VHL Welireg

EMA Approves Welireg (Belzutifan): A Breakthrough for VHL-Associated Tumors and Advanced Kidney Cancer

by with No Comment Disease & DrugsNew Drug Approval

Written By Yogita Bhadane, B.Pharm

 Reviewed and Fact Checked by Vikas Londhe M.Pharm (Pharmacology)

VHL Welireg

Introduction
Welireg (belzutifan), a significant advancement, has been approved by the European Medicines Agency (EMA) as the first clinically approved pharmaceutical therapy for tumors associated with von Hippel-Lindau (VHL) disease and for adults with advanced renal cell carcinoma (RCC) who have already received treatment. As a new targeted therapy for unmet medical needs, this approval holds promise for clinicians treating these difficult conditions.

Understanding VHL Disease and RCC

Von Hippel-Lindau disease (VHL) is a rare genetic disorder that predisposes people to develop tumors and cysts in the kidneys, pancreas, and central nervous system, with kidney cancer being the most common type. Renal cell carcinoma occurs in an abnormal 70% of individuals with VHL syndrome. These tumors are caused by mutations in the VHL gene, which affects how the gene regulates the breakdown of proteins called hypoxia-inducible factor (HIF), which are sensitive to tissue oxygen levels. Tumor formation results from aberrant HIF activation brought on by VHL mutation. Conventional management techniques involved frequent surgical procedures and constant monitoring, which increased risks and lowered patient living standards. Immunocheckpoint inhibitors and anti-angiogenic therapies are used in the treatment of advanced renal cell carcinoma; however, post-progression care options are still scarce.

Hemangioblastomas

These non-cancerous growths mostly appear in the retina, spinal cord, and brain tissue. Brain hemangioblastoma patients are more likely to experience symptoms like headaches, vision issues, and neurological impairments.

Renal Cell Carcinomas (RCC)

The risk of kidney cancer, primarily clear cell renal carcinoma, is increased in people with VHL disease. In addition to renal impairment, these disorders often manifest bilaterally and cause hematuria and dysuria. Some examples show that (heterogeneous) petrocalcic deposits give rise to saddle-shaped inclusions.

 Pheochromocytomas:

High blood pressure, headaches, sweating, and palpitations are some of the symptoms caused by these tumors growing on the adrenal gland, which strictly adhere to EPI while binding to norepinephrine. Although phenochromocytomas usually appear as benign tumors, if left untreated, they have the potential to become fatal.

 Pancreatic Cysts and Tumors:

Patients with VHL may develop pancreatic cysts. Although the majority of them are benign, tiny molecules have the potential to develop into pancreatic neuroendocrine tumors, which may release hormones that result in various symptoms.

 Endolymphatic Sac Tumors (ELSTs):

Almost all of these are tumors that are located in the patient’s ear near the inner ear. Tinnitus, instability, and hearing loss are possible symptoms for those who have this condition. Chemotherapy or even stereotactic radiation may be used to treat general growth and low-grade ELSTs.

 Retinal Angiomas:

Hemangioblastomas, also known as retinal angiomas, are tumors of the blood vessels that frequently develop in the membrane of the eye and can cause partial blindness. Hemangioblastomas appear when they cause bleeding or retinal detachment, or when they are discovered during an eye exam.

Welireg’s Mechanism:

Angiogenesis (the formation of blood vessels), erythropoiesis (the production of red blood cells), and tumor growth are all regulated by HIF-2α.
The Von Hippel-Lindau (VHL) protein breaks down HIF-2α under normal oxygen conditions.
HIF-2α builds up in tumors that lack VHL, such as clear cell renal cell carcinoma and von Hippel-Lindau disease-associated tumors, which causes the tumor to grow out of control.

 Blocking HIF-2α Dimerization with HIF-1β:

By binding specifically to HIF-2α, belzutifan stops it from interacting with HIF-1β, which is a prerequisite for HIF-2α to activate target genes.
VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), and EPO (erythropoietin) are among the genes involved in tumor survival whose transcription is inhibited by this.

 Anti-Tumor Effects:

Welireg is effective in cancers caused by HIF-2α overactivity, especially VHL-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors, because it inhibits HIF-2α signaling, which in turn reduces tumor growth, angiogenesis, and erythropoiesis.

An important tumor growth pathway is disrupted by the oral hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor belzutifan. HIF-2α builds up in low oxygen environments, activating genes that support angiogenesis and cell division. Welireg deprives tumors of these signals by blocking HIF-2α, which slows growth and causes shrinkage. This mechanism is revolutionary because it provides a precision medicine approach that is specific to the molecular drivers of RCC and VHL.

Clinical Trial Efficacy

VHL-Associated Tumors: Belzutifan is being evaluated in patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) in the Phase 2 open-label clinical trial NCT03401788 (Study 004). 61 adults with at least one detectable RCC tumor and a germline VHL alteration were enrolled. Additionally, patients may have pancreatic neuroendocrine tumors (pNETs) or CNS hemangioblastomas. Prior use of HIF-2α inhibitors, systemic therapy, surgical necessity, and metastatic disease were excluded. Until toxicity or progression, participants were given 120 mg of belzutifan every day. Overall response rate (ORR), the main outcome, was 49% in RCC, 63% in CNS hemangioblastomas, and 83% in pNETs. With more than half of respondents continuing to respond for more than 12 months, the median response duration was not reached.

Advanced RCC: Belzutifan, a hypoxia-inducible factor 2α (HIF-2α) inhibitor, is being evaluated in patients with advanced solid tumors as part of the LITESPARK-001 trial (NCT02974738), a phase 1 clinical study. 55 patients with advanced ccRCC who had previously received treatment were given 120 mg of belzutifan orally once daily as part of this cohort. The objective response rate (ORR), which included one complete response and thirteen partial responses, was 25% following a median follow-up of more than three years. The median progression-free survival (PFS) was 14.5 months, and the disease control rate (DCR) was 80%. Anaemia (24% grade 3) and hypoxia (13% grade 3) were the most common treatment-related adverse events; no grade 4 or grade 5 treatment-related adverse events were noted. These findings show that belzutifan has a manageable safety profile and long-lasting antitumor activity in patients with ccRCC who have received extensive pre-treatment.

Glioblastoma (GBM) Cohort: A cohort of 25 patients with recurrent IDH wild-type glioblastoma after radiation therapy and temozolomide was also included in the trial. Belzutifan 120 mg was given orally to the patients twice a day. There were no objective responses after a median follow-up of 1.9 months; the median PFS was 1.4 months, and the clinical benefit rate was 8%. Every patient had at least one adverse event, and 60% of them had grade 3-5 events. Anaemia (64%), exhaustion (52%), headache (32%), and muscle weakness (32%), were the most frequent adverse events. There were no deaths brought on by the treatment. These results imply that in this GBM cohort, belzutifan did not exhibit antitumor activity.
Belzutifan’s potential for treating advanced ccRCC is generally highlighted by the LITESPARK-001 trial, but its effectiveness in treating GBM has not yet been established.

