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

Finerenone shows superior survival and kidney protection over spironolactone in diabetic kidney disease

In continuation of my update on Finerenone

Researchers from National Taiwan University Hospital and collaborating institutions have demonstrated that finerenone, a new-generation nonsteroidal mineralocorticoid receptor antagonist (MRA), significantly reduces the risk of death and major heart and kidney events compared with spironolactone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).

The study, published in Nature Communications, analyzed real-world clinical data from over 2,200 patients across global health databases, using an advanced "target trial emulation" framework to mimic randomized clinical trials.

A safer and more effective alternative

Among adults with CKD and T2D, treatment with finerenone led to:

• 69% lower all-cause mortality (adjusted hazard ratio 0.31)
• 53% lower risk of kidney failure or rapid kidney decline (MAKE)
• 26% fewer cardiovascular complications (MACE)
  compared to spironolactone.

Moreover, finerenone users experienced fewer episodes of hyperkalemia (high blood potassium), a common side effect that often limits spironolactone use.

"Finerenone appears not only safer but also more effective in protecting both the heart and kidneys," said Professor Vin-Cent Wu, senior author and nephrologist at National Taiwan University Hospital. "Our findings provide real-world confirmation that this drug may transform care for diabetic kidney disease."

Advanced analytics with real-world evidence

Using the Global Health Network, encompassing over 146 health care systems worldwide, the team applied target trial emulation—a novel data-science approach—to overcome the limitations of traditional observational studies.

This method enabled researchers to simulate the design of a randomized clinical trial using real-world data, yielding robust comparative results that align with previous landmark studies (FIDELIO-DKD and FIGARO-DKD).

"This is the first real-world head-to-head comparison of finerenone and spironolactone," noted Dr. Chung-An Wang, first author. "The results show that finerenone provides meaningful survival benefits even over a relatively short 1.3-year follow-up

Clinical implications

Both finerenone and spironolactone block the effects of the hormone aldosterone, which contributes to inflammation and fibrosis in the kidneys and heart.

However, finerenone's more selective mechanism reduces the risk of electrolyte disturbances while maintaining strong protective effects on organ health.

This study suggests that finerenone could become a preferred treatment for patients with CKD and T2D, particularly those at higher risk of cardiovascular or renal complications.

"These results could help refine international treatment guidelines and improve outcomes for millions of people living with diabetic kidney disease," said Professor Wu.

The study applied a rigorous target trial emulation framework using global real-world data from over 2,000 matched patients across 21 countries, closely mirroring a randomized clinical trial.

By employing propensity score matching to balance key clinical variables, the study minimized bias and produced consistent, statistically robust results showing finerenone's lower risks of death, kidney failure, and cardiovascular events compared with spironolactone.

Supported by strong biological rationale, transparent methodology, and public data sharing, the findings are credible, reproducible, and clinically meaningful for improving outcomes in diabetic kidney disease.

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

Chung-An Wang et al, Finerenone versus spironolactone in patients with chronic kidney disease and type 2 diabetes: a target trial emulation, Nature Communications (2025). DOI: 10.1038/s41467-025-64640-3

Finerenone shows superior survival and kidney protection over spironolactone in diabetic kidney disease

FDA Approves Journavx (suzetrigine), a First-in-Class Treatment for Adults With Moderate-to-Severe Acute Pain

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX)   announced   U.S. Food and Drug Administration (FDA)   approval of  Journavx (suzetrigine), an oral, non-opioid, highly selective NaV1.8 pain signal inhibitor for the treatment of adults with moderate-to-severe acute pain. Journavx is an effective, well-tolerated medicine without evidence of addictive potential indicated for use across all types of moderate-to-severe acute pain.

“Today’s approval is a historic milestone for the 80 million people in America who are prescribed a medicine for moderate-to-severe acute pain each year,” said Reshma Kewalramani, M.D., Chief Executive Officer and President of Vertex. “With the approval of Journavx, a non-opioid, pain signal inhibitor and the first new class of pain medicine approved in more than 20 years, we have the opportunity to change the paradigm of acute pain management and establish a new standard of care.”

“This is an incredible day for patients and physicians alike who now have an approved non-opioid treatment that delivers effective acute pain relief and a favorable safety profile without addictive potential,” said Jessica Oswald, M.D., M.P.H., Associate Physician in Emergency Medicine and Pain Medicine in San Diego and Vertex Acute Pain Steering Committee Member. “I believe Journavx could redefine the management of pain and become a foundational treatment option for people with all types of moderate-to-severe acute pain, where options aside from opioids have been so desperately needed.”

As part of Vertex’s ongoing commitment to patients, the company has established patient support programs to help ensure that qualified patients can access Journavx. For more information visit Journavx.com.

About Acute Pain

Acute pain is a serious and potentially disabling condition often caused by surgery, accident or injury. Over 80 million Americans are prescribed medicine to treat their moderate-to-severe acute pain every year. Of these, about 40 million are prescribed an opioid. Nearly 10% of acute pain patients treated initially with an opioid will go on to have prolonged opioid use, and about 85,000 patients will develop opioid use disorder annually. Poorly controlled acute pain can lead to reduced quality of life, development of chronic pain, and increased burden on the health care system and society.

