2149158051

After Second Liver Failure Death, Sarepta Therapeutics Halts Global Elevidys Dosing in Non-Ambulatory Duchenne Muscular Dystrophy Patients; Phase III ENVISION Trial Impacted

by with No Comment Disease & Drugs

Medically Written and Reviewed By:

Vikas Londhe, MPharm

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Source: Freepik.com

On June 15, 2025, Sarepta Therapeutics announced the second death of a teenage male patient linked to acute liver failure (ALF) following its one-time gene therapy drug Elevidys in a non ambulatory Duchenne Muscular Dystrophy (DMD) patient, someone who is no longer able to walk due to this condition. The first fatality occurred in March 2025, when a 16-year-old boy succumbed to liver failure months after his treatment with Elevidys.

Official response

As soon as Sarepta was aware about adverse event, they suspended all commercial shipments of Elevidys to non‑ambulatory patients. Sarepta has completely paused dosing to non-ambulatory patient cohort in ENVISION Phase III trial which is going on in ambulatory and non-ambulatory older patient globally; as they are focusing on designing and enhancing more acceptable immunosuppressant regimen along with Elevidys.

Sarepta summon an independent panel of DMD and liver experts to evaluate alternate therapies like sirolimus in combination with corticosteroids to mitigate liver failure risk.

Alongside, Sarepta is continuously discussing with the FDA and other regulatory bodies their proposed plan for this event.   

Roche, which is partnered with Sarepta and is responsible for Elevidys’ marketing outside the United States, has equally halted dosing and shipments of Elevidys for non‑ambulatory patients globally.

Sarepta has particularly reported that both fatalities were associated with non-ambulatory patients who were no longer able to walk, a subgroup with advanced DMD. Approximately 140 such patients have been treated, and now, with two ALF-related deaths, this is considered to be a serious safety signal.

However ambulatory patients (those still walking) can continue treatment under the current corticosteroid regimen, as company has not amended protocols for them.

Elevidys & liver risk

Elevidys (delandistrogene moxeparvovec) is an innovative gene therapy that uses an Adeno-Associated Virus (AAV) as a delivery system to transport a micro‑dystrophin genetic material into the body via a single IV infusion. AAV-based gene therapies are known to cause acute liver injury, which can lead to liver failure, though fatalities were rare.

The Elevidys’ previous FDA approval already requires corticosteroid administration one day before initiating treatment and continuing for 60 days post-administration, along with close monitoring for liver function, but those measures have not prevented these rare, severe outcomes. Sarepta is now working on an enhanced safety regimen, which may include the addition of the extra immunosuppressant drug sirolimus into the current corticosteroid regimen. This modification of treatment is held up by preclinical data, which demonstrated sirolimus’ effectiveness in suppressing certain liver enzymes, which may help to mitigate this potential safety signal.

Implications for patients and the market

The tragic loss of two non-ambulatory patients highlights the importance of carefully analyzing Elevidys’s further benefits against the serious risks of liver failure in this subgroup. The ENVISION trial will be amended to include stronger immunosuppressant protocols by the addition of sirolimus; however, this change must receive FDA clearance before dosing resumes. While the FDA has agreed to the pause and is reviewing emerging safety data, full restoration of the trial and treatment depends on how effectively Sarepta is mitigating liver risk in non-ambulatory patient populations.

Summary

Sarepta Therapeutics has reported a second death from acute liver failure in a non-ambulatory patient treated with its Duchenne Muscular Dystrophy gene therapy, Elevidys. Both fatalities occurred in patients who were no longer able to walk, prompting Sarepta and its partner Roche to suspend dosing and commercial shipments of Elevidys for this subgroup globally; however, treatment continues for ambulatory patients. For the time being, dosing to the non-ambulatory cohort group in the Phase III ENVISION trial is on hold pending regulatory review of enhanced immunosuppressant protocols, possibly for the addition of sirolimus into the regimen. The company is working with an independent panel of experts to evaluate stronger liver-protection strategies. These developments have deepened inspection of Elevidys’s safety profile, particularly in advanced-stage DMD. At the same time, it is raising questions about gene therapy risks.

References

Sarepta Community Letter: Safety Update regarding Elevidys in non-ambulatory individuals with Duchenne, Sarepta Therapeutics, June 15, 2025, https://www.parentprojectmd.org/wp-content/uploads/2025/06/Elevidys-Community-Letter-6.15.2025.pdf

Highlights of prescribing information, Elevidys, https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert-ELEVIDYS_1.pdf

Sarepta Reports Second Death of Patient Using Its Gene Therapy, Bloomberg, https://www.bloomberg.com/news/articles/2025-06-15/sarepta-reports-second-death-of-patient-using-its-gene-therapy

Sarepta reports second case of liver failure death after its gene therapy treatment, Reuters, https://www.reuters.com/business/healthcare-pharmaceuticals/sarepta-reports-second-case-liver-failure-death-after-its-gene-therapy-treatment-2025-06-15/

A safety update on Elevidys, June-2025, Parent Project Muscular Dystrophy, https://www.parentprojectmd.org/a-safety-update-on-elevidys-june-2025/?utm_source=chatgpt.com

Second DMD Patient Dies after Treatment with Sarepta Gene Therapy, https://www.genengnews.com/topics/genome-editing/second-dmd-patient-dies-after-treatment-with-sarepta-gene-therapy/

Sarepta Provides Safety Update for ELEVIDYS and Initiates Steps to Strengthen Safety in Non-Ambulatory Individuals with Duchenne, Sarepta Therapeutics, https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-provides-safety-update-elevidys-and-initiates-steps

2148920822

Moderna Launches mNEXSPIKE: New FDA-Approved COVID Vaccine for High-Risk Groups

by with No Comment New Drug Approval

Written By: Dewanshee Ingale, BPharm

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Source: Freepik.com

In a landmark move, the FDA has granted approval to Moderna’s mNEXSPIKE, marking a new chapter in COVID-19 vaccine evolution. Approved on May 30, 2025, was a historic landmark towards the continuous development and evolution of messenger RNA (mRNA) technology based vaccines. The vaccine is such created that it acts as a next generation booster to improve the COVID-19 protection primarily focusing on the high-risk people. High risk populations include older adults from the age of 65 and above as well as smaller adults from the age of 12-24 with serious medical conditions defined by the Centres’ for Disease Control and Prevention (CDC) and that can increases the worsening of the outcomes if they are infected by virus. With the grand approval, Moderna now expects to provide mNEXSPIKE in addition to its original Spikevax® vaccine during this upcoming 2025-2026 respiratory virus season.          

Present data and background

COVID-19 still serves as a major public health risk in the world. In 2024, the virus took more than 47,000 lives in America, which translates to a death every 11 minutes. Older adults usually experience very severe sickness, hospitalization, and death as compared to other groups. CDC surveillance data from October 2023 to April 2024 show that this older age group represented 70% of adult hospitalizations. Adults aged 65 and older comprised approximately 70% of all COVID-19-related hospitalizations among adults in the U.S. Among the adults who died in the hospital due to COVID-19, 80% were aged 65 and above.

The high prevalence of certain medical conditions further compounds this vulnerability. For example, obesity may increase the risk of severe COVID-19 outcomes by 1.4 times, diabetes by 1.8 times, and chronic lung diseases by as much as 3.2 times. These conditions significantly raise the likelihood of serious health complications. This data underscores the urgent need for effective and targeted vaccination strategies such as Moderna’s next-generation mNEXSPIKE vaccine to protect those most at risk, especially as the COVID-19 virus continues to evolve.

mNEXSPIKE is built upon Moderna’s mRNA-1273 (Spikevax) platform, but with an updated design, which primarily focusing on the key regions of the SARS-CoV-2 spike protein instead of targeting the whole structure. This invention, when combined with a lower dose (10 µg vs. Spikevax’s 50 µg), aims to improve efficiency while reducing reactogenicity. The development of mNEXSPIKE was guided by real-time data and advancements in prognostic analytics, reflecting Moderna’s commitment to continuous innovation and optimization.

A Novel Approach

Moderna’s mNEXSPIKE characterizes an important step ahead in COVID-19 vaccine. It is created on the basic foundation of mRNA technology but is designed in such a way that it is more efficient and can address present and future challenges as compared to previously present COVID-19 vaccines. mNEXSPIKE offers an enhanced mRNA technique that targets the specific region of the SARS-CoV-2 spike protein. This enables the human’s immune system to react strongly while it delivers a significantly low dose at 10 micrograms, which is one-fifth of the dose of Moderna’s original Spikevax vaccine.

The lowered-dose formulation is not only responsible for reducing the side effects but also for rationalizing manufacturing and distribution. mNEXSPIKE can be stored at regular refrigerator temperatures (2-8°C) for 90 days, overcoming the logistical difficulties of the prior existing mRNA vaccines and enabling use in a wide geographic area, particularly in areas where the facility of cold storage does not exist.

Individuals who have already received the COVID-19 vaccine are advised to use this vaccine as a booster vaccine to protect adults 65 years and above or 12-64 years old with other comorbidities. Clinical trials have established that this new vaccine offers more protection or equivalent protection in comparison to the previously existing vaccine. A stronger immune response is elicited against both the Omicron subvariants and the original virus strain.

With a designed antigen, reduced doses, and improved storage stability, mNEXSPIKE bears a very clever strategy for pandemic protection. This leads to increased efficiency, adaptability, and patient friendliness for those who are at risk. 

Clinical trials and approval

Rigorous clinical trial data support the FDA approval of Moderna’s mNEXSPIKE COVID-19 vaccine, which represents efficacy and safety in different populations. The efficacy and safety of mNEXSPIKE were evaluated in a randomized, active-controlled NextCOVE clinical trial (NCT05815498) that was conducted in the United States, the United Kingdom, and Canada. The conducted large-scale evaluation included 11,417 individuals who were aged 12 years and above, with a median follow-up of 8.8 months.

The study population was distinct, with an average age of 56 years (range: 12-96 years). Demographically, the trial included

8.7% adolescents (12-17 years)

62.6% of adults (18-64 years)

28.7% older adults (65+ years)

The NextCOVE trial enrolled participants who were evenly divided between the mNEXSPIKE group (n = 5,706) and the comparator vaccine group (n = 5,711). Nearly all participants had received at least one prior COVID-19 vaccine dose, with an average interval of 9.8 months since their most recent vaccination. Notably, 74.3% of participants showed evidence of prior SARS-CoV-2 infection at baseline.

The mNEXSPIKE vaccine used in the study was a bivalent formulation, delivering a 10 microgram total dose comprising 5 µg targeting the original SARS-CoV-2 (Wuhan strain) and 5 µg targeting the Omicron variant. This represents a substantial dose reduction compared to the 50 µg dosage of the comparator vaccine. Participants received a single 0.2 mL intramuscular injection, administered at least three months after their previous COVID-19 vaccine dose.

