Hyftor Receives EU Approval, Entering the Market for Facial Angiofibromas in Tuberous Sclerosis Complex
First Approved Topical Treatment in the EU
The European Commission approved Hyftor (sirolimus 2mg/g gel) from PlusUltra Pharma on May 15, 2023, for the treatment of facial angiofibromas associated with Tuberous Sclerosis Complex (TSC). Intended for use in patients aged 6 years and older, Hyftor inhibits the mammalian target of rapamycin (mTOR), a key regulator of cell growth and proliferation, to treat these benign skin lesions. Unlike systemic mTOR inhibitors, which involve whole-body exposure, Hyftor is a topical formulation applied twice daily to the affected facial areas, with local efficacy and ease of use being key factors in its approval.
Clear Efficacy Demonstrated in Phase 3 Clinical Trial
The approval is based on the results of a Japanese, randomized, double-blind, placebo-controlled Phase 3 trial (NCT02635789), which showed that at week 12, 60% (18 out of 30) of patients in the Hyftor group experienced improvement or marked improvement in lesion size and erythema, compared to 0% (0 out of 32) in the placebo group. The difference in response rates was statistically significant, with a p-value of less than 0.001, leading the EMA to conclude that the benefits outweigh the risks. The label includes a recommendation to discontinue treatment if no effect is observed by week 12, which aims to minimize the cost of long-term non-responsive treatment while also encouraging early assessment of treatment response in clinical practice.
Orphan Drug Status and Limited Patient Population
Hyftor was designated as an orphan medicine in the EU on August 23, 2017, and the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion on February 23, 2023. The EMA estimates the prevalence of TSC in the EU to be approximately 1 in 10,000, and concluded at the time of approval that there were no other satisfactory treatments available for this indication. While the patient population is limited, the orphan drug designation, specialist-driven prescribing, and the need for repeat use create a market that supports pricing and revenue per patient.
Competitive Landscape and Commercialization Challenges
Existing treatments have relied on laser therapy, surgery, and unapproved topical sirolimus preparations. Novartis's (NVS) Votubia (everolimus) is an mTOR inhibitor used for TSC-associated subependymal giant cell astrocytomas (SEGAs), renal angiomyolipomas, and seizures, but it is not a topical formulation specifically for facial angiofibromas. The combined sales of Votubia and Afinitor in 2023 were approximately USD 0.5 billion, demonstrating the commercial potential of the mTOR class while also highlighting the pressure from generic competition. While the EU centralized approval eliminates regulatory risk, the actual expansion of sales will depend on pricing and reimbursement in individual countries, as well as distribution. PlusUltra Pharma has established a distribution agreement with WEP Clinical for supply outside of Germany within the EU and EEA.
From an investment perspective, Hyftor represents a de-risked asset with EU approval, supported by a Phase 3 trial showing a 60% response rate compared to 0% in the placebo group, and orphan drug status. However, given the ultra-rare market with an EU prevalence of approximately 1 in 10,000, short-term sales will depend on pricing and reimbursement in individual countries, as well as the speed of distribution. For researchers, Hyftor represents an innovative formulation that improves the therapeutic index by delivering the drug directly to the lesion site, rather than systemically. For the industry, it marks a shift from laser therapy, surgery, and unapproved compounded formulations to an approved topical treatment, and differentiates itself from Novartis's (NVS) Votubia. The combined sales of Afinitor and Votubia in 2023 of approximately USD 0.5 billion demonstrate the market potential for mTOR inhibitors, but Hyftor's long-term value will depend on repeat prescription rates and reimbursement coverage across Europe.
Source: EMA (ema)