About Journavx (suzetrigine)

Journavx (suzetrigine) is a first-in-class, oral, non-opioid, highly selective pain signal inhibitor that is selective for NaV1.8 relative to other NaV channels. NaV1.8 is a voltage-gated sodium channel that is selectively expressed in peripheral pain-sensing neurons (nociceptors), where its role is to transmit pain signals (action potentials). Because Journavx blocks pain signals only found in the periphery, not in the brain, Journavx provides effective relief of pain without the limitations of currently available therapies, including the addictive potential of opioids.

The U.S. Food and Drug Administration approved twice-daily Journavx for the treatment of adults with moderate-to-severe acute pain. Vertex has established a wholesale acquisition cost for Journavx in the United States of $15.50 per 50mg pill.

Vertex is also evaluating suzetrigine in peripheral neuropathic pain (PNP). The company’s Phase 3 pivotal program for suzetrigine in patients with painful diabetic peripheral neuropathy is ongoing, and Vertex plans to advance its pivotal program evaluating suzetrigine in patients with painful lumbosacral radiculopathy pending discussions with regulators.

INDICATION and IMPORTANT SAFETY INFORMATION

INDICATION AND USAGE

Journavx is a prescription medicine used to treat adults with moderate-to-severe short term (acute) pain.

It is not known if Journavx is safe and effective in children.

IMPORTANT SAFETY INFORMATION

Patients should not take Journavx if they take certain medicines that are strong inhibitors of an enzyme called CYP3A. Patients should ask their healthcare providers if they are not sure.

Before taking Journavx, patients should tell their healthcare provider about all of their medical conditions, including if they: have liver problems. People with liver problems may have an increased risk of getting side effects from taking Journavx; are pregnant or plan to become pregnant as it is not known if Journavx will harm an unborn baby. Patients and their healthcare providers should decide if they will take Journavx while they are pregnant, are breastfeeding, or are planning to breastfeed, as it is not known if Journavx passes into breast milk. Patients and their healthcare providers should decide if they will take Journavx while they are breastfeeding.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Journavx with certain other medicines may affect the way Journavx and the other medicines work and may increase patients’ risk of side effects. Patients should ask their healthcare provider or pharmacist for a list of these medicines if they are not sure.

Patients should especially tell their healthcare provider if they take hormonal birth control medicine (contraceptives) containing progestins other than levonorgestrel or norethindrone. If they take one of these contraceptives (progestins other than levonorgestrel or norethindrone), they may not work as well during treatment with Journavx. Patients should also use nonhormonal contraceptives such as condoms or use other forms of hormonal birth control during treatment with Journavx and for 28 days after they stop taking Journavx. Medicines that are substrates of the CYP3A enzyme may become less effective during treatment with Journavx. Their healthcare provider may need to adjust the dose of patients’ medicine when starting or stopping Journavx. Patients should know the medicines they take and keep a list of them to show their healthcare provider and pharmacist when they get a new medicine. Patients should not take food or drink containing grapefruit while taking Journavx.

Journavx can cause side effects: The most common side effects for patients treated with Journavx include itching, muscle spasms, increased blood level of creatine phosphokinase, and rash. Journavx may temporarily reduce the chance of females becoming pregnant while on treatment. Patients should talk to their healthcare provider if they have concerns about becoming pregnant. If patients are using contraceptives, continue to use contraceptives during treatment with Journavx. Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away. These are not all of the possible side effects of Journavx. Patients should call their healthcare provider for medical advice about side effects. Patients may report side effects to the FDA at 1-800-FDA-1088.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple serious diseases and conditions — cystic fibrosis, sickle cell disease, transfusion-dependent beta thalassemia and acute pain — and continues to advance clinical and research programs in these areas. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, primary membranous nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes and myotonic dystrophy type 1.

https://en.wikipedia.org/wiki/Suzetrigine#:~:text=Concomitant%20use%20of%20suzetrigine%20with%20strong%20CYP3A4%20inhibitors%20is%20contraindicated.

FDA Approves Arbli (losartan potassium) Oral Suspension as the First Ready-to-Use Oral Liquid Losartan in the U.S.

In continuation of my update on losartan

Scienture Holdings, Inc.   announced the U.S. Food and Drug Administration (FDA)  approval of SCN-102, one of the products being developed by Scienture, LLC, a wholly owned subsidiary of Scienture Holdings, Inc., with the brand name Arbli (losartan potassium) Oral Suspension, 10 mg/mL. Arbli is meant for the treatment of hypertension in patients greater than 6 years old, for the reduction of risk of stroke in patients with hypertension and left ventricular hypertrophy and for the treatment of diabetic nephropathy in certain patients with type 2 diabetes. Arbli is the first and only FDA approved ready-to-use oral liquid losartan in the U.S. market.