Results

The primary endpoint of the NextCOVE Phase 3 trial (NCT05815498) was to evaluate the efficacy of Moderna’s mNEXSPIKE (mRNA-1283) vaccine in preventing symptomatic COVID-19, starting 14 days after a single booster dose, compared to the existing Spikevax (mRNA-1273) vaccine. The study enrolled over 11,400 participants aged 12 years and older, with nearly all having received at least one prior COVID-19 vaccination. The results demonstrated that mNEXSPIKE met the criteria for non-inferiority to Spikevax and showed a relative vaccine efficacy (rVE) of 9.3% in preventing symptomatic COVID-19 across all adults. Notably, in adults aged 65 and older, mNEXSPIKE showed an even higher rVE of 13.5%, indicating stronger protection in this high-risk group. The vaccine was also well tolerated, with a safety and reactogenicity profile comparable to or slightly improved over Spikevax, despite using a significantly lower dose of just 10 µg (versus 50 µg for Spikevax).

Safety profile

Moderna’s mNEXSPIKE has established a favorable safety profile across all age groups, with most side effects being mild to moderate and transient. Commonly reported adverse reactions included pain at the injection site, fatigue, headache, muscle pain, joint pain, chills, and nausea or vomiting, with slightly lower frequencies observed in adults aged 65 and older.

A key safety consideration is the rare risk of myocarditis and pericarditis, particularly in males aged 12–24 years, typically occurring within one week of vaccination. The estimated rates are approximately 8 cases per million doses in recipients under 64 years and 25 per million in males aged 12–25.

The vaccine is contraindicated in individuals with a history of severe allergic reactions (e.g., anaphylaxis) to any mNEXSPIKE component or prior Moderna COVID-19 vaccine dose. Syncope may also occur post-vaccination, as seen with other injectables.

Overall, the safety profile of mNEXSPIKE is consistent with other mRNA vaccines, and combined with its 9.3% higher relative vaccine efficacy, especially in older adults, it is a strong candidate for protecting high-risk populations during the ongoing COVID-19 threat.

Impact and future viewpoint

The sanction of Moderna’s mNEXSPIKE COVID-19 vaccine demonstrates an important invention in the pandemic protection, particularly for high risk groups like elderly people and those who have comorbidities. mNEXSPIKE offers an improved efficiency at a reduced dose and storage requirements, and is expected to increase the accessibility of vaccines and uptake, usually in areas with limited cold storage requirements. The vaccine’s improved safety and effectiveness characteristics are likely to reduce the total number of hospitalizations and deaths caused the COVID-19 which has taken thousands of lives in the U.S. over a year.

Looking at the future, mNEXSPIKE has undoubtedly set an entirely new standard for the upcoming next-generation vaccines, showcasing the potential for design and innovation that can protect the vulnerable population better. The approval also depicts the transformation toward personalized and adaptable vaccine planning strategies, which are of utmost importance due to the continuous evolution of the virus.

Overall, the newly created booster vaccine, Moderna’s mNEXSPIKE, is not only capable of strengthening the present pandemic preparedness but also lays the way for future innovation in mRNA vaccine technology and protection of public health.

References

mNEXSPIKE FDA Approval History https://www.drugs.com/history/mnexspike.html

Introducing mNEXSPIKE: Moderna’s New COVID-19 Vaccine https://www.modernatx.com/media-center/all-media/blogs/introducing-mnexspike-modernas-new-covid-19-vaccine

Moderna Receives U.S. FDA Approval for COVID-19 Vaccine mNEXSPIKE https://investors.modernatx.com/news/news-details/2025/Moderna-Receives-U-S–FDA-Approval-for-COVID-19-Vaccine-mNEXSPIKE/default.aspx

FDA approves Moderna’s new COVID-19 vaccine https://www.cidrap.umn.edu/covid-19/fda-approves-modernas-new-covid-19-vaccine

FDA Package Insert – MNEXSPIKE  https://www.fda.gov/media/186738/download

Spyros Chalkias, Antionette Pragalos, Adebayo Akinsola, et al, Safety and Immunogenicity of SARS-CoV-2 Spike Receptor-Binding Domain and N-Terminal Domain mRNA Vaccine, The Journal of Infectious Diseases, Volume 231, Issue 4, 15 April 2025, Pages e754–e763, https://doi.org/10.1093/infdis/jiaf022

A Study of mRNA-1283.222 Injection Compared With mRNA-1273.222 Injection in Participants ≥12 Years of Age to Prevent COVID-19 (NextCOVE), moderna clinical trials, https://trials.modernatx.com/study/?id=mRNA-1283-P301&Latitude=27.6648274&Longitude=-81.5157535&LocationName=Florida,%20USA&MileRadius=100

The article is reviewed  and fact-checked by the editorial team of Pharmacally.com

104939

The Hidden Pain Pathway: Paracetamol (Acetaminophen) Metabolite AM404 Blocks Peripheral Sodium Channels – A New Mechanism Uncovered

by with No Comment Research

Medically Written and Reviewed By: Vikas Londhe, M.Pharm, Pharmacology

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Source: Freepik.com

For over a century, paracetamol (acetaminophen) has been one of the world’s most widely used analgesics and antipyretics. Despite its widespread use, its exact mechanism of action has remained unclear. It was long believed to work mainly by blocking certain enzymes called cyclooxygenases (COX), especially COX-2. These enzymes are responsible for producing prostaglandins, which are chemicals that promote pain, inflammation, and fever. By reducing prostaglandin production, paracetamol helps lower pain and fever without significantly reducing inflammation like other NSAIDs. However, it is believed that paracetamol is only effective in mild inflammations, like after tooth extraction, and it is not effective in severe inflammation that arises from rheumatoid arthritis and acute gout.

Another pathway involves the TRPV1 receptor, short for Transient Receptor Potential Vanilloid 1, which plays a role in sensing heat and pain. Some research suggests that an active metabolite of paracetamol, the fatty acid amide N-arachidonoylphenolamine (AM404), may activate TRPV1 in a way that leads to pain relief by desensitizing these pain-sensing receptors.

However, new research conducted at Hebrew University of Jerusalem and the findings are published in The Proceedings of the National Academy of Sciences (PNAS) has uncovered a previously unknown mechanism of paracetamol. The new research proposed that paracetamol acts directly at peripheral nerve endings. Its metabolite AM404 can block sodium channels in the nerves, which are essential for sending pain signals to the brain. This discovery adds a new dimension to our understanding of how paracetamol relieves pain: not just through the inhibition of certain enzymes and receptors, but also by directly inhibiting the body’s ability to send pain signals to the brain.

The Breakthrough Study

A team led by Professors Alexander Binshtok and Avi Priel from the Hebrew University of Jerusalem published these game-changing findings in the prestigious PNAS, titled “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels”

The key findings of the Research Includes

Local production of AM404: After oral intake of paracetamol, the body converts it to p-aminophenol in the liver, which is subsequently transformed into AM404 by fatty acid amide hydrolase (FAAH) in primary sensory neurons, essentially at the nerve endings where pain signals originate.

Inhibition of nociceptive sodium channels: AM404 directly blocks voltage-gated sodium channels Na_V1.7 and Na_V1.8, both crucial for generating action potentials in pain-sensing neurons. The blockade occurs via the local anesthetic binding site.

Peripheral analgesia: Through this localized mechanism, AM404 prevents pain signals at their source, producing potent relief in both regular and inflammatory pain models in rodents.

Researchers found that AM404, a metabolite formed from paracetamol in the body, accumulates in peripheral sensory neurons where it directly inhibits voltage-gated sodium channels Na_V1.7 and Na_V1.8. These channels are critical for the initiation and conduction of pain signals at the site of injury or inflammation. By blocking these sodium channels, AM404 effectively diminishes nociceptive signal transmission at its source, preventing pain before it even reaches the spinal cord. This peripheral action represents a fundamental shift in our understanding of how paracetamol works. It positioned paracetamol not only as a central analgesic but also as a locally acting modulator of neuronal excitability.

Results

AM404 significantly reduced sodium current amplitude in isolated dorsal root ganglion (DRG) neurons in a dose-dependent manner. The greatest effect was observed on tetrodotoxin-resistant (TTX-R) sodium currents, which are characteristic of Nav1.8, a key player in chronic and inflammatory pain. AM404 had minimal effect on potassium and calcium currents, indicating a selective action on sodium channels.

In pharmacological profiling, AM404 showed the strongest inhibition of Nav1.7 and Nav1.8, both of which are highly expressed in nociceptive (pain-sensing) neurons. Other Nav subtypes, such as Nav1.5 (cardiac) and Nav1.6 (CNS), were minimally affected, suggesting a favorable safety profile by avoiding cardiac or CNS toxicity.

In formalin-induced inflammatory pain models, peripheral injection of AM404 significantly reduced both early (neurogenic) and late (inflammatory) phases of pain behaviors (licking, flinching). In the hot plate and tail flick thermal assays, AM404 increased latency to pain response, indicating effective thermal analgesia. Systemic or central (intrathecal) administration of AM404 had less prominent effects, highlighting that peripheral action is essential for its analgesic activity.

Computational docking predicted that AM404 binds to a hydrophobic fenestration site within the channel’s domain IV S6 segment, a region known to influence channel gating and drug binding.

Implications

This research challenges the traditional view of paracetamol as a centrally acting analgesic. It highlights that peripheral mechanisms, particularly in the context of inflammatory pain, are also crucial to its analgesic action. A key finding is the active pharmacological role of AM404, a metabolite of paracetamol, which is not just a metabolic byproduct but a potent modulator contributing to its pain-relieving effects. This adds to the recognition of the importance of drug metabolites in determining therapeutic efficacy. Moreover, the study strengthens the therapeutic relevance of targeting sodium channel subtype Na_V 1.7, positioning AM404 as a promising lead compound or molecular scaffold for the development of new, non-opioid analgesics.

Broader Impact: Beyond Paracetamol

This study opens exciting new avenues in the field of pain research. It triggers a re-evaluation of some metabolites that have been silent since their discovery and are also traditionally overlooked, but may possess key pharmacological actions, suggesting that other commonly used drugs could harbor unexplored therapeutic potential through their metabolites.

Additionally, the findings strengthen the scientific rationale for targeting peripheral sodium channels, particularly in managing chronic and inflammatory pain conditions. AM404, a paracetamol metabolite, exerts analgesic effects without causing sedation or respiratory depression, positioning it as a promising foundation for developing safer, non-addictive alternatives to opioids.

Conclusion

The discovery that AM404 blocks peripheral NaV channels redefines how we understand one of the worlds’s most commonly used analgesics. By uncovering this hidden peripheral pain pathway, researchers at the Hebrew University of Jerusalem have significantly advanced the field of analgesic pharmacology. This work not only deepens our molecular understanding of paracetamol but also opens up new possibilities for developing better pain medicines and emphasizing the vital role of peripheral targets in pain relief.

