to psychological disorders or addiction, levels of the neurotransmitter are regulated by dopamine transporters (DATs) that remove excess dopamine from synapses. Protein modifications can modulate DAT activity. Palmitoylation enhances DAT reuptake of dopamine, whereas phosphorylation by the enzyme protein kinase C decreases reuptake.

Methamphetamine can slow reuptake by stimulating phosphorylation, but Roxanne Vaughan, James Foster, and colleagues at the University of North Dakota wanted to see whether the drug also affects DAT palmitoylation.

In a rat model and in in vitro experiments, methamphetamine rapidly reduced DAT palmitoylation and DAT transporter activity. Palmitoylation returned to normal levels much more quickly than transporter activity, which suggests that additional processes are involved in keeping DAT activity suppressed after palmitoylation recovers.

The methamphetamine effects were specific—cocaine did not impact palmitoylation. In vitro experiments revealed that protein kinase C was necessary for the reduction in palmitoylation. Additional experiments with DAT mutated at a position where half of the palmitoylation typically occurs reduced palmitoylation to about half of wild-type levels, and the mutant took up even less dopamine in methamphetamine-treated cells.

"By revealing that methamphetamine suppresses dopamine transporter palmitoylation, this study identifies a previously unknown mechanism through which the drug alters dopamine signaling," says Vaughan. "Understanding this process could guide the development of treatments aimed at stabilizing or restoring transporter regulation, potentially reducing the long-term dopamine imbalances and neurochemical damage linked to methamphetamine addiction."

https://en.wikipedia.org/wiki/Methamphetamine

Methamphetamine impairs dopamine uptake by targeting a protein modification

Polyphenol-rich diets associated with lower long-term cardiovascular disease risk

In continuation of my update on Polyphenol-rich diets

 People who regularly consume polyphenol-rich foods and drinks, such as tea, coffee, berries, cocoa, nuts, whole grains and olive oil, may have better long-term heart health

The research, led by King's College London, found that those with higher adherence to polyphenol-rich dietary patterns had lower predicted cardiovascular disease (CVD) risk.

Polyphenols are natural compounds found in plants that are linked to various health benefits, including improved heart, brain, and gut health.

The study, published today in BMC Medicine, followed more than 3,100 adults from the TwinsUK cohort for over a decade, found that diets rich in specific groups of polyphenols were linked to healthier blood pressure and cholesterol profiles, contributing to lower CVD risk scores.

For the first time, the researchers also analyzed a large number of metabolites in the urine that are produced when the body breaks down polyphenols.

These biomarkers confirmed that individuals with higher levels of polyphenol metabolites—especially those derived from specific groups of polyphenols, flavonoids and phenolic acids—had lower cardiovascular risk scores. They also had increased HDL cholesterol, also know as "good" cholesterol.

The study used a newly developed polyphenol dietary score (PPS) to capture intake of 20 key polyphenol-rich foods commonly consumed in the U.K., ranging from tea and coffee to berries, olive oil, nuts, and whole grains.

This score showed stronger associations with cardiovascular health than estimates of total polyphenol intake, likely because it captures overall dietary patterns rather than individual compounds. This finding suggests that considering the whole diet provides a more accurate picture of how polyphenol-rich foods work together to support long-term heart health

Professor Ana Rodriguez-Mateos, senior author and Professor of Human Nutrition at King's College London, said, "Our findings show that long-term adherence to polyphenol-rich diets can substantially slow the rise in cardiovascular risk as people age. Even small, sustained shifts towards foods like berries, tea, coffee, nuts, and whole grains may help protect the heart over time."

Dr. Yong Li, first author of the study, added, "This research provides strong evidence that regularly including polyphenol-rich foods in your diet is a simple and effective way to support heart health. These plant compounds are widely available in everyday foods, making this a practical strategy for most people."

The researchers note that while cardiovascular risk naturally increases with age, higher polyphenol intake was associated with a slower progression of risk over the 11-year follow-up period. They also emphasize the need for future dietary intervention studies to further validate these associations.

Polyphenol-rich diets associated with lower long-term cardiovascular disease risk

Polyphenol-rich diets associated with lower long-term cardiovascular disease risk

People who regularly consume polyphenol-rich foods and drinks, such as tea, coffee, berries, cocoa, nuts, whole grains and olive oil, may have better long-term heart health.