Arbli is a novel proprietary formulation of losartan, a proven therapy for treating hypertension, which provides a tailored approach to patients that require or prefer an oral liquid option of losartan. Appropriate dosing is now easier, safe and effective, while providing the assurance of quality as an FDA-approved product. Arbli provides a safe and convenient option to patients requiring a liquid formulation and addresses the intrinsic risks associated with potential inconsistencies in the process of crushing tablets to extemporaneously compound losartan prescriptions. Arbli has two issued patents from the USPTO, which are also expected to be listed in the FDA Orangebook.

Losartan is classified as an angiotensin receptor blocker (ARB) for treating hypertension and is one of the highest prescribed molecules for this indication. Current products in the market containing losartan are available only as oral solids, which can be further compounded to a liquid formulation. Arbli is the first liquid formulation of losartan on the market that does not require compounding and has reduced dosing volume and long-term shelf life at room temperature storage. IQVIA data (MAT December 2024) indicates a total annual sales of approximately $292 million and a prescription volume of 68 million (TRx) for losartan in the US market.

“The approval of Arbli exemplifies our deep commitment to develop high value products that address unique and underserved patient needs. A significant number of patients can benefit from a safe and efficacious ready-to-use oral liquid formulation of losartan. We are excited with the approval of our first brand product which is part of our upcoming pipeline of novel specialty products,” remarked Shankar Hariharan, CEO of Scienture, LLC.

“We are pleased to bring to market, Arbli, a transformative therapy option containing losartan, one of the most widely prescribed molecules in its class, to patients, caregivers and healthcare professionals (HCPs). We expect to commercially launch and make Arbli available to patients in the U.S. in Q3 2025,” said Narasimhan Mani, President of Scienture, LLC.

“This announcement is extremely exciting and is a clear demonstration of the value Scienture, LLC brings to the combined company and its shareholders,” said Suren Ajjarapu, Chairman of the Board, Scienture Holdings, Inc.

REF ;https://en.wikipedia.org/wiki/Losartan

FDA Approves Brenzavvy (bexagliflozin) for the Treatment of Adults with Type 2 Diabetes

TheracosBio  announced  the U.S. Food and Drug Administration (FDA)   approval of  Brenzavvy (bexagliflozin), an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor. Brenzavvy is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Brenzavvy is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Brenzavvy is contraindicated in patients who are hypersensitive to bexagliflozin or any tablet ingredient and is not indicated for the treatment of type 2 diabetes in patients with end stage renal disease or who are receiving dialysis.

The FDA approval is based on results from a clinical program that evaluated the safety and efficacy of Brenzavvy in 23 clinical trials enrolling more than 5,000 adults with type 2 diabetes mellitus. Phase 3 studies showed Brenzavvy significantly reduced hemoglobin A1c and fasting blood sugar after 24 weeks, either as a monotherapy, in combination with metformin, or as an add-on to standard-of-care treatment consisting of a variety of regimens, including metformin, sulfonylureas, insulin, DPP4 inhibitors, or combinations of these agents. Although Brenzavvy is not approved for weight or blood pressure reduction, modest decreases in both weight and systolic blood pressure have been observed in the clinical program.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Dr. Mason Freeman, M.D., Director of the Translational Research Center at Massachusetts General Hospital. “Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

Brenzavvy treatment can be initiated in adults with type 2 diabetes with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. Patients with eGFR less than 60 and greater than 30 mL/min/1.73 m2 are said to be in stage 3 chronic kidney disease, and for these patients metformin is often avoided due to the risk of lactic acidosis.

“Today's FDA approval represents a significant milestone for TheracosBio and provides an important treatment option to patients who suffer from type 2 diabetes. We look forward to bringing Brenzavvy to market,” said Albert R. Collinson, Ph.D., President and CEO of TheracosBio. “The approval of the Brenzavvy NDA is a result of the tireless work of the TheracosBio team and investigators. I want to thank all of the patients who took part in our clinical trials.”

According to the U.S. Centers for Disease Control and Prevention, more than 33 million Americans have type 2 diabetes, which means their bodies don’t use insulin correctly and as a result their blood sugar levels are too high. While some people can control their blood sugar levels with exercise and a healthy diet, others may need additional help to achieve good blood sugar (glycemic) control.

SGLT2 inhibitors are a class of prescription medicines that lower blood sugar by causing the kidneys to remove sugar from the body through urine.

Brenzavvy is available as 20 mg oral tablets recommended to be taken once daily, in the morning with or without food.

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

FDA Approves Brenzavvy (bexagliflozin) for the Treatment of Adults with Type 2 Diabetes

FDA Approves Amvuttra (vutrisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the U.S. Food and Drug Administration (FDA) approved Amvuttra (vutrisiran), an RNAi therapeutic administered via subcutaneous injection once every three months (quarterly) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. hATTR amyloidosis is a rare, inherited, rapidly progressive, and fatal disease with debilitating polyneuropathy manifestations, for which there are few treatment options. The FDA approval is based on positive 9-month results from the HELIOS-A Phase 3 study, where Amvuttra significantly improved the signs and symptoms of polyneuropathy, with more than 50 percent of patients experiencing halting or reversal of their disease manifestations.