Safety and Tolerability

Administration of Welireg during pregnancy can cause embryo-fetal harm. It was highly recommended to confirm the pregnancy status before initiating Welireg.

Anaemia (71%), Hypoxia (48%), and nausea (31%), which are usually mild to moderate, are common side effects. It is advised to regularly check oxygen and hemoglobin levels. When compared to intravenous treatments, the ease of oral administration (120 mg once daily) improves patient adherence.

EMA Approval and Patient Impact

With the EMA’s support, access is made possible throughout the EU, changing the way that care is provided. Welireg preserves organ function and quality of life for VHL patients by lowering the need for invasive surgeries. It closes a crucial gap left by post-standard therapies for advanced RCC. “Belzutifan represents a paradigm shift, offering a non-invasive option with meaningful clinical benefits,” says oncologist Dr. Maria Ruiz.

 Future Directions

Belzutifan is being studied for combination treatments and other cancers driven by HIF-2α. Its success highlights how hypoxia pathways can be targeted in oncology.

Conclusion
The approval of Welireg, which addresses long-standing issues in the management of VHL and RCC, is a victory for precision medicine. Belzutifan sets a new standard by focusing on innovation in rare and complex cancers and coordinating treatment with disease biology. This milestone opens the door for future advancements in targeted therapies in addition to providing immediate clinical benefits.

References:

1. First medicine to treat rare genetic disorder causing cysts and tumours, European Medicine Agency, 13 December 2024

2. WELIREG® (belzutifan) Receives First European Commission Approval for Two Indications, Merck, 18 February 2025

3. Kim E, Zschiedrich S. Renal Cell Carcinoma in von Hippel-Lindau Disease-From Tumor Genetics to Novel Therapeutic Strategies. Front Pediatr. 2018 Feb 9;6:16. doi: 10.3389/fped.2018.00016. PMID: 29479523; PMCID: PMC5811471.

4. Ashouri K, Mohseni S, Tourtelot J, Sharma P, Spiess PE. Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma. J Kidney Cancer VHL. 2015 Sep 25; 2(4):163-173. Doi: 10.15586/jkcvhl.2015.41. PMID: 28326271; PMCID: PMC5345519.

5. Eric Jonasch, Frede Donskov, Othon Iliopoulos, Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease, n engl j med 385;22, November 25, 2021.

6. Hu, J., Tan, P., Ishihara, M. et al.Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma. Sig Transduct Target Ther8, 155 (2023). https://doi.org/10.1038/s41392-023-01362-2

7. Roy E. Strowd et al., Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort. JCO 42, 2054-2054(2024). DOI:10.1200/JCO.2024.42.16_suppl.2054

epv

Earth Day Spotlight: How Ecopharmacovigilance Protects the Planet from Pharmaceutical Pollution

by with No Comment Disease & DrugsResearch

Medically Written and Reviewed by Vikas Londhe M.Pharm (Pharmacology)

epv

As we honour Earth Day and reflect on our collective duty to protect the environment, a lesser-known but critical issue deserves the spotlight: Ecopharmacovigilance. In the era where much attention is given to industrial emissions and plastic waste, Very few people are aware of the silent threat created by pharmaceuticals entering the ecosystems. That’s where ecopharmacovigilance comes in

What is Ecopharmacovigilance?

Pharmaceuticals are meant to be developed for the consumption of humans; however, once humans consume pharmaceuticals, the by-products or remains are excreted into the environment in different ways, and once they enter the environment, they start polluting nature and harming the aquatic animals and other species, including soil and trees. Hence, where pharmacovigilance is the detection and understanding of the side effects of pharmaceuticals on humans, ecopharmacovigilance refers to the science and activities related to the detection, evaluation, understanding, and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment. On a broader scale, it is monitoring the presence of pharmaceuticals in the environment, assessing the impact on non-target organisms, understanding it thoroughly, and developing the preventive strategies in a way that any harm to nature due to the presence of pharmaceuticals in the environment should be avoided timely and appropriately.

According to the World Health Organization, treated sewage water, surface water, drinking water, groundwater, sediment, soil, and biota contain hundreds of pharmaceuticals. Increasing use of drugs worldwide, and some of them are resistant to degradation, are the main reasons behind their presence in harmful quantities in nature. The most notable pathways of these pharmaceuticals are excretion of used drugs, drug manufacturing, industrial and home wastewater, aquaculture, manure application, landfills, and incineration.

Why Should We Care?

While pharmaceuticals are essential for human and animal health, their unintended environmental footprint is becoming increasingly evident. Studies have shown:

Increasing Antibiotic Resistance: Antibiotic resistance, or antimicrobial resistance (AMR), poses a global threat due to the irrational use of antibiotics; however, the presence of antibiotics in the environment makes the condition worse, as the exposed antibiotics in open environments make bacterial infections hard to treat. AMR caused an estimated 1.27 million deaths globally in 2019.

Effect on aquatic life: As most of the drugs end up in aquatic bodies like rivers, streams, ponds, and oceans through pathways mentioned above, they are not designed to be there or show a positive effect on wildlife present in waters. They show a negative effect on aquatic animals like fish and affect their ability to reproduce, cause behavior changes, or have direct toxic effects. Hormonal drugs, like estrogens from contraceptives, are supposed to be causing these types of effects. Some reports show that male fish were feminized by ethinyl estradiol and frogs were killed by contraceptive tablets. Psychiatric and cardiovascular drugs have been linked to altered behavior and physiological changes in aquatic animals. Some reports related to it show that aggression is caused in lobsters due to antidepressants and spawning in shellfish by fluoxetine.

Current Status of Ecopharmacovigilance

Regulatory Recognition

The OECD report Pharmaceutical Residues in Freshwater: Hazards and Policy Responses highlights the growing concern over pharmaceutical contamination in global freshwater systems due to human and veterinary use, manufacturing, and improper disposal.

The report emphasizes the need for a life cycle, multi-sectoral approach involving source-directed, use-oriented, and end-of-pipe solutions. This includes better monitoring, green pharmaceutical design, responsible prescription and use, proper disposal systems, and advanced wastewater treatment.

International Cooperation Needed: The report also emphasizes the importance of data sharing, international standards, public education, and financial strategies to implement sustainable pharmaceutical pollution control.

EMA and FDA integrated environmental risk assessments (ERAs) into the drug approval process

The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have taken significant steps to integrate Environmental Risk Assessments (ERAs) into the drug approval process, marking a growing recognition of the environmental impact of pharmaceuticals.

Environmental risk assessments evaluate the potential environmental impact of a pharmaceutical substance once it enters ecosystems, typically through human excretion, improper disposal, or manufacturing waste. These assessments analyze factors such as persistence in the environment, bioaccumulation in wildlife, toxicity to aquatic and terrestrial organisms, and potential for environmental transformation into harmful by-products.

Since 2005, the EMA has required ERAs for all new marketing authorization applications in the EU.

The FDA has also implemented environmental reviews under the National Environmental Policy Act (NEPA). For human drugs, applicants typically submit an Environmental Assessment (EA) or a claim for categorical exclusion, depending on the drug’s characteristics. The FDA assesses factors such as expected introduction into the environment, manufacturing and disposal practices, and the cumulative impact of widespread use.