The research, led by King's College London, found that those with higher adherence to polyphenol-rich dietary patterns had lower predicted cardiovascular disease (CVD) risk.

Polyphenols are natural compounds found in plants that are linked to various health benefits, including improved heart, brain, and gut health.

The study, published today in BMC Medicine, followed more than 3,100 adults from the TwinsUK cohort for over a decade, found that diets rich in specific groups of polyphenols were linked to healthier blood pressure and cholesterol profiles, contributing to lower CVD risk scores.

For the first time, the researchers also analyzed a large number of metabolites in the urine that are produced when the body breaks down polyphenols.

These biomarkers confirmed that individuals with higher levels of polyphenol metabolites—especially those derived from specific groups of polyphenols, flavonoids and phenolic acids—had lower cardiovascular risk scores. They also had increased HDL cholesterol, also know as "good" cholesterol.

The study used a newly developed polyphenol dietary score (PPS) to capture intake of 20 key polyphenol-rich foods commonly consumed in the U.K., ranging from tea and coffee to berries, olive oil, nuts, and whole grains.

This score showed stronger associations with cardiovascular health than estimates of total polyphenol intake, likely because it captures overall dietary patterns rather than individual compounds. This finding suggests that considering the whole diet provides a more accurate picture of how polyphenol-rich foods work together to support long-term heart health.

Professor Ana Rodriguez-Mateos, senior author and Professor of Human Nutrition at King's College London, said, "Our findings show that long-term adherence to polyphenol-rich diets can substantially slow the rise in cardiovascular risk as people age. Even small, sustained shifts towards foods like berries, tea, coffee, nuts, and whole grains may help protect the heart over time."

Dr. Yong Li, first author of the study, added, "This research provides strong evidence that regularly including polyphenol-rich foods in your diet is a simple and effective way to support heart health. These plant compounds are widely available in everyday foods, making this a practical strategy for most people."

The researchers note that while cardiovascular risk naturally increases with age, higher polyphenol intake was associated with a slower progression of risk over the 11-year follow-up period. They also emphasize the need for future dietary intervention studies to further validate these associations.

https://link.springer.com/article/10.1186/s12916-025-04481-5

Polyphenol-rich diets associated with lower long-term cardiovascular disease risk

Lilly's announces results from Phase III clinical trial of Jaypirca

In continuation of my update on pirtobrutinib

Eli Lilly and Company announced results from the Phase 3 BRUIN CLL-322 clinical trial of Jaypirca (pirtobrutinib), a non-covalent Bruton tyrosine kinase (BTK) inhibitor, plus venetoclax and rituximab versus venetoclax and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The study met its primary endpoint of independent review committee (IRC)-assessed progression-free survival (PFS), demonstrating that the addition of pirtobrutinib to a two-year venetoclax plus rituximab regimen reduced the risk of disease progression or death by 45%.

These data will be highlighted in a late-breaking oral presentation at the 2026 European Hematology Association (EHA) Annual Meeting taking place in Stockholm, Sweden, as well as featured in the meeting's press program.

"These results from BRUIN CLL-322 show that the addition of pirtobrutinib as part of a time-limited regimen further enhanced an already effective treatment and extended the duration of remission for patients with previously treated CLL. Importantly, the study provides the first robust evidence for such an approach in patients who received a prior BTK inhibitor," said Matthew S. Davids, M.D., M.M.Sc., Chief of the Division of Lymphoma at Dana-Farber Cancer Institute, who is the lead author on the study.

"Time-limited regimens are an important option in CLL care and provide patients with meaningful treatment-free intervals. In the context of the modern CLL treatment landscape, where many patients may only receive two lines of therapy, these results speak to the potential benefits that improving second-line therapy can have. Our study has the potential to establish a new standard of care in this population."

BRUIN CLL-322 enrolled 639 relapsed or refractory patients, with 79.8% having prior covalent BTK inhibitor exposure, who were randomized 1:1 to receive pirtobrutinib plus venetoclax and rituximab (PVR, n=321) or venetoclax and rituximab alone (VR, n=318). Patients in the PVR arm received three cycles of pirtobrutinib and the first three cycles of rituximab before venetoclax was introduced.