References

Y Maatuf, Y. Kushnir, A.Nemirovski, et al, The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels, Proc. Natl. Acad. Sci. U.S.A. 122 (23) e2413811122, https://doi.org/10.1073/pnas.2413811122

Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct; 18(10):915-21. Doi: 10.1111/j.1460-9592.2008.02764.x. PMID: 18811827

Israeli study finds acetaminophen drug works by first blocking pain in nerves, The Times of Israel, https://www.timesofisrael.com/israeli-study-finds-acetaminophen-drug-works-by-first-blocking-pain-in-nerves/

New discovery: Tylenol stops pain at the nerves, before it hits the brain, ScienceDaily, https://www.sciencedaily.com/releases/2025/06/250610074247.htm#:~:text=Summary%3A,channels%20in%20pain%2Dsensing%20nerves.

Mallet C, Desmeules J, Pegahi R, Eschalier A. An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact. J Pain Res. 2023 Mar 29;16:1081-1094. Doi: 10.2147/JPR.S393809. PMID: 37016715; PMCID: PMC10066900.

Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V, First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid. J Pain Res. 2017; 10:2703-2709 https://doi.org/10.2147/JPR.S143500

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Yutrepia (Treprostinil) Inhalation Powder developed on Liquidia’s PRINT technology Gets FDA Approval for Pulmonary Hypertension and Pulmonary Hypertension Associated with Interstitial Lung Disease (PH-ILD)

by with No Comment New Drug Approval

Written By: Dewanshee Ingale (B.Pharm)

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Source: Freepik.com

Yutrepia is an FDA-approved, inhaled dry-powder dosage form of treprostinil for treating pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). This approval provides patients with a novel, practical, and efficient therapy alternative, marking a substantial development in caring for these complicated conditions. Even though treprostinil has been in practice since 2002 in various dosage forms, recently treprostinil (Yutrepia) was approved by the FDA on May 23, 2025, especially as an inhalation powder formulation for the management and control of pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). Earlier, other inhaled forms, most remarkably an inhalation solution of treprostinil, were sanctioned in 2009 for the same indications (Tyvaso). The fundamental difference is that Yutrepia introduced the first FDA-approved dry powder inhalation dosage form of treprostinil, which proposes an entirely novel delivery technique and is based on Liquidia’s proprietary PRINT™ technology, which yields uniform, free-flowing particles intended for enhanced deep lung delivery via an easy-to-use, low-effort device requiring less inspiratory effort as compared to the prior nebulized solution.

Present data and background

Pulmonary arterial hypertension (PAH) and pulmonary hypertension with interstitial lung disease (PH-ILD) are progressive conditions that increase pulmonary artery pressure. This can be followed by right heart failure (associated with the right ventricle) and exercise intolerance. PAH was initially treated with four main mechanisms: endothelin-1, nitric oxide, prostacyclin, and bone morphogenetic protein/activin signaling, more recently. In recent times, physicians increasingly prescribe combination therapy, which is more effective for symptoms and outcomes compared to single treatment.

People with fibrotic lung diseases often develop a serious complication called pulmonary hypertension (PH-ILD), which makes their condition worse and increases the risk of death. Until recently, there were no approved treatments for this. Now, fast and effective treatment is important to manage the disease and improve outcomes. Initially the agents were unsuccessful and not safe, which revealed a lack of therapy and the need for effective and nontoxic treatment. The advent of inhaled treprostinil was innovative. The recent trials enhanced exercise capacity and reduced the severity of disease in patients with PH-ILD, which led to approval of the drug. As the traditional nebulized form was clumsy and time taking, led to decreased patient compliance. The dry inhalational powder of treprostinil was developed to provide a suitable, handy delivery system. The novel delivery technology is an enhancement in the therapy of PAH and PH-ILD, improving patient convenience and compliance in treatment.

Yutrepia: a novel approach

Treprostinil is a prostacyclin (PGI₂) analogue primarily used to treat Pulmonary Arterial Hypertension (PAH). It mimics the action of endogenous prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. Treprostinil binds to IP receptors (prostacyclin receptors) on vascular smooth muscle cells. This activates adenylate cyclase, increasing cyclic AMP (cAMP) levels, which leads to smooth muscle relaxation and vasodilation, particularly in the pulmonary and systemic circulation. Treprostinil also inhibits platelet aggregation through the same cAMP-mediated pathway, which helps reduce the risk of thrombosis, a big alarm in PAH. Elevated cAMP levels also exert anti-proliferative effects on vascular smooth muscle cells, helping to prevent vascular remodelling, a characteristic of PAH progression. By mimicking prostacyclin, treprostinil can enhance endothelial cell function and reduce oxidative stress and inflammation in pulmonary arteries.

About Yutrepia and PRINT technology

Lungs_Graphic-new
Source:liquidia.com

Yutrepia is developed meticulously using Liquidia’s PRINT technology. The new drug is administered via a tiny, compact device that is lightweight and could be placed in the palms of hands. Development of Yutrepia efficiently utilizes Liquidia’s PRINT technology to formulate drug particles that are precise as well as uniform in size, shape, and composition in such a way that they can deliver more in the lungs when inhaled. The particle’s diameter is found to be 1.3 μm, which implies that the size of the particles is well controlled. The particles have a three-leaf clover shape, which facilitates their ability to effectively deliver drug.

Clinical trials and approval

The sanction of Yutrepia (Treprostinil) dry inhalational powder for pulmonary arterial hypertension(PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD) was supported on the pivotal, open-label, multicentre Phase 3 INSPIRE trial (ClinicalTrials.gov Identifier: NCT03399604). Furthermore, the ongoing ASCENT study (ClinicalTrials.gov Identifier: NCT06129240) is estimating the long-term safety criteria and acceptability of Yutrepia in patients with PH-ILD.

NCT03399604 an open-label, multicentre INPSPIRE trial phase III study was designed to assess the safety and tolerability of Yutrepia (dry-powder inhalational formulation of treprostinil) in adults with PAH. Overall 121 patients aged 18 years or above were registered, including the ones who transformed from nebulized treprostinil and prostacyclin naive patients which receive up to two non-prostacyclin oral therapies. Transition patients were started with Yutrepia at a dose that is equivalent to the prior nebulized dosing. The prostacyclin-naive patients were treated with 26.5 mcg four times daily, with dose modification in 26.5mcg in which growth can be allowed for both the groups.

The preliminary aims were to evaluate the occurrence of adverse events (AEs) and serious adverse (SAEs) throughout the entire study. Investigative efficacy parameters including changes in the 6-minute walk distances, NYHA (New York heart association), NT-proBNP levels (N-terminal pro-B-type natriuretic peptide) exposed that most patients stayed stable or enhanced over the one-year treatment time lapse. Moreover, quality of life scores enhanced, it was being observed that most of the patients preferred the Yutrepia inhaler over earlier used nebulized devices. In general, Yutrepia was discovered to be a suitable and very well-tolerated inhaled prostacyclin treatment therapy for PAH patients, assisting its use as a novel therapy option in this population.

The primary endpoints were the occurrence of AEs and SAEs. Throughout the one-year treatment period, 80% of the transition group and 96% of the prostacyclin-naive group modified to a dose of not less than 79.5 mcg four times daily, with at least one patient reaching 212 mcg daily four times. Majority of adverse effects were found to be mild to modest and steady prostacyclin therapy, comprising cough, headache, upper respiratory infection, dyspnoea, and throat irritation. Most of the patients remained stable or improved during the study.

Clinical trial NCT06129240, known as the ASCENT study, is an ongoing Phase 3, open-label, multicenter trial. It is designed to evaluate the long-term safety and tolerability of Yutrepia, a dry powder inhaled formulation of treprostinil, in patients with pulmonary hypertension (PH) and PH associated with interstitial lung disease (PH-ILD). The trial is still ongoing and recruiting participants.

Safety profile

Yutrepia (treprostinil) inhalation powder has established an appropriate safety and tolerability outline n clinical trials, remarkably in the pivotal phase III INSPIRE study. Approximately all the patients (99.2%) observed at least one adverse event (AE), while most of these being mild (47.9%) or moderate (28.1%) in seriousness. Harmful AEs were unusual (3.3%). In this clinical trials there were no serious adverse effects or mortality reported throughout the study.

The frequently reported adverse reactions <10% included not so serious side effects like cough, headache, and upper respiratory tract infections. The side effects were consistent with the known safety profile of the inhalational powder therapies and did not prevent patients from continuing treatment.

The patients who received higher percentage of prostacyclin-naive observed dose related AEs as compared the ones who were transitioned from the nebulized treprostinil (84.8% vs 72.7%). Although in general the incidence of moderate or severe AEs were quite controllable. Approximately 12.4% of patients did not continue the treatment due to AEs, among which 9.1% of these events were related to Yutrepia.

The medical monitor significantly did not observe any of the SAEs related to the Yutrepia in the trials. The maximum number of hospitalizations was because of unrelated causes like accidents, comorbidities, or any kind of viral infection, for example, COVID-19. There were no deaths reported during the study of the drug.

Impact and future viewpoint

The FDA approval of Yutrepia (treprostinil) provides with a new delivery system of inhalation dosage form by using dry inhalation powder for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated interstitial lung disease this led to enhanced exercise capability, suitability, and quality of life of patients who have limited treatment alternatives. The importance of constant research and invention in cardiopulmonary diseases were highlighted by the approval. Directing to extend therapeutic pathways and improve patient results.  

The upcoming research will discover the longstanding profits, ideal dosing approaches and the ability of Yutrepia to be utilized in wider patient populations. The present and upcoming studies, like the ASCENT trials, will moreover provide extra data on long-term safety and efficacy. With Yutrepia being more widely available, its distinctive dry powder dosage form and simple inhaler are probably to expand patient acceptance to prostacyclin therapy, leading to improved disease treatment for patients with PAH and PH-ILD.         