As awareness of pharmaceutical pollution grows, both agencies are expected to tighten guidelines, enhance transparency, and collaborate internationally on standardized ERA methodologies. This reflects a shift toward sustainable drug development that balances therapeutic benefit with environmental responsibility.

What Can You Do?

On Earth Day and every day individuals can play a role in supporting ecopharmacovigilance:

Proper Medication Disposal

Don’t flush unused meds in the toilet or sink.

Use take-back programs: Many pharmacies and communities have medication disposal programs.

If no programs are available, follow the FDA’s or local authority’s guidelines for trash disposal (e.g., mix with unpalatable substances like coffee grounds or cat litter, then seal in a bag).

Buy Only What You Need

Avoid stockpiling medications. It reduces waste and environmental load from expired drugs.

Use Medications Responsibly

Follow prescriptions exactly—using less or more than necessary not only harms health but also leads to excess drugs in the environment.

Spread Awareness

Talk to friends and family about why proper disposal matters

Share posts or articles about EPV and pharmaceutical pollution.

Ask Your Pharmacist

If unsure about disposal or environmentally safer alternatives, ask to your pharmacist. Pharmacist is the healthcare provider who is easily accessible compare to other HCPs. Added to it possesses good knowledge about medicine use and disposal. So some may offer eco-friendly info or take-back services.

Support Green Pharmacies

Support pharmacies and drug companies who are committed to reducing environmental impact (e.g., sustainable packaging, greener drug production).

Advocate for Change

Encourage local governments and health organizations to implement and promote better environmental drug policies.

Avoid Unnecessary Use of Over-the-Counter Drugs

Many people take OTC drugs like painkillers or antacids unnecessarily. This leads to increased production, use, and environmental excretion.

Looking Ahead

Ecopharmacovigilance is still evolving, but it’s becoming an essential part of environmental health strategies. With collaborative efforts from the healthcare industry, regulators, and the public, we can reduce the ecological footprint of lifesaving medicines.

References:

1. Ecopharmacovigilance: Ensuring Environmental Safety from Pharmaceuticals, Uppsala Reports, 15 Oct 2024, available form https://uppsalareports.org/articles/ecopharmacovigilance-ensuring-environmental-safety-from-pharmaceuticals/

2. The Impact of Pharmaceuticals Released to the Environment, United state environmental Protection Agency.

3. Dutta A, Banerjee A, Chaudhry S. Ecopharmacovigilance: Need of the hour. Indian J Pharm Pharmacol 2022;9(2):77-80.

4. Eapen JV, Thomas S, Antony S, George P, Antony J. A review of the effects of pharmaceutical pollutants on humans and aquatic ecosystem. Explor Drug Sci. 2024; 2:484–507. https://doi.org/10.37349/eds.2024.00058

5. OECD (2019), Pharmaceutical Residues in Freshwater: Hazards and Policy Responses, OECD Studies on Water, OECD Publishing, Paris, https://doi.org/10.1787/c936f42d-en

6. Paut Kusturica M, Jevtic M and Ristovski JT (2022), minimizing the environmental impact of unused pharmaceuticals: Review focused on prevention. Front. Environ. Sci. 10:1077974. Doi: 10.3389/fenvs.2022.1077974

7. Guideline on the environmental risk assessment of medicinal products for human use, Committee for Medicinal Products for Human Use (CHMP), European Medicine Agency.

8. Environmental Impact Review at CDER, 07 Jan 2025, US Food and Drug Administration, available fromhttps://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/environmental-impact-review-cder

MS

Could High-Dose Vitamin D Help Fight Early Multiple Sclerosis? New Evidence Says Yes

by with No Comment Disease & DrugsResearch

Written and Reviewed by Vikas Londhe M.Pharm (Pharmacology)

MS

A recent study published in JAMA on March 10, 2025, titled “High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial,” investigated the efficacy of high-dose cholecalciferol (vitamin D) as a monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). This randomized clinical trial enrolled participants diagnosed with CIS, a condition characterized by a single episode of neurological symptoms indicative of MS. The objective was to determine whether high-dose vitamin D supplementation could delay or prevent the progression from CIS to clinically definite MS.​ The trial’s results indicated that participants receiving high-dose vitamin D exhibited a significant reduction in disease activity compared to those in the placebo group. Specifically, MRI scans revealed fewer new or enlarging lesions in the vitamin D group, suggesting a potential neuroprotective effect of high-dose cholecalciferol in the early stages of MS.

Link between Vitamin D and MS

Multiple sclerosis (MS) is a long-term disease that affects the central nervous system by damaging the protective covering of nerves (myelin). This damage disrupts nerve signals, causing symptoms that vary from mild fatigue to severe paralysis and cognitive issues. The exact cause is unknown, but it likely involves both genetics and environmental factors. MS affects over 2.8 million people worldwide and is a major cause of disability in young adults.

Vitamin D is a fat-soluble vitamin that is important for strong bones and maintaining calcium levels in the body. It also plays a role in regulating the immune system. Vitamin D works by interacting with a specific receptor Vitamin D receptor (VDR) found in many immune cells. Research suggests that it can affect the immune system by reducing the growth of certain T cells, supporting regulatory T cells, and influencing the production of inflammatory substances like cytokines. Because of these effects, scientists are interested in studying whether vitamin D supplements could help manage multiple sclerosis (MS), a disease linked to immune system dysfunction.

The D-Lay MS Trial (NCT01817166): The D-Lay MS trial was a rigorous, double-blind, placebo-controlled study conducted across 36 MS centers in France. Recruitment spanned from July 2013 to December 2020, with final follow-ups completed in January 2023. The study aimed to determine whether high-dose cholecalciferol (vitamin D3) could reduce disease activity in individuals diagnosed with CIS or early-stage relapsing-remitting MS (RRMS).

A total of 316 patients aged 18–55 years, diagnosed with CIS within the previous 90 days, were enrolled. Inclusion criteria required a serum vitamin D concentration below 100 nmol/L and MRI findings consistent with the 2010 MS diagnostic criteria. Notably, participants had not received any prior disease-modifying treatments.

Intervention and Study Groups: Participants were randomly assigned to one of two groups:

High-dose cholecalciferol (100,000 IU) every two weeks (n = 163)

Placebo group receiving a matching supplement (n = 153)

The intervention period lasted 24 months, during which disease activity and clinical outcomes were closely monitored.

Key Outcomes and Findings The primary endpoint of the study was disease activity, defined as the occurrence of relapses and/or MRI activity (new or contrast-enhancing lesions). Secondary outcomes included MRI-based disease activity measures, clinical relapses, and safety assessments.

Primary Outcome Results

60.3% of patients in the vitamin D group experienced disease activity, compared to 74.1% in the placebo group. The time to disease activity was significantly longer in the vitamin D group (432 days) compared to the placebo group (224 days).

MRI-Based Findings: Patients in the vitamin D group demonstrated significant reductions in MRI-based disease activity: MRI activity: 57.1% in the vitamin D group vs. 65.3% in the placebo group.