The efficacy results are based on a February 2, 2026 data cutoff. At a median follow-up of 27.3 months, the primary endpoint of IRC-assessed PFS was significantly improved with the addition of pirtobrutinib to VR compared to VR alone (HR=0.55 [95% CI, 0.40-0.75]; p=0.0001). Median PFS in the PVR arm was not reached (95% CI, 43.3-NE), versus 39.7 months (95% CI, 35.9-NE) in the VR arm.

The PFS results were consistent across prespecified subgroups, including patients with prior covalent BTK inhibitor exposure (PVR: not reached [95% CI, 41.5-NE] versus VR: 36.2 months [95% CI, 33.2-NE]), those who discontinued prior covalent BTK inhibitor due to progressive disease (PVR: 43.3 months [95% CI, 39.2-NE] versus VR: 33.2 months [95% CI, 28.3-37.5]), as well as those with high-risk features such as unmutated IGHV, TP53 mutation and/or 17p deletion, and/or complex karyotype. In an exploratory analysis of second-line patients whose disease progressed after a first-line covalent BTK inhibitor, the median PFS was not reached (95% CI, 30.1-NE) in the PVR arm and was 28.3 months (95% CI, 20.5-NE) in the VR arm (HR=0.32 [95% CI, 0.14-0.73]), with 24-month PFS rates of 88% (95% CI, 75.7-94.6) and 52% (95% CI, 34.7-66.2), respectively, and consistent benefit was observed regardless of the specific prior covalent BTK inhibitor received, said the company.

Overall survival (OS), a key secondary endpoint, was not yet mature at this analysis (HR=0.89 [95% CI, 0.57-1.40]), and final testing of OS superiority is planned at a future date. An additional secondary endpoint, time to next treatment (TTNT), consistently favored the pirtobrutinib combination regimen.

The overall safety profile of this regimen in BRUIN CLL-322 was consistent with the known safety profile of each medicine, with little additive toxicity observed with the addition of pirtobrutinib to venetoclax and rituximab. Rates of Grade =3 adverse events (AEs) were similar with PVR compared to VR (78.8% versus 73.0%, respectively). Low rates of any grade atrial fibrillation/flutter (3.5% versus 2.6%, respectively), hypertension (12.0% versus 7.4%, respectively), and hemorrhage (14.2% versus 10.6%, respectively) were seen with PVR versus VR.

Grade =3 clinical AEs of interest included neutropenia (50.3% versus 43.7%, respectively) and tumor lysis syndrome (0.9% versus 3.9%, respectively) in the PVR and VR arms. Discontinuation rates due to treatment-related AEs were similar across the PVR and VR study arms (5.4% versus 5.1%, respectively). The addition of pirtobrutinib to VR also allowed for downgrading of tumor lysis risk, with 78% of high-risk patients downgraded to medium (n=20) or low risk (n=18), and 61% of medium-risk patients downgraded to low risk.

"These remarkable findings support the potential addition of two years of Jaypirca to a time-limited venetoclax-based regimen in relapsed or refractory CLL," said Jacob Van Naarden, executive vice president and president of Lilly Oncology.

"BRUIN CLL-322 enrolled a mostly covalent BTK inhibitor-pretreated population, ensuring that these results have applicability to the modern CLL treatment landscape where covalent BTK inhibitor use is now common. Additionally, these data further strengthen the unique body of evidence for Jaypirca across the CLL continuum, from monotherapy to combination therapy and across multiple settings where CLL patients need effective treatment."

Lilly plans to submit results from the BRUIN CLL-322 study to global regulatory authorities with the goal of further expanding Jaypirca's label. The company is studying Jaypirca in CLL/SLL in multiple Phase 3 studies.

Lilly's announces results from Phase III clinical trial of Jaypirca

Alternative sweetener sorbitol linked to liver disease

Sweeteners such as aspartame, found in Equal packets, sucralose (Splenda), or sugar alcohols are often seen as healthier alternatives to food with refined sugar (glucose). But that assumption is being challenged with new research, including the recent finding that the sugar alcohol sorbitol is not as harmless a sugar substitute as once thought.

The study, published recently in Science Signaling, follows a line of research detailing the harmful effects of fructose on the liver and other systems from the lab of Gary Patti, at Washington University in St. Louis.