Refrences

YUTREPIA is an FDA-approved, inhaled dry-powder formulation of treprostinil indicated for the treatment of pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD)  https://liquidia.com/pipeline-and-products

FDA approval history for Yutrepia (treprostinil) used to treat Pulmonary Arterial Hypertension; Pulmonary Hypertension Associated with Interstitial lung disease (PH-ILD)https://www.drugs.com/history/Yutrepia.html

U.S. FDA Approves Liquidia’s YUTREPIA™ (treprostinil) Inhalation Powder for Patients with Pulmonary Arterial Hypertension (PAH) and Pulmonary Hypertension Associated with Interstitial Lung Disease (PH-ILD)https://liquidia.com/news-releases/news-release-details/us-fda-approves-liquidias-Yutrepiatm-treprostinil-inhalation

FDA approval history for Tyvaso (treprostinil) used to treat Pulmonary Arterial Hypertension. Supplied by United Therapeutics Corporation https://www.drugs.com/history/tyvaso.html

Pulmonary Hypertension in Interstitial Lung Disease: Management Options to Move beyond Supportive Care https://pmc.ncbi.nlm.nih.gov/articles/PMC10200699/

Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date https://pmc.ncbi.nlm.nih.gov/articles/PMC11162632/

INSPIRE: Safety and tolerability of inhaled Yutrepia (treprostinil) in pulmonary arterial hypertension (PAH) https://pmc.ncbi.nlm.nih.gov/articles/PMC9400582/

Liquidia Announces the Publication of Long-Term Clinical Data from Completed INSPIRE Study in the Journal Pulmonary Circulation https://liquidia.com/news-releases/news-release-details/liquidia-announces-publication-long-term-clinical-data-completed

FDA Approves Yutrepia (treprostinil) Inhalation Powder for Pulmonary Arterial Hypertension (PAH) and Pulmonary Hypertension Associated with Interstitial Lung Disease (PH-ILD) https://www.drugs.com/newdrugs/fda-approves-Yutrepia-treprostinil-inhalation-powder-pulmonary-arterial-hypertension-pah-pulmonary-6529.html

Transitioning from Parenteral Treprostinil to LIQ861 in a Patient with PAH San Francisco, CA https://liquidia.com/publications

Hill, N.S. et al., INSPIRE: A Phase 3 Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension (PAH) (Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil NCT03399604), The Journal of Heart and Lung Transplantation, Volume 38, Issue 4, S11

Hill NS, Feldman JP, Sahay S, INSPIRE study investigators. INSPIRE: Safety and tolerability of inhaled Y et al, utrepia (treprostinil) in pulmonary arterial hypertension (PAH). Pulm Circ. 2022 Jul 1;12(3):e12119. doi: 10.1002/pul2.12119. PMID: 36034402; PMCID: PMC9400582.

Roscigno R, Vaughn T, Anderson S, Wargin W, Hunt T, Hill NS. Pharmacokinetics and tolerability of LIQ861, a novel dry-powder formulation of treprostinil. Pulm Circ. 2020 Nov 19; 10(4):2045894020971509. Doi: 10.1177/2045894020971509. PMID: 33282202; PMCID: PMC7682229.

An Open-Label ProSpective MultiCENTer Study to Evaluate Safety and Tolerability of Dry Powder Inhaled Treprostinil in PH (ASCENT), ClinicalTrials.gov ID NCT06129240, https://clinicaltrials.gov/study/NCT06129240

The article is extensively reviewed and fact-checked by the editorial team team of pharmacally.com

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“Treating Spinal Muscular Atrophy (SMA) in the Womb: Early Evidence for Prenatal Risdiplam Therapy”

by with No Comment Research

Written and Reviewed By:  Vikas Londhe (M.Pharm, Pharmacology)

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Source: Freepik.com

Spinal muscular atrophy (SMA) is a rare but serious genetic neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord. This leads to progressive muscle weakness, respiratory failure, and early mortality. The severity of the disease varies depending on the number of SMN2 gene copies an individual has, with type 0 SMA being the most severe and typically fatal in the prenatal or neonatal period.

A pioneering new study, recently published in The New England Journal of Medicine, presents the administration of risdiplam, a gene-modifying therapy, during pregnancy to a fetus who is at risk of being diagnosed with SMA. Risdiplam, an orally available small-molecule drug, works by modifying the splicing of the SMN2 gene to increase production of functional SMN protein, which is essential for motor neuron survival.

This is the first-of-its-kind prenatal intervention that has shown potential to revolutionize the treatment of SMA, particularly for the most lethal forms of the disease. By initiating therapy before birth, researchers hope to prevent the irreversible loss of motor neurons in utero, offering the potential for normal neuromuscular development and vastly improved outcomes. The implications of this study are thoughtful which indicates a proactive and early management of this devastating condition.

Background: Understanding SMA and Risdiplam

Spinal muscular atrophy (SMA) is primarily caused by a genetic mutation in the SMN1 gene, which leads to a deficiency of the survival motor neuron (SMN) protein. This protein is essential for the health and function of motor neurons, nerve cells that control voluntary muscle activity such as walking, breathing, and swallowing.

In healthy individuals, the SMN1 gene produces adequate amounts of full-length SMN protein. However, in individuals with SMA, the SMN1 gene is either missing or nonfunctional, resulting in a reduction in SMN protein levels.

The body does have a natural backup in the form of the SMN2 gene, a nearly identical copy of SMN1. But due to a single nucleotide difference, the SMN2 gene undergoes inefficient splicing, leading to the exclusion of exon 7 in most transcripts. As a result, only a small fraction of functional SMN protein is produced from SMN2 typically not enough to fully counterbalance for the loss of SMN1. This imbalance in SMN protein production leads to motor neuron degeneration and the progressive muscle weakness characteristic of SMA. The number of SMN2 copies a person has can influence disease severity: more copies generally correlate with milder forms of SMA.

Risdiplam is a small molecule SMN2 splicing modifier approved for treating SMA in patients two months and older. It works by promoting exon 7 inclusions during SMN2 pre-mRNA splicing, thus increasing the production of functional SMN protein.

Study Highlights: N-of-1: A case study of prenatal risdiplam 

This study represents the first documented case of prenatal risdiplam therapy in a foetus that was at risk of developing type 1 spinal muscular atrophy (SMA). This inference was drawn because the fetus’s older deceased sibling had a genetically confirmed diagnosis of type 1 SMA. The fetus was tested by amniocentesis and confirmed to have Type 1 SMA, which is characterized by a complete absence of the SMN1 gene and two copies of the SMN2 gene. This genetic profile leads to minimal production of functional SMN protein, resulting in early motor neuron degeneration, evident as reduced fetal movement, joint contractures, and respiratory failure shortly after birth. Without intervention, type 1 SMA usually leads to death in the neonatal period, making early diagnosis and potential treatment critical.

Key Aspects of the Study

This landmark case of prenatal risdiplam therapy began with early genetic detection and a carefully monitored treatment strategy:

Prenatal Diagnosis: The foetus was diagnosed with spinal muscular atrophy (SMA) type 1 through amniocentesis and also from the previous family history of type 1 SMA diagnosed in older sibling who is unfortunately died at 16 months of age. To add this, the parents were both known carriers of SMA genetic variants. Genetic testing revealed a complete absence of the SMN1 gene and the presence of two copies of SMN2. This pattern is diagnostic of type 1 SMA, the severe form, which often results in death shortly after birth.

Approval and availability of risdiplam: The local institutional board, followed by the USFDA, has approved the single-patient investigational therapy. F. Hoffmann-La Roche has provided advice on the safety of prenatal exposure to risdiplam, along with a supply of risdiplam at no cost due to a confidentiality agreement with sponsor St. Jude Children’s Research Hospital. Parents have provided informed consent.

Initiation of Therapy: With a confirmed diagnosis and serious prognosis, the risdiplam was administered to the mother orally. The dosing was adjusted to 5 mg once per day. The risdiplam was administered from 32 weeks 5 days of gestation up to delivery at 38 weeks 6 days of gestation. However, the fetus continued to be administered risdiplam daily post-delivery from 8 days of birth to the present time (30 months of age in February 2025).

Monitoring: The mother had weekly checkups to monitor her pregnancy health and for any side effects from the medication. The fetus was also regularly checked using ultrasound to monitor growth, movement, and overall development.

Outcomes and Findings

The infant appeared healthy at birth but was later found to have a heart murmur caused by a ventricular septal defect, which resolved on its own. The child also has slightly reduced vision and experienced brief episodes transient fixation nystagmus, linked to underdevelopment of the optic nerves in both eyes. Additionally, mild weakness on the right side of the body (right hemiparesis) was observed, associated with underdevelopment of the left midbrain. The infant has shown global developmental delays but has not experienced any waning of skills. The child has not shown any signs of spinal muscular atrophy (SMA) such as low muscle tone, muscle weakness, absence of reflexes, or muscle twitching. Motor function, muscle imaging (ultrasound), and nerve tests (electrophysiology) have been conducted every six months and consistently show normal development of nerves and muscles for the child’s age.

The blood sample results revealed increased levels of SMN protein and lower neurofilament levels, which indicates the drug successfully reached its intended target and had a positive effect on motor neuron development. The above-mentioned congenital abnormalities seen in the infant were believed to have occurred early in fetal development before risdiplam treatment began, and no specific cause was identified. Animal studies also support this claim, where risdiplam was given during prenatal and postnatal stages, and no abnormalities have occurred in them.

While this is just a single case and the results cannot be widely applied, the findings suggest that prenatal risdiplam therapy could be a promising option for treating SMA when diagnosed before birth.

Significance and Implications

This study represents the first documented case of prenatal risdiplam therapy in humans, offering proof-of-concept that in utero intervention can alter the course of spinal muscular atrophy (SMA) even in its severe form, type 1. By initiating treatment during fetal development, before irreversible motor neuron loss occurs, this case displays the potential to preserve neuromuscular function, improve survival outcomes, and redefine the clinical management of SMA.

While results are based on a single case, the findings open the door to a new era of prenatal therapies for genetic neurodegenerative disorders. Future research will determine whether prenatal risdiplam should become part of the standard of care for high-risk SMA pregnancies. For now, it offers a glimpse of hope for families facing this devastating diagnosis.

Reference

Finkel RS, Hughes SH, Parker J, Civitello M, Lavado A, Mefford HC, Mueller L, Kletzl H; Prenatal SMA Risdiplam Study Group. Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy. N Engl J Med. 2025 Mar 13;392(11):1138-1140. doi: 10.1056/NEJMc2300802. Epub 2025 Feb 19. PMID: 39970420.

Promising results from first prenatal therapy for spinal muscular atrophy, 19 Feb 2025, St. Jude’s Childrens Hospital, https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/promising-results-from-first-prenatal-therapy-for-spinal-muscular-atrophy.html

Treating spinal muscular atrophy in the womb, nature medicine, https://www.nature.com/articles/d41591-025-00017-9

Kakazu J, Walker NL, Babin KC, et al, Risdiplam for the Use of Spinal Muscular Atrophy. Orthop Rev (Pavia). 2021 Jul 12;13(2):25579. Doi: 10.52965/001c.25579. PMID: 34745484; PMCID: PMC8567805.

Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015 Nov;33(4):831-46. Doi: 10.1016/j.ncl.2015.07.004. PMID: 26515624; PMCID: PMC4628728.

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“Saarvienin A: A Novel Antibiotic from Rare Earth Mine in China Targets Vancomycin-Resistant Gram-Positive Bacteria”

by with No Comment Research

Written by: Utkarsha Patil (M.Pharm, Pharmacology)

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Source: Freepik.com

The growing threat of antimicrobial resistance (AMR) strengthens the urgent need to search for novel therapeutic agents. Amid this growing worry, a promising new antibiotic known as Saarvienin A has surfaced. Saarvienin A was isolated from a rare environmental actinomycete Amycolatopsis species.