New lesion occurrence: 46.2% in the vitamin D group vs. 59.2% in the placebo group.

Contrast-enhancing lesions: 18.6% in the vitamin D group vs. 34.0% in the placebo group.

Clinical Outcomes and Safety While MRI-based improvements were evident, no significant differences in relapse rates were observed:

17.9% of patients in the vitamin D group experienced relapses vs. 21.8% in the placebo group

Regarding safety, severe adverse events were reported in 17 patients in the vitamin D group and 13 patients in the placebo group. However, none of the adverse events were directly attributed to vitamin D supplementation.

Interpretation and Clinical Implications

This study provides strong evidence that high-dose vitamin D can reduce MRI-based disease activity in CIS and early MS. These findings suggest potential neuroprotective and immunomodulatory effects, possibly delaying progression to clinically definite MS. However, the lack of significant impact on relapse rates indicates that vitamin D supplementation may not be a stand-alone treatment but could serve as an adjunct to existing disease-modifying therapies.

Conclusion and Future Directions

The D-Lay MS trial highlights the benefits of high-dose vitamin D (100,000 IU biweekly) in reducing MRI-based disease activity. Although it did not significantly impact relapse rates, the delayed onset of disease activity suggests its potential as an early intervention strategy. Further research is needed to optimize dosing, assess long-term safety, and evaluate the role of vitamin D in combination with other MS treatments.

References

  1. Feige J, Moser T, Bieler L, et al, Vitamin D Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats. Nutrients. 2020 Mar 16;12(3):783. Doi: 10.3390/nu12030783. PMID: 32188044; PMCID: PMC7146466.
  2. Aderinto, N., Olatunji, G., Kokori, E. et al.High-dose vitamin D supplementation in multiple sclerosis: a systematic review of clinical effects and future directions. Discov Med1, 12 (2024). https://doi.org/10.1007/s44337-024-00023-9
  3. Thouvenot E, Laplaud D, Lebrun-Frenay C, et al. High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. JAMA.Published online March 10, 2025. doi:10.1001/jama.2025.1604

4. Sintzel, M.B., Rametta, M. & Reder, A.T. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther 7, 59–85 (2018). https://doi.org/10.1007/s40120-017-0086-4

eaf610ae-287d-4ef2-8592-b3c44d059196

FDA Approves Blujepa: First-in-Class Topoisomerase Inhibitor Antibiotic for UTIs

by with No Comment Disease & Drugs

Written by Lavanya Chavhan (B.Pharm) and Aishwarya Shinde (B.Pharm)

Reviewed and Fact Checked by Vikas Londhe M.Pharm (Pharmacology)

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In a significant development in the fight against urinary tract infections (UTIs), the U.S. Food and Drug Administration (FDA) has approved Blujepa (gepotidacin), a groundbreaking oral antibiotic designed to treat uncomplicated UTIs in female patients aged 12 and older. This marks the first new class of oral antibiotics for UTIs in nearly three decades, offering hope to millions of women who suffer from recurrent infections that are increasingly resistant to traditional treatments.

Background and Need for New Treatments

UTIs are primarily caused by bacteria, most commonly Escherichia coli (E. coli) (75-95% of cases). Other pathogens include Klebsiella pneumoniae, Proteus mirabilis Staphylococcus saprophyticus (common in young women) and Enterococcus faecalis potentially affecting the bladder (cystitis), urethra (urethritis), or kidneys (pyelonephritis).

Conventional treatment for Uncomplicated UTIs includes first-line antibiotics Nitrofurantoin, Trimethoprim-sulfamethoxazole (TMP-SMX), Fosfomycin. Alternatives treatment includes Cephalexin and Amoxicillin-clavulanate if resistance is low.

In Complicated UTIs like UTI in pregnancies, diabetes, or kidney involvement (pyelonephritis) broad-spectrum antibiotics are implemented like Ciprofloxacin, Levofloxacin, and intravenous Ceftriaxone. More severe infections may need piperacillin/tazobactam, meropenem, ertapenem, or doripenem.

UTI is one of the most commonly affecting bacterial infection affecting 150 million people per year globally. Women are at higher risk (50-60% experience ≥1 UTI in their lifetime) due to shorter urethras. Elderly & catheterized patients also have increased susceptibility.

Antibiotic resistance is the rising concern in UTI treatment, resistance to TMP-SMX, fluoroquinolones (e.g., Ciprofloxacin), and beta-lactams complicated the treatment process. ESBL-producing E. coli which is resistant to penicillin/Cephalosporins is a growing concern and which can leads to longer infections, higher recurrence rates, and increased use of IV antibiotics.

These increased concerns of antibiotic resistance necessitating the development of new antibiotics with novel mechanisms of action.

Blujepa (Gepotidacin): A Novel Approach

Blujepa is developed by GlaxoSmithKline (GSK) is a novel first-in-class triazaacenaphthylene antibiotic that belongs to a new category called bacterial topoisomerase inhibitors. It exhibits a unique mechanism of action distinct from other antibiotics, targeting bacterial type II topoisomerases.

Gepotidacin selectively inhibits bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, both critical enzymes for DNA replication and transcription. Unlike fluoroquinolones (which stabilize topoisomerase-DNA cleavage complexes), gepotidacin blocks the ATP-independent strand-passage reaction, preventing DNA relaxation and decatenation.

It binds to a novel site on the GyrB (gyrase) and ParE (topoisomerase IV) subunits, distinct from fluoroquinolone binding sites.

This reduces the likelihood of cross-resistance with existing antibiotics. By interfering with DNA replication and repair, gepotidacin causes lethal double-stranded DNA breaks, leading to bacterial cell death.

This unique mechanism reduces the likelihood of antimicrobial resistance, making it a promising solution for recurrent or treatment-resistant UTIs

Clinical Trials and Approval

The FDA’s approval of Blujepa was based on results from two pivotal Phase III clinical trials, EAGLE-2 and EAGLE-3.

The EAGLE-2 trial was a Phase III, randomized, double-blind study evaluating the efficacy and safety of gepotidacin. Trial was conducted across multiple centres worldwide, the trial enrolled non-pregnant females weighing at least 40 kg who exhibited symptoms such as dysuria, frequency, urgency, or lower abdominal pain, along with evidence of urinary nitrite or pyuria. Participants were randomly assigned to receive either oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days). The primary endpoint was therapeutic success, defined as complete symptom resolution and microbiological eradication of the uropathogen without the need for additional antimicrobial treatment. ​ In the EAGLE-2 trial, therapeutic success was achieved in 50.6% of patients treated with gepotidacin compared to 47.0% of those receiving nitrofurantoin demonstrating non-inferiority of gepotidacin to nitrofurantoin.

EAGLE-3 trial was randomized, double-blind, double-dummy, non-inferiority trial compared gepotidacin (1500 mg twice daily for 5 days) to nitrofurantoin (100 mg twice daily for 5 days), a standard uUTI treatment. The results demonstrated that gepotidacin was statistically superior to nitrofurantoin in achieving therapeutic success at the test-of-cure visit (days 10–13). Specifically, therapeutic success was observed in 58.5% of patients receiving gepotidacin compared to 43.6% in the nitrofurantoin group.