Patti, the Michael and Tana Powell Professor of Chemistry, in Art & Sciences, and of genetics and medicine, at WashU Medicine, has previously published research about how fructose processed in the liver can be hijacked to supercharge cancer cells. Previous research has also found that fructose is a key contributor to steatotic liver disease, affecting 30% of the adult population worldwide.

Sorbitol's effects on the body

The most surprising finding from the current work is that because sorbitol is essentially "one transformation away from fructose," it can induce similar effects, Patti said.

The research involved experiments with zebrafish demonstrating that sorbitol, often used in "low-calorie" candy and gum, and commonly found in stone fruits, can naturally be made by enzymes in the gut and eventually converted into fructose in the liver.

Patti's team found there are many roads to fructose in the liver, and potential detours, depending on a person's sorbitol and glucose consumption patterns, along with the bacterial populations colonizing their gut.

The role of gut bacteria

For starters, although most of the research on sorbitol metabolism has focused on its production due to glucose overload in pathological settings such as diabetes, sorbitol can be naturally produced in the gut from glucose after eating, Patti said.

The enzyme that produces sorbitol has a low affinity for glucose, so glucose levels must be high for it to take effect. That is why sorbitol production has primarily been associated with diabetes, where blood glucose levels can become elevated. But, even in healthy settings, glucose levels in the gut become high enough after feeding to drive sorbitol production within the intestine, according to the team's zebrafish experiments.

"It can be produced in the body at significant levels," said Patti. "But if you have the right bacteria, turns out, it doesn't matter."

Sorbitol-degrading Aeromonas bacterial strains convert the sugar alcohol into a harmless bacterial byproduct. "However, if you don't have the right bacteria, that's when it becomes problematic. Because in those conditions, sorbitol doesn't get degraded and as a result, it is passed on to the liver," he said.

Once in the liver, it is converted to a derivative of fructose. It's important to determine if alternative sweeteners are providing a healthy alternative to table sugar, since people with diabetes and other metabolic disorders may be relying on them as "sugar-free" products.

Dietary habits and health implications

Gut bacteria do a good job of clearing sorbitol when it is present at modest levels, such as those found in fruit. But problems arise when sorbitol quantities become higher than what gut bacteria can degrade. This can occur when excessive amounts of glucose are consumed in the diet, which lead to high levels of glucose-derived sorbitol, or when dietary sorbitol itself is too high.

The more glucose and sorbitol consumed, then, even if someone has the friendly bacteria that clears it, those gut microbes may be overwhelmed with the task.

Avoiding both sugar and alternative sweeteners is increasingly complicated, as many foods are packed with multiple varieties of all the above. Patti was bemused to discover his own favorite protein bar was chock full of sorbitol.

The lab will need to do more research to understand the specific mechanisms for how bacteria clears sorbitol, but the basic idea that these sugar alcohols, called polyols, are harmlessly expelled, may not hold true. "We do absolutely see that sorbitol given to animals ends up in tissues all over the body," he said.

Bottom line: it's becoming more apparent that "there is no free lunch" when trying to find sugar alternatives, with many roads leading to liver dysfunction.

https://en.wikipedia.org/wiki/Sorbitol

Madelyn M. Jackstadt et al, Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria, Science Signaling (2025). DOI: 10.1126/scisignal.adt3549

Alternative sweetener sorbitol linked to liver disease

Drug developed for inherited bleeding disorder shows promising trial results

Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder worldwide, affecting one in 3,800 persons. HHT's hallmark symptom is chronic nosebleeds, which often occur alongside other internal bleeding and vascular malformations that impact quality of life and longevity.

Study explores new treatment option

A study from Mass General Brigham tested the safety and efficacy of engasertib, a drug specifically designed to target the condition. This 75-participant, double-blind, placebo-controlled trial found engasertib was safe and decreased nosebleed frequency and duration.

Their results are published in the New England Journal of Medicine.

"HHT causes serious vascular abnormalities throughout the body, often leading to dangerous, abnormal blood vessels in the brain, lungs, and liver, which bring with them major complications including stroke, heart failure, and brain hemorrhage—yet an FDA-approved treatment doesn't exist," said co-lead principal investigator and first author Hanny Al-Samkari, MD, a Mass General Brigham hematologist and co-director of the Hereditary Hemorrhagic Telangiectasia Center of Excellence at Massachusetts General Hospital.

