Proptosis_and_lid_retraction_from_Graves'_Disease

Tepezza (Teprotumumab) A first Targeted Drug Receives Positive CHMP Opinion from EMA and Approval from MHRA to Treat Moderate to Severe Thyroid Eye Disease (TED) by Targeting IGF-1 Receptor

by with No Comment New Drug Approval

Written by: Shakuntala Kawhale (Pharmacology), Utkarsha Patil (Pharmacology) and Shital Gaikwad (Pharmacology)

eye bulging
Source: Freepik.com

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of Tepezza (teprotumumab) for the treatment of adults with moderate to severe Thyroid Eye Disease (TED). This marks the first time a non-surgical therapy for this debilitating condition has been authorized in the European Union. The marketing authorization for Tepezza in Europe is Amgen Europe B.V., following Amgen’s acquisition of Horizon Therapeutics in October 2023. In May 2025, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) also approved Tepezza, making it the first licensed treatment for moderate-to-severe TED in the United Kingdom. The EU and UK approvals represent a historic advancement, introducing the first and only approved medical therapy for TED to patients across Europe holder.

Thyroid Eye Disease (TED)

Thyroid Eye Disease (TED), also known as Graves’ ophthalmopathy, is a rare autoimmune disorder in which the immune system mistakenly attacks the muscles and fat surrounding the eyes. This immune response leads to inflammation and swelling, causing symptoms such as double vision, eye pain, and eye bulging (proptosis). In severe cases, TED can result in vision loss and facial disfigurement.

According to the American Academy of Ophthalmology and the National Organization for Rare Disorders, TED is classified as a rare disease. Notably, only about 3% to 5% of cases progress to severe disease, making such presentations especially uncommon. 30 to 50% of all Graves’ disease patients are affected by this condition. Some reports show that it increases suicidal risk in patients with TED. The disease typically begins with an active inflammatory phase, characterized by redness of the eyes, pain around and behind the eyes, and swelling of the tissues surrounding the orbits. If inflammation persists, it can lead to structural changes in the retroorbital fat and muscles, resulting in proptosis, diplopia (double vision), and, in advanced cases, corneal damage or optic nerve compression.

The pathophysiological basis of typical orbital inflammation and tissue expansion in thyroid eye disease (TED) is well established. Orbital fibroblasts in TED patients overexpress thyroid-stimulating hormone receptors (TSHR). These receptors can be activated either by excess thyroid hormone or by thyroid-stimulating antibodies (TSAb), leading to the transformation of orbital preadipocytes, a subset of fibroblasts, into fat cells. This contributes to an increase in orbital adipose tissue volume.

Another alternate pathway that plays a key role is the Insulin-like growth factor-1 (IGF-1) pathway. In patients with Graves’ disease, IGF-1 and its receptors are overexpressed on T and B lymphocytes. Graves’ IgG autoantibodies targeting the IGF-1 receptor stimulate orbital fibroblasts, triggering their proliferation, the release of inflammatory cytokines, and the production of hyaluronan, a molecule that draws in water and causes further tissue swelling.

Decisively, TSH receptors (TSHR) and IGF-1 receptors (IGF-1R) are co-expressed on the surface of orbital fibroblasts and are believed to function synergistically. Evidence suggests significant cross-talk between these signaling pathways, which enhances the inflammatory response and tissue remodeling that are hallmarks of thyroid eye disease (TED).

Conventional treatments for Thyroid Eye Disease (TED) such as corticosteroids, radiation therapy, and surgical procedures come with considerable limitations. Corticosteroids can effectively reduce inflammation, their benefits are often short-lived, with symptoms normally recurring once the treatment is tapered. Also they are associated with a range of systemic side effects, including weight gain, high blood pressure, elevated blood sugar levels, mood disturbances, and a increased risk of infections. Surgical interventions like orbital decompression and strabismus correction are invasive, irreversible, and often require multiple procedures to manage the full spectrum of TED manifestations. These traditional therapies primarily focus on symptom relief rather than addressing the root autoimmune cause of the disease, emphasizing the need for more targeted, disease-modifying treatment options.

Tepezza (Teprotumumab): A Breakthrough Treatment

Tepezza is the first and only medication that targets the underlying cause of thyroid eye disease, rather than just improving its symptoms. Tepezza is a monoclonal antibody that inhibits orbital fibroblast activation and reduces inflammation linked to TED by targeting the insulin-like growth factor 1 receptor (IGF-1R). Tepezza, which is administered intravenously, is a nonsurgical option for treating moderate to severe TED. Tepezza will be available as a 500 mg powder concentrate for solution for infusion.

Clinical Trial Results

Amgen’s application to the EMA for Tepezza (teprotumumab) is supported by a series of clinical trials demonstrating its efficacy, safety, and tolerability in treating thyroid eye disease (TED). The Phase 2 study (NCT01868997) enrolled 88 patients with active, moderate-to-severe TED in a randomized, double-masked, placebo-controlled trial. Participants received teprotumumab infusions every three weeks over 24 weeks. The primary endpoint involved composite improvement in proptosis (≥2 mm) and Clinical Activity Score (CAS) (≥2-point reduction) and was met by 69% of treated patients compared to 20% receiving placebo. Improvements were observed as early as week 6, and the treatment was generally well-tolerated, with hyperglycemia reported in diabetic patients as the most notable side effect.

The pivotal Phase 3 OPTIC trial (NCT03298867) enrolled 83 patients and confirmed the benefits of teprotumumab in active TED. At week 24, 83% of patients in the treatment group achieved a proptosis response (≥2 mm reduction without deterioration in the fellow eye) versus 10% in the placebo group. The average reduction in proptosis was 3.32 mm, comparable to surgical outcomes. Secondary endpoints also favored teprotumumab, including a 78% overall response rate (proptosis and CAS improvement) and significant reductions in diplopia and inflammation. The treatment showed a consistent safety profile with mostly mild to moderate adverse events.

The Phase 4 trial (NCT04583735, HZNP-TEP-403) is evaluating teprotumumab in 57 patients with chronic (inactive) TED, those with stable disease but persistent symptoms. This double-masked, placebo-controlled study uses the same 24-week infusion regimen and focuses on changes in proptosis as the primary endpoint. Secondary endpoints include the proportion of responders, improvements in diplopia and GO-QOL scores, and monitoring for adverse events such as hearing issues, hyperglycemia, and infusion reactions. This trial aims to extend the therapeutic scope of teprotumumab beyond active TED.

The OPTIC-J trial (jRCT2031210453), a Phase 3 study conducted in Japan, evaluated teprotumumab in 54 patients with active TED. Using the same regimen as the OPTIC trial, 89% of patients receiving teprotumumab achieved the primary endpoint of ≥2 mm proptosis reduction without fellow eye deterioration, compared to 11% in the placebo group. The safety profile was consistent with earlier studies, with drug-related adverse events in 52% of the treatment group, most commonly hyperglycemia and hearing impairment. OPTIC-J supported regulatory approval of Tepezza in Japan and underscored its efficacy in diverse populations.

These clinical trials collectively demonstrated statistically significant and clinically meaningful improvements in various aspects of thyroid eye disease (TED), including proptosis and diplopia, among a total of 287 patients. The studies also evaluated key signs and symptoms of TED such as pain, inflammation, redness, and functional vision. Notable clinical improvements in proptosis were observed as early as six weeks into treatment, with continued progress throughout the 24-week treatment period. Teprotumumab has also shown a well-established safety profile.

Safety Profile and Risk Management

Tepezza is generally well-tolerated; however, like all biologic therapies, it is associated with several adverse reactions and safety considerations. The most commonly reported adverse reactions (occurring in ≥5% of patients and at a higher rate than placebo) include muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dysgeusia, headache, dry skin, decreased weight, nail disorders, and menstrual irregularities. Tepezza carries specific warnings and precautions, including the risk of infusion reactions, which may present with symptoms such as increased blood pressure, headache, or muscle pain, typically during or shortly after infusion. Patients with preexisting inflammatory bowel disease (IBD) may experience disease exacerbation and should be monitored closely. Hyperglycemia is another concern, particularly in patients with diabetes or impaired glucose tolerance, requiring regular glucose monitoring and management. Additionally, Tepezza may cause hearing impairment, including potential permanent hearing loss, necessitating hearing assessments before, during, and after treatment.

Imapct, Future Study and Conclusion

Tepezza (teprotumumab) is a breakthrough biologic therapy that has significantly transformed the treatment landscape for thyroid eye disease (TED), a condition that previously had limited non-surgical options. As the first FDA-approved, EMA positive opinion andMHRA approved therapy specifically targeting the underlying pathophysiology of TED, Tepezza offers a well-characterized safety and efficacy profile for patients with moderate-to-severe disease. Clinical trials consistently demonstrated statistically significant and clinically meaningful improvements in key outcomes such as proptosis, diplopia, and inflammation, with benefits often observed as early as six weeks. Its efficacy has been shown in both active and chronic (inactive) forms of TED, reducing the need for surgical interventions and greatly enhancing patients’ quality of life. Ongoing and future studies aim to further expand its therapeutic scope, assess long-term safety and efficacy, and explore its use in broader patient populations.

Reference

Amgen to submit teprotumumab marketing authorization application to the European Medicines Agency, Press Release, Amgen, 26 April 2025, https://www.amgen.com/newsroom/press-releases/2024/04/amgen-to-submit-teprotumumab-marketing-authorization-application-to-the-european-medicines-agency

Highlights of prescribing information, Tepezza, https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/tepezza/tepezza_fpi_english.pdf

First treatment against severe thyroid eye disease, 25 April 2025, European Medicine Agency, https://www.ema.europa.eu/en/news/first-treatment-against-severe-thyroid-eye-disease

MHRA approves teprotumumab as the first UK treatment for adults with moderate to severe Thyroid Eye Disease (TED), 7 May 2025, https://www.gov.uk/government/news/mhra-approves-teprotumumab-as-the-first-uk-treatment-for-adults-with-moderate-to-severe-thyroid-eye-disease-ted

Weiler DL. Thyroid eye disease: a review. Clin Exp Optom. 2017 Jan;100(1):20-25. doi: 10.1111/cxo.12472. Epub 2016 Oct 4. PMID: 27701774.

Wang Y, Sharma A, Padnick-Silver L, Francis-Sedlak M, Holt RJ, Foley C, Massry G, Douglas RS. Trends in Treatment of Active, Moderate-to-Severe Thyroid Eye Disease in the United States. J Endocr Soc. 2020 Sep 25;4(12):bvaa140. doi: 10.1210/jendso/bvaa140. PMID: 33195953; PMCID: PMC7645612.

Couch SM. Teprotumumab (Tepezza) for Thyroid Eye Disease. Mo Med. 2022 Jan-Feb;119(1):36-41. PMID: 36033157; PMCID: PMC9312457.

