Breakthrough Clinical Results
Palvella Therapeutics announces a publication in Lymphatic Research and Biology highlighting advances in understanding venous malformation pathogenesis and the use of rapamycin. The publication includes a systematic review of 26 studies evaluating rapamycin for venous malformations, emphasizing the unmet clinical need and advocating for an FDA-approved topical rapamycin formulation. Palvella's QTORIN™ 3.9% rapamycin anhydrous gel is under evaluation in a Phase 2 trial for cutaneous VMs, with top-line data expected in December 2025.
Key Highlights
- Publication highlights the PI3K/AKT/mTOR pathway as a key driver of venous malformation proliferation.
- Systematic review covers 26 studies on rapamycin for treating venous malformations.
- Advocates for an FDA-approved topical rapamycin formulation for cutaneous venous malformations.
- Palvella's QTORIN™ 3.9% rapamycin anhydrous gel is in Phase 2 trial for cutaneous VMs.
Incidence and Prevalence
Latest Estimates of Venous Malformation Incidence and Prevalence
According to the most recent epidemiological data from a 2023 nationwide population-based study that evaluated 70,517 patients with vascular malformations over a 13-year period (2008-2021), the annual incidence of venous malformations was found to be 1.48 cases per 100,000 population in Korea.
This study represents one of the most comprehensive recent analyses of vascular malformation epidemiology. For context, the same research found that the annual incidence of overall vascular malformations was 9.85 cases per 100,000 population, with specific rates for other subtypes being 2.31 for capillary malformations, 0.24 for arteriovenous malformations, and 5.82 for lymphatic malformations (all per 100,000 population).
Earlier research from 1997 examining 746 inhabitants in central Italy suggested that venous and/or arteriovenous malformations causing clinical problems were relatively rare, affecting less than 1% of subjects. However, this same study noted that approximately 12% of the evaluated population had been affected by some form of venous problem, with half of those individuals receiving treatment.
Multiple studies confirm that venous malformations are the most frequent vascular malformation overall, as reported in a 10-year multidisciplinary experience published in 2021. The exception is in pediatric populations under 16 years, where capillary malformations predominate.
Diagnostic challenges remain significant, with a 2011 study revealing that 46.3% of malformations were initially misdiagnosed upon referral, potentially affecting accurate prevalence estimates.
A 2021 study of 352 patients at a vascular anomaly center found that patients with venous malformations typically presented at a later age compared to those with other vascular anomalies such as lymphatic malformations.
Regarding mortality, the 2023 nationwide study found that patients with vascular malformations generally had higher mortality than matched controls, with the notable exception of those with venous malformations. Among all vascular malformation subgroups, the adjusted hazard ratio of mortality was highest for arteriovenous malformations.
Treatment approaches for venous malformations typically involve sclerotherapy or surgery, which differs from approaches used for other vascular malformation types.
These findings represent the most current understanding of venous malformation epidemiology based on large-scale population studies, though regional variations likely exist globally.
Key Unmet Needs and Target Populations for Venous Malformations
Diagnostic Challenges
Despite being considered standard of care, genetic testing for venous malformations (VMs) faces significant barriers that constrain treatment options. These include lack of administrative support, unclear institutional requirements, insurance denials, and insufficient clinician education. While testing volume has increased 2- to 10-fold over the past three years, the effort to obtain genetic testing for VM patients is perceived as excessive compared to cancer patients.
Small vascular anomaly centers often rely on oncology-based platforms that potentially miss low-frequency allelic variants. Additionally, mosaicism and insufficient sequencing depth impede identification of molecular etiology. Novel diagnostic techniques like liquid biopsy-based methods and ultra-deep sequencing of CD31+ cells or cell-free DNA are needed to uncover pathogenic somatic variants down to a variant allele fraction of 0.15%.
Treatment Limitations
A lack of standardized treatment protocols exists, particularly for arteriovenous malformations (AVMs), highlighting the growing need for pharmacological targeted therapies. Current approaches include compression garments, pain control, surgery, laser therapy, sclerotherapy, and medical management.