Saarvienin A was identified by an international research team led by scientists from the University of Vienna and the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS). The antibiotic was isolated from a strain of Amycolatopsis sp. YIM10, a soil-dwelling actinobacterium collected from a rare earth mine in China. Amycolatopsis is known for producing clinically important antibiotics like vancomycin.

Saarvienin A has attracted significant scientific interest due to its potent activity against multidrug-resistant infections. It is thought that Saarvienin A operates by a new mechanism due to its unique structure, which does not resemble any other glycopeptides, including vancomycin. This uniqueness will be the factor that works against drug-resistant bacteria, particularly against Staphylococcus aureus, especially methicillin-resistant strains (MRSA), making it a convincing candidate in the fight against resistant pathogens.

A Unique Habitat

The rare earth mining environment of Southern China is harsh, mineral-rich, and has biologically unique conditions that challenge microbial life and promote the production of uncommon secondary metabolites. During a targeted bioprospecting journey, researchers collected soil samples from this ecosystem. After doing an extensive analysis of this sample, scientists isolated Amycolatopsis sp. YIM10, a previously uncultured strain of actinobacteria.

This strain belonged to the prolific genus Amycolatopsis, known for producing the clinically important rifamycin antibiotics. Still, YIM10 was distinctive because scientists discovered something unusual harbored by this species: biosynthetic gene cluster (BGCs) that encodes previously unexplored compounds.

Saarvienin A

Amycolatopsis sp. YIM10 having rich reservoir of biosynthetic gene clusters (BGCs). Scientist discovered only few secondary metabolites identified in fermentation broth or via genome mining and all of these metabolites had no or very weak antimicrobial activity.  However, some culture extracts showed a significant antimicrobial effect. Further fractionation of these extracts identified a new glycopeptide, which they named it Saarvienin A, to recognize and show appreciation for Saarland, Germany, where part of the research was conducted.

Detailed NMR and mass spectrometry analyses revealed that the compound features a pentasugar/aminosugar chain attached to a halogenated peptide core, with three of its four amino acids forming a macrocyclic structure via a urea-type carbonyl linkage. A SciFinder structural similarity search identified vancomycin derivatives as the closest known compounds, even though they are structurally distinct. This suggests that the compound referred to as saarvienin A represents a novel class of glycopeptides. It can distinguish by its ability to overcome vancomycin resistance and exhibit selective antibacterial activity against Gram-positive pathogens.

The spectrum of activity

The in vitro antibacterial activity of Saarvienin A was evaluated against a range of Gram-positive and Gram-negative pathogens. It exhibited potent activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE), methicillin-resistant and vancomycin-intermediate Staphylococcus aureus (MRSA/VISA), and Daptomycin-resistant S. aureus (DRSA).

Saarvienin A showed minimum inhibitory concentrations (MICs) of 1 µg/mL against Enterococcus faecalis (vanB-positive) and Enterococcus faecium (vanA-positive), significantly surpassing the efficacy of vancomycin. It also demonstrated low MICs against MRSA/VISA and DRSA strains. Saarvienin A showed moderate activity against Mycobacterium smegmatis but was less effective against Mycobacterium tuberculosis.

In contrast, it lacked activity against Gram-negative bacteria, including Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa. This lack of efficacy is likely due to its inability to penetrate the outer membrane barrier of Gram-negative organisms.

Mechanism of Action

In the initial discovery and characterization studies, researchers identified its strong antibacterial activity especially against Gram-positive, drug-resistant pathogens but did not yet determine the precise molecular target or how it exerts its antibacterial effect. However, some early evidence suggests that Saarvienin A may represent a new class of glycopeptides-like compounds, structurally distinct from existing antibiotics such as vancomycin. Because it shows activity against vancomycin-resistant and daptomycin-resistant strains, it likely acts through a novel or modified mechanism, different from known glycopeptides antibiotics.

Safety

The cytotoxicity of Saarvienin A was evaluated using the HepG2 human liver carcinoma cell line, revealing an IC₅₀ of 13 µg/mL, This suggests a potential therapeutic window. The observed cytotoxic effects highlight the need for further structural optimization to improve selectivity and minimize toxicity, despite the compound’s promising antibacterial activity.

Implications and Conclusion

The discovery of Saarvienin A represents a significant milestone in the ongoing battle against antimicrobial resistance, especially among Gram-positive pathogens. Isolated from Amycolatopsis sp. YIM10, a strain collected from a rare earth mine in China. These novel glycopeptides show potent antibacterial activity against vancomycin-resistant and daptomycin-resistant strains, including VRE and MRSA/VISA.

Saarvienin A’s novel structure and potential mechanism of action, suggesting it could form the basis of a new class of glycopeptides. Despite its promising activity, particularly against drug-resistant Gram-positive bacteria, its limited effect on Gram-negative pathogens and observed cytotoxicity underscore the need for further structural optimization and preclinical evaluation.

The findings highlight the potential of extreme and underexplored ecosystems, such as rare earth mining environments, in yielding unique microbial metabolites with therapeutic potential. As resistance to existing antibiotics continues to rise, Saarvienin A serves as a gripping lead compound for the development of next-generation antibiotics capable of overcoming established resistance mechanisms.

References

Amninder Kaur, Jaime Felipe Guerrero-Garzón, Sari Rasheed, et al, Saarvienin A—A Novel Glycopeptide with Potent Activity against Drug-Resistant Bacteria, Angew. Chem. Int. Ed. 2025, e202425588, doi.org/10.1002/anie.202425588

Liu L, Liu Y, Liu S, Nikandrova, et al, (2023) Bioprospecting for the soil-derived actinobacteria and bioactive secondary metabolites on the Western Qinghai-Tibet Plateau. Front. Microbiol. 14:1247001. doi: 10.3389/fmicb.2023.1247001

Scientists discover first “Saar-drug“, Saarvienin A shows promising properties for combating resistant hospital germs, Helmholtz Centre for Infection Research, https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/scientists-discover-first-saar-drug/

Li T, Yu X, Li M, Rong L, Xiao X, Zou X. Ecological insight into antibiotic resistome of ion-adsorption rare earth mining soils from south China by metagenomic analysis. Sci Total Environ. 2023 May 10;872:162265. doi: 10.1016/j.scitotenv.2023.162265. Epub 2023 Feb 17. PMID: 36801324.

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

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Beyond Weight Loss: First-Generation GLP-1 Drugs Like Liraglutide and Exenatide Show Promising Anti-Cancer Effects

by with No Comment Clinical Trails

Written By: Smaiksha Benke, M.Pharm Pharmacology

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Source: Freepik.com

Obesity is a major global health concern and a known risk factor for at least 13 different types of cancer. The increasing prevalence of obesity-related cancers highlights the urgent need for effective and widely accessible prevention strategies. Conventional weight loss approaches often provide only transitory benefits, while bariatric surgery though effective is invasive and not appropriate for everyone. However, first-generation GLP-1 receptor agonists (GLP-1 RAs) such as liraglutide and exenatide, initially designed to manage type 2 diabetes and obesity, are now showing encouraging anti-cancer potential, according to a recent study published in eClinicalMedicine, part of The Lancet Discovery Science series. This discovery indicates that the benefits of these medications may go beyond weight control. They appear to exert anti-cancer effects through mechanisms such as reducing inflammation, inhibiting the growth of cancer cells, and promoting programmed cell death (apoptosis).

Study Design

The study was a retrospective, observational cohort study using electronic medical records from Clalit Health Services in Israel. Researchers compared adults aged ≥24 years with obesity and type 2 diabetes who received either bariatric metabolic surgery (BMS) or first-generation glucagon-like peptide-1 receptor agonists (GLP-1RAs), primarily liraglutide, between 2010 and 2018. A total of 3178 matched pairs (N=6356) were followed for a median of 7.5 years (up to 12.9 years). Matching was based on age, sex, BMI, treatment initiation year, and smoking status. The primary endpoint was the incidence of obesity-related cancers (ORCs), including colorectal, postmenopausal breast, pancreatic, and other specified malignancies. Secondary analysis assessed mediation effects through changes in BMI and HbA1c.

Results

The final study cohort consisted of 6356 individuals (3178 pairs), matched on sex, age, baseline BMI, year of treatment initiation, and smoking status. At baseline, the mean age was 52.3 years, and the average BMI was 41.5 kg/m². The median follow-up time was 7.5 years, with some individuals followed for up to 12.9 years.

During the follow-up period, obesity-related cancers (ORCs) were diagnosed in 298 individuals:

150 cases occurred among those who underwent bariatric metabolic surgery (BMS), with an incidence rate of 5.76 cases per 1000 person-years.

148 cases occurred among those treated with GLP-1 receptor agonists (GLP-1RAs), with an incidence rate of 5.64 per 1000 person-years.

The adjusted hazard ratio (HR) for developing ORC in the GLP-1RA group compared to the BMS group was 1.03, indicating no statistically significant difference in overall cancer risk between the two treatment modalities.

Mediation Analysis

To explore potential mechanisms beyond weight loss, a mediation analysis was conducted:

Patients in the BMS group experienced a mean BMI reduction of 31.1%, whereas those in the GLP-1RA group had a mean decrease of 12.9%.

When the change in BMI was included in the adjusted model, the hazard ratio for GLP-1RA vs. BMS shifted to 0.59, indicating a direct effect of GLP-1RA therapy beyond weight loss, equivalent to a 41% relative risk reduction.

In contrast, when the change in HbA1c levels was tested as a mediator, it did not alter the main association. The adjusted HR remained non-significant, suggesting glycemic control alone does not explain the protective effect of GLP-1RAs.

Subgroup Observations

Among all diagnosed ORC cases:

Breast cancer (postmenopausal) was the most common (26%),

Followed by colorectal (16%) and uterine cancer (15%)

These distributions are aligning with known obesity-related cancer patterns.

Broader Implications

These findings are important in view of the current rising use of newer GLP-1 RAs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). While most attention has focused on weight loss and diabetes control, these early-generation drugs may offer additional therapeutic value as cancer-preventive agents.

Conclusions

The study’s findings suggest that treatment with first-generation GLP-1 receptor agonists (GLP-1RAs) like Liraglutide and exenatide may be doing more than helping patients lose weight or manage blood sugar they could also be reducing cancer risk. Also they are not associated with an increased risk of obesity-related cancers when compared to bariatric metabolic surgery (BMS) in patients with obesity and type 2 diabetes. Despite the greater weight loss achieved through BMS, the incidence of obesity-related cancers was statistically similar between the two groups over a long-term follow-up. Importantly, mediation analysis revealed that GLP-1RAs may exert a protective effect against these cancers independent of weight loss, potentially through other mechanisms such as anti-inflammatory pathways. These results position GLP-1RA therapy as a viable, non-surgical alternative for reducing obesity-associated cancer risk in this population. However, confirmation through larger prospective studies and randomized controlled trials is warranted to strengthen causal inference and explore the underlying biological mechanisms.