Terry J. Smith, George J. Kahaly, Daniel G. Ezra, et al, Teprotumumab for Thyroid-Associated Ophthalmopathy, N Engl J Med 2017;376:1748-61. DOI: 10.1056/NEJMoa1614949

Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382(4):341-352. doi:10.1056/NEJMoa1910434.

Douglas RS, Couch S, Wester ST, et al, OR27-04 Efficacy And Safety Results From The Randomized, Placebo-controlled Multicenter Trial With Teprotumumab In Chronic-Low Clinical Activity Score Thyroid Eye Disease Patients. J Endocr Soc. 2023 Oct 5;7(Suppl 1):bvad114.2055. doi: 10.1210/jendso/bvad114.2055. PMCID: PMC10554583

Raymond S Douglas, Steven Couch, Sara T Wester, et al  Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity, The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 1, January 2024, Pages 25–35, https://doi.org/10.1210/clinem/dgad637

Hiromatsu Y, Ishikawa E, Kozaki A, et al, randomised, double-masked, placebo-controlled trial evaluating the efficacy and safety of teprotumumab for active thyroid eye disease in Japanese patients. Lancet Reg Health West Pac. 2025 Jan 18;55:101464. doi: 10.1016/j.lanwpc.2025.101464. PMID: 39896230; PMCID: PMC11787687.

Moledina, M., Damato, E.M. & Lee, V. The changing landscape of thyroid eye disease: current clinical advances and future outlook. Eye 38, 1425–1437 (2024). https://doi.org/10.1038/s41433-024-02967-9

hands-patient-suffering-from-psoriasis_11zon

Qoyvolma: A More Affordable Biologic Option for Plaque Psoriasis and Inflammatory Diseases like Psoriatic Arthritis, Cohn’s Disease, and Ulcerative Colitis

by with No Comment New Drug Approval

Written by Rikesh Dighore (Pharmacology) and Soniya Hajare (Pharmacology)

hands-patient-suffering-from-psoriasis_11zon
Source: Freepik.com

The European Medicines Agency’s (EMA) Committee for Medicinal Product for Human Use (CHMP) has accepted a positive opinion for Qoyvolma (ustekinumab), a biosimilar of the reference biologic Stelara. This approval is a significant step towards treatment of chronic inflammatory diseases. Qoyvolma is approved for use in adults and children aged six and older with plaque psoriasis, as well as in adults with psoriatic arthritis, Crohn’s disease, and ulcerative colitis. These immune-mediated conditions are marked by chronic inflammation that can significantly affect patients’ quality of life. Developed by Celltrion Healthcare Hungary Kft, the biosimilar’s approval ensures persistent therapeutic benefits at the same time it lowers the financial burden and increases access to biological treatment by potentially lowering healthcare costs.

Background and Need for New Treatment

Plaque psoriasis is a chronic, immune-mediated skin condition that affects both adults and children. In pediatric populations, it represents about one-third of all psoriasis cases and is often linked to serious co-morbidities, including a heightened risk of developing psoriatic arthritis and inflammatory bowel diseases such as Crohn’s disease. Psoriatic arthritis (PsA), a diverse form of inflammatory arthritis, occurs in up to 41% of individuals with psoriasis and can result in progressive joint damage and disability if not identified and managed early.

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases marked by recurrent episodes of inflammation in the gastrointestinal tract. Although several treatment options exist, including biologic therapies, many patients continue to face challenges such as suboptimal disease control, a lack of effect over time, or intolerable side effects. These limitations underline the ongoing need for new and effective therapeutic approaches.

Despite several progressions in the treatment of plaque psoriasis, psoriatic arthritis (PsA), Crohn’s disease, and ulcerative colitis (UC), there remains a need for more effective, safer, and longer-lasting therapies. In plaque psoriasis includes pediatric cases, biologics targeting TNF-α, IL-17, and IL-23 pathways which generally deliver only partial or short-term relief, with many patients experiencing relapse or an inadequate response. Psoriatic arthritis poses similar challenges, as a significant number of patients fail to achieve or sustain remission, emphasizing the need for treatments with novel mechanisms. Likewise, in Crohn’s disease and ulcerative colitis, even with the emergence of newer agents, an ample proportion of patients do not achieve deep, lasting remission, and treatment-related adverse effects remain a concern.

Also, Biologics have revolutionized the treatment of chronic and complex diseases, but their high prices often place them out of reach for many patients and healthcare systems, especially in low- and middle-income regions.

These persistent limitations and the need for cost-effective options highlight the ongoing demand for innovative therapies that can provide durable disease control, lower financial burden, and significantly enhance patient quality of life across this spectrum of immune-mediated conditions.

Qoyvolma (ustekinumab): A Novel Approach

Qoyvolma is a biosimilar of ustekinumab. Ustekinumab is a fully human IgG1κ monoclonal antibody that targets the p40 subunit common to interleukins IL-12 and IL-23. By blocking their interaction with the IL‑12Rβ1 receptor on immune cells, it disrupts the activation of the Th1 and Th17 cytokine pathways, which are key drivers in the inflammatory processes underlying these chronic immune-mediated conditions.

Being a biosimilar, the approval of Qoyvolma introduces a more accessible and cost-effective approach to the treatment of chronic inflammatory diseases. By offering clinically comparable alternatives to the reference biologic, these biosimilar have the potential to expand patient access to advanced therapies while alleviating the financial burden on healthcare systems. Their availability supports broader, more sustainable management strategies for conditions like plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

Qoyvolma is offered in multiple formulations: 45 mg and 90 mg solutions for subcutaneous injection and a 130 mg concentrate for intravenous infusion, providing flexibility in administration to suit individual patient needs. The arrival of Qoyvolma and other ustekinumab biosimilars marks a meaningful advancement in the treatment for chronic inflammatory diseases, delivering effective, more accessible therapeutic options that can improve patient outcomes and support long-term disease management.

Clinical Trials and Approval

As per EMA, Qoyvolma has comparable quality, safety, and efficacy to Stelara

Safety profile

As being biosimilar to Stelara, Qoyvolma (Ustekinumab) has a favorable safety profile similar to Stelara and is generally well tolerated. Common side effects include upper respiratory infections, headache, fatigue, and mild injection site reactions. Serious adverse events are rare but can include infections such as tuberculosis and opportunistic infections, so screening is recommended before starting therapy. There is a very low risk of malignancy, hypersensitivity reactions, and rare neurologic effects like reversible posterior leukoencephalopathy syndrome (RPLS). The drug has low immunogenicity, meaning the development of anti-drug antibodies is uncommon. Long-term studies have shown no significant increase in infections or malignancy rates over time. It is considered relatively safe in pregnancy and breastfeeding, and no dose adjustments are required in elderly patients or those with liver or kidney issues.

Impact and Conclusion

Qoyvolma is anticipated to significantly lower treatment costs for healthcare systems while broadening access to advanced therapies, especially in regions where biologic medications were previously out of reach due to financial constraints. Its introduction strengthens competition in the biosimilar market, encourages innovation, improves pricing dynamics, and enhances trust in the use of biosimilars across Europe. Looking ahead, Qoyvolma is well-positioned to contribute to the continued expansion of the biosimilar market. Potentially accelerating the development and regulatory approval of additional ustekinumab biosimilars. Its success may also lead to expanded indications, including pediatric Crohn’s disease, as patent exclusivity expires. Moreover, regulatory approval in Europe could serve as a model for market entry in other global regions, supporting wider acceptance and integration of biosimilars into the healthcare system worldwide.

Ultimately, Qoyvolma marks a shift in treatment paradigms, helping establish biosimilars as a mainstream option in the long-term management of chronic inflammatory disease.

References

Kim HO, Kang SY, Kim JC, Park CW, Chung BY. Pediatric psoriasis: From new insights into pathogenesis to updates on treatment. Biomedicines. 2021 Aug 2;9(8):940.

Summary of opinion, Qoyvolma, 27 march 2025 available form https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-qoyvolma_en.pdf

Ferrara F, Verduci C, Laconi E, et al, Current therapeutic overview and future perspectives regarding the treatment of psoriasis. International Immunopharmacology. 2024 Dec 25;143:113388.

Ghosh S, Gensler LS, Yang Z, Gasink C, Chakravarty SD, Farahi K, Ramachandran P, Ott E, Strober BE. Ustekinumab safety in psoriasis, psoriatic arthritis, and Crohn’s disease: an integrated analysis of phase II/III clinical development programs. Drug safety. 2019 Jun 4;42:751-68.

Highlights of Prescribing Information, STELARA (Ustekinumab), available from https://janssenlabels.com/package-insert/product-monograph/prescribing-information/STELARA-pi.pdf

The Article is Extensively Reviewed and Fact-Checked By the Editorial Team Pharmacally.com. 

Sephience

EMA’s CHMP Recommends Sephience (sepiapterin) for Hyperphenylalaninaemia (HPA) in Adults and Children with Phenylketonuria (PKU)

by with No Comment New Drug Approval

Written by: Priya Bhaware M.Pharm (Pharmacology) and Samiksha Benke M.Pharm (Pharmacology)

Sephience
In image the newborn baby's heel is being prepared for Guthrie Test to detect Phenylketonuria (Source: Freepik.com)

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has accepted a positive opinion recommending the approval of Sephience (sepiapterin) for the treatment of hyperphenylalaninaemia (HPA) in both adult and pediatric patients with phenylketonuria (PKU). Sephience most likely will be approved with orphan drug designation. Sephience will be made available as an oral powder in 250 mg and 1000 mg strengths. PTC Therapeutics International, the creator of the drug, is expected to receive marketing authorization based on this recommendation. Sephience is in position to represent a major advancement in the treatment of this rare metabolic condition.

Background and Need for New Treatments

Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by the body’s inability to break down phenylalanine, an amino acid present in many protein-rich foods. This condition arises from mutations in the gene responsible for producing phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine into tyrosine. When PAH is deficient or malfunctioning, phenylalanine accumulates in the blood, leading to a condition known as hyperphenylalaninemia (HPA). Without treatment, elevated phenylalanine levels can result in severe neurological impairments, developmental delays, and neuropsychiatric complications.

The current conventional treatment is mostly consisting of lifelong commitment to a phenylalanine-restricted diet, which is often begun in infancy. Even if effective in lowering phenylalanine levels, dietary reduction is difficult to maintain, particularly during adolescence and adulthood, and has a significant impact on quality of life. The pharmacological options are limited; however, sapropterin dihydrochloride, a synthetic version of the cofactor tetrahydrobiopterin (BH4), is approved for use in some BH4-responsive individuals. The therapeutic response to sapropterin differs, and many patients do not attain appropriate metabolic control.

There is still a considerable need for effective, well-tolerated, and easier-to-manage medicines for both pediatric and adult patients with PKU. Sephience is a promising therapeutic innovation that can improve metabolic regulation, reduce reliance on restrictive diets, and improve long-term clinical results and quality of life.