“Twenty years ago, Alnylam was founded with the bold vision for RNA interference to make a meaningful impact on the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs, such as hATTR amyloidosis. Today, Amvuttra has the potential to change the standard of care for people living with the polyneuropathy of this devastating disease,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam Pharmaceuticals. “We are so thankful to the patients, families and investigators involved in making Amvuttra a reality for the hATTR amyloidosis community. As the fifth RNAi therapeutic developed by Alnylam to receive regulatory approval in less than four years, we believe Amvuttra represents an important milestone that brings us one step closer to achieving our P5x25 goals aimed at Alnylam’s transition to a leading biotech company.”

The FDA approval of Amvuttra is based on positive 9-month results from HELIOS-A, a global, randomized, open-label, multicenter, Phase 3 study that evaluated the efficacy and safety of Amvuttra across a diverse group of patients with hATTR amyloidosis with polyneuropathy. 164 patients with hATTR amyloidosis were randomized 3:1 to receive either 25 mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (reference group) for 18 months. The efficacy of Amvuttra was assessed by comparing the Amvuttra group in HELIOS-A with the placebo group (n=77) from the landmark APOLLO Phase 3 study of patisiran, a randomized controlled study in a comparable patient population.

Amvuttra met the primary endpoint of the study, the change from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) at 9 months. Treatment with Amvuttra (N=114) resulted in a 2.2 point mean decrease (improvement) in mNIS+7 from baseline as compared to a 14.8 point mean increase (worsening) reported for the external placebo group (N=67), resulting in a 17.0 point mean difference relative to placebo (p<0.0001); by 9 months, 50 percent of patients treated with Amvuttra experienced improvement in neuropathy impairment relative to baseline.

Amvuttra also met all secondary endpoints in the study at 9 months, with significant improvement in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) score and timed 10-meter walk test (10-MWT), and improvements were observed in exploratory endpoints, including change from baseline in modified body mass index (mBMI), all relative to external placebo. Efficacy results at 18 months were consistent with 9-month data, with Amvuttra achieving statistically significant improvements compared to external placebo for all secondary endpoints including mNIS+7, Norfolk QoL-DN, 10-MWT and mBMI, and non-inferiority in serum TTR reduction relative to the within-study patisiran reference group.

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FDA Approves Amvuttra (vutrisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Melatonin shown to protect kidney damage caused by obesity with diabetes

In continuation of my update on Melatonin

Scientists from the University of Granada (UGR), the Hospital Universitario La Paz (Madrid), and the University of Texas (U.S.) have taken an important step in the fight against kidney damage and its progression toward kidney failure, which is closely related to diabesity (obesity with type 2 diabetes) and its complications.

Specifically, in two new studies recently published in the Journal of Clinical Medicine and Pharmaceuticals, researchers have developed an obese and diabetic rodent model and have shown that melatonin protects from kidney damage caused by diabesity.

The scientists have shown that chronic administration of melatonin at doses (10 mg/kg body weight/day) prevents mitochondrial and endoplasmic reticulum disruption, which play a critical role in the development and pathogenesis of kidney cell (nephron) damage, and its progression to renal failure.

Thus, it has been shown that melatonin prevents the impairment of the function and dynamics of cellular mitochondria, decreasing the increased production of oxygen free radicals (responsible for oxidative stress). It also prevents pathological alteration in the function of the endoplasmic reticulum (another cell cytoplasmic organelle), which, in conditions of abnormally high oxidative stress, is related to an increase in programmed cell death (of the nephron) leading to the loss of renal functionality, as a preliminary step to the development of renal failure and the need for hemodialysis or transplantation.

The studies coordinated by the UGR show the efficacy of melatonin in halting the progression of renal damage mediated by mitochondrial damage and excess endoplasmic reticulum stress.

As the lead author of this study, Ahmad Agil, a researcher at the Department of Pharmacology of the UGR, says, "Kidney damage is caused by metabolic complications of obesity, such as diabetes, hypertension, blood lipid disorders or fatty liver disease. Given that the prevalence of these pathologies (collectively recognized as metabolic syndrome) continues to increase, kidney damage and its progression over time to kidney failure has become a health problem that affects millions of people worldwide, with a great socioeconomic cost, requiring hemodialysis facilities and/or kidney transplant services, with the corresponding compatibility studies required."

The importance of the work lies not only in the efficacy of melatonin in counteracting the two proposed mechanisms of renal damage (based on the alteration of mitochondrial function and dynamics and the function of the endoplasmic reticulum (ER)), but they also propose an alternative preventive treatment that would improve this renal function with a well-studied drug with a very high safety profile such as melatonin, which is a drug that in the EU must be prescribed by a doctor and is already administered in the treatment of insomnia.