Safety Profile

Blujepa carries the warning signs of QTc prolongation and hypersensitivity reactions. The safety profile of gepotidacin was consistent with previous studies. Common adverse events were gastrointestinal-related, such as diarrhea (16%) and nausea (4%). Most of these adverse events were mild or moderate, with severe events occurring in less than 1% of participants.

Impact and Future Directions

The approval of Blujepa is a crucial milestone in addressing the growing challenge of antibiotic resistance in UTIs. It provides a new treatment option for patients experiencing recurrent infections and offers hope for reducing the strain on healthcare systems.

As noted by GSK’s Chief Scientific Officer, Tony Wood, this approval is significant for women who face recurrent infections and rising resistance rates.

In conclusion, the FDA’s approval of Blujepa marks a significant advancement in the treatment of uncomplicated UTIs, offering a new and effective option for managing these common infections. As the first new oral antibiotic for UTIs in nearly 30 years, Blujepa represents a promising step forward in combating antimicrobial resistance and improving patient outcomes.

References

1. Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and paediatric patients 12 years of age and older, GSK, 25 March 2025, available from https://www.gsk.com/en-gb/media/press-releases/blujepa-gepotidacin-approved-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections/

2. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection, and treatment options. Nat Rev Microbiol. 2015 May; 13(5):269-84. DOI: 10.1038/nrmicro3432. Epub 2015 Apr 8. PMID: 25853778; PMCID: PMC4457377

3. Bono MJ, Leslie SW. Uncomplicated Urinary Tract Infections. [Updated 2025 Feb 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.  Available from: https://www.ncbi.nlm.nih.gov/books/NBK470195/

4. Sabih A, Leslie SW. Complicated Urinary Tract Infections. [Updated 2024 Dec 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.  Available from: https://www.ncbi.nlm.nih.gov/books/NBK436013/

5. Mareș C, Petca RC, Popescu RI, et al, Update on Urinary Tract Infection Antibiotic Resistance-A Retrospective Study in Females in Conjunction with Clinical Data. Life (Basel). 2024 Jan 9;14(1):106. Doi: 10.3390/life14010106. PMID: 38255721; PMCID: PMC10820678

6. Emina K. Sher, Amina Džidić-Krivić, et al, Current state and novel outlook on prevention and treatment of rising antibiotic resistance in urinary tract infections, Pharmacology & Therapeutics, Volume 261, 2024, 108688, https://doi.org/10.1016/j.pharmthera.2024.108688

7. Blujepa (gepotidacin), Highlights Of Prescribing Information, available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218230s000lbl.pdf

8. Wagenlehner, Florian et al, Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials, The Lancet, Volume 403, Issue 10428, 741 – 755

9. Clinical Implications, Study Takeaways of Gepotidacin for Uncomplicated UTIs, 28 March 2025, Contagion Live, available from https://www.contagionlive.com/view/clinical-implications-study-takeaways-of-gepotidacin-for-uncomplicated-utis

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VykaT XR (Diazoxide Choline) Gets FDA Approval for Prader-Willi Syndrome-Related Hyperphagia

by with No Comment Disease & Drugs

Written by Pavan Reddy (Biomedical Engineer) and Pragati Ekamalli (B.Pharm)

Reviewed and Fact Checked by Vikas Londhe M.Pharm (Pharmacology)

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Introduction
The U.S. Food and Drug Administration (FDA) have recently approved VykaT XR (diazoxide choline extended-release) for the treatment of hyperphagia an insatiable hunger and food-seeking behaviour—in patients with Prader-Willi Syndrome (PWS). This marks a significant milestone in addressing one of the most challenging and life-threatening aspects of PWS.

Understanding Prader-Willi Syndrome and Hyperphagia

Prader-Willi Syndrome is a rare genetic disorder characterized by hypotonia, developmental delays, behavioural challenges, and endocrine abnormalities. One of the most debilitating symptoms is hyperphagia, an extreme and unrelenting hunger that can lead to severe obesity, diabetes, and life-threatening complications if not carefully managed.

Hyperphagia in Prader-Willi Syndrome (PWS) is a hallmark symptom and one of the most challenging aspects of the condition to manage.

Hyperphagia refers to an abnormally increased appetite for and consumption of food. In PWS, this goes beyond typical overeating — it’s a compulsive drive to eat that often leads to life-threatening obesity if not carefully managed.

Prader-Willi Syndrome is a complex genetic disorder caused by the loss of function of specific genes on chromosome 15 (most often from the paternal side). One of the primary areas affected is the hypothalamus, the brain region responsible for regulating hunger and satiety.

Because of this hypothalamic dysfunction:

Individuals with PWS don’t receive normal signals of fullness.

Ghrelin, the “hunger hormone,” is often found at abnormally high levels.

This creates a constant feeling of hunger, regardless of how much food is consumed.

PWS-related eating behaviour typically progresses in stages:

Infancy – Poor muscle tone (hypotonia) and feeding difficulties, often requiring tube feeding.

Early Childhood (2–4 years) – Weight gain begins without an apparent increase in food intake.

Later Childhood – An insatiable appetite emerges; the drive to eat intensifies, often leading to food-seeking behaviors, hoarding, and even food theft.

Until now, treatment options for hyperphagia have been limited tostrict dietary supervision, behavioural therapy, and growth hormone therapy (which help with some symptoms but do not directly address hyperphagia).

VykaT XR offers the first FDA-approved pharmacological treatment specifically targeting this symptom.

What is VykaT XR (Diazoxide Choline)?

Diazoxide choline is a salt form of diazoxide, a medication that has been around for decades, primarily used to treat conditions like hypoglycemia (low blood sugar) due to its ability to inhibit insulin secretion and hypertension (high blood pressure). The choline salt form is designed to potentially improve the bioavailability and tolerability of diazoxide, especially in oral formulations.

VykaT XR is an extended-release formulation of diazoxide choline, a modified version of diazoxide.

Key Benefits of VykaT XR

Reduces excessive hunger by acting on brain pathways involved in appetite regulation.

Extended-release formulation allows for once-daily dosing, improving compliance.

Potential to improve quality of life by reducing food-related anxiety and obsessive behaviors.

Clinical Trials and Efficacy

The approval of VykaT XR was based on data from Phase 3 clinical trials demonstrating its effectiveness in reducing hyperphagia symptoms. Key findings included

The C602-RWP (Randomized Withdrawal Period) was a phase of the C602 clinical study evaluating the efficacy and safety of Diazoxide Choline Extended-Release (DCCR) tablets for treating Prader-Willi Syndrome (PWS). This phase was specifically assessed the impact of discontinuing DCCR on hyperphagia-related behaviors in individuals with PWS.

Study design includes 77 individual participants with PWS who had previously been enrolled in the C602 open-label extension study and had received DCCR treatment for two to four years. Participants were randomized in a 1:1 ratio to either continue DCCR treatment or switch to a placebo for duration of 16 weeks. Primary Endpoint include Change from baseline in hyperphagia-related behaviors, measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT).