Sephience (sepiapterin): A Novel Approach

Sephience offers a novel therapeutic approach. It works through a dual mechanism of action to reduce elevated phenylalanine levels in patients with PKU.

BH4 Precursor: Sepiapterin is a naturally occurring precursor of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase (PAH). It is converted to BH4 through the salvage pathway, allowing it to bypass deficiencies in BH4 synthesis. This process helps boost residual PAH activity, thereby facilitating the breakdown of phenylalanine.

Molecular Chaperone: Sepiapterin also functions as a pharmacological chaperone, helping to stabilize misfolded phenylalanine hydroxylase (PAH) enzymes resulting from specific genetic mutations. By promoting proper folding, cellular trafficking, and functional activity of PAH within liver cells, sepiapterin enhances the enzyme’s overall effectiveness in metabolizing phenylalanine.

Clinical trial and approval

The CHMP’s positive opinion is supported by strong clinical evidence, primarily from the Phase 3 APHENITY trial (NCT05099640). This multinational, randomized, double-blind, placebo-controlled study enrolled 156 patients with hyperphenylalaninemia (HPA) across 13 countries. Participants, including children as young as one year old, had a baseline blood phenylalanine (Phe) level of ≥ 360 μmol/L, with individuals diagnosed with primary BH4 deficiency excluded.

The trial began with a 14-day open-label run-in phase to identify responders who achieved at least a 15% reduction in Phe levels. These responders then entered a 6-week double-blind phase, receiving either sepiapterin or a placebo. Sepiapterin demonstrated a significant therapeutic effect, reducing blood Phe levels by 63%, compared to just a 1% reduction in the placebo group. The study also assessed the drug’s safety and tolerability, both of which were favorable.

Following the Phase 3 APHENITY trial, the Open-Label Extension Study (NCT05166161) was conducted to evaluate the long-term safety and efficacy of sepiapterin in patients with PKU. Participants who responded to initial treatment continued on sepiapterin and maintained sustained metabolic control along with greater dietary flexibility. Over 97% of patients were able to increase their intake of natural protein by an average of 126% while keeping phenylalanine levels within the therapeutic range. Additionally, 66% of participants met or surpassed age-appropriate daily protein intake recommendations, reflecting a meaningful reduction in dietary restrictions.

The Phase 3 comparative trial (ISRCTN79102999) investigated the efficacy and safety of sepiapterin versus sapropterin in patients aged 2 years and older with phenylketonuria (PKU) over a treatment period of up to 173 days. This randomized open-label study monitored blood phenylalanine (Phe) levels to evaluate the extent and speed of Phe reduction, along with overall tolerability of the treatments. Preliminary results from this study indicated that sepiapterin may offer superior efficacy compared to sapropterin, suggesting its potential as a more effective therapeutic option for managing PKU.

Safety Profile

Sepiapterin has shown a favourable safety profile across clinical trials, including the Phase 3 APHENITY study and its Open-Label Extension trial. Most adverse events reported were mild to moderate, with the most common being temporary gastrointestinal symptoms such as nausea, abdominal discomfort, and diarrhea. No serious adverse events were attributed to sepiapterin, and there were no significant changes in laboratory values or vital signs. Long-term treatment further confirmed its tolerability and consistent metabolic control, with no safety issues. These results support the safe use of sepiapterin in both adults and children with phenylketonuria.

Conclusion

The EMA’s approval of Sephience represents a major progress in the treatment of hyperphenylalaninemia in both adults and children with phenylketonuria (PKU). Sepiapterin works by increasing tetrahydrobiopterin (BH4) levels, which helps restore phenylalanine hydroxylase (PAH) activity and reduces the accumulation of toxic phenylalanine (Phe). In the Phase 3 APHENITY trial, sepiapterin led to a 63% reduction in blood Phe levels compared to placebo. These benefits are maintained in the open-label extension study. Many patients were also able to increase their intake of natural protein while keeping Phe levels under control. Sepiapterin provides a valuable new treatment option, particularly for individuals who do not respond to sapropterin. Its dual mechanism of action may offer benefits across a broader spectrum of PKU patients. Ongoing research will focus on long-term cognitive outcomes, dosing strategies, and potential combination therapies to get maximum benefits.

References

Sephience™ (sepiapterin) Granted by EMA for treatment of hyperphenylalaninaemia (HPA) in both adult and pediatric patients with phenylketonuria (PKU), April 25, 2025, available from https://www.ema.europa.eu/en/medicines/human/EPAR/sephience#:~:text=information%20on%20Sephience-,Overview,children%20with%20phenylketonuria%20(PKU).

Van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet journal of rare diseases. 2017 Dec; 12:1-56.

Genetic and Rare Diseases Information Center (GARD), National Institutes of Health. Phenylketonuria (PKU). 2023. Available from: https://rarediseases.info.nih.gov/diseases/7383/phenylketonuria

Muntau AC, Longo N, Ezgu F, Schwartz IV, Lah M, Bratkovic D, Margvelashvili L, Kiykim E, Zori R, Plana JC, Bélanger-Quintana A. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. The Lancet. 2024 Oct 5; 404(10460):1333-45.

PTC Therapeutics Presents New Sepiapterin Data from Ongoing Studies, PTC Therapeutics, 20 March 2025, available from https://ir.ptcbio.com/node/17646/pdf

Nicola Longo, Francjan van Spronsen, Ania Muntau, et al, P047: Interim results from the APHENITY extension study: Sepiapterin reduces blood Phe with improved dietary Phe tolerance in participants with phenylketonuria, Genetics in Medicine Open, Volume 3, Supplement 2, 2025, 102891, https://doi.org/10.1016/j.gimo.2025.102891

A Phase III study of sepiapterin versus sapropterin in participants with phenylketonuria ≥2 years of age, ISRCTN79102999 https://doi.org/10.1186/ISRCTN79102999

The Article is Extensively Reviewed and Fact-Checked By The Editorial Team of Pharmacally.com

IgAN

FDA Grants Accelerated Approval to Novartis’ Vanrafia (Atrasentan): First and Only Endothelin-1 Receptor Blocker for Proteinuria Reduction in IgA Nephropathy (IgAN)

by with No Comment New Drug Approval

Written by: Priyanka Khamkar (M. Pharm., Pharmacology) and Sakshi Thakare (M. Pharm., Pharmacology)

IgAN
Source: Freepik.com

The U.S. Food and Drug Administration (FDA) have granted accelerated approval to Novartis Pharmaceuticals Corporation for Vanrafia (atrasentan). It is a potent and highly selective Endothelin A (ETA) receptor antagonist. This once-daily, oral, non-steroidal medication is approved to reduce proteinuria in adults with primary Immunoglobulin A nephropathy (IgAN) who are at high risk of rapid disease progression. Disease progression typically indicated by a urine protein-to-creatinine ratio (UPCR) of ≥1.5 g/g. Vanrafia is intended for use alongside standard supportive treatments, including renin-angiotensin system (RAS) inhibitors, with or without sodium-glucose co-transporter-2 (SGLT2) inhibitors. FDA approved Vanrafia under accelerated approval based on reduction of proteinuria and it has not been confirmed yet that it slows kidney function decline in patient with IgAN. The confirmatory trial results and clinical benefits will be verified to continue this approval. This approval marks a significant advancement in the treatment of IgAN, a chronic kidney disease that can lead to kidney failure in up to 50% of patients within 10 to 20 years of diagnosis.

What is IgAN?

Immunoglobulin A (IgA) nephropathy, also known as IgAN or Berger’s disease, is one of the most common causes of glomerulonephritis and can lead to kidney failure. This widespread kidney disorder is marked by the build-up of IgA antibodies in the glomerular basement membrane, which triggers immune-related damage where the immune system attacks the kidneys. Clinically, it is commonly seen as blood in the urine (hematuria), protein in the urine (proteinuria), and a gradual decline in kidney function. On histological examination, a range of changes in the glomeruli might be observed, with mesangial cell proliferation and prominent IgA deposits being the most notable features.

In IgA nephropathy (IgAN), the accumulation of IgA in the kidneys happens due to a problem with how the body produces and handles a specific type of antibody called IgA1. It all started when the body produced an abnormal form of IgA1, known as galactose-deficient IgA1 (Gd-IgA1), which has a faulty sugar moiety attached to it. The immune system recognized this altered IgA1 as abnormal and generated autoantibodies that bind to it, forming immune complexes in the bloodstream.

These immune complexes travel to the kidneys and become deposited in the mesangium the central part of the glomeruli, which are the kidneys’ filtering units. This deposition triggers inflammation and immune-mediated injury, progressively damaging the kidney tissue. Over time, this leads to symptoms such as blood in the urine (hematuria), protein in the urine (proteinuria), and a gradual decline in kidney function. Due to this self-directed immune response, IgAN is considered an autoimmune-like kidney disease.

Background and Need for New Treatments

Conventional treatment for IgA nephropathy primarily involves supportive care, including blood pressure control and the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to reduce proteinuria. However, these approaches are not very successful in significantly extending the progression of chronic kidney disease (CKD) to end-stage renal disease.

The role of sodium–glucose co transporter 2 (SGLT2) inhibitors in IgA nephropathy is not yet fully understood. Although nonspecific immunosuppressive treatments such as systemic or enteric-coated glucocorticoids have shown some benefit in high-risk patients, these effects are often not sustained without continued therapy. Long-term use is limited due to safety concerns and adverse side effects. As a result, there is a need for a safe and targeted therapy specifically for IgAN that can reliably slow disease progression in patients with IgA nephropathy.

Vanrafia (atrasentan): A Novel Approach

Vanrafia (atrasentan) is a once-daily, non-steroidal oral medication approved for adults with primary Immunoglobulin A Nephropathy (IgAN) to help lower protein levels in the urine (proteinuria), especially in those at high risk of fast disease progression. It works by blocking the Endothelin A (ETA) receptor, a key part of the pathway that contributes to kidney damage.

Endothelin-1 (ET-1) is elevated in IgA nephropathy (IgAN) due to ongoing inflammation and injury in the kidneys triggered by immune complex deposition. This immune activation leads to the release of various pro-inflammatory molecules, such as TNF-alpha, IL-6, TGF-beta, these substances stimulate the local production of endothelin-1 by endothelial and mesangial cells in the kidneys. Once produced, ET-1 worsens kidney injury by constricting blood vessels, reducing blood flow and oxygen to kidney tissue (ischemia), promoting mesangial cell proliferation and matrix expansion, increasing inflammation and fibrosis, and enhancing protein leakage into urine (proteinuria). This entire process is mediated by activation of Endothelin Type A Receptor (ETAR), a protein found on kidney cells.   Vanrafia belongs to a class of drugs known as ETA receptor antagonists. It works by selectively blocking the ETAR, thereby helping to protect kidney function and reduce proteinuria in patients with IgAN. This unique mechanism makes Vanrafia a specific drug of choice that selectively acts on the actual cause of the IgAN.