The new findings have also been associated with an improvement in glomerular filtration rate and renal damage of the nephron, manifested in a decrease in creatinine clearance levels (the best marker of renal function), proteinuria, and in the improvement of renal structure, observed after histopathological study of the kidney.

These results are in line with those previously published by these researchers in the last 10 years, demonstrating that the pharmacological administration of melatonin constitutes another new strategy in the therapeutic approach to diabesity (central obesity and its type 2 diabetes) and its complications (such as hepatic steatosis, hypertension, lipid alteration, etc.).

"Our main challenge is the application of melatonin and other strategies such as intermittent fasting in the field of medicine, especially to address the possibility of a treatment perspective for the aforementioned pathologies (diabesity and its complications) that involve an increase in oxidative stress, and mitochondrial damage and associated meta-inflammation (inflammation of metabolic origin)," Agil says.

According to the results, melatonin could help treat kidney damage, which establishes the need to develop new clinical trials to test its effectiveness in humans. The next step is to investigate how it helps in the maintenance of mitochondrial and endoplasmic reticulum homeostasis, and to a greater extent, if melatonin therapy would allow delaying or stopping progressive renal damage by promoting its chronic pharmacological use in kidney repair and regeneration.

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

Melatonin shown to protect kidney damage caused by obesity with diabetes

Acid reflux drug may be a promising therapy to reduce preterm birth

In continuation of my update on Lansoprazole

Lansoprazole, an over-the-counter acid reflux drug that is often taken by pregnant women, may be a promising therapy to reduce preterm birth, according to a computational drug repurposing study that also tested several of the drugs in mice.

The study also identified 12 other FDA-approved drugs that are deemed safe in pregnancy. While the drugs encompass a variety of modalities, the scientists said they all appear to act on biological pathways that affect the immune response, which is implicated in preterm birth.

"Inflammation clearly plays a role in initiating labor and preterm birth," said Marina Sirota, PhD, assistant professor of pediatrics, a member of the Bakar Computational Health Sciences Institute at UCSF, and the senior author of the study, published Feb. 13, 2020, in JCI Insight. "Immune pathways are very significantly dysregulated in women who end up delivering preterm, and they're also dysregulated in babies who are born early. However, we have seen from our previous work that there is an interaction between the maternal and fetal immune systems and a breakdown in maternal-fetal tolerance."

To identify candidate drugs that might be effective in preventing preterm birth, the scientists first looked at which genes were up- or down-regulated in the blood cells of women who experienced spontaneous preterm birth to identify a gene expression "signature." Then they looked for the opposite signature in cells that had been exposed to 1,309 different drugs, reasoning that if a drug could correct the effects that preterm birth had on the women's blood cells, the drugs might also prevent preterm birth itself.

The scientists identified 83 drug candidates, but when they excluded those found to have pregnancy risks in animal or human studies, they wound up with 13 drugs, ranked according to their "reversal score," a measure of the extent to which they were able to reverse the gene expression signature of preterm birth.

The other drugs identified by the computational screen included progesterone, which is already used to treat recurrent spontaneous preterm birth, folic acid, which is given to women during pregnancy to prevent birth defects, three antibiotics, an antifungal, an antidepressant, an anti-diabetic, and a blood pressure medication.

The fact that predictable drugs like progesterone came up in the screen gave the scientists confidence that the drugs they identified may turn out to be effective once they are tested in pregnant women. Three of the other drugs that came up in the screen--folic acid, clotrimazole and metformin--have also been shown in previous studies to be effective against preterm birth.

Finding progesterone on the list was a promising validating step. Four of the drugs on our list have seen effectiveness in past studies that were either experimental or retrospective. This leads us to believe in the biology behind the identification of these drugs."

Brian Le, PhD, postdoctoral scholar in the UCSF Department of Pediatrics and the Bakar Computational Health Sciences Institute, and the first author of the study

The scientists chose lansoprazole for further testing because, in addition to its high reversal score, it is available over the counter, and they know from their previous work that it affects a stress-response protein, heme oxygenase-1, that has been linked with pregnancy disorders. Lansoprazole, which is a proton-pump inhibitor marketed as Prevacid, had the second-highest reversal score of the 13 drugs identified as being safe and effective. Progesterone was further down the list.

The scientists tested lansoprazole in pregnant mice that had been given a bacterial component to induce inflammation, which causes some fetuses to die in utero, where they are reabsorbed. When these mice were given lansoprazole, they had more viable fetuses. Lansoprazole also worked better in these mice than progesterone.

Although it is a good measure of how inflammation affects pregnancy in mice, the scientists said the fetal resorption mouse model is not an adequate model of human preterm birth. They said more work, including studies in people, would need to be done before lansoprazole or any of the dozen other drugs they identified could be proven effective in pregnant women at risk for preterm birth. But the computational study provides leads for a condition that currently has few treatment options.