Key Findings of the trial in hyperphagia Assessment at week 16, participants who switched to placebo showed a significant worsening in hyperphagia-related behaviors, with an increase of 5.0 points in the HQ-CT total score compared to those who continued DCCR treatment

Secondary endpoints, including the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I), indicated trends toward worsening conditions in the placebo group compared to the DCCR group.

DCCR was generally well-tolerated, with no new or unexpected safety signals reported during the randomized withdrawal period.​

These results suggest that continuous treatment with DCCR may be beneficial in managing hyperphagia in individuals with PWS, and discontinuation could lead to a significant worsening of symptoms. Based on these findings, Soleno Therapeutics planned to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA).

Implications for Patients and Families

For individuals with PWS and their caregivers, VykaT XR offers new hope in managing a symptom that has long been a major source of distress. Many caregivers view VykaT XR as a long-awaited option that addresses one of the most difficult aspects of PWS.

Patient advocacy groups Prader-Willi Syndrome Association USA have shared cautiously optimistic statements, emphasizing the potential impact on family dynamics, independence, and safety. However Community discussions indicate concerns about insurance coverage, cost, and provider awareness.

Conclusion

The FDA’s approval of VykaT XR represents a groundbreaking advancement in the treatment of Prader-Willi Syndrome. While ongoing research will further define its long-term benefits and safety profile, this therapy provides a much-needed tool in managing hyperphagia a symptom that profoundly impacts the lives of those with PWS.

Patients and healthcare providers are encouraged to discuss VykaT XR as part of a comprehensive PWS management plan, which should continue to include nutritional support, behavioural interventions, and endocrine care.

For now, VykaT XR stands as a landmark therapy, offering new possibilities for individuals and families affected by Prader-Willi Syndrome.

References

  1. US FDA approval of VykaT XR, Soleno Therapeutics, 26 March 2025, available from https://investors.soleno.life/static-files/9e8f0f73-ea3b-47fe-8c8e-fbd276a31333
  2. Soleno therapeutics announces U.S. FDA approval of VykaT XR to treat hyperphagia in Prader-Willi Syndrome, Soleno Therapeutics, 26 March 2025, available from https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-us-fda-approval-vykattm-xr-treat
  3. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. 1998 Oct 6 [Updated 2024 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/

4. Prader-Willi Syndrome, Foundation for Prader Willi Research, available from https://www.fpwr.org/what-is-prader-willi-syndrome#definition

  1. Rahman QFA, Jufri NF, Hamid A. Hyperphagia in Prader-Willi syndrome with obesity: From development to pharmacological treatment. Intractable Rare Dis Res. 2023 Feb; 12(1):5-12. Doi: 10.5582/irdr.2022.01127. PMID: 36873672; PMCID: PMC9976092.
  2. S.A. Bellis, I. Kuhn, S. Adams, L. Mullarkey, A. Holland, The consequences of hyperphagia in people with Prader-Willi Syndrome: A systematic review of studies of morbidity and mortality, European Journal of Medical Genetics, Volume 65, Issue 1, 2022,104379, https://doi.org/10.1016/j.ejmg.2021.104379
  3. Holsen LM, Zarcone JR, Brooks WM, Butler MG, Thompson TI, Ahluwalia JS, Nollen NL, Savage CR. Neural mechanisms underlying hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring). 2006 Jun;14(6):1028-37. Doi: 10.1038/oby.2006.118. PMID: 16861608; PMCID: PMC1535344
  4. Miller JL, Gevers E, Bridges N, et al, Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1676-1685. Doi: 10.1210/clinem/dgad014. PMID: 36639249; PMCID: PMC10271219.

9. Vykat XR FDA Approval History, Drugs.com, available from https://www.drugs.com/history/vykat-xr.html

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No More Implants? Lab-Grown Teeth Might Be the Future of Dentistry

by with No Comment Disease & Drugs

Written By Yogita Bhadane B.Pharm

Reviewed and Fact Checked By Vikas Londhe M.Pharm (Pharmacology)

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Lost tooth has been a challenge in oral healthcare since log time; it has been often treated with artificial replacements like implants or dentures. But what if an idea of re-growing tooth outside body became real? A recent study published in ACS Macro Letters brings this idea closer to reality by using advanced hydrogel-based matrix to grow tooth organoids miniature, a lab-grown versions of developing teeth.

Introduction: Why We Need Biological Tooth Replacement

Tooth loss can happen for many reasons, like decay, gum disease, injury, or illness. Missing teeth can hurt a person’s confidence, speech, and health. Current solutions like dental implants and dentures can replace teeth, but they cannot create real tooth tissue or fully restore how a natural tooth works.

Regenerative dentistry, a field focused on regenerating and repairing an oral tissue in event of damage by stimulating a body’s natural processes instead of merely replace it, is aims to fill this gap by creating bioengineered teeth using living cells and materials that mimic how natural teeth develop. A key step in this work is making tooth organoids, which are 3D models that copy how teeth grow.

Conventional Methods for Tooth Repair and Their Limitations

Traditionally, broken or missing teeth are fixed with; fillings and crowns to rebuild structure, bridges or removable dentures to replace teeth and dental implants that attach to the jawbone.

Although implants are widely used, they are not biological. They do not grow or heal and can fail due to infection or other issues. Also, implants do not interact with surrounding tissues like real teeth.

Attempts to engineer teeth in the lab

Researchers have tried to create teeth in the lab using materials like collagen matrix, decellularized tooth buds and synthetic polymers like PLGA, PGA, PLLA and Matrigel. However, these materials provide structure but lack tunable physical properties. Also they don’t provide enough information on how physical factors like stiffness affect tooth growth.

The New Approach: Engineering a Better Matrix for Tooth Growth

In this revolutionizing study, scientists created a tunable hydrogel system to help as a matrix to teeth grow. They modified gelatine and cross linked using the inverse-electron demand Diels−Alder reaction with specific chemical group’s in between Tetrazine (Tz) and Norbornene (Nb). By modifying the gelatine concentration (8% or 12%) and Tz: Nb ratio (1:1 or 0.5:1), they created hydrogels with different properties. These hydrogels were soft, able to swell, and stable for growing cells.

Tooth Organoid generation

To make tooth organoids, researchers took dental epithelial and mesenchymal cells from embryonic mouse tooth germs and mixed them into the hydrogel matrix to form cell pellets. They then cultured these cells in vitro for 8 days to form tooth organoids.

 How Teeth were Regrown in the Lab

Three different hydrogel types were tested:

  1. GEL_8%_R05: 8% Tz: Nb ratio 0.5:1
  2. GEL_8%_R1: 8% Tz: Nb ratio 1:1
  3. GEL_12%_R05: 12% gelatin, Tz: Nb ratio 0.5:1

Only the GEL_8%_R05 group consistently produced well-structured tooth organoids that looked like natural teeth. The study showed that the softness of the hydrogel was important for the cells to self-organize into tooth-like structures.

Implications and Future Steps

This research is a big step for regenerative dentistry. It helps us understand how teeth develop and allows for customized hydrogels that can be used to study tooth formation.