Clinical Trials and Approval

The efficacy and safety of Vanrafia is being studied in ALIGN trial (NCT04573478), is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of atrasentan in patients with IgA nephropathy (IgAN) at risk of progressive loss of renal function. Participants receive either 0.75 mg of atrasentan or a placebo daily for 132 weeks. An open-label extension allows eligible participants to receive atrasentan for an additional 48 weeks. All participants are required to be on a stable dose of a renin-angiotensin system (RAS) inhibitor, unless contraindicated. A separate cohort includes participants on a stable dose of a sodium-glucose co-transporter-2 inhibitor (SGLT2) who have been under study. The primary endpoint of the trial is the change in proteinuria as measured by the urine protein-to-creatinine ratio (UPCR). Secondary endpoints include change in kidney function over time as measured by eGFR, safety and tolerability assessments, and quality of life evaluations.

The interim results of the Phase 3 ALIGN trial were presented at the European Reanl Association (ERA) Congress in May 2024. In the prespecified interim analysis involving 270 patients (135 per group), atrasentan achieved a 36.1% greater reduction in 24-hour urinary protein-to creatinine ratio (UPCR) compared to placebo at week 36. Specifically, the geometric mean percentage change from baseline was 38.1% in the atrasentan group versus 3.1% in the placebo group. This reduction in proteinuria is clinically meaningful, as persistent proteinuria is associated with a higher risk of progression to kidney failure in IgAN patients. 

Based on these interim results, Novartis submitted an application to the U.S. Food and Drug Administration (FDA) for accelerated approval of atrasentan. In May 2025, the FDA granted accelerated approval for atrasentan based on the condition of verification of the final results of the ALIGN study, which will serve as a confirmatory trial

Safety profile

Vanrafia exhibited a favourable safety profile consistent with previously reported data. The most frequently observed adverse events (occurring in ≥2% of patients and more often than with placebo) included peripheral edema, anemia, and elevated liver transaminases. Given the potential for hepatotoxicity associated with certain endothelin receptor antagonists, liver function should be assessed before initiating Vanrafia and monitored throughout treatment as clinically indicated.

Vanrafia is strictly contraindicated during pregnancy due to the risk of serious birth defects. Pregnancy must be ruled out before starting treatment with Vanrafia. Patients should be advised to use effective contraception before beginning therapy, throughout treatment, and for at least two weeks after discontinuing Vanrafia. If a patient becomes pregnant while on Vanrafia, the medication should be discontinued as soon as possible.

Conclusion

The FDA’s accelerated approval of Vanrafia represents a significant milestone in the management of primary IgA nephropathy. With its demonstrated efficacy in reducing proteinuria and favorable safety profile, Vanrafia offers a promising new option for patients at risk of rapid disease progression. As ongoing studies continue to evaluate its long-term benefits, Vanrafia may play a crucial role in transforming the care of individuals living with IgAN.

References

Novartis receives FDA accelerated approval for Vanrafia® (atrasentan), the first and only selective endothelin A receptor antagonist for proteinuria reduction in primary IgA nephropathy (IgAN), Novartis, https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-vanrafia-atrasentan-first-and-only-selective-endothelin-receptor-antagonist-proteinuria-reduction-primary-iga-nephropathy-igan

Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J; ALIGN Study Investigators. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):544-554. doi: 10.1056/NEJMoa2409415. Epub 2024 Oct 25. PMID: 39460694.

Rout P, Limaiem F, Hashmi MF. IgA Nephropathy (Berger Disease) [Updated 2024 Apr 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538214/

Highlights of Prescribing Information, VANRAFIA (atrasentan), https://www.novartis.com/us-en/sites/novartis_us/files/vanrafia.pdf

FDA Grants Accelerated Approval for Vanrafia (atrasentan) for Proteinuria Reduction in Primary IgA Nephropathy, Drugs.com, https://www.drugs.com/newdrugs/fda-grants-accelerated-approval-vanrafia-atrasentan-proteinuria-reduction-primary-iga-nephropathy-6493.html

Floege J, Rauen T, Tang SCW. Current treatment of IgA nephropathy. Semin Immunopathol. 2021 Oct;43(5):717-728. Doi: 10.1007/s00281-021-00888-3. Epub 2021 Sep 8. PMID: 34495361; PMCID: PMC8551131.

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FDA Approves Imaavy (nipocalimab-aahu), a Neonatal Fc Receptor (FcRn) Blocker, Offering New Hope for People Living with Generalized Myasthenia Gravis (gMG)

by with No Comment New Drug Approval

Written by Priya Bhaware (M.Pharm. Pharmacology)

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Source: Freepik.com

The Food and Drug Administration approved Imaavy (Nipocalimab-aahu) for the treatment of generalized myasthenia gravis (gMG) in adult and paediatric patients 12 years of age and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. Imaavy is a monoclonal antibody that functions as a neonatal Fc receptor (FcRn) blocker. Imaavy is developed by Johnson & Johnson and is the first treatment of its kind. It offers a new option for both adolescent and adult patients living with generalized myasthenia gravis, aiming to reduce symptoms and improve daily life.

Background and Need for New Treatments

Generalized Myasthenia Gravis (gMG) is a rare and chronic autoimmune disorder that leads to muscle weakness, making simple daily activities such as lifting your arms, chewing, swallowing, or even breathing feel extremely strenuous. The condition occurs when the immune system mistakenly attacks the neuromuscular junction and disrupts the communication pathway between nerves and muscles. This immune response, often involving harmful antibodies that target proteins like AChR or MuSK, interferes with the brain’s ability to send signals to the muscles, resulting in reduced muscle function.

Current treatments of myasthenia gravis include acetylcholinesterase inhibitors, corticosteroids, immunosuppressive drugs, plasmapheresis, plasma exchange, and intravenous immunoglobulin (IVIG). While conventional treatments can control symptoms and improve quality of life, they often come with significant side effects, invasive procedures, delayed action, flare-ups, or only temporary relief. Thus, there is a real need for more targeted and gentler treatment options, and this need and limitation have led to the development of newer, targeted therapies like monoclonal antibodies (e.g., eculizumab, ravulizumab) that aim for more precise immune modulation with fewer systemic effects, and Imaavy (nipocalimab) is the latest addition to this list of monoclonal antibodies.

Imaavy (nipocalimab-aahu): A Novel Approach

Imaavy is a targeted therapy developed to reduce specific pathogenic IgG antibodies associated with myasthenia gravis without suppressing the entire immune system. For patients who have not achieved adequate symptom control with conventional therapies, Imaavy provides a more precise mechanism of action that may improve symptom management and enhance daily functioning and quality of life.

The treatment was initially discovered by Momenta Pharmaceuticals, Inc., and subsequently licensed to Janssen Biotech, NC., a subsidiary of Johnson & Johnson, for further development and commercialization. 

Imaavy exerts its therapeutic effect by binding with high affinity to the neonatal Fc receptor (FcRn) under both acidic and neutral pH conditions. This interaction prevents the recycling of IgG antibodies including the autoantibodies implicated in myeasthenia gravis leading to their accelerated degradation and substantial reduction in total circulating IgG levels.

Clinical Trials and Approval

The U.S. Food and Drug Administration (FDA) approved Imaavy based on robust efficacy and safety data from the Phase 3 Vivacity-MG3 trial (NCT04951622), supported by findings from the ongoing Vibrance-MG pediatric study (NCT05265273).

In the Vivacity-MG3 trial, 199 adults with generalized myasthenia gravis (gMG), including both antibody-positive and antibody-negative patients inadequately controlled by existing standard therapies, were randomized to receive either nipocalimab (30 mg/kg IV loading dose followed by 15 mg/kg every two weeks) in combination with standard of care or placebo plus standard of care.

Nipocalimab demonstrated clinically meaningful benefits, including a statistically significant improvement in Myasthenia Gravis–Activities of Daily Living (MG-ADL) scores. Over the 24-week treatment period, patients receiving nipocalimab experienced an average -4.70 point improvement in MG-ADL scores, compared to -3.35 points in the placebo group. 

The clinical trial (NCT05265273), known as the Vibrance-MG study, is an ongoing Phase 2/3 open-label trial evaluating the safety, pharmacokinetics, and efficacy of nipocalimab in pediatric patients aged 2 to less than 18 years with generalized myasthenia gravis (gMG). The study aims to assess the effect of nipocalimab on total serum immunoglobulin G (IgG) levels, safety and tolerability, and pharmacokinetics in this population. Participants receive intravenous infusions of nipocalimab every two weeks during a 24-week active treatment phase, followed by a long-term extension phase and an 8-week safety follow-up. The primary outcome measures include changes in total serum IgG levels, while secondary endpoints assess improvements in Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores.

The result of these two trials underscore Imaavy’s potential as a targeted and effective treatment option for adults and adolescents (ongoing) living with generalized myasthenia gravis

Safety Profile

Most reported adverse events (AEs) were mild to moderate in severity. The most commonly reported adverse reactions (occurring in ≥10% of patients) in individuals with generalized myasthenia gravis treated with Imaavy were respiratory tract infections, peripheral edema, and muscle spasms.  Serious side effects and treatment discontinuations were less common in the group receiving nivolumab than in those receiving placebo.

Patients receiving Imaavy should be monitored for infections, and administration should be delayed in those with active infections. If a serious infection develops during treatment, appropriate therapy should be initiated, and Imaavy should be withheld until the infection resolves.

Hypersensitivity reactions such as angioedema, anaphylaxis, rash, urticaria, and eczema have been reported with Imaavy. If such a reaction occurs, the infusion should be discontinued immediately, and appropriate medical management should be provided. 

In the event of a severe infusion-related reaction, treatment with Imaavy should be stopped, and appropriate intervention should be initiated. Re-administration should only be considered after carefully weighing the risks and benefits. If a mild to moderate infusion-related reaction occurs, rechallenging may be considered with close monitoring, slower infusion rates, and premedication to minimize recurrence. 

Conclusion

The approval of imaavy represents a significant advancement in addressing the complex challenges of autoimmune diseases such as generalized myasthenia gravis. By specifically targeting and reducing pathogenic IgG antibodies that interfere with nerve-to-muscle communication, Imaavy provides a novel and focused treatment option for patients whose symptoms are not adequately managed by current therapies. 

In essence, imaavy targeted mechanism of action offers new hope for individuals living with gMG, particularly those who have not responded well to conventional treatments. Furthermore, its potential applicability to a broader range of autoimmune conditions underscores its versatility and the meaningful impact it may have within the field of immunology. 