Reference

Wolff Sagy, Y., Ramot, N., Battat, E., Arbel, R., Reges, O., Dicker, D., & Lavie, G. (2025). Glucagon-like peptide-1 receptor agonists compared with bariatric metabolic surgery and the risk of obesity-related cancer: An observational, retrospective cohort study. eClinicalMedicine, 83, 103213. https://doi.org/10.1016/j.eclinm.2025.103213

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

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“The Curious Case of KJ: How the World’s First CRISPR-Cas9 Gene Editing Therapy Saved a Child from Fatal CPS1 Deficiency”

by with No Comment Research

Written by: Shital Gaikwad M.Pharm (Pharmacology)

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Source: Freepik.com

In a landmark medical breakthrough, a young child identified only as KJ became the first known patient to be successfully treated for a fatal genetic disorder using CRISPR gene editing inside the body. Researchers used a customized, CRISPR-based therapy to treat carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and life-threatening genetic condition. This represents the first clinical application of a personalized CRISPR treatment tailored to an individual patient. KJ’s remarkable recovery is not only his triumph but also a significant milestone for genomic medicine, which offers a new hope for treating ultra-rare genetic diseases and paving the way for future individualized therapies.

What Is CPS1 Deficiency?

Carbamoyl Phosphate Synthetase 1 (CPS1) deficiency is an ultra-rare genetic disorder characterized by the liver’s inability to fully break down byproducts of protein metabolism, leading to a toxic buildup of ammonia in the body. The enzyme carbamoyl phosphate synthetase 1, encoded by the CPS1 gene, is essential for the urea cycle; a process that converts ammonia, a byproduct of protein breakdown, into urea to prevent harmful accumulation. Urea is then safely excreted from the body. Mutations in the CPS1 gene results in CPS1 deficiency, a hereditary urea cycle disorder that impairs the body’s ability to eliminate excess nitrogen. In the absence of this enzyme, ammonia accumulates in the blood, a condition known as hyperammonemia, which can lead to serious brain damage, coma, or even death, particularly in infants.

This condition typically presents within the first few days after birth, with symptoms like vomiting, lethargy, seizures, and difficulty breathing. The prognosis is poor, even with aggressive treatment such as dialysis or protein-restricted diets. Medication includes ammonia-scavenging agents and citrulline supplementation. These short-term management strategies are limited in effectiveness, as even slight sickness or dehydration can trigger sudden and potentially fatal organ failure.

Enter CRISPR: A Genetic Scalpel

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a cutting-edge gene-editing technology that allows scientists to cut, remove, or replace faulty DNA sequences formed during mutation with high precision. Originally discovered as a natural defense system in bacteria, CRISPR functions like an immune system. Bacteria use it to recognize and destroy invading viral DNA. Scientists discovered that this bacterial defense mechanism could be adapted to precisely edit genes in other organisms, including humans.

While CRISPR has been widely used in research laboratories and clinical trials, editing DNA directly inside a living human body represents a giant leap in medicine and has never before been attempted to treat CPS1 deficiency.

How CRISPR Works: Step-by-Step

Guide RNA Design: Scientists create a synthetic RNA molecule called a guide RNA (gRNA) that matches the specific faulty DNA sequence targeted for editing.

Cas9 Binding: The guide RNA directs the Cas9 enzyme to the exact location of the faulty DNA within the genome.

DNA Cutting: Cas9 acts like molecular scissors, cutting the DNA precisely at the target site.

Repair or Rewrite: Scientists introduce a healthy copy of the gene, a template or blueprint which the cell can use to repair the cut DNA through a process called homology-directed repair (HDR). This allows the faulty gene to be corrected accurately.

KJ’s Journey: From Diagnosis to a CRISPR-Enabled Recovery

A Shocking Diagnosis

KJ was born as a healthy baby. But within 48 hours of birth, his condition deteriorated, he began vomiting, became unusually sleepy, and had trouble breathing. The blood test results were shocking. KJ’s blood showed extremely high levels of ammonia, 1000 μmol/liter (reference range, 9 to 33 μmol/liter). The plasma amino acid report revealed a vitally elevated level of glutamine, undetectable citrulline, and a normal level of urinary orotic acid. These findings were indicative of a proximal urea-cycle defect, a clear sign that something was wrong with his metabolism. Further genetic testing confirmed that the Q335X variant is absent in the Genome Aggregation Database. The absence of the Q335X variant suggests that this mutation is extremely rare or not typically found in the general population. However, it has been previously reported in one case of neonatal-onset CPS1 deficiency. Based on this genetic finding, the rare and life-threatening diagnosis of CPS1 deficiency was made. This disorder is so rare that it affects fewer than 1 in 1 million babies worldwide.

This condition meant that KJ’s liver lacked a critical enzyme needed to remove ammonia from his blood. Every time he ate protein, even small amounts found in baby formula, his body built up toxic levels of ammonia that could damage his brain or cause death within hours.

Early Treatments: A Desperate Race against Time

KJ’s care team at Children’s Hospital of Philadelphia (CHOP) immediately began intensive treatment to manage his condition. The treatment plan included:

Dialysis, to rapidly remove excess ammonia from his bloodstream

Nitrogen-scavenger medication (glycerol phenylbutyrate), to help eliminate nitrogen through alternative pathways

Citrulline supplementation, administered at 200 mg per kilogram of body weight per day, a dose that remained consistent throughout his clinical course

Strict protein restriction, to minimize ammonia production

Frequent hospitalizations, triggered even by minor infections or dietary errors

Despite these aggressive interventions, the severity of KJ’s condition continued to deteriorate. By the age of five months, he was scheduled to undergo a liver transplant, a last-resort option for managing his life-threatening disorder.

A Radical Option: CRISPR Gene Editing

As the time running out, doctors decided to use CRISPR technology to correct mutated gene. As a result, the therapy was created by a team at the Children’s Hospital of Philadelphia (CHOP), specifically within the Raymond G. Perelman Centre for Cellular and Molecular Therapeutics, in collaboration with genetic medicine experts, including Dr. Kiran Musunuru and Dr. Rebecca C. Ahrens-Nicklas, as well as Acuitas Therapeutics, which provided the lipid nanoparticle (LNP) delivery system. This was not a commercial pharmaceutical effort but rather a personalized, hospital-based investigational therapy, an example of an N-of-1 gene editing treatment tailored for a single patient.

To develop the therapy, researchers needed to correct the patient’s Q335X nonsense mutation in the CPS1 gene. Since primary human hepatocytes with the mutation were not available, they used a HuH-7 liver cancer cell line as a surrogate. Into these cells, they inserted a synthetic DNA cassette containing the patient’s specific mutation and other relevant sequences using a lentiviral vector. They then tested a range of adenine base editors (ABEs) and guide RNAs (gRNAs) to find the most effective and precise combination for correcting the mutation. The final chosen tools were NGC-ABE8e-V106W, a highly specific base editor, and a gRNA that positioned the target adenine in the ideal editing location. Their tests confirmed that the edits were successful and that any bystander edits were synonymous, meaning they did not alter the resulting protein.

The components of this custom therapy were uniquely named to reflect their personalized design. The selected guide RNA (gRNA) was called “kayjayguran“ and the messenger RNA (mRNA) encoding the base editor was named “abengcemeran.” The complete therapy, comprising both components and delivered via lipid nanoparticles, was referred to as “k-abe.” These names helped distinguish the patient-specific formulation from general-purpose gene editing tools.

The administration of the therapy was carried out intravenously. The gRNA and base editor mRNA were encapsulated in lipid nanoparticles using Acuitas Therapeutics’ proprietary LNP technology, including ionizable lipids and stabilizers designed for efficient liver targeting. The patient received three intravenous infusions of the therapeutic particles. This delivery method ensured that the gene-editing components reached the liver, the organ responsible for expressing the CPS1 gene. Post-treatment monitoring showed evidence of successful gene editing and improvement in metabolic function, marking this as a milestone in personalized medicine.

freepik__an-abstract-artistic-representation-of-crisprcas9-__28061

Source: The Children’s Hospital of Philadelphia (YouTube)

A Breakthrough in Medicine: Personalized Gene Editing to Save KJ

Source: Freepik.com

Successful Outcome and Impact

KJ experienced significant clinical improvement following treatment. Blood ammonia levels returned to normal, significantly lowering the risk of neurological injury. Liver function tests also began to normalize, suggesting that metabolic function was being restored. Remarkably, KJ avoided additional metabolic crises, which are often fatal in untreated CPS1 deficiency.

In terms of nutritional recovery, KJ was able to tolerate increased dietary protein, a key sign of improved urea cycle function. Additionally, there was a reduced dependence on ammonia-scavenging medications, reflecting the therapy’s effectiveness in correcting the underlying metabolic defect.

Broader Implications

This achievement not only saved the life of a KJ but also represents a potential paradigm shift in how rare genetic disorders are treated. The project received support through various federal initiatives, including the NIH’s Somatic Cell Genome Editing (SCGE) program, and benefited from in-kind contributions by biotech collaborators such as Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and the Danaher Corporation.

“This is a platform technology with the potential to lead in a new era of precision medicine for hundreds of rare diseases,” said Dr. Joni Rutter, Director of the National Centre for Advancing Translational Sciences (NCATS).

Dr. Kiran Musunuru added, “Our ambition is to apply this strategy across a wide range of rare diseases so more patients can access life-saving therapies. This represents the future of medicine.”

Conclusion

This case powerfully demonstrates the practicability  of individualized gene editing, often referred to as N of 1 therapy, “highly customized treatments designed for a single patient. It highlights the adaptability and precision of CRISPR-Cas9 technology in addressing even the rarest and life-threatening genetic disorders.

Beyond its scientific success, the therapy offers renewed hope to patients and families affected by ultra-rare conditions that were once considered untreatable due to their uniqueness. Notably, in this case, the FDA played a key role by allowing the therapy to proceed based on preclinical studies, enabling a rapid response to a life-threatening condition. This pioneering effort may influence future regulatory frameworks, promoting more compassionate and flexible pathways that support the accelerated development and approval of personalized genetic therapies.

The scientists presented their groundbreaking work at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting on May 15 and published the study in The New England Journal of Medicine.