Improved understanding of dental embryogenesis, by replicating the process in controllable lab conditions

Personalized dental therapies: In the future, patient-specific cells could be used to regrow teeth in customized hydrogels.

However Xuechen Zhang one of the researchers says that “We have different ideas to put the teeth inside the mouth. We could transplant the young tooth cells at the location of the missing tooth and let them grow inside mouth. Alternatively, we could create the whole tooth in the lab before placing it in the patient’s mouth. For both options, we need to start the very early tooth development process in the lab.”

Dr Ana Angelova Volponi, King’s College London, added that “as the field progresses, the integration of such innovative techniques hold the potential to revolutionise dental care, offering sustainable and effective solutions for tooth repair and regeneration.

Next steps of the research includes use of human cells to move towards clinical translation, testing how well these organoids grow over time, adding growth factors to guide development, and exploring the possibility of transplanting mature organoids into living models.

Conclusion

In conclusion, this study shows that the mechanical properties of hydrogels are important for developing tooth organoids in the lab. By adjusting the stiffness and make-up of the matrix, researchers were able to help cells communicate and organize themselves, closely resembling natural tooth development.

References:

1. Lab-grown teeth might become an alternative to fillings following research breakthrough, Kings College London, 14 April 2025, available from https://www.kcl.ac.uk/news/lab-grown-teeth-might-become-an-alternative-to-fillings-following-research-breakthrough

2. Zhang X, Contessi Negrini N, Correia R, Sharpe PT, Celiz AD, Angelova Volponi A. Generating Tooth Organoids Using Defined Bioorthogonally Cross-Linked Hydrogels. ACS Macro Lett. 2024 Dec 17;13(12):1620-1626. Doi: 10.1021/acsmacrolett.4c00520. Epub 2024 Nov 12. PMID: 39532305; PMCID: PMC11656705

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“Age-Related Macular Degeneration: What’s New in Treatment and Research?”

by with No Comment Disease & Drugs

Medically Reviewed by Dr. Mayur Jawale (MBBS, MS- Ophthalmology, Fellowship in Phacoemulsification)

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Introduction 

Age-related macular degeneration (AMD) creates haziness on central vision and is a leading cause of irreversible vision loss in individuals over 50. It affects the macula, the central part of the retina responsible for sharp, detailed vision. AMD is affecting central vision without causing complete blindness. This can make everyday activities such as reading, driving, recognizing faces, and detailed tasks much more challenging. While there is no cure for AMD, recent advancements in medical research have led to groundbreaking treatments that slow disease progression and, in some cases, restore vision. This article explores the latest innovations in AMD therapy, including gene therapy; stem cell treatments, and novel drug delivery systems.

Types of AMD

Age-related macular degeneration (AMD) is classified into two main forms: dry (atrophic) AMD and wet (neovascular) AMD. They differ in progression, symptoms, and treatment approaches.

Dry AMD (Non-Exudative or Atrophic AMD)

Most common type (about 80-90% of AMD cases)

Slow progression over years, leading to gradual central vision loss.

Caused by thinning of the macula and accumulation of drusen (yellow protein deposits) under the retina

Advanced stage: Geographic atrophy (GA), where retinal cells degenerate, causing permanent blind spots

Current treatments: No cure, but AREDS2 supplements may slow progression

Wet AMD (Exudative or Neovascular AMD)

Less common but more severe (10-15% of AMD cases)

Rapid progression, often leading to sudden vision loss

Caused by abnormal blood vessel growth (choroidal neovascularisation) that leak fluid/blood, damaging the macula

Symptoms: Distorted vision (metamorphopsia), dark spots, rapid central vision decline

Treatments: Anti-VEGF injections (e.g., Lucentis, Eylea), laser therapy, and photodynamic therapy

Current Standard Treatments 

Before delving into new advancements, it’s essential to understand the existing treatments: 

Anti-VEGF Injections – The gold standard for wet AMD, these drugs (e.g., ranibizumab, aflibercept, bevacizumab) block vascular endothelial growth factor (VEGF), preventing abnormal blood vessel growth. No clinically major variation in the effectiveness and safety of different anti-VEGF treatments.

Laser Therapy – Laser photocoagulation is a type of laser therapy Used in certain cases of wet AMD to destroy abnormal blood vessels.

Laser photocoagulation is only used in wet AMD, where irregular blood vessels develop, but it’s not suitable for all patients.”

Vitamin Supplements (AREDS2 Formula): According to the NIH-funded AREDS2 research, taking certain vitamin and mineral supplements reduces the risk of dry AMD progressing to sight-threatening stages by 25 percent.

This formula involve Vitamin C: 500 mg, Vitamin E: 400 IU, Zinc: 80 mg (as zinc oxide), Copper: 2 mg (as cupric oxide), Lutein: 10 mg, Zeaxanthin: 2 mg

While effective, these treatments have limitations, such as frequent injections and incomplete efficacy in dry AMD. Researchers are now developing next-generation therapies to overcome these challenges. 

Cutting-Edge Advancements in AMD Treatment 

Gene Therapy for AMD 

Gene therapy is emerging as a promising approach for treating age-related macular degeneration (AMD), particularly its neovascular (wet) form. Traditional treatments for wet AMD often require frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents to control abnormal blood vessel growth in the retina. Gene therapy aims to provide a more sustainable solution by enabling the eye to produce therapeutic proteins internally, potentially reducing or eliminating the need for repeated injections.​

Advancements in Gene Therapy for Wet AMD

RGX-314 (REGENXBIO): This therapy utilizes an adeno-associated virus (AAV) vector to deliver a gene encoding a monoclonal antibody fragment that inhibits VEGF. It is designed for subretinal or suprachoroidal delivery, with the goal of providing long-term suppression of VEGF activity. Clinical trials are ongoing to evaluate its safety and efficacy

Ixo-vec, formerly ADVM-022 (Adverum Biotechnologies): Ixo-vec employs an AAV vector to deliver a gene encoding an anti-VEGF protein. Following favourable results from Phase 1 and Phase 2 trials, Adverum is preparing to initiate Phase 3 clinical trials in the first half of 2025.

Gene Therapy for Dry AMD (Geographic Atrophy)

While much focus has been on wet AMD, gene therapy is also being explored for geographic atrophy (GA), the advanced form of dry AMD.

GT005 (Gyroscope Therapeutics): This investigational gene therapy aims to increase the production of complement factor I, a protein that regulates the complement system implicated in GA. Clinical trials are underway to assess its safety and efficacy. ​

OCU410 (Ocugen): A Phase 1/2 study is evaluating the safety and efficacy of OCU410 for GA secondary to dry AMD. The study involves randomized, sequential assignment with single masking and aims to enroll 63 patients.

Stem Cell Therapy 

Stem cell therapy is emerging as a promising avenue for treating age-related macular degeneration (AMD), particularly its dry form, known as geographic atrophy (GA). Recent advancements have led to several clinical trials aimed at evaluating the safety and efficacy of stem cell-based treatments for AMD. Scientists are focusing on replacing damaged retinal pigment epithelium (RPE) cells, which are crucial for supporting photoreceptors, the cells responsible for detecting light.