References

IMAAVY™ (nipocalimab-aahu) approved by FDA for treatment of Myasthenia Gravis (gMG) in ) in people aged 12 and older who test positive for AChR or MuSK antibodies, April 30, 2025, available from https://www.prnewswire.com/news-releases/johnson–johnson-receives-fda-approval-for-imaavy-nipocalimab-aahu-a-new-fcrn-blocker-offering-long-lasting-disease-control-in-the-broadest-population-of-people-living-with-generalized-myasthenia-gravis-gmg-302442650.html

 Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia gravis: epidemiology, pathophysiology and clinical manifestations. Journal of clinical medicine. 2021 May 21;10(11):2235.

IMAAVY™ (nipocalimab-aahu),Highlights of Prescribing Information, available from https://www.drugs.com/imaavy.html

Nipocalimab pivotal Phase 3 trial demonstrates longest sustained disease control in FcRn class. Johnson & Johnson. June 28, 2024. https://www.jnj.com/media-center/press-releases/nipocalimab-pivotal-phase-3-trial-demonstrates-longest-sustained-disease-control-in-fcrn-class

Nipocalimab demonstrates sustained disease control in adolescents living with generalized myasthenia gravis in Phase 2/3 study. Johnson & Johnson. October 15, 2024. https://www.jnj.com/media-center/press-releases/nipocalimab-demonstrates-sustained-disease-control-in-adolescents-living-with-generalized-myasthenia-gravis-in-phase-2-3-study

Highlights of Prescribing Information, Imaavy (nipocalimab-aahu) injection,  https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761430s000lbl.pdf

Antozzi C, Vu T, Ramchandren S, et al, Vivacity-MG3 Study Group. Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2025 Feb;24(2):105-116. Doi: 10.1016/S1474-4422(24)00498-8. PMID: 39862879.

A Study of Nipocalimab in Children Aged 2 to Less Than 18 Years With Generalized Myasthenia Gravis, All clinical trials, NCT05265273, https://www.allclinicaltrials.com/study/NCT05265273

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

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FDA Approval of Atzumi Marks a New Era in Migraine Treatment with SMART MucoAdhesive Delivery

by with No Comment New Drug Approval

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

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Source: Freepik.com

The U.S. Food and Drug Administration (FDA) have approved Atzumi (dihydroergotamine mesylate) nasal powder for the acute treatment of adult migraine with or without aura, marking a major breakthrough in migraine care. This approval offers millions of migraine sufferers’ quick and efficient relief by introducing a new, non-invasive delivery method for a proven migraine medication. However the approval comes with some limitations like it is not indicated for preventive treatment of migraine or for the management of hemiplegic migraine or migraine with brainstem aura. Satsuma pharmaceuticals are known for their innovative products have been given this landmark approval by FDA. Atzumi has been developed on the SMART platform (Simple Mucoadhesive Release Technology) which uses to combines a proprietary advanced powder and device technology to simplify delivery of medicine.

Migraine and Need of the Novel Therapy

Migraine is defined as a severe, throbbing, and unilateral headache that is usually associated with photophobia (light sensitivity), phonophobia (sound sensitivity), nausea, and vomiting. It is generally considered a neurological disorder that comes in episodic attacks or presents in chronic form with or without aura.

Conventional therapy for migraine includes acute and preventive (prophylactic) treatment with various drug classes used depending on the frequency and severity of attacks. Like NSAIDs, triptans, ergotamines, and antiemetics. Preventive therapy includes anti-seizure drugs, beta-blockers, calcium channel blockers, antidepressants, and Botox treatment. 

Despite the availability of numerous medicines and these medicine have effect to minimise migraine to some extent, many patients still suffer from terrible side effects, treatment failure, or delayed relief.

Triptans, one of the most commonly prescribed classes, act as serotonin receptor agonists and work by causing vasoconstriction. However, this mechanism makes them unsuitable for individuals with cardiovascular disease. They are most effective when taken early during a migraine attack but can cause side effects such as dizziness, fatigue, and nausea. Additionally, frequent use can lead to rebound headaches or medication-overuse headaches (MOH).

NSAIDs are often used to relieve mild to moderate migraine pain, but they are typically ineffective for more severe attacks. Prolonged or frequent use can result in gastrointestinal complications, including ulcers and bleeding.

Antiemetics, which are used to alleviate nausea associated with migraines, can cause extrapyramidal symptoms such as dystonia and akathisia. They may also lead to sedation and, with long-term use, carry a risk of tardive dyskinesia.

Although Dihydroergotamine (DHE) has been used for decades to treat migraine attacks, it is associated with poor tolerability, variable absorption, and serious side effects like vasospasm and ischemia. Their use requires careful dosing to avoid toxicity.

Atzumi: A Novel Powdered Nasal Ingredient

FDA is approved Atzumi is a powdered nasal inhaler that delivers dihydroergotamine mesylate (DHE) in the form of a dry nasal powder. It provides migraineurs with a quick-acting, convenient, and needle-free alternative. Atzumi harbour various advantages over its older form of dosage and also over other therapies which includes Innovative Delivery System where it utilizes the SMART (Simple MucoAdhesive Release Technology) platform, combining advanced powder formulation with a proprietary nasal delivery device. This system ensures consistent and accurate dosing, enhancing drug absorption and patient convenience. Rapid and Sustained Absorption: Clinical studies demonstrated that Atzumi achieves rapid absorption, with mean DHE plasma concentrations of 2.0 ng/mL within approximately 15 to 20 minutes. This rapid onset is coupled with sustained plasma levels, providing prolonged relief from migraine symptoms. Improved Tolerability: Compared to injectable and liquid nasal spray forms, Atzumi’s dry powder formulation reduces issues like nasal dripping and throat irritation. Common adverse events were generally mild, including rhinitis, nausea, and altered taste. Ease of Use: The portable, single-use device allows for self-administration without the need for refrigeration, making it more accessible for patients. Non-Oral Administration: By bypassing the gastrointestinal tract, Atzumi avoids issues related to nausea and vomiting that can come with migraines, which often hinder the effectiveness of oral medications. Suitable for Triptan Non-Responders: For patients who do not respond to or cannot tolerate triptans, Atzumi provides an alternative with a different mechanism of action.

Hence, the approval of Atzumi marks an important milestone, offering a new option for the acute treatment of migraine that blends the long-established effectiveness of DHE with a user-friendly, convenient delivery system.

Ryoichi Nagata, Satsuma Pharmaceuticals said in a statement. “We believe that Atzumi will contribute to improving the quality of life of patients struggling for relief from these highly disabling problems.”

FDA Approval and Evidence from Clinical Trials

Even though DHE is in practice since long, Atzumi approval comes from rigorous clinical trials in which DHE underwent A Phase 1 pharmacokinetics (PK) trial and the Phase 3 open-label trials called ASCEND Trial, aassessed the long-term safety and tolerability of Atzumi in adults with migraine.

Phase 1 study (NCT03874832), is randomized, open-label, three-period crossover study that evaluated the pharmacokinetics, safety, and tolerability of STS101 (Atzumi), a dihydroergotamine (DHE) nasal powder, in 43 healthy adult volunteers. The study compared single doses of STS101 with intravenous (IV) DHE and DHE nasal spray, aiming to assess parameters like maximum plasma concentration (C_max) and time to reach maximum concentration (T_max). STS101 demonstrated rapid absorption, reaching effective plasma levels within 10 minutes, and achieved higher bioavailability than the DHE nasal spray. It also showed a favorable safety profile, with lower C_max than IV DHE, reducing the risk of nausea. These promising results supported the advancement of STS101 into later-phase trials, including the Phase 3 ASCEND study (NCT04406649).

The ASCEND trial (NCT04406649) was a Phase 3, open-label, multicenter study evaluating the long-term safety, tolerability, and exploratory efficacy of STS101 (Atzumi), for the acute treatment of migraine in adults aged 18 to 65 years. Participants with a history of migraine with or without aura self-administered STS101 as needed over a 12-month period, with some continuing up to 18 months. The study found that STS101 was well tolerated, with a low incidence of treatment-emergent adverse events (TEAEs), most of which were mild or moderate. Efficacy assessments showed that 36.6% of treated attacks achieved pain freedom at 2 hours post-dose, increasing to 85.5% at 24 hours. Additionally, freedom from the most bothersome symptom was reported in 54.3% of attacks at 2 hours, rising to 91.3% at 24 hours. The favorable safety and efficacy profiles observed in the ASCEND trial supported the FDA approval of Atzumi for the acute treatment of migraine with or without aura in adults.

Safety Profile

During clinical trials Atzumi shows common adverse reactions (incidence > 1%) including rhinitis, nausea, altered sense of taste, application site reactions, dizziness, vomiting, somnolence, pharyngitis, and diarrhea. However Atzumi carries a warning of serious drug interaction with strong CYP3A4 inhibitors where serious and potentially life-threatening peripheral ischemia has been linked to the combined use of dihydroergotamine and strong CYP3A4 inhibitors. These inhibitors can raise dihydroergotamine blood levels, increasing the risk of vasospasm, which may lead to cerebral or limb ischemia. Therefore, Atzumi should not be used in combination with strong CYP3A4 inhibitors.

Conclusion

Atzumi approval marks a significant advancement in migraine therapy by addressing the limitations of conventional DHE formulations. Unlike intravenous DHE, which requires administration in clinical settings and is often associated with nausea, or nasal sprays with inconsistent absorption, Atzumi delivers rapid, consistent, and sustained drug levels through a user-friendly nasal powder system. However, due to the risk of vasospasm and ischemia, Atzumi is contraindicated in patients taking strong CYP3A4 inhibitors, which can elevate DHE plasma concentrations. Overall, Atzumi provides an effective, non-invasive, and well-tolerated treatment alternative for patients seeking fast and reliable relief from migraine attacks, with clear advantages over traditional DHE therapies.

Referances

Satsuma Pharmaceuticals (2025, April 30). Satsuma Pharmaceuticals Announces U.S. FDA Approval for Atzumi™ (Dihydroergotamine) Nasal Powder for the Acute Treatment of Migraine. [News Release]. Retrieved May 2025 https://investors.satsumarx.com/2025-04-30-Satsuma-Pharmaceuticals-Announces-U-S-FDA-Approval-for-Atzumi-TM-Dihydroergotamine-Nasal-Powder-for-the-Acute-Treatment-of-Migraine

Burch R. (2024). Acute Treatment of Migraine. Continuum (Minneap Minn), 30(2), 344–363. https://doi.org/10.1212/CON.0000000000001402. PMID: 38568487.

