Long-acting therapeutics are becoming one of the most active areas in modern drug development. Across endocrinology, obesity, ophthalmology, and metabolic diseases, pharmaceutical companies are increasingly pursuing once-weekly or even longer-acting therapies to improve patient adherence and reduce treatment burden.
Among emerging long-acting platforms, TransCon® (Transient Conjugation), developed by Ascendis Pharma, has attracted growing attention. Unlike permanent molecular modification approaches, TransCon combines transient conjugation, controlled release, and PEG carrier technology to enable predictable exposure of the active drug while maintaining its native biological activity.
For PEG suppliers and drug developers, TransCon also highlights an important trend: PEG is increasingly serving as a functional carrier in advanced prodrug and sustained-release systems rather than merely an excipient.
What is TransCon Technology?
TransCon is an innovative long-acting prodrug delivery platform. It combines known biology with the benefits of prodrug and sustained-release technologies to potentially optimize therapeutic effect.
A complete TransCon prodrug molecule consists of three essential components:
- ● Unmodified Parent Drug: A biologically validated active molecule (such as a protein, peptide, or small molecule). In its conjugated state, the drug's biological activity is temporarily masked.
- ● Inert Carrier: Typically, a high-molecular-weight methoxypolyethylene glycol (mPEG) matrix that inactivates and shields the parent drug from clearance.
- ● TransCon Linker: Engineered to release the parent drug at a predictable rate under physiological conditions
Figure 1. TransCon Prodrug, source: reference [1]
Following administration, physiological conditions (pH and temperature) trigger the cleavage of the linker. This cleavage event results in the controlled release of the active, unmodified parent drug predictably at a predetermined rate.
Unlike permanent molecular modifications, the key advantage of TransCon technology is that it preserves the original mode of action of the parent drug.
Why PEG Matters in TransCon Technology
In TransCon-based therapeutics, PEG is not simply an inactive formulation ingredient—it acts as a functional carrier that directly influences drug stability, pharmacokinetics, and release behavior.
The inert carrier, commonly based on mPEG, temporarily shields the active drug from enzymatic degradation and rapid systemic clearance. Combined with a cleavable linker, the PEG carrier enables controlled and predictable release under physiological conditions.
As demonstrated in multiple approved TransCon products, carefully engineered PEG carrier systems can help enable weekly or extended dosing while preserving the activity of the parent drug.
Approved TransCon Therapeutics
To date, three TransConed therapies have received regulatory approval, validating both the scientific and commercial potential of the platform.
Figure 2. Approved TransCon Therapeutics, source: reference [1]
YUVIWEL® (navepegritide)
In February 2026, the FDA granted accelerated approval to YUVIWEL for the treatment of children aged 2 years and older with achondroplasia and open growth plates.
YUVIWEL is the first and only once-weekly therapy designed to provide continuous systemic exposure of C-type natriuretic peptide (CNP) throughout the dosing interval. The drug is a CNP analog prodrug, in which the active CNP peptide is transiently conjugated to two branched 20 kDa mPEG moieties through a proprietary TransCon linker.
YORVIPATH® (palopegteriparatide)
YORVIPATH is a long-acting parathyroid hormone (PTH) replacement therapy developed for adults with hypoparathyroidism. The drug received approval from the European Medicines Agency (EMA) in 2023 and later gained FDA approval in August 2024, becoming the first FDA-approved treatment for adult hypoparathyroidism.
YORVIPATH consists of PTH(1-34) transiently conjugated to an mPEG carrier via a TransCon linker, allowing sustained and controlled hormone release. By maintaining more physiological PTH exposure, the therapy aims to reduce disease burden and improve long-term disease management.
SKYTROFA® (lonapegsomatropin)
Approved by the U.S. FDA in 2021, SKYTROFA is the first once-weekly growth hormone therapy for pediatric growth hormone deficiency (GHD) in the United States.
SKYTROFA consists of three components: the parent drug somatropin, an inert mPEG carrier, and a proprietary TransCon linker that transiently binds the other two elements. After subcutaneous injection, the linker automatically cleaves, gradually releasing fully active human growth hormone over one week. In 2025, the FDA expanded SKYTROFA approval to include adult growth hormone deficiency, further strengthening the commercial success of the platform.
Expanding Applications Beyond Endocrinology
Beyond endocrine disorders, TransCon technology is being explored in broader therapeutic areas, including obesity, ophthalmology, and oncology.
Metabolism & Obesity (Novo Nordisk Partnership)
In November 2024, Ascendis secured an exclusive global licensing agreement with Novo Nordisk worth up to $285 million in upfront, development, and regulatory milestones. Novo Nordisk aims to utilize the TransCon™ platform to develop and commercialize metabolic therapeutics for obesity and Type 2 diabetes. The lead asset, TransCon Semaglutide, is poised to enter clinical trials. The collaboration reflects growing interest in long-acting metabolic therapeutics and less frequent GLP-1 dosing strategies.
Ophthalmology (Dedicated Focus via Eyconis)
In 2024, Ascendis Pharma partnered with Frazier Life Sciences and other investors to launch Eyconis, Inc., a new company dedicated to the global development and commercialization of TransCon ophthalmology products. Ascendis granted Eyconis exclusive worldwide rights to its ophthalmology assets and may receive up to $248 million in milestone payments, plus royalties on future product sales. Lead program TransCon aVEGF (EYC-0305) is in development for wet AMD and other retinal diseases, anticipated to enter the clinic in 2026. This technology is designed to significantly extend the interval between intravitreal injections, substantially reducing clinical burden.
Oncology (High-Potential In-House Immunotherapy)
In oncology, Ascendis advances an independent pipeline. Its prominent immuno-oncology asset, TransCon IL-2 β/γ (onvapegleukin alfa), is currently under evaluation in the phase 1/2 IL-BELIEVE trial. Topline median overall survival (OS) data from 70 patients with platinum-resistant ovarian cancer (PROC) is anticipated in Q2 2026. By providing sustained release of highly selective IL-2, the drug amplifies anti-tumor immunity while effectively circumventing the severe systemic toxicities historically associated with conventional IL-2 therapies
Conclusion & Outlook
Long-acting therapeutics are rapidly reshaping modern drug development, particularly in endocrine, metabolic, ophthalmic, and oncology applications. Through approved products such as SKYTROFA®, YORVIPATH®, and YUVIWEL®, Ascendis Pharma has demonstrated the clinical and commercial feasibility of the TransCon platform.
Beyond validating a novel long-acting strategy, TransCon also highlights the increasingly important role of PEG carriers and linker technologies in enabling controlled and sustained drug release.
As a supplier of high-purity PEG derivatives, Biopharma PEG provides polydispersed & monodisperse PEGs and customized PEG solutions to support the development of next-generation long-acting therapeutics from early research through commercial manufacturing.
References:
[1] https://ascendispharma.com/
[2] https://investors.ascendispharma.com/news-releases/news-release-details/fda-approves-once-weekly-yuviwelr-navepegritide-children
[3] https://investors.ascendispharma.com/news-releases/news-release-details/ascendis-pharma-provides-business-and-strategic-roadmap-update-0
[4] https://investors.ascendispharma.com/news-releases/news-release-details/ascendis-pharma-and-novo-nordisk-sign-collaboration-development