"This, basically, is a proof of concept that this drug has anti-inflammatory properties, which are not the properties the drug was designed for," said David K. Stevenson, MD, a professor of pediatrics at Stanford University and an author of the study. "This is a short way to get to new therapeutics for known diseases."

https://www.ucsf.edu/news/2020/02/416631/acid-reflux-drug-surprising-candidate-curb-preterm-birth

Novel drug combination discovered to induce high rates of human beta cell proliferation

Harmine

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that, together, cause the highest rate of proliferation ever observed in adult human beta cells- the cells in the pancreas that produce insulin- without harming most other cells in the body. The result is an important step toward a diabetes treatment that restores the body's ability to produce insulin.

The finding involved one type of drug that is known to cause beta cells to proliferate and another that is already in widespread use in people with diabetes. Together, they caused the cells to proliferate at a rate of 5 to 6 percent per day. The study was published today in Science Translational Medicine online.

We are very excited about this new drug combination because for the first time ever, we are able to see rates of human beta cell replication that are sufficient to replenish beta cell mass in humans with diabetes."

Andrew Stewart, MD, Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study

Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Approximately 30 million people in the United States have diabetes and nearly 50 to 80 million more are living with prediabetes (also called "metabolic syndrome"). Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation.

In type 1 diabetes, the immune system mistakenly attacks and destroys beta cells. A deficiency of functioning beta cells is also an important contributor to type 2 diabetes, the most common type of diabetes. Thus, developing drugs that can increase the number of healthy beta cells is a major priority in diabetes research.

According to Dr. Stewart, none of the diabetes drugs currently on the market can induce beta cell regeneration in people with diabetes. In parallel with the Mount Sinai work, other researchers are studying pancreatic transplantation, beta cell transplantation, and stem cell replacement of beta cells for people with diabetes, but none of these approaches is in widespread use.

"This is a very exciting discovery in the field of diabetes and is a key next step in drug development for this disease," said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai. "This important work truly holds promise for so many people."

In 2015, Dr. Stewart and his team published a paper in Nature Medicine that showed that harmine, a drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A), induced multiplication of adult human beta cells. In that study, his team also discovered that harmine treatment led to normal control of blood sugar and proliferation in human beta cells in diabetic mice whose beta cells had been replaced with small numbers of transplanted human beta cells. While this was a major advance, the proliferation rate was lower than needed to rapidly expand beta cells in people with diabetes.

This current paper builds upon a study that Dr. Stewart and his team published in Cell Metabolism in December 2018 where they discovered that DYRK1A inhibitors combined with another drug that inhibits transforming growth factor beta superfamily members (TGFβSF), also known as a family of proteins with various biological processes such as growth, development, tissue homeostasis and immune system, could cause beta cells to proliferate at a rate of 5 to 8 percent per day. However, according to Dr. Stewart, TGFβSF's would likely have side effects on other organs in the body that would prevent clinical use.

The next challenge was developing ways to target regenerative drugs to the beta cells while avoiding other cells and organs in the body where they may elicit adverse effects.

In the study published today, titled "GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human beta cell regeneration," Dr. Stewart and his team combined DYRK1A inhibitors like harmine with a class of beta cell-targeting drugs, also known as GLP1R agonists, which are already in widespread use in people with type 2 diabetes. They showed-;in beta cells from normal people and people with type 2 diabetes, both in the tissue culture dishes and in human beta cells transplanted into mice-;that combining harmine (or any other DYRK1A inhibitor) with any of the many GLP1R agonist drugs currently on the market for diabetes yields high rates of human beta cell replication, and does so in a way that is highly selective for the beta cell.

The project arose from the PhD thesis of an Icahn School of Medicine graduate student, Courtney Ackeifi, now a postdoctoral fellow in Dr. Stewart's lab and first author of the paper, who explored a broad spectrum of potential drug partners that could enhance the beta cell regenerative efficacy and selectivity of harmine.

Said Dr. Ackeifi of the discovery, "The beauty here is that the combination of DYRK1A inhibitors with GLP1R agonists achieves the highest rate of human beta cell replication possible, and does so in a highly specific way. This is an important advance in the field of diabetes because we may have found a way to convert a widely used class of diabetes drugs into a potent human beta cell regenerative treatment for all forms of diabetes."

"We know that a critical pathway to drive a cure for type 1 diabetes includes transplanting insulin-producing beta cells into people or enticing their existing beta cells to start multiplying," explains Francis Martin, PhD, JDRF Director of Research. "It is exciting to learn from the work of Dr. Stewart and his team that GLP1R agonists could increase the effect of the recently discovered agents that promote multiplication. Using GLP1R offers a means to boost the effect while also improving the safety of this type of drug."

The next goals of the project are to perform long-term studies in animals transplanted with human beta cells, and to determine if any cells or organs in the body other than beta cells are affected by the new drug combination.