Villar-Martinez MD, Goadsby PJ. (2022). Pathophysiology and Therapy of Associated Features of Migraine. Cells, 11(17), 2767. https://doi.org/10.3390/cells11172767. PMID: 36078174; PMCID: PMC9455236

U.S. Food & Drug Administration (FDA). (2025). Drugs@FDA: FDA-Approved Drugs – Atzumi (Dihydroergotamine Mesylate). https://www.accessdata.fda.gov

Satsuma Pharmaceuticals. (2025). Product Pipeline and Clinical Trial Data – Atzumi https://www.satsumarx.com/pipeline

Johra Khan, Lubna Ibrahim Al Asoom, et al, Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine, Biomedicine & Pharmacotherapy, Volume 139, 2021, 111557, https://doi.org/10.1016/j.biopha.2021.111557

Albrecht D, Iwashima M, Dillon D, Harris S, Levy J. A Phase 1, Randomized, Open-Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects. Headache. 2020 Apr; 60(4):701-712. Doi: 10.1111/head.13737. Epub 2020 Jan 27. PMID: 31985049; PMCID: PMC7154716.

Tepper SJ, Albrecht D, Ailani J, Kirby L, Strom S, Rapoport AM. Long-Term (12-Month) Safety and Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine: Data from the Phase 3 Open-Label ASCEND Study. CNS Drugs. 2024 Dec; 38(12):1017-1027. Doi: 10.1007/s40263-024-01118-8. Epub 2024 Oct 7. PMID: 39373843; PMCID: PMC11543709.

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

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FDA Approves PD-1 Inhibitor Penpulimab-kcqx for Advanced Nasopharyngeal Carcinoma (NPC)

by with No Comment New Drug Approval

Written By:  Samiksha Benke (M.Pharm., Pharmacology) and  Dr. Vinay Manocha (Pharm.D)

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Source: Freepik.com

In the landmark development, U.S. Food and Drug Administration have approved innovative PD-1 monoclonal antibody, penpulimab-kcqx, in combination with cisplatin or carboplatin and gemcitabine for the initial treatment of adult recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (NPC). Penpulimab-kcqx has also been approved as a monotherapy for adult metastatic non-keratinizing NPC in patients who had progression on or after platinum-based therapy and have at least one previous line of treatment. The Food and Drug Administration has approved Penpulimab to Akeso Biopharma Co. Ltd..

Present Data and Background

Based on the WHO 2020 Global Cancer Statistics, more than 133,000 new cases of NPC occur each year worldwide, and more than 70% of the patients have locally advanced disease. Recurrent or metastatic NPC is not only associated with a poor prognosis but also with short survival. Approval of penpulimab-kcqx by the FDA will increase the number of NPC patients who can benefit from its treatment.

Nasopharyngeal carcinoma is a virulent form of squamous cell carcinoma of nasopharyngeal epithelial tissue. It is distinct from other types of head and neck cancers due to its unique epidemiology, pathology, and strong association with the Epstein-Barr virus (EBV). Penpulimab-kcqx is a PD-1 inhibitor antibody that functions to inhibit NPC tumor growth by binding to PD-1 and preventing its engagement with PD-L1 and PD-L2.

Penpulimab has earlier been approved in China for multiple indications, including as a first-line treatment along with chemotherapy for locally advanced or metastatic squamous non-small cell lung cancer, third-line treatment of relapsed or refractory classical Hodgkin’s lymphoma, and third-line treatment of recurrent or metastatic NPC.

Penpulimab: A Novel Approach

Penpulimab, also referred to as AK105, is a human IgG1 monoclonal antibody targeting PD-1. It features a distinct Fc region mutation that eliminates interactions with Fc gamma receptors (FcƴRs) and the complement component C1 system, effectively preventing antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These functions are typically triggered by binding to FcγR-IIIa, FcγR-Ia, and C1q, respectively. Moreover, the IgG1 backbone provides structural stability, helping to reduce immune escape.

Clinical trials and approval

The approval of penpulimab-kcqx as a first-line treatment was based on the randomized, double-blind AK105-304 trial (ClinicalTrials.gov Identifier: NCT04974398), and the approval of penpulimab-kcqx as a single agent for NPC was based on the open-label, single-arm AK105-202 study (ClinicalTrials.gov Identifier: NCT03866967).

The AK105-304 trial was a Phase III, multi-center, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Penpulimab (AK105) in combination with chemotherapy as a first-line treatment for non-keratinizing nasopharyngeal carcinoma (NPC). A total of 291 patients with histologically confirmed NPC who had not received prior systemic therapy for metastatic disease were enrolled and randomized in a 1:1 ratio to receive Penpulimab plus chemotherapy or placebo plus chemotherapy.

The chemotherapy regimen consisted of cisplatin (80 mg/m²) and gemcitabine (1,000 mg/m²), administered every three weeks for up to six cycles. Patients in the experimental arm received Penpulimab (200 mg IV) every two weeks, followed by Penpulimab monotherapy as maintenance. In the control arm, patients were allowed to switch to Penpulimab monotherapy upon disease progression.

Penpulimab demonstrated a 55% reduction in the risk of disease progression or death. The median progression-free survival (PFS) was 9.6 months in the Penpulimab group compared to 7.0 months in the placebo group. At the 12-month mark, 31% of patients in the Penpulimab arm remained progression-free, versus only 11% in the placebo arm.

The AK105-202 trial was a Phase II, open-label, single-arm study involving 125 patients with metastatic or unresectable non-keratinizing nasopharyngeal carcinoma (NPC) who had experienced disease progression following platinum-based chemotherapy and at least one additional prior line of therapy. Participants received penpulimab-kcqx monotherapy for up to 24 months, or until disease progression or unacceptable toxicity occurred.

The primary endpoints objective response rate (ORR) and duration of response (DOR) were assessed by an independent radiology review committee based on RECIST v1.1 criteria. The results showed a partial response in 27% of patients, with an ORR of 28% the median DOR was not reached and 46% of responders maintained a DOR of at least 12 months.

Safety profile

Penpulimab, when used in combination with cisplatin, carboplatin, and gemcitabine, was most commonly associated with adverse events such as vomiting, nausea, hypothyroidism, constipation, decreased appetite, weight loss, cough, COVID-19, infections, fatigue, rash, and fever, each reported in at least 20% of patients.

For patients treated with penpulimab as a single agent, the most frequently observed adverse events, affecting at least 20% of individuals, were musculoskeletal pain and hypothyroidism.

Serious and potentially fatal adverse drug reactions, including pneumonitis, colitis, septic shock, and hepatitis, were reported in approximately 1% of cases. Immune-mediated toxicities, particularly pneumonitis and colitis, require careful monitoring.

Overall, penpulimab exhibited a manageable safety profile, with the majority of adverse events classified as mild to moderate in severity. 

Impact and Future Viewpoint

This FDA approval provides a new immunotherapy option for patients with advanced NPC, potentially improving outcomes and offering hope for those with limited treatment alternatives. The approval also emphasizes the importance of continuing research and development in rare cancers, aiming to enhance patient care and survival rates.

Future research will explore long-term benefits, optimal uses, and potential drug combinations, including targeted agents or radiation therapy. Its global approval will increase patient access to this promising immunotherapy, offering new hope for NPC treatment.

References

Akeso Announces FDA Approval for Penpulimab-kcqx in Two BLA Indications for Comprehensive Treatment of Advanced Nasopharyngeal Carcinoma, 25 April 2025, Akesobio, https://www.akesobio.com/en/media/akeso-news/250425/

FDA approves penpulimab-kcqx for non-keratinizing nasopharyngeal carcinoma, US Food and Drug Administration, 24 April 2025 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-penpulimab-kcqx-non-keratinizing-nasopharyngeal-carcinoma

Chen X, Wang W, Zou Q, et al, Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study. Signal Transduct Target Ther. 2024 Jun 19;9(1):148. Doi: 10.1038/s41392-024-01865-6. PMID: 38890298; PMCID: PMC11189389.

Song Y, Zhou K, Jin C, et al, Penpulimab for Relapsed or Refractory Classical Hodgkin Lymphoma: A Multicenter, Single-Arm, Pivotal Phase I/II Trial (AK105-201). Front Oncol. 2022 Jul 7;12:925236. doi: 10.3389/fonc.2022.925236. PMID: 35875118; PMCID: PMC9301139. https://pmc.ncbi.nlm.nih.gov/articles/PMC9301139/

Akeso announces FDA approval for penpulimab-kcqx in two BLA indications for comprehensive treatment of advanced nasopharyngeal carcinoma. News release. Akeso. April 24, 2025. https://www.prnewswire.com/news-releases/akeso-announces-fda-approval-for-penpulimab-kcqx-in-two-bla-indications-for-comprehensive-treatment-of-advanced-nasopharyngeal-carcinoma-302437965.html.

Chaosu Hu, Xiaozhong Chen, Tingting Xu, et al, Penpulimab versus placebo in combination with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma: A global, multicenter, randomized, double-blind, phase 3 trial (AK105-304) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT011.

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

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FDA Approves Zevaskyn (Prademagene Zamikeracel) for Recessive Dystrophic Epidermolysis Bullosa (RDEB): Gene Therapy Targets COL7A1 Gene and Boosts Type VII Collagen (C7)

by with No Comment New Drug Approval

Written by:  Rikesh Dighore (M Pharm., Pharmacology) , and  Soniya Hajare (M Pharm.., Pharmacology)

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Source: Freepik.com

For the treatment of Recessive Dystrophic Epidermolysis Bullosa (RDEB), the FDA has approved Zevaskyn (prademagene zamikeracel), the first autologous cell-based gene therapy. The treatment of RDEB, a rare and disabling genetic skin condition marked by fragile skin, prone to blistering and recurrent wounds, has advanced significantly with this approval. Abeona Therapeutics has developed Zevaskyn, a novel cell-based gene therapy scientifically known as prademagene zamikeracel (previously referred to as pz-cel or EB-101). By directly addressing the genetic mutation responsible for the disease, it represents a significant advancement in the treatment of RDEB. By using genetically modifying skin cells to create type VII collagen, Zevaskyn provides a novel therapeutic approach that improves wound healing and quality of patient’s life.

About Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is one of the subtypes of various Epidermolysis Bullosa. Epidermolysis Bullosa is the heterogeneous group of inherited mechanobullous disorders triggered by mutations in genes that encode structural proteins in the skin. RDEB involves mutations in the COL7A1 gene, which codes for type VII collagen (C7). Type II collagen protein is essential to the skin’s structural integrity. The mutation in this gene leads to anomalous synthesis of type II collagen or faulty compilation of the protein into anchoring fibrils, which results in poor epidermal-dermal cohesion.

As a result skin is become very delicate because the layers do not attach correctly without this protein. Hence, even with little contact or impact, people with RDEB experiences open wounds and persistent blistering. A complication which arises due to this condition includes severe infections, malnourishment, scarring, joint contractures, and an elevated risk of aggressive squamous cell carcinoma (SCC). The disease affects both the skin and internal mucous membranes. Many patients have a shorter life expectancy and frequently do not live past their 30s or 40s.

However, there is currently no cure for RDEB. Symptomatic treatment which includes pain management, infection prevention and control, and careful wound care, has been the main focus of standard care. Despite being necessary, these supportive treatments are quite strenuous, necessitate intensive daily interventions, and fail to address the underlying genetic problem. Additionally, current topical treatments like Vyjuvek which was approved for Dystrophic Epidermolysis Bullosa are insufficient for large, chronic, or deep wounds that considerably lower quality of life and raise the risk of death, even though they work well for minor, superficial wounds.