References

Musunuru K, et al. “Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.” New England Journal of Medicine. Published online May 15, 2025. DOI: 10.1056/NEJMoa25

Regalado, A. (2024, May 17). CRISPR gene editing used to treat baby with rare genetic disease. MIT Technology Review. https://www.technologyreview.com/2024/05/17/crispr-therapy-cps1-deficiency

Infant with rare, incurable disease is first to successfully receive personalized gene therapy treatment, News Releases, National Institute of Health, May 15, 2025, https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatment

World’s First Patient Treated with Personalized CRISPR Gene Editing Therapy at Children’s Hospital of Philadelphia, May 15, 2025, Children’s Hospital of Philadelphia, https://www.chop.edu/news/worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital

Noori M, Jarrah O, Al Shamsi A. Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review. Mol Genet Metab Rep. 2024 Oct 18;41:101156. Doi: 10.1016/j.ymgmr.2024.101156. PMID: 39469307; PMCID: PMC11513499.

Carbamoyl phosphate synthetase I deficiency, Health Resource and Service Administration, https://newbornscreening.hrsa.gov/conditions/carbamoyl-phosphate-synthetase-i-deficiency

Li Q, Gao Y, Wang H. CRISPR-Based Tools for Fighting Rare Diseases. Life (Basel). 2022 Nov 24; 12(12):1968. Doi: 10.3390/life12121968. PMID: 36556333; PMCID: PMC9787644.

Amneet Kaur Badwal, Sushma Singh, A comprehensive review on the current status of CRISPR based clinical trials for rare diseases, International Journal of Biological Macromolecules, Volume 277, Part 2, 2024, 134097, https://doi.org/10.1016/j.ijbiomac.2024.134097.

Li, T., Yang, Y., Qi, H. et al. CRISPR/Cas9 therapeutics: progress and prospects. Sig Transduct Target Ther 8, 36 (2023). https://doi.org/10.1038/s41392-023-01309-7

American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, 15 May 2025, Conference presentation and press release.

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

cervical cancer

“Teal Wand Becomes First FDA Approved At Home Cervical Cancer Screening Device for High-Risk HPV – A Breakthrough for Women’s Health”

by with No Comment New Drug Approval

Written by: Priya Bhaware M.Pharm (Pharmacology)

cervical cancer
Source: Freepik.com

On May 9, 2025, the U.S. Food and Drug Administration (FDA) approved the Teal Wand medical device. Teal Health, the first FDA-authorized at-home cervical cancer screening device in the United States, developed Teal Wand. This innovative medical tool empowers women to self-collect vaginal samples for human papillomavirus (HPV) testing, which is the primary cause of cervical cancer.

The Teal Wand Device is the direct replacement of the traditional Pap smear test. By offering a more private, comfortable, and accessible alternative to traditional in-clinic Pap smears, the Teal Wand has the potential to radically improve early detection rates. It also encourages more women to participate in routine cervical cancer screening, especially those women who face barriers to in-person care.

As per Teal Health, they are working hard to roll out the product, with initial distribution set to begin in June 2025 in California first. Nationwide expansion is planned to follow soon thereafter, as the company aims to increase accessibility and convenience for women across the country. This FDA approval is seen as a transformative step toward modernizing women’s healthcare and reducing preventable deaths from cervical cancer.

Background and Need for New Treatments

Cervical cancer is the third most common cancer among women in the United States. The physiology of disease typically develops as a result of persistent infection with high-risk types of human papillomavirus (HPV), most notably the HPV-16 and HPV-18 variants. The virus enters into the basal epithelial cells of the cervix through microscopic abrasions, where it expresses oncogenic proteins E6 and E7. These proteins inactivate crucial tumor suppressor pathways, p53 and retinoblastoma (Rb), leading to loss of cell cycle control. This disruption promotes genomic instability, setting the stage for the development of cervical intraepithelial neoplasia (CIN), which can progress to invasive cervical cancer if not identified and managed early.

In the U.S., over 20 million women are currently overdue for their cervical cancer screenings. Common obstacles include limited time, demanding work, childcare responsibilities, and financial constraints. Many individuals also avoid screenings due to fear, discomfort, or pain associated with the traditional clinic-based speculum exam. For some, especially those with a history of sexual trauma, the experience can be particularly distressing. This includes the estimated 1 in 4 women who have experienced sexual assault or childhood abuse, as well as individuals who are transgender. For these groups, the standard screening process can feel invasive and create a barrier to essential preventive care.

Traditional cervical cancer screening tools, including Pap smears and physician-collected HPV tests, are effective enough; however, these tools are alleged to involve a small surgery-like procedure, are uncomfortable, and require in-person clinical appointments, which can discourage participation, particularly among underserved or timid patients. In contrast, the Teal Wand offers an at-home alternative that is non-invasive, private, and user-friendly. Another reason was that the younger women are being diagnosed with cervical cancer more often, which requires immediate early detection and treatment. This alarming situation needs correction immediately. By making screening more accessible and less intimidating, the Teal Wand has the potential to increase early detection rates, improve screening adherence, and ultimately reduce the burden of cervical cancer across the country.

Teal Wand: A Novel Approach

Source: tealhealth.com

Teal Health is a women’s healthcare company based in San Francisco that has developed the Teal Wand, a pioneering at-home cervical cancer screening device that allows women to self-collect vaginal samples for human papillomavirus testing. Teal Wand is designed as per FDA-approved standards. The Teal Wand offers a private, convenient, and clinically validated alternative to traditional in-clinic procedures. To carry out the collection of the sample at home with the help of the teal wand, patients can follow the following steps:

Request kit: Requesting a Teal Wand collection kit at-home order. Once confirmed, the kit will be directly shipped to the address.

Collect your sample & mail it to the lab: Once the kit is received, collect the sample from the comfort of your home. Once done, seal the sample and send it to the lab for further testing.

Processed at CLIA-certified labs: The sample will be collected at CLIA-certified labs, analyzed with an FDA-approved primary HPV test, and the results on the Teal Wand portal.

Clinical trial—the SELF-CERV Study

The FDA approval of Teal Wand comes after the extensive nationwide clinical trial called the SELF-CERV nonrandomized clinical trial (ClinicalTrials.gov ID: NCT06120205) conducted by Teal Health to validate the performance of Teal Wand. This study aimed to compare the effectiveness of self-collected vaginal samples (SC) using the Teal Wand with clinician-collected (CC) cervical samples collected using a speculum and brush for detecting high-risk human papillomavirus (hrHPV).

The 609 eligible participants aged between 25 to 65 years of age were recruited from 16 different sites in the USA with an intact cervix. Exclusion criteria included pregnancy, vaginal bleeding, and a cervical alteration in the prior 5 months.

Source: tealhealth.com

Procedure for the collection of a  sample using a teal wand during trial

Participants conducted self-collection (SC) in a private space designed to simulate an at-home environment. Following the provided instructions, they inserted the device into the vagina, extended the collection sponge using the dial, rotated it ten times, and then removed the device. After collection, the sponge was detached and placed into an empty vial.

For method comparison, a clinician subsequently collected a cervical sample using a Rovers Cervex-Brush, which was deposited into a 20-mL PreservCyt vial. Both self-collected and clinician-collected (CC) samples were sent to a designated laboratory for analysis.

Self-collected samples were stored dry in their vials for up to nine days. Before processing, a lab technician eluted each sponge into 20 mL of PreservCyt solution. All samples were then analyzed using the Roche cobas high-risk HPV test on the Roche cobas 8800 System.

Results

Out of total 609 eligible participants 599 paired SC-CC samples (262 aged 30-39 years [43.7%]; 583 identified as female [97.3%]) were scrutinized. 362 individuals (59.4%) were recruited from a high-risk HPV-enriched population, while the remaining 247 participants (40.6%) were enrolled from the general cervical cancer screening population.

The SC method showed 95.2% agreement with CC method in detecting high-risk HPV and 95.8% sensitivity for detecting high-grade cervical dysplasia, matching CC performance. Most participants (over 92%) found the instructions easy and said they would prefer SC if results were comparable to CC. The study found that the SC device was a safe and accurate option for cervical screening suitable for at-home use. The intersection of increased health autonomy and highly sensitive diagnostic tools make this an optimal time to implement at-home SC cervical cancer screening in the US, thereby improving access and accelerating progress toward cervical cancer elimination.

Safety Profile

Clinicians visually examined the cervix and vagina after both self-collection (SC) and clinician collection (CC). All observed events were expected and mostly mild, typically linked to CC or later procedures like colposcopy or biopsy. Only 2 of 602 participants (0.3%) experienced mild issues directly related to the SC device: one minor cervical abrasion and one case of spotting (not confirmed on exam). Mild spotting or bleeding from either method was reported in 0.5% of participants (3 of 602).

Conclusion

 The U.S. Food and Drug Administration’s approval of the Teal Wand represents a pioneering landmark in the evolution of cervical cancer screening. As the first FDA-authorized at-home self-collection device for HPV testing, the Teal Wand introduces a new era of accessibility, sovereignty, and innovation in women’s healthcare.

The teal wand is backed by clinical evidence demonstrating safety and diagnostic accuracy comparable to traditional clinician-collected methods. The device empowers women to take charge of their reproductive health in a more comfortable and private setting, removing common barriers such as discomfort, inconvenience, and limited access to in-clinic appointments.

This advancement is particularly important in reaching populations that are underserved or under-screened, potentially boosting participation rates and enabling earlier detection of high-risk human papillomavirus (hrHPV), the leading cause of cervical cancer. By allowing users to collect their sample from the comfort of home, the teal wand supports public health efforts to increase screening adherence and reduce cervical cancer incidence.

References

FDA Approves Teal Health’s Teal Wand™—The First and Only At-Home Self-Collection Device for Cervical Cancer Screening, Introducing a Comfortable Alternative to In-Person Screening, teal health, 09 May 2025, https://www.getteal.com/news/fda-approves-teal-healths-teal-wand-tm—the-first-and-only-at-home-self-collection-device-for-cervical-cancer-screening-introducing-a-comfortable-alternative-to-in-person-screening

Teal Health Completes Clinical Trial at Record Speed and Receives FDA Breakthrough Designation for Its At-Home Cervical Cancer Screening Device, the Teal Wand https://www.prnewswire.com/news-releases/teal-health-completes-clinical-trial-at-record-speed-and-receives-fda-breakthrough-designation-for-its-at-home-cervical-cancer-screening-device-the-teal-wand-302138565.html

https://tealhealth.webflow.io/teal-wand

Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003 Jan; 16(1. Doi: 10.1128/CMR.16.1.1-17.2003. PMID: 12525422; PMCID: PMC145302.

Teal Health Self-Cerv Report, May 2025, https://cdn.prod.website-files.com/63d5330e6841081487be0bd6/681d6148758c5c1fe0c81f2e_Teal-Health-SELF-CERV-Report-May92025-sml.pdf

Fitzpatrick MB, Behrens CM, Hibler K, Parsons C, Kaplan C, Orso R, Parker L, Memmel L, Collins A, McNicholas C, Crane L. Clinical Validation of a Vaginal Cervical Cancer Screening Self-Collection Method for At-Home Use: A Nonrandomized Clinical Trial. JAMA Network Open. 2025 May 1;8(5):e2511081-. DOI: 10.1001/jamanetworkopen.2025.11081

 Allen-Leigh B, Uribe-Zúñiga P, León-Maldonado L, Brown BJ, Lörincz A, Salmeron J, Lazcano-Ponce E. Barriers to HPV self-sampling and cytology among low-income indigenous women in rural areas of a middle-income setting: a qualitative study. BMC cancer. 2017 Dec;17:1-1.