"This engasertib trial is a step toward a better life for these patients, and I'm thrilled we found it to be both safe and effective at decreasing bleeding in HHT."

How engasertib targets HHT

HHT's impact can be both pervasive and devastating. HHT mutates the activin receptor-like kinase 1 (ALK1) pathway, which normally controls new blood vessel formation and vascular maintenance. With these mutations come an excess of the protein AKT—which is the target of engasertib, an oral, once-daily AKT inhibitor developed by Vaderis Therapeutics.

To test the drug's safety and efficacy, 75 people with HHT were randomly split into three treatment groups to take 30 milligrams of engasertib, 40 milligrams of engasertib, or placebo once daily for 12 weeks. The trial was sponsored by Vaderis Therapeutics and was designed by the sponsor in collaboration with the investigators.

Results and future implications

At the end of 12 weeks, patients who received engasertib experienced fewer and shorter nosebleeds relative to the placebo group. Additionally, 61% of the 40-milligram group and 37% of the 30-milligram group reported feeling "much better" at the end of 12 weeks, while only 27% of the placebo group said the same.

The drug was deemed safe, with the most common side effect being a mild and reversible rash and serious adverse events not differing significantly between treatment and placebo groups.

The trial positions engasertib as a potential future treatment for patients with HHT, but bigger, longer studies are still needed to validate the findings.

Drug developed for inherited bleeding disorder shows promising trial results

Eylea HD (aflibercept) Approved by FDA for the Treatment of Macular Edema Following Retinal Vein Occlusion (RVO) and for Monthly Dosing Across Approved Indications

Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced the U.S. Food and Drug Administration (FDA) approval of Eylea HD (aflibercept) Injection 8 mg for the treatment of patients with macular edema following retinal vein occlusion (RVO) with up to every 8-week dosing after an initial monthly dosing period. The FDA also approved an every 4-week (monthly) dosing option for some patients who may benefit from resuming this dosing schedule across approved indications: wet age-related macular degeneration (wAMD), diabetic macular edema (DME), diabetic retinopathy (DR) and RVO. 

Aflibercept is a combination of fluorouracil, leucovorin, and irinotecan,

flurouracil 

Folinic acid,

Irinotecan

"We believe these approvals further position Eylea HD as a treatment of choice for certain retinal diseases and underscore our relentless commitment to meeting the needs of patients and the retina specialists who treat them,” said George D. Yancopoulos, M.D., Ph.D., co-Founder, Board Co-Chair, President and Chief Scientific Officer, at Regeneron. “Eylea HD is the first treatment for retinal vein occlusion that can potentially cut the number of injections that patients receive in half compared to existing therapies. And with the addition of a monthly dosing option for all four approved Eylea HD indications, physicians now have greater flexibility and optionality to tailor treatment to meet individual patient needs.”

The FDA approval for the treatment of RVO is based on data from the Phase 3 QUASAR trial that evaluated the efficacy and safety of Eylea HD compared to Eylea® (aflibercept) Injection 2 mg in patients with RVO. QUASAR met its primary endpoint at 36 weeks, with Eylea HD patients dosed every 8 weeks (after either 3 or 5 monthly doses) achieving non-inferior visual acuity gains compared to those receiving Eylea dosed every 4 weeks. The Eylea HD results were consistent across patients with branch retinal vein occlusions, and those with central retinal or hemiretinal vein occlusions. In RVO, the most common adverse reactions reported in ≥3% of patients treated with Eylea HD were intraocular pressure increased, vision blurred, cataract, conjunctival hemorrhage, ocular discomfort/eye pain/eye irritation and vitreous detachment.

In regard to the Eylea HD pre-filled syringe (PFS), Regeneron continues to coordinate with Catalent Indiana, LLC (part of Novo Nordisk A/S) as it works to resolve the outstanding issues identified from a July 2025 FDA general site inspection (not specific to Eylea HD). As previously disclosed, Regeneron also plans to submit to the FDA an application to include an alternate PFS manufacturing filler for the Eylea HD BLA by January 2026.