Hence, a targeted, long-lasting treatment alternative was in urgent need as evident from the significant morbidity and mortality rates linked to RDEB.

Zevaskyn (prademagene zamikeracel): A Novel Approach

Zevaskyn (prademagene zamikeracel) received FDA approval in April 2025, tackled a critical gap in treatment. This autologous, ex vivo gene therapy uses a retroviral vector to modify a patient’s own keratinocytes, allowing them to produce functional type VII collagen. The corrected cells are then grafted onto the patient’s chronic wounds. Unlike topical treatments that require ongoing application, Zevaskyn is designed as a one-time therapy offering long-lasting effects by providing permanent structural repair to the skin.

By enhancing skin integrity, reducing infection rates, and maybe slowing the growth of skin malignancies, this therapeutic breakthrough not only lessens the burden of care and discomfort, but also has the potential to extend life. Zevaskyn thus fills a long standing medical gap in the treatment of RDEB and marks a significant breakthrough.

Clinical Trials and FDA Approval

The FDA approval of ZEVASKYN (prademagene zamikeracel) was primarily based on the pivotal Phase 3 VIITAL™ study (NCT04227106). This multicenter, randomized, intrapatient-controlled trial evaluated the efficacy of a single application of ZEVASKYN in treating large, chronic wounds in patients with recessive dystrophic epidermolysis bullosa (RDEB). Patients with RDEB received skin grafts made of their own genetically modified cells as part of this randomized, controlled study. The study met its two co-primary endpoints.

Wound Healing: 81% of wounds treated with ZEVASKYN achieved 50% or more healing at six months, compared to 16% in control wounds treated with standard care (P<0.0001).

Pain Reduction: Patients reported significant pain reduction from baseline, as assessed by the Wong-Baker FACES scale.

Additionally, the FDA considered data from a Phase 1/2a study (NCT01263379), demonstrating long-term improvement in treated sites over a median follow-up of 6.9 years. These studies collectively supported the approval of ZEVASKYN for treating wounds in adult and pediatric patients with RDEB.

Rowan is a 3-year-old girl living with Recessive Dystrophic Epidermolysis Bullosa in her daily life.

Source: EB Research Partnership (YouTube) _ Rowan’s Story 

Safety Profile

In clinical trials, Zevaskyn has shown a good safety profile. Localized to the treatment site, the most often reported side effects included itching and soreness during the grafting process. Significantly, the trials showed no significant side effects that were directly linked to the treatment.

The risk of immunological rejection and other issues related to allogeneic transplants is decreased when the patient’s own cells are used in the treatment.

Impact

Zevaskyn’s approval gives patients with RDEB new hope and marks a major advancement in the field of gene therapy. Zevaskyn has the potential to change the standard of care and enhance the lives of those badly affected by this debilitating illness by offering a medication that targets the underlying cause of the illness and not just symptoms.

Additionally, Zevaskyn enhances current treatments like Vyjuvek (beremagene geperpavec), a topical gene therapy that was authorized in 2023 to treat minor wounds in people with DEB. The dual-action armament in treatments like Vyjuvek, treating smaller lesions, and Zevaskyn, targeting larger, chronic wounds, enables a more thorough approach to disease management.

Conclusion

Zevaskyn’s FDA clearance represents a major advancement in the management of recessive dystrophic epidermolysis bullosa a rare and devastating genetic skin disorder that has long imposed a severe burden on patients and families. ZEVASKYN, the first approved topical gene therapy for this condition, offers new hope by directly addressing the underlying genetic defect.

Its approval was backed by compelling data from the pivotal Phase 3 VIITAL™ trial, which showed significant improvements in wound healing and pain reduction two of the most debilitating aspects of RDEB. Unlike traditional therapies focused only on symptom management, ZEVASKYN delivers a corrected COL7A1 gene to the skin, promoting true biological repair.

Zevaskyn may open the door to more personalized and efficient treatments for uncommon genetic illnesses as research advances and availability increases.

References

Zevaskyn approval letter, US Food and Drug Administration, available from https://www.fda.gov/media/186513/download?attachment

Bischof J, Hierl M, Koller U. Emerging Gene Therapeutics for Epidermolysis Bullosa under Development. Int J Mol Sci. 2024 Feb 13;25(4):2243. doi: 10.3390/ijms25042243. PMID: 38396920; PMCID: PMC10889532.

Luis Soro, Do, Cynthia Bartus, Stephen Purcell et al, Recessive Dystrophic Epidermolysis Bullosa A Review of Disease Pathogenesis and Update on Future Therapies, May 2015, Volume 8, Number 5, The Journal of Clinical and Aesthetic Dermatology. https://pmc.ncbi.nlm.nih.gov/articles/PMC4445895/pdf/jcad_8_5_41.pdf

Hon KL, Chu S, Leung AKC. Epidermolysis Bullosa: Pediatric Perspectives. Curr Pediatr Rev. 2022; 18(3):182-190. Doi: 10.2174/1573396317666210525161252. PMID: 34036913.

Gurevich I, Agarwal P, Zhang P, Dolorito JA, Oliver S, Liu H, Reitze N, Sarma N, Bagci IS, Sridhar K, Kakarla V, Yenamandra VK, O’Malley M, Prisco M, Tufa SF, Keene DR, South AP, Krishnan SM, Marinkovich MP. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat Med. 2022 Apr;28(4):780-788. Doi: 10.1038/s41591-022-01737-y. Epub 2022 Mar 28. PMID: 35347281; PMCID: PMC9018416.

Abeona Therapeutics (2025). Zevaskyn (prademagene zamikeracel): Product Information and VIITAL Study Results. https://www.abeonatherapeutics.com

Koutsoukos SA, Bilousova G. Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis. Dermatol Ther (Heidelb). 2024 Sep;14(9):2379-2392. Doi: 10.1007/s13555-024-01239-4. Epub 2024 Aug 7. PMID: 39112824; PMCID: PMC11393223.

Phase 3, Open-label Clinical Trial of EB-101 for the Treatment of Recessive Dystrophic Epidermolysis Bullosa (RDEB), ClinicalTrials.gov ID NCT04227106, https://clinicaltrials.gov/study/NCT04227106

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

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FDA Grants Accelerated Approval to Avmapki Fakzynja Co-Pack for KRAS-Mutated Low Grade Serous Ovarian Cancer (LGSOC) Targeting RAS/MAPK Pathway

by with No Comment New Drug Approval

Written By: Shital Gaikwad (M.Pharm Pharmacology) and Shital Doifode (M.Pharm Pharmacology)

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In image ovarian cancer cells (Source: Freepik.com)

In a significant progress in ovarian cancer treatment, the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Avmapki Fakzynja Co-Pack (avutometinib capsules and defactinib tablets) for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This approval represents the first and only FDA-approved treatment specifically for this rare subtype of ovarian cancer, marking a significant step forward in the fight against RAS/MAPK pathway-driven tumors. The approval is granted to Verastem Oncology, a biopharmaceutical company dedicated in the advancement of new treatments for patients with RAS/MAPK pathway-determined cancers. The FDA confirmed that this approval is under the accelerated approval, dependent on tumor response rate and duration of response; however, continuous approval for this indication will be subject to the results of the confirmatory trial. The FDA has also granted this combination Orphan Drug Designation.

Background and Need for New Treatments

Low-grade serous ovarian cancer (LGSOC) is a rare and recurrent form of epithelial ovarian cancer that mainly affects younger women and has a poor response to conventional chemotherapy. Approximately 30%–60% of LGSOC tumors carry KRAS mutations, activating the RAS/MAPK pathway and promoting uncontrolled tumor growth. KRAS mutation leads to continuous activation of the RAS/MAPK pathway.

There has been no FDA-approved treatment particularly targeting KRAS-mutated recurrent LGSOC, and patients have had limited treatment options like surgery, chemotherapy hormonal However each treatment options had certain limitations like low sensitivity to chemotherapy, high recurrence rate, toxicity of hormonal therapy and lacking of options of personalising treatment. This need highlighted the urgent demand for a targeted, effective, and tolerable treatment for this patient population.

Avmapki Fakzynja Co-Pack: A First-in-Class Combination

Avmapki Fakzynja Co-Pack is a novel oral combination therapy that includes:

Avutometinib: Avutometinib is an inhibitor of MEK1 that promotes the formation of inactive RAF/MEK complexes, thereby blocking RAF-mediated phosphorylation of MEK1/2. RAF and MEK are key components in the RAS/RAF/MEK/ERK (MAPK) signaling pathway. Avutometinib suppresses phosphorylation of MEK1/2 and ERK1/2, as well as the growth of tumor cell lines with KRAS mutations. Additionally, avutometinib treatment leads to an increase in phosphorylated focal adhesion kinase (FAK) levels in cancer cells.

Defactinib: Defactinib is a selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), both part of the FAK family of non-receptor tyrosine kinases. It has been shown to block FAK autophosphorylation in cancer cells in vitro and in mouse xenograft models.

This synergistic effect of both drugs leads to enhanced tumor response by concurrently inhibiting both tumor cell proliferation and survival mechanisms, making it a breakthrough option for KRAS-mutant LGSOC.

Clinical Trials and FDA Approval Basis

The accelerated approval of Avmapki Fakzynja Co-Pack was based on the results of the Phase II RAMP 201 clinical trial, which evaluated the safety and efficacy of avutometinib, a RAF/MEK inhibitor, alone and in combination with defactinib, a FAK inhibitor, in patients with recurrent low-grade serous ovarian cancer (LGSOC), particularly those with KRAS mutations.

Study Design

RAMP 201 (NCT04625270) was a multicenter, randomized, open-label Phase II study. It enrolled patients aged 18 years or older with histologically confirmed LGSOC or peritoneal cancer, measurable disease per RECIST 1.1 criteria, and disease progression or recurrence following at least one prior systemic therapy in the metastatic setting. The trial included patients with both KRAS-mutated and wild-type tumors. The primary objective was to assess the overall response rate (ORR) of the treatments.

Key findings from the trial:

Efficacy: In patients receiving the combination of avutometinib (3.2 mg twice weekly) and defactinib (200 mg twice daily), the confirmed ORR was 31%, with a complete response rate of 2% and a partial response rate of 29%. Among patients with KRAS-mutated tumors, the ORR was higher at 44%, compared to 17% in those with KRAS wild-type tumors.

Progression-Free Survival (PFS): The median PFS for the combination therapy was reported as 12.9 months, with longer durations observed in patients carrying KRAS mutations.

Confirmatory Trials

The continuous approval of this combination therapy is reliant on confirmatory evidence from the ongoing Phase III RAMP 301 trial, which will further evaluate clinical benefit in a broader population, including patients with and without KRAS mutations.