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

https://en.wikipedia.org/wiki/Glucagon-like_peptide-1_receptor_agonist

Statin use alone or with metformin may increase survival in high-risk prostate cancer patients

In continuation of my update on metformin

Among high-risk prostate cancer patients - those with high PSA and Gleason scores of 8 or more - many will develop a difficult-to-treat disease. Preliminary research suggests that two commonly prescribed medications, cholesterol-lowering statins and the diabetes therapy metformin may have anticancer effects. However, it is unclear which of these two medications - commonly prescribed together -- contributes the most and whether they can impact high-risk prostate cancer. New research shows that statins, alone or with metformin, increase survival in men with high-risk prostate cancer.

"Both metformin and statins have been associated with longer life in prostate cancer patients, yet because they are commonly prescribed together, no study we know of has looked at these two medications separately," says senior author Grace Lu-Yao, PhD, associate director of Population Science at the Sidney Kimmel Cancer Center--Jefferson Health, one of only eight NCI-designated cancer centers nationwide with a prostate cancer program of excellence.

The study, published in Cancer Medicine on Feb 8th, looked at a number of statin therapies, and metformin, an anti-diabetic medication, in high-risk prostate cancer populations.

Using data from the Surveillance, Epidemiology and End Results (SEER-18) database linked with Medicare files, Dr. Lu-Yao and colleagues looked at patients diagnosed with cancer from 2007 through to 2011. Based on 12,700 patients, the researchers observed that statins alone or in combination with metformin was significantly associated with reduced mortality from all causes.

Dr. Lu-Yao and colleagues saw the highest median survival of 3.9 months in men who took both metformin and statins, 3.6 with statins alone and 3.1 years with metformin alone. The median survival for those who did not use either drug was also 3.1 years.

With respect to prostate mortality, metformin plus statin was associated with a 36% reduction in risk of death followed by statins alone. Those taking metformin alone were relatively rare, and there was no significant association with all-cause mortality."

Interestingly, the study revealed that men who took atorvastatin, pravastatin, or rosuvastatin - but not lovastatin - demonstrated a reduction in mortality compared with non-users, which is consistent with the findings from a recent population-based cohort study using Taiwan National Health Insurance Research Data. The Taiwanese research showed that these three statins are more effective at lowering triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol than other statins in patients with hypercholesterolemia.

Of the three statins studied, men on atorvastatin did have a longer median time to progression on androgen deprivation therapy compared to those who weren't treated with statins. "Although the exact mechanisms remain unknown, it is worth noting that atorvastatin exhibits a potent lipid-lowering effect per dose of any statin, and has the greatest bioavailability and one of the longest half-lives," says to Dr. Lu-Yao.

The data presented in the current study provide crucial insight for the design of future randomized clinical trials of statin for high-risk patients with prostate cancer. Based on the existing evidence, a well-designed clinical trial is warranted to investigate the roles of statins and combination statins/metformin to reduce the mortality cancer of the prostate.

"Our study showed that the effects were more pronounced in patients taking statins after the diagnosis of prostate cancer, 54% reduction in PCA mortality among patients with high-risk prostate cancer," says Lu-Yao. "This magnitude of reduction is comparable to the results of men treated with androgen signaling inhibitors." Statins are relatively inexpensive with good safety records. Further studies to understand the mechanisms of the observed association and its potential clinical utility are warranted.

https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2862

Team finds that their cancer-fighting compound fights obesity and diabetes, too

Eric Prossnitz, Ph.D., and his team hope to help 93 million obese Americans fight their fat.

In a paper published in Science Translational Medicine, they reported that G-1, a cancer-fighting compound they discovered some years ago, reduces fat in obese mice. Although G-1 is currently in phase 1 clinical trials for cancer, Prossnitz and his team are planning preclinical studies to use G-1 to fight fat in obese people.

Obesity affects 40% of adults in the United States, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the U.S. Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity don't effectively reduce it or have undesirable side effects.

Prossnitz and his team have been studying GPER, the G protein-coupled estrogen receptor that G-1 activates, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block estrogen receptors in a cell's nucleus, they also activate GPER, which is found in cell membranes.

Prossnitz's previous studies showed that GPER may play a role in resistance to tamoxifen and similar drugs, and that led him to wonder how G-1 affects non-cancerous cells when estrogen is lacking.

Estrogen is considered a female hormone, although men produce it at low levels. Low estrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. So to understand whether G-1 might affect metabolism in postmenopausal women, Prossnitz and his team studied mice with low estrogen levels.

In their studies, low-estrogen female mice gained weight rapidly, even on a normal diet, and quickly became obese and diabetic. When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went away.

The researchers determined that the weight loss wasn't due to the mice eating less or moving around more; it resulted from what their bodies did with the calories they ate. Instead of storing calories as fat, the mice used them as fuel.

"Their metabolism changed," Prossnitz says. "The mice showed an increased energy expenditure."

Prossnitz's team also studied male mice, which have naturally low levels of estrogen. The male mice were fed a high-fat diet, which made them obese and diabetic, and then some were treated with G-1. Although the treated mice did not lose weight, they did not gain additional weight either, like the untreated mice. More importantly, their diabetes improved.