Eylea HD is approved with dosing intervals from every 8 to 16 weeks for patients with wAMD and DME (following 3 initial monthly doses), every 8 to 12 weeks for patients with DR (following 3 initial monthly doses), and every 8 weeks for patients with RVO (following 3 to 5 initial monthly doses). In clinical trials, some Eylea HD patients did not maintain a response with extended dosing intervals after successful response to initial monthly doses; these patients may benefit from resuming every 4-week dosing.

https://en.wikipedia.org/wiki/Aflibercept#:~:text=Aflibercept%20is%20a%20recombinant%20fusion%20protein%20consisting%20of%20vascular%20endothelial,of%20the%20human%20IgG1%20immunoglobulin.

https://en.wikipedia.org/wiki/Fluorouracil

https://en.wikipedia.org/wiki/Folinic_acid

https://en.wikipedia.org/wiki/Irinotecan

Eylea HD (aflibercept) Approved by FDA for the Treatment of Macular Edema Following Retinal Vein Occlusion (RVO) and for Monthly Dosing Across Approved Indications

Ofirnoflast (HT-6184) Receives Orphan Drug Designation from U.S. FDA for Myelodysplastic Syndromes

Halia Therapeutics, Inc., a clinical-stage biopharmaceutical company pioneering therapies that target the root causes of inflammation-driven diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its investigational medicine ofirnoflast (HT-6184) for the treatment of Myelodysplastic Syndromes (MDS) — a group of bone marrow disorders characterized by ineffective blood cell production and a risk of progression to acute myeloid leukemia (AML).

The FDA grants Orphan Drug Designation to therapies intended for the treatment, prevention, or diagnosis of rare diseases or conditions that affect fewer than 200,000 people in the United States at the time of designation.

"This designation underscores the potential of our approach in Myelodysplastic Syndromes and supports our commitment to developing new treatment options for patients living with MDS," said David Bearss, PhD, Chief Executive Officer of Halia Therapeutics. "Ofirnoflast represents a first-in-class approach to modulating inflammasome biology, an upstream driver of inflammation, with the goal of restoring healthy bone marrow function."

Ofirnoflast is a selective NEK7 allosteric modulator designed to prevent the formation and promote the disassembly of the NLRP3 inflammasome, a central driver of chronic inflammation in multiple diseases. In MDS, inflammasome activation is increasingly recognized as a key contributor to ineffective hematopoiesis and bone marrow failure. By modulating NEK7, ofirnoflast aims to restore immune balance and improve blood-cell production without broad immunosuppression.

"Inflammasome biology represents a promising frontier for hematologic innovation," said Alan F. List, MD, member of Halia Therapeutics' Scientific Advisory Board and former President and CEO of Moffitt Cancer Center. "Ofirnoflast's approach is distinctive in that it seeks to modulate the underlying inflammatory drivers of MDS rather than just its downstream effects. This strategy has the potential to redefine how inflammation-linked bone marrow failure is treated."

Under the FDA's Orphan Drug Act, orphan-drug status provides several incentives, including tax credits for qualified clinical testing, exemption from FDA user fees, and potential for seven years of U.S. market exclusivity upon approval. The FDA also administers grant programs to support clinical research and advance the development of therapies for rare diseases.

About Myelodysplastic Syndromes (MDS)

Myelodysplastic Syndromes are a group of bone marrow disorders characterized by defective blood-cell formation, leading to anemia, infection risk, and bleeding complications. MDS primarily affects older adults and can progress to acute myeloid leukemia (AML). Current therapies, including hypomethylating agents and growth factors, often provide limited benefit and do not address the underlying inflammatory biology of the disease.

About Ofirnoflast (HT-6184)

Ofirnoflast (HT-6184) is Halia Therapeutics' lead investigational compound and a first-in-class NEK7 modulator that regulates activation of the NLRP3 inflammasome — an upstream molecular complex involved in chronic inflammation. The drug is currently being evaluated across multiple disease areas, including:

• Myelodysplastic Syndromes (MDS) – completed Phase 2 study evaluating safety and hematologic outcomes
• Obesity (in combination with semaglutide) – ongoing Phase 2 study targeting adipose inflammation and metabolic dysregulation
• Alzheimer's Disease – early-stage program focused on genetically at-risk populations

About Halia Therapeutics, Inc.