If the clinical benefit is confirmed, this would harden the combination as the standard of care for this difficult-to-treat cancer.

Side effects

Common (≥25%) Adverse Reactions (including lab abnormalities):

Elevated creatine phosphokinase, nausea, fatigue, increased AST and ALT, rash, diarrhea, musculoskeletal pain, edema, low hemoglobin, high bilirubin and triglycerides, low lymphocytes, abdominal pain, dyspepsia, acneiform dermatitis, vitreoretinal disorders, high alkaline phosphatase, stomatitis, itching, visual impairment, low platelets, constipation, dry skin, shortness of breath, cough, urinary tract infection, and low neutrophils.

Impact

The accelerated approval of Avmapki Fakzynja marks an important step in personalized oncology, especially for women fighting recurrent LGSOC with KRAS mutations, in view of few effective conventional treatment options.

This is the first FDA-approved therapy targeting KRAS-mutated LGSOC, reflecting a significant advancement in precision medicine. It also validates the potential of combining MEK and FAK inhibition to address tumor growth and resistance mechanisms.

Expert Opinion from Investigators

Dr. Rachel Grisham of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, and lead investigator of the RAMP 301 study, stated:

“This approval marks a much-needed therapeutic option and establishes this combination as the new standard of care for women with recurrent LGSOC harbouring a KRAS mutation.”

Prof. Susana Banerjee of The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, National Cancer Research Institute (NCRI), London also noted:

“To see this combination advance from early trials to become the first-ever FDA-approved therapy for LGSOC is inspiring and opens a new chapter in treating RAS/MAPK-pathway-driven cancers.”

Conclusion

The FDA’s accelerated approval of Avmapki Fakzynja Co-Pack introduces a much-needed targeted therapy for patients with KRAS-mutated recurrent low-grade serous ovarian cancer. With its novel dual-mechanism approach and promising clinical results, this combination therapy offers new hope for improving survival and quality of life in a population with limited options for LGSOC. However, its continuous approval and use depend on the success of the ongoing phase III trial. As precision oncology advances, the success of treatments like Avmapki underscores the importance of genetic profiling and personalized treatment strategies in overcoming rare and resistant cancers.

References

U.S. Food and Drug Administration. (2025, May 8). FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low

Verastem Oncology. (2025, May 8). Verastem Oncology announces FDA approval of Avmapki Fakzynja Co-Pack for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer [Press release]. https://verastem.com/news/fda-approval-avmapki-fakzynja

ClinicalTrials.gov. (n.d.). A study of avutometinib (VS-6766) and defactinib in patients with recurrent low grade serous ovarian cancer (RAMP 201) (NCT04625270). National Library of Medicine. https://clinicaltrials.gov/study/NCT04625270

National Cancer Institute. (2024). Low-grade serous carcinoma of the ovary. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-gynecologic-tumors/low-grade-serous-carcinoma

Highlights of Prescribing Information, Avmapkitm Fakzynjatm Co-Pack, available from https://www.verastem.com/pdf/avmapki-fakzynja-co-pack-full-prescribing-information.pdf

FDA Grants Accelerated Approval to Avmapki Fakzynja Co-Pack, Drugs.com,available from https://www.drugs.com/newdrugs/fda-grants-accelerated-approval-avmapki-fakzynja-co-pack-avutometinib-capsules-defactinib-kras-6516.html

Susana N. Banerjee et al. ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of VS-6766 (RAF/MEK clamp) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).. JCO 40, TPS5615-TPS5615(2022). DOI:10.1200/JCO.2022.40.16_suppl.TPS5615

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

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Japan First-in-the-World to approve Elevidys (Delandistrogene Moxeparvovec), one-of-the Costliest Gene Therapy Drug for Duchenne Muscular Dystrophy (DMD) in Children less than 4 years of age

by with No Comment New Drug Approval

Written By: Pragati Ekamalli (B.Pharm)

Reviewed By: Vikas Londhe M.Pharm (Pharmacology)

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Source: Freepik.com

In a groundbreaking step forward for genetic medicine, Japan has become the first country in the world to approve the use of Elevidys (delandistrogene moxeparvovec), a gene therapy created by Sarepta Therapeutics, for children under 4 years old diagnosed with Duchenne muscular dystrophy (DMD). DMD is a rare and life-threatening genetic disorder that leads to the progressive weakening and loss of muscle function, typically appearing in early childhood and worsening over time. Elevidys works by delivering a modified gene to help produce a version of the dystrophin protein, which is missing or defective in children with DMD. This approval represents a major milestone in the global effort to treat genetic disorders and could bring new hope to families affected by DMD. It also highlights Japan’s leadership in adopting cutting-edge medical treatments that may slow disease progression and improve quality of life for young patients.

Understanding Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, inherited disorder that mainly affects boys due to its X-linked pattern of inheritance, meaning the faulty gene is carried on the X chromosome. The condition results from mutations in the DMD gene, which is responsible for producing dystrophin a protein critical for maintaining the strength and stability of muscle fibers. In the absence of functional dystrophin, muscles are unable to protect themselves from everyday stress, leading to ongoing damage, muscle fibres breakdown, and replacement by fat and scar tissue. Symptoms usually begin in early childhood, often with difficulty walking, running, or climbing stairs. As the disease progresses, most affected children lose their ability to walk by the age of 12 to 14. In later stages, DMD can lead to serious complications involving the heart and lungs, often reducing life expectancy into the twenties or thirties without advanced medical care.

Understanding Dystrophin Protein

Dystrophin is large structural protein (427kDa) present in cytoplasmic face of the sarcolemma. Dystrophin protein plays a crucial role in maintaining the integrity and function of muscle cells including skeletal muscle and cardiac muscle.

Dystrophin is act like an anchor which link internal cytoskeleton of a muscle fibre to the surrounding extracellular matrix by dystrophin-glycoprotein complex. This complex stabilizes muscle fibre during contraction. Dystrophin protein is coded with DMD gene on X-Chromosome and it is one of the largest human genes. Any mutation or deletion of DMD genes affects the dystrophin protein production, either less or completely diminished.

Elevidys: A Novel Gene Therapy Approach

Elevidys is an innovative gene therapy that uses an adeno-associated virus (AAV) as a delivery system to transport genetic material into the body. Specifically designed for Duchenne muscular dystrophy (DMD), Elevidys delivers a shortened but functional version of the dystrophin gene, called micro-dystrophin, directly into muscle cells. Although smaller than the full-length gene, micro-dystrophin includes the critical domains needed for the protein to support muscle fibre structure and function. By enabling cells to produce this essential protein, Elevidys targets the root cause of DMD — the absence of functional dystrophin. Administered as a single intravenous infusion, this therapy offers the promise of a one-time treatment that may slow disease progression and improve muscle strength, potentially transforming the standard of care for children living with DMD.

Japan’s Regulatory Approval

On August 14, 2024, Chugai Pharmaceutical Co., Ltd., a member of the Roche Group, submitted a regulatory application to Japan’s Ministry of Health, Labour and Welfare (MHLW) seeking approval for Elevidys, a gene therapy for Duchenne muscular dystrophy (DMD). The application specifically targeted ambulatory boys aged 3 to 7 years who do not have deletions in exons 8 and/or 9 of the DMD gene and who are not immune to the AAVrh74 viral vector used to deliver the treatment. This submission was supported by data from the global Phase III EMBARK study, which evaluated the safety and effectiveness of Elevidys. The trial did not meet its primary endpoint improving motor function as measured by the North Star Ambulatory Assessment (NSAA), however clinically meaningful benefits were observed in key secondary outcomes, including faster time to rise from the floor and improved 10-meter walk speed. Despite the mixed results, Japan’s MHLW granted priority review to the application and ultimately approved Elevidys for use in children less than 4 years of age. With this decision, Japan became the first country to authorize Elevidys for this younger age group, reflecting its proactive approach to approving innovative therapies for rare and serious diseases like DMD. This landmark approval offers new hope for patients and families affected by this devastating condition.

Global Context

Before Japan’s historic approval, the U.S. Food and Drug Administration (FDA) granted Elevidys accelerated approval in June 2023 for ambulatory children aged 4 through 5 years with Duchenne muscular dystrophy (DMD). The FDA’s decision was based on evidence that the therapy successfully prompted the production of micro-dystrophin, the shortened version of the dystrophin protein essential for muscle health. However, this approval was conditional, with continued authorization depending on the confirmation of meaningful clinical benefits in ongoing follow-up trials. Japan’s more inclusive approval for children under 4 years old not only marks a significant expansion of access to this gene therapy but also sets a global precedent. It signals to other regulatory agencies the potential value of early intervention in DMD. As new clinical data emerges and confirmatory studies continue, more countries may follow suit, potentially reshaping the global treatment landscape for this devastating disease and offering hope for earlier and more effective management of DMD in young patients.

Conclusion

The approval of Elevidys in Japan for children younger than 4 years of age marks a major breakthrough in the treatment of Duchenne muscular dystrophy (DMD). Unlike traditional therapies that mainly manage symptoms, Elevidys directly targets the genetic root of the disease by introducing a functional version of the dystrophin gene. This approach offers the potential not just to slow the progression of muscle degeneration, but to meaningfully alter the course of the disease, particularly when administered early in life. The decision by Japan’s health authorities highlights the critical role of early intervention and paves the way for improving long-term outcomes for children affected by DMD. Moreover, this milestone emphasizes the value of ongoing scientific research, clinical trials, and international collaboration in developing transformative therapies for rare and life-threatening conditions.

References

1. Sarepta Therapeutics Announces Approval in Japan of ELEVIDYS, a Gene Therapy to Treat Duchenne Muscular Dystrophy, 13 May 2025, Sarepta Therapeutics https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-approval-japan-elevidys-gene

2. A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec (SRP-9001) in Participants With Duchenne Muscular Dystrophy (DMD) (EMBARK), NCT05096221, ClinicalTrials.gov, available from https://clinicaltrials.gov/study/NCT05096221

3. Roche announces new results from EMBARK demonstrating significant sustained benefits of Elevidys in ambulatory individuals with Duchenne muscular dystrophy (DMD), 27 January 2025, https://www.roche.com/media/releases/med-cor-2025-01-27

4. Gao QQ, McNally EM. The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol. 2015 Jul 1; 5(3):1223-39. Doi: 10.1002/cphy.c140048. PMID: 26140716; PMCID: PMC4767260.

5. Venugopal V, Pavlakis S. Duchenne Muscular Dystrophy. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482346/

6. Chugai Receives Regulatory Approval for “ELEVIDYS” as a Gene Therapy Product for Duchenne Muscular Dystrophy in Japan, 13 May 2025, Chugai Pharmaceuticals,https://www.chugaipharm.co.jp/english/news/detail/20250513181500_1160.html