"This result suggests that G-1 has separate effects on obesity and diabetes," Prossnitz says. "The G-1-treated male mice were metabolically healthier, even though they were still obese."

Finally, the team also fed a high-fat diet to low-estrogen female mice. These mice became obese very quickly, but just like their sisters on a normal mouse diet, they lost weight and their diabetes improved when they were treated with G-1. These results, says Prossnitz, could point to a sex difference in the effects of the drug or in the way GPER signals in the cells of males and females.

To learn about how G-1 increases energy expenditure, the team studied brown fat cells, which generate heat instead of storing excess calories as fat. What they found surprised them: when treated with G-1, the cells expended more energy.

"This fits nicely with what we saw in mice," Prossnitz says, "and suggests that G-1 may reduce obesity by targeting brown fat cells that burn extra calories."

In a future series of experiments, Prossnitz plans to study how signals from GPER induce the cellular changes that cause more energy to be used. He hopes that one day soon G-1 could revolutionize the treatment of metabolic disorders.

In the meantime, he and his team are starting the long path toward clinical trials that will test the ability G-1 to fight obesity and diabetes in people.

https://stm.sciencemag.org/content/12/528/eaau5956/tab-figures-data

FDA Approves Trijardy XR (empagliflozin/linagliptin/metformin) for Type 2 Diabetes in Adults

In continuation of my update on empagliflozin/linagliptin/metformin 

    

The U.S. Food and Drug Administration (FDA) has approved Trijardy XR (empagliflozin/linagliptin/metformin hydrochloride extended release tablets) to lower blood sugar in adults with type 2 diabetes, along with diet and exercise. Trijardy XR provides three type 2 diabetes medicines in one pill, including Jardiance® (empagliflozin), Tradjenta® (linagliptin) and metformin hydrochloride extended release. Trijardy XR is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company (NYSE: LLY).

"Many adults living with type 2 diabetes who are already on a treatment plan including multiple medications still struggle to keep their blood sugar under control, and may require additional agents to reach their A1C targets," said Ralph DeFronzo, M.D., professor and diabetes division chief, UT Health San Antonio. "Adding new medicines to an individual's plan can be challenging for some, which is why new treatment options that can help improve blood sugar without the burden of an increased pill count are important. In addition, type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment."

In the U.S., both Jardiance and Tradjenta are once-daily tablets used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. Jardiance is also approved to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease. Jardiance is not for people with type 1 diabetes or for people with diabetic ketoacidosis (increased ketones in the blood or urine). Tradjenta is not for people with type 1 diabetes or for the treatment of diabetic ketoacidosis. Tradjenta has not been studied in people with a history of pancreatitis and it is unknown if using Tradjenta increases the risk of developing pancreatitis in these people. 

"We are proud to offer Trijardy XR as a new once-daily option combining three well-established medicines, including an extended-release version of metformin, the most commonly prescribed initial treatment for type 2 diabetes, Jardiance, the most prescribed SGLT2 inhibitor, and Tradjenta, the only single-dose DPP-4 inhibitor," said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, Boehringer Ingelheim Pharmaceuticals, Inc. "We believe Trijardy XR has the potential to help adults with type 2 diabetes conveniently manage their treatment, especially those who are taking other medications and working on the necessary lifestyle changes."

Trijardy XR is not recommended for people with type 1 diabetes or diabetic ketoacidosis (increased ketones in the blood or urine). Trijardy XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Trijardy XR. The labeling for Trijardy XR contains a warning for lactic acidosis, a rare but serious complication that can occur due to metformin accumulation, and is common to all products containing metformin.

The FDA approval of Trijardy XR is based on two randomized open-label trials that assessed the bioequivalence of empagliflozin, linagliptin and metformin hydrochloride extended release fixed-dose combination tablets and their individual components in healthy adults. The safety profile of Trijardy XR was found to be consistent with its individual components.

"The approval of Trijardy XR reflects our commitment to the diabetes community and to innovation that addresses evolving needs," said Jeff Emmick, M.D. Ph.D., vice president, Product Development, Lilly. "We developed Trijardy XR because many people with type 2 diabetes need help managing this complex condition without adding more pills to their treatment plan. We look forward to making this new option available soon."

Trijardy XR is not for people who have severe kidney problems, end stage renal disease, or are on dialysis, have a serious condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine), or are allergic to Jardiance, Tradjenta, metformin, or any of the ingredients in Trijardy XR. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin, a component of Trijardy XR. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue Trijardy XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Trijardy XR.

Trijardy XR will be available in four different dosages, including: 5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release; 12.5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; and 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release.

What is Trijardy XR?

Trijardy XR is a prescription medicine that contains 3 diabetes medicines, empagliflozin (JARDIANCE), linagliptin (TRADJENTA), and metformin hydrochloride. Trijardy XR can be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes, and in adults with type 2 diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in Trijardy XR, is needed to reduce the risk of cardiovascular death.

Trijardy XR is not for people with type 1 diabetes, or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take Trijardy XR.

https://www.drugs.com/history/trijardy-xr.html