Embryonic and Induced Pluripotent Stem Cells (iPSCs) – Researchers are implanting retinal pigment epithelium (RPE) cells derived from stem cells to replace damaged tissue. 

Phase I/II Clinical Trials – One notable initiative is a Phase I/IIa clinical trial conducted by the National Eye Institute (NEI), focusing on the transplantation of autologous induced pluripotent stem cell-derived retinal pigment epithelium (iRPE) cells. This trial aims to assess the safety of implanting iRPE patches into areas adjacent to GA in patients with advanced dry AMD.

Complement Inhibitors (For Dry AMD)

Significant advancements have been made in the development of complement inhibitors for the treatment of dry age-related macular degeneration (AMD), particularly in addressing geographic atrophy (GA), an advanced form of dry AMD.​

Approved Treatments

Pegcetacoplan (Syfovre): This C3 inhibitor received approval from the U.S. Food and Drug Administration (FDA) in February 2023 for the treatment of GA. Administered via intravitreal injection every 25 to 60 days, pegcetacoplan has demonstrated a reduction in the progression of GA lesions over time. ​

Avacincaptad Pegol (Izervay): Approved by the FDA in August 2023, this C5 inhibitor is administered through monthly intravitreal injections. Clinical trials have shown that avacincaptad pegol can slow the growth of GA lesions, with its protective effect increasing over

There are multiple clinical trial are going on to investigate new complement inhibitors like NGM621, ANX007, IONIS-FB-LRx (ASO Factor B).

Sustained Drug Delivery Systems 

Reducing injection frequency is a major focus. 

 Port Delivery System (Susvimo, Roche) – A refillable implant that continuously releases ranibizumab, requiring only biannual refills. 

Extended-Release Anti-VEGF Formulations – Drugs like KSI-301 (Kodiak Sciences) use antibody biopolymers to prolong therapeutic effects. 

Artificial Intelligence (AI) in AMD Diagnosis & Monitoring 

AI is revolutionizing early detection and personalized treatment. 

Retinal Imaging Analysis – AI algorithms (e.g., IDx-DR, Optos) detect AMD progression earlier than traditional methods. 

Predictive Modelling – AI helps predict which patients will progress to advanced AMD, enabling timely intervention

Future Directions 

CRISPR Gene Editing – Potential to correct genetic mutations causing AMD. 

Bionic Retina Implants – Devices like the PRIMA implant restore partial vision in late-stage AMD. 

Conclusion 

The landscape of AMD treatment is rapidly evolving, with gene therapy, stem cells, and sustained drug delivery systems offering hope for long-term solutions. While challenges remain, these innovations promise to transform AMD management, reducing treatment burden and improving quality of life for millions. Continued research and clinical trials will be crucial in bringing these therapies to mainstream ophthalmology. 

References

Age-Related Macular Degeneration (AMD), National Eye Institute, 22 June 2021 available from https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration

Understanding Macular Degeneration, American Academy of Ophthalmology, 01 Oct 2024 available from https://www.aao.org/eye-health/diseases/amd-macular-degeneration

New Treatments for Age-Related Macular Degeneration, American Academy of Ophthalmology, 23 May 2024 available from https://www.aao.org/eye-health/tips-prevention/promising-new-treatments-amd

Hao Q, Bailey S, Anti–Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration: CADTH Health Technology Review [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Oct. Available from: https://www.ncbi.nlm.nih.gov/books/NBK598219/

Laser Photocoagulation for Age-Related Macular Degeneration, Health, Johns Hopkins Medicine, available from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/laser-photocoagulation-for-agerelated-macular-degeneration

Joshua Dunaief, MD, PhD,  Vitamins for Age-Related Macular Degeneration: Do You Have the Correct Formula? Macular Degeneration Research, available from https://www.brightfocus.org/resource/vitamins-for-age-related-macular-degeneration-do-you-have-the-correct-formula/

Blasiak J, Pawlowska E, Ciupińska J, New Generation of Gene Therapies as the Future of Wet AMD Treatment. Int J Mol Sci. 2024 Feb 17;25(4):2386. doi: 10.3390/ijms25042386. PMID: 38397064; PMCID: PMC10888617

Khanani AM, Thomas MJ, Aziz AA, Weng CY, Danzig CJ, Yiu G, Kiss S, Waheed NK, Kaiser PK. Review of gene therapies for age-related macular degeneration. Eye (Lond). 2022 Feb;36(2):303-311. doi: 10.1038/s41433-021-01842-1. Epub 2022 Jan 11. PMID: 35017696; PMCID: PMC8807824

Gene Therapy for Age-Related Macular Degeneration, Nuffield Department of Clinical Neurosciences, available from https://www.ndcn.ox.ac.uk/research/clinical-ophthalmology-research-group/trials/amd-gene-therapy

Qin S, Dong N, Yang M, Wang J, Feng X, Wang Y. Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option. J Immunol Res. 2021 Jul 29;2021:9945725. Doi: 10.1155/2021/9945725. PMID: 34368372; PMCID: PMC8346298

Cruz-Pimentel M, Wu L. Complement Inhibitors for Advanced Dry Age-Related Macular Degeneration (Geographic Atrophy): Some Light at the End of the Tunnel? J Clin Med. 2023 Aug 4; 12(15):5131. Doi: 10.3390/jcm12155131. PMID: 37568533; PMCID: PMC10420150

Sarkar I, Sodha SJ, Junnuthula V, Novel and investigational therapies for wet and dry age-related macular degeneration, Drug Discovery Today, Volume 27, Issue 8, 2022, Pages 2322-2332 https://doi.org/10.1016/j.drudis.2022.04.013

Tzoumas N, Riding G, Williams MA, Steel DH. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst Rev. 2023 Jun 14;6(6):CD009300. Doi: 10.1002/14651858.CD009300.pub3. PMID: 37314061; PMCID: PMC10266126

Port Delivery System for AMD, American Academy of Ophthalmology, 01 Nov 2021 available from https://www.aao.org/eyenet/article/port-delivery-system-for-amd

Stewart, M. W. (2016). Extended release anti-VEGF systems: a strategy whose time has come? Or already gone? Expert Review of Ophthalmology, 11(3), 167–169 https://doi.org/10.1080/17469899.2016.1186546

Crincoli E, Sacconi R, Querques L, Querques G. Artificial intelligence in age-related macular degeneration: state of the art and recent updates. BMC Ophthalmol. 2024 Mar 15;24(1):121. Doi: 10.1186/s12886-024-03381-1. PMID: 38491380; PMCID: PMC10943791.

Gao Y, Xiong F, Xiong J, Recent advances in the application of artificial intelligence in age-related macular degeneration. BMJ Open Ophthalmol. 2024 Nov 13;9(1):e001903. Doi: 10.1136/bmjophth-2024-001903. PMID: 39537399; PMCID: PMC11580293.

Dongchun Xie, Yuxi Chen, Sihui Hu, CRISPR-based gene therapy for wet age-related macular degeneration in mouse model, Clin. Transl. Disc 2024;4:e278,Doi: 10.1002/ctd2.278