Sirolimus, while effective, requires frequent blood draws, causes systemic toxicity, and patients experience rebound symptoms upon cessation. Side effects are common (53%) though usually mild, with mucositis and bone marrow suppression being most frequent. Regrowth or recurrence occurred in 49% of patients who discontinued treatment.
Target Populations
Several specific patient populations are being targeted for interventions:
-
Patients with PIK3CA or TEK-related capillary venous malformations resistant to usual therapies have shown improvement with alpelisib
-
Patients with localized intravascular coagulopathy secondary to VMs are being treated with direct oral anticoagulants (DOACs) as an alternative to low-molecular-weight heparin
-
Children and adults experiencing impaired health-related quality of life due to symptoms (pain, swelling, bleeding) and psychosocial distress
-
Patients with complex AVMs in the head and neck region where surgery may not be feasible
Emerging Solutions
Molecular diagnosis is critical as it can lead to new medical therapies, with 63% of patients receiving new therapies based on molecular diagnosis and showing improvement. Genetic diagnosis is increasingly recommended to establish personalized treatment strategies.
Promising approaches include:
- Low-target level sirolimus treatment improving quality of life in 77.8% of children and 57.7% of adults
- Direct stick embolization with mTOR inhibitors (Yale-OCR7737)
- ART-001 (serabelisib), an orally available selective PI3Kα inhibitor
- Lovastatin to inhibit endothelial-mesenchymal transition in KRAS-mutant vascular cells
- Ultrasound-target microbubble destruction (UTMD) treatment
The development of these targeted therapies represents a significant advancement in addressing the unmet needs of patients with venous malformations.
Recent Studies
Recent Studies on Venous Malformation Interventions
2021 Study on Slow-Flow Vascular Malformations
This study evaluated 25 patients (median age 15 years) undergoing laser and/or sclerotherapy procedures. Using thromboelastography (TEG) to assess coagulation dynamics, researchers found significant decreases in fibrinogen, D-dimer, hemoglobin, and platelet count post-procedure. For safety outcomes, no patients experienced bleeding or thrombotic complications during or within one week post-procedure.
2021 10-Year Retrospective Study
This research examined vascular malformations over a decade (2009-2019), finding that venous malformations (VeM) were the most frequent type. Venous malformations were primarily treated with sclerotherapy or surgery. The study noted that venous malformations were threefold more likely to be symptomatic compared to capillary malformations.
2023 Sirolimus Study
This study examined 50 patients (19 children, 31 adults) with vascular malformations receiving sirolimus treatment using low target levels. For efficacy outcomes, the 6-month treatment improved health-related quality of life in 29 patients (77.8% of children and 57.7% of adults). Effect sizes ranged from 0.19 to 1.02, with moderate-to-high clinically relevant changes in multiple domains.
2024 Sirolimus Study
Researchers analyzed 25 patients with complicated vascular malformations treated with sirolimus (and corticosteroid). For efficacy outcomes, 19 patients (76.0%) responded positively to treatment. The study found that a starting dose of 1.5-2 mg/m sirolimus was both effective and safe in vascular malformation treatment.
2024 Alpelisib Study
This study created a genetic mouse model of PIK3CA-related capillary venous malformations and compared efficacy of different drugs. Alpelisib demonstrated improvement in all 25 patients with PIK3CA or TEK-related capillary venous malformations resistant to usual therapies. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively over 6 months.
2024 Topical Sirolimus Gel Trial
This phase II randomized clinical trial evaluated topical sirolimus gel for treatment of cutaneous vascular anomalies, including 27 patients with venous malformation. Patients applied either placebo or 0.2% or 0.4% topical sirolimus gel twice daily for 12 weeks. For efficacy outcomes, improvement in target lesion size was significantly higher in the 0.4% sirolimus gel group than placebo (p=0.031), with 65.0% of patients showing ≥20% reduction in lesion area.