Halia Therapeutics is a clinical-stage biopharmaceutical company developing therapies that leverage genetic resilience to restore the body's natural ability to resolve inflammation. By targeting the NEK7–NLRP3 inflammasome axis, Halia's pipeline addresses a spectrum of chronic inflammatory and degenerative diseases, including hematologic disorders, metabolic disease, and neurodegeneration.

https://www.guidetomalariapharmacology.org/GRAC/LigandDisplayForward?ligandId=13227

Ofirnoflast (HT-6184) Receives Orphan Drug Designation from U.S. FDA for Myelodysplastic Syndromes - Drugs.com MedNews

Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that the first Phase III (FENhance 2) of two pivotal, similarly-designed Phase III studies (FENhance 1 and 2) in patients with relapsing multiple sclerosis (RMS) met its primary endpoint. Fenebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, significantly reduced the annualized relapse rate (ARR) compared to teriflunomide over a period of at least 96 weeks of treatment.

Additionally, the Phase III FENtrepid pivotal study evaluating fenebrutinib, compared with Ocrevus® (ocrelizumab) in patients with primary progressive multiple sclerosis (PPMS), met its primary endpoint. The results showed that fenebrutinib was non-inferior compared to ocrelizumab, the only approved therapy in PPMS, as measured by a delay in the onset of composite confirmed disability progression over a period of at least 120 weeks of treatment. A numerical benefit for fenebrutinib compared to ocrelizumab was seen as early as week 24, and lasted throughout the observation period.

“Fenebrutinib substantially reduced the number of relapses in RMS and slowed disability progression in PPMS. These unprecedented results suggest that fenebrutinib could potentially become a best-in-disease medicine as the first high-efficacy, oral treatment for people with RMS or PPMS,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. "Therefore, these pivotal results for fenebrutinib may offer new hope for people living with MS, and they reaffirm our enduring commitment to the MS community.”

Liver safety was consistent with previous fenebrutinib studies. Additional safety data is being further evaluated. The results of the second RMS Phase III trial (FENhance 1) are expected by the first half of 2026.

Fenebrutinib targets cells in the immune system known as B cells and microglia. Targeting B cells helps control the acute inflammation that causes relapses, while targeting microglia inside the brain addresses the chronic damage that is thought to drive long-term disability progression. Fenebrutinib, a non-covalent BTKi, is designed to have high potency, selectivity and reversibility. This design allows it to act throughout the body, and also to cross the blood-brain barrier into the central nervous system (CNS) targeting chronic inflammation.

About the FENhance 1 and 2 studies

FENhance 1 and 2 are similarly designed Phase III multicenter, randomized, double-blind, double-dummy, parallel-group studies to evaluate the efficacy and safety of investigational fenebrutinib compared with teriflunomide in a total of 1,497 adult patients with RMS. Eligible participants were randomized 1:1 to receive treatment with either oral fenebrutinib twice a day (and placebo matched to oral teriflunomide once a day) or oral teriflunomide once a day (and placebo matched to oral fenebrutinib twice a day) for at least 96 weeks.

The primary endpoint is annualized relapse rate (ARR). Key secondary endpoints include the time to onset of composite 24-week confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).

Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.

About the FENtrepid study

FENtrepid is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of fenebrutinib compared with Ocrevus in 985 adult patients with PPMS. Eligible participants were randomized 1:1 to receive treatment with either daily oral fenebrutinib (and placebo matched to intravenous [IV] Ocrevus) or IV Ocrevus (and placebo matched to oral fenebrutinib) for at least 120 weeks.

The primary endpoint is the time to onset of 12-week composite confirmed disability progression (cCDP12). The cCDP incorporates three measures of disability – total functional disability measured by the Expanded Disability Status Scale (EDSS), walking speed measured by the timed 25-foot walk (T25FW), and upper limb function measured by the nine-hole peg test (9HPT). This comprehensive composite endpoint offers greater sensitivity than the EDSS alone, capturing additional aspects of disability and often earlier. Key secondary endpoints include the time to onset of 24-week composite confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).