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

vaccine-bottle-syringe-held-by-doctor-with-gloves

“England Rolls Out 5-Minute Subcutaneous Opdivo (Nivolumab) for 15+ Cancer Types, Enhancing Treatment Speed and Patient Convenience”

by with No Comment New Drug Approval

Written by Priyanka Khamkar (M. Pharm) Pharmacology and Vikas Londhe M.Pharm, Pharmacology

vaccine-bottle-syringe-held-by-doctor-with-gloves
Source: Freepik.com

The UK’s National Health Service (NHS) has rolled out Opdivo, an immunotherapy drug in a 3-5 minute injectable form, effective in 15 types of cancers. Opdivo is nivolumab, a monoclonal antibody that attaches to T-cells’ PD-1 (programmed death-1). The jab can be used to treat 15 different types of cancer, such as melanoma, esophageal, bladder, and skin cancer. The approval history of Nivolumab dates back to 2014, when it was first approved by the USFDA, followed by the EMA in 2015 for unresectable or metastatic melanoma. Since then, to date, nivolumab has been approved for a dozen cancer treatments, up to 15 cancers, by the FDA, EMA, and MHRA. Nivolumab was first developed by Medarex Inc., which was later acquired by Bristol Myers Squibb (BMS). BMS is now the marketing authorization holder of Opdivo in the EU and the MHRA. Nivolumab was earlier administered intravenously over a 30- to 60-minute IV drip, depending on the regimen and for which cancer it was being administered. 

Bristol Myers-Squibb’s injectable form of nivolumab (Opdivo) is now available through NHS England, the first national health agency in Europe to do so. It allows treatment to be given in five minutes via the subcutaneous route as opposed to up to a one-hour administration via IV drip earlier. The announcement comes after approval from the Medicines and Healthcare Products Regulatory Agency (MHRA).

Opdivo (Nivolumab)

Opdivo has been approved for numerous cancers, including melanoma, non-small cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, liver cancer, esophageal squamous cell carcinoma, gastric cancer, and gastroesophageal junction cancer.

Before the latest injectable form, Opdivo was administered as an intravenous infusion (IV drip) over 30 minutes every two to four weeks, depending on the type of cancer.

Opdivo is fully human immunoglobulin G4 (IgG4) monoclonal antibody that target programmed Death-1 receptor. By binding to PD-1, it inhibits its interaction with its natural ligands, PD-L1 and PD-L2. PD-1 is an immune checkpoint receptor that negatively regulates T-cell activation and function. When PD-1 binds to PD-L1 or PD-L2 molecules found on antigen-presenting cells, more often on tumor cells, it suppresses T-cell proliferation and cytokine production, thereby limiting the immune response.

By blocking PD-1 from connecting with its ligands, nivolumab restores and enhances T-cell activity, which promotes anti-tumor immune responses.

Due to its broader cancer indications, approved for almost 20+ cancers, its global recognition, almost approved in 60+ countries, undergone 1000+ clinical trials worldwide and massive commercial success almost generated 1 billion annual revenue Nivolumab (Opdivo) is one of the most well-known and widely used anticancer drugs globally, especially in the field of immune-oncology.

Clinical Trial-CheckMate-67T  Trial

The CheckMate-67T trial was a pivotal Phase 3 study that led to the approval of subcutaneous nivolumab in the UK.

The CheckMate-67T trial was a pivotal Phase 3, randomized, open-label, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of a new subcutaneous (SC) formulation of nivolumab, compared to its standard intravenous (IV) formulation. The trial enrolled 495 patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC), all of whom had received up to two prior systemic therapies. Patients were randomized to receive either SC nivolumab at 1200 mg every four weeks, co-formulated with recombinant human hyaluronidase (rHuPH20), or IV nivolumab at 3 mg/kg every two weeks.

The primary endpoints focused on comparing pharmacokinetics between the two formulations. The SC version demonstrated noninferior serum drug levels, with a geometric mean ratio for the 28-day average concentration of 2.098 and a trough steady-state concentration ratio of 1.774 compared to IV nivolumab. These results confirmed that the SC formulation delivers adequate and sustained drug levels in the bloodstream.

In terms of efficacy, the objective response rate (ORR) evaluated by blinded independent central review was 24.2% in the SC group and 18.2% in the IV group. Median progression-free survival (PFS) was also slightly better in the SC arm (7.23 months) compared to the IV arm (5.65 months), indicating at least comparable clinical benefit.

The safety profile of the SC formulation was consistent with that of IV nivolumab. Grade 3–4 adverse events were reported in 35.2% of SC-treated patients versus 40.8% in the IV group. Treatment-related adverse events occurred in 9.7% of patients in the SC arm and 14.7% in the IV arm. While injection site reactions occurred in 8.1% of SC patients, these were all low-grade and transient.

Overall, the CheckMate-67T trial established that the subcutaneous formulation of nivolumab offers a comparable safety and efficacy profile to the traditional IV infusion, with the added benefit of a much shorter administration time (3–5 minutes).

Impact of this approval on Patient and Healthcare System

The approval of the subcutaneous (SC) injectable form of nivolumab, administered in just 3–5 minutes, represents a significant advancement not only in cancer immunotherapy but also in the operational efficiency of healthcare systems.

Operational Efficiency

Oncology centres can treat more patients per day, improving access and reducing waiting lists, especially critical in high-demand settings.

Subcutaneous delivery bypasses the need for IV lines, infusion pumps, and extended monitoring.

The switch from a 30–60 minute IV infusion to a 3–5 minute SC injection frees up infusion chairs and resources significantly.

Workforce and Nursing Burden

Reduced Nursing Time: Nurses spend less time preparing, administering, and monitoring SC injections than IV infusions

Simplified Workflow: SC administration is quicker and easier to train and perform, reducing staff fatigue and increasing capacity.

Financial and Economic Impact

Lower Resource Utilization: Shorter administration time and less equipment usage lower direct costs.

Reduced Hospital Stay/Daycare Costs: Especially beneficial in settings where infusion visits are billed by duration or require hospital resources.

Potential to Shift to Community/At-Home Care: Future models may allow SC nivolumab to be delivered in community settings, reducing hospital dependency even further.

Patient Experience and Convenience

Reduces time spent at the hospital from over an hour to just minute a major improvement for working patients and caregivers.

Fewer disruptions to daily life, particularly beneficial for patients receiving long-term or adjuvant immunotherapy

Patients prefer less invasive, faster treatments. This translates into higher satisfaction and potentially better adherence, which is crucial for chronic or prolonged regimens.

Given nivolumab’s approvals across 15+ cancer types (e.g., NSCLC, melanoma, RCC, bladder, oesophageal, head and neck), it is used in thousands of patients weekly in oncology clinics worldwide. The frequency of its use amplifies the system-level benefits:

System-Wide Impact: Even minor time and cost savings per patient scale dramatically across large populations.

Increased Flexibility in Scheduling: Reduces bottlenecks in oncology services.

Improved Continuity of Care: Less clinic fatigue and improved morale for both patients and healthcare workers

Conclusion

The approval of the 3–5 minute subcutaneous (SC) injectable form of nivolumab marks a pivotal advancement in cancer care, blending clinical efficacy with logistical innovation. By delivering comparable safety, pharmacokinetics, and anti-tumor activity to the intravenous formulation while reducing administration time, this new approach addresses several critical challenges in modern oncology.

Its benefits are multifold: patients gain convenience, comfort, and reduced treatment burden; clinicians and nurses experience lower workload and increased efficiency; and healthcare systems benefit from optimized resource utilization, cost containment, and expanded capacity. For a drug like nivolumab, already approved for various cancers, these improvements are especially impactful given the large and growing patient population receiving immunotherapy.

Looking ahead, the SC formulation of nivolumab sets a new standard for biologic cancer therapies. It concretizes the way for more accessible outpatient and potentially home-based cancer care models. As the oncology field continues to prioritize patient-centric, high-efficiency solutions, this advancement is not just a technical improvement; it is a strategic leap toward the future of cancer treatment.

References

NHS rolls out 5-minute ‘super-jab’ for 15 cancers, NHS England, 30 April 2025, https://www.england.nhs.uk/2025/04/nhs-rolls-out-5-minute-super-jab-for-15-cancers/

MHRA authorises cancer treatment variation with an administration time of 3–5 minutes, Medicines and Healthcare products Regulatory Agency, 30 April 2025, https://www.gov.uk/government/news/mhra-authorises-cancer-treatment-variation-with-an-administration-time-of-3-5-minutes

Summary of Product Characteristics, Opdivo, Bristol-Myers Squibb Pharma EEIG, https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf

Saby George et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. JCO 42, LBA360-LBA360 (2024). DOI:10.1200/JCO.2024.42.4_suppl.LBA360

L. Albiges, MT Bourlon de los Rios,   et al, 1691P Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients (pts) with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Updated efficacy and safety results from CheckMate 67T, Annals of Oncology, Volume 35, Supplement 2S1013-S1014September 2024

Subcutaneous Nivolumab (nivolumab and hyaluronidase) Shows Noninferiority Compared to Intravenous Opdivo (nivolumab) in Advanced or Metastatic Clear Cell Renal Cell Carcinoma in CheckMate -67T Trial, Bristol, Myers Squibb, 27 Jan 2024 https://news.bms.com/news/details/2024/Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase-Shows-Noninferiority-Compared-to-Intravenous-Opdivo-nivolumab-in-Advanced-or-Metastatic-Clear-Cell-Renal-Cell-Carcinoma-in-CheckMate–67T-Trial/default.aspx

Joshi DC, Sharma A, Prasad S, et al. Novel therapeutic agents in clinical trials: emerging approaches in cancer therapy. Discover Oncology. 2024 Aug 11; 15(1):342.

Ryan Scot, The subcutaneous approval of opdivo makes waves in future of cancer care, Jan 15 2025, https://www.curetoday.com/view/the-subcutaneous-approval-of-opdivo-makes-waves-in-future-of-cancer-care

Subcutaneous Nivolumab Reduces Burden of Melanoma Care, Expert Says, 13 March 2025, Oncology News Centre, https://www.oncologynewscentral.com/melanoma/subcutaneous-nivolumab-reduces-burden-of-melanoma-care-expert-says

Bristol Myers Squibb Receives MHRA Approval for the Subcutaneous Formulation of Opdivo (nivolumab), FirstWorld Pharma, https://firstwordpharma.com/story/5955874

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com