Following the double-blind treatment period, patients have the option to enter an open-label extension (OLE) phase, in which all patients receive treatment with fenebrutinib.

https://en.wikipedia.org/wiki/Fenebrutinib

Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis - Drugs.com MedNews

U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Iberdomide in Patients with Relapsed or Refractory Multiple Myeloma

Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for iberdomide combined with standard treatment (daratumumab + dexamethasone - IberDd) in patients with relapsed or refractory multiple myeloma (RRMM). Iberdomide is part of an investigational, new class of medicines called cereblon E3 ligase modulator (CELMoD) agents. The FDA has granted a Prescription Drug User Fee Act (PDUFA) date of August 17, 2026 for this indication.

• Iberdomide has the potential to be the first approved CELMoD agent
• The U.S. FDA has granted Breakthrough Therapy Designation and Priority Review for this indication and assigned a target action date of August 17, 2026

“The FDA’s acceptance of this application is a testament to the potential of iberdomide, in combination with anti-CD38 monoclonal antibodies, as a novel, potent, oral treatment option, with a manageable safety profile, for patients with multiple myeloma,” said Cristian Massacesi, executive vice president and chief medical officer, Bristol Myers Squibb. “Furthermore, our filing for iberdomide based on the MRD endpoint, underscores our commitment to pioneering new ways of advancing life-saving therapies for patients living with cancer.”

The filing was based on results from a planned analysis of MRD negativity rates in the Phase 3 EXCALIBER-RRMM study evaluating iberdomide as a treatment for RRMM patients. The EXCALIBER-RRMM trial is ongoing and patients continue to be evaluated for progression-free survival (PFS).

The FDA also granted Breakthrough Therapy designation for iberdomide based on these data.

This review is being conducted under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in several other countries.

https://en.wikipedia.org/wiki/Iberdomide

U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Iberdomide in Patients with Relapsed or Refractory Multiple Myeloma

Deciphera Pharmaceuticals Announces U.S. Food and Drug Administration Acceptance for Filing of New Drug Application for Tirabrutinib in Patients with Relapsed or Refractory PCNSL

Deciphera Pharmaceuticals, a member of Ono Pharmaceutical Co., Ltd. (Headquarters: Osaka, Japan; President and COO: Toichi Takino; “Ono”), today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing the New Drug Application (NDA) under the accelerated approval pathway for tirabrutinib, a highly selective irreversible, second generation Bruton tyrosine kinase inhibitor, for the treatment of relapsed or refractory primary central nervous system lymphoma (R/R PCNSL). The FDA has set an action date of December 18, 2026, under the Prescription Drug User Fee Act (PDUFA).

Regulatory submission is based on positive results from the Phase 2 PROSPECT Study

FDA sets PDUFA Date of December 18, 2026

“R/R PCNSL is a rare and aggressive form of non-Hodgkin lymphoma with particularly poor clinical outcomes. Patients often experience difficulty and delay in diagnosis, and once they are diagnosed, there is a high unmet need for a treatment with a favorable safety profile,” said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. “The FDA’s acceptance of tirabrutinib’s NDA for filing is an exciting milestone as it brings us one step closer to our goal of providing patients with R/R PCNSL an important new treatment option.”

“We are very pleased that the NDA for tirabrutinib has been accepted for filing,” said Toichi Takino, President and COO of Ono Pharmaceutical Co., Ltd. “This is an important milestone on the way to expanding our commercial pipeline and achieving our goal of becoming a global specialty pharma. Tirabrutinib’s potential to address unmet patient needs embodies our corporate philosophy and we will continue to focus on developing and delivering innovative medicines to benefit patients worldwide.”

The NDA is supported by the positive results from the Phase 2 PROSPECT study, presented at the 2025 American Society for Clinical Oncology (ASCO) Annual Meeting, in which tirabrutinib demonstrated an overall response rate of 67%, a complete response rate of 44%, and a manageable safety profile. If approved, tirabrutinib will be the first BTK inhibitor therapy commercially available in the U.S. for the treatment of patients with R/R PCNSL, and the third commercial therapy for Ono group available in the U.S. The study is currently recruiting patients with R/R PCNSL in a global Phase 3 randomized trial, which will serve as a confirmatory study for this indication (ClinicalTrials.gov NCT07104032.)

https://en.wikipedia.org/wiki/Tirabrutinib