FDA Grants Fast Track Designation to VAD044 for Treatment of Adults With HHT

The FDA has granted a fast track designation to VAD044 (Vaderis Therapeutics) for the treatment of hereditary hemorrhagic telangiectasia (HHT). Currently, the therapy is undergoing evaluation in a phase 1b clinical trial (NCT05406362).¹

Image credit: luchschenF | stock.adobe.com

According to prior research, in the small vascular malformations—called telangiectases—there is a protein called AKT that is more active than in other parts of the vessels where there is no telangiectases. The genetic mutations that cause HHT appear to indirectly activate AKT. Although there are methods of managing HHT, there are currently no approved treatments for the condition, even though it is the second most common inherited bleeding disorder in the world. HHT frequently causes severe disease burden, reduced life expectancy, and impaired quality of life.^1,2

VAD044 is an oral, once-daily allosteric AKT-inhibitor and the first novel therapy that is specifically intended for the treatment of HHT. It is intended to bind to AKT and make it less active. The treatment is currently undergoing investigation in a clinical proof of concept study and is in a 12-month open label extension.^1,2

The randomized, placebo-controlled, double-blind, multicenter phase 1b proof of concept study (NCT05406362) aims to assess the safety and efficacy of 2 doses of VAD044 in adult patients with HHT. On day 0, all patients who are eligible for the study were randomly assigned to receive either 30 mg or 40 mg of VAD044, or placebo, all of which are administered once per day. Additionally, oral capsules are administered over a 12-week duration.^2,3

The trial’s primary outcome measure is the type and severity of adverse events (AEs), which will be assessed at the 12-week period. Additionally, secondary outcome measures include the change in epistaxis frequency, pharmacokinetics, change in nasal outcome for epistaxis in HTT score, and quality of life, which will also be assessed at the 12-week period.³

Analysis results—which will be presented at the 2024 American Society of Hematology Annual Meeting & Exposition—show that the mean epistaxis frequency of patients treated with 40 mg of VAD044 who completed the treatment duration decreased by approximately 33%. Additionally, this group also experienced epistaxis duration and intensity of flow decreases of about 43% and 17%, respectively. Those in the placebo group experienced smaller reductions of epistaxis frequency (17%), duration (17%), and intensity of flow (7%). Epistaxis-free days increased by 5 days per month in the 40-mg group compared with 2.7 days per month in the placebo group. Additionally, the investigators observed similar effects on epistaxis between the 30-mg and 40-mg VAD044 groups.⁴

A total of 6 patients (30-mg: n = 4; 40-mg: n = 1; and placebo: n = 1) discontinued treatment because of AEs. Additionally, grade 1 AEs (30-mg: 83%; 40-mg: 75%; and placebo: 65%) and 2 AEs (30-mg: 46%; 40-mg: 54%; and placebo: 31%) were the most common. Grade 3 AEs occurred in 17%, 13%, and 15% of patients in the 30-mg, 40-mg, and placebo groups, respectively, and all serious AEs (30-mg: 13%; 40-mg: 4%; and placebo: 12%) were assessed as unrelated to study drug. The most common AEs were mild, manageable, and reversible, and included rash (30-mg: 25%; 40-mg: 46%; and placebo: 8%), hyperglycemia (40-mg: 12%), and diarrhea (30-mg: 12%; 40-mg: 8%; and placebo: 4%). Most rashes resolved with topical corticosteroids and without discontinuation of the study drug.⁴

“The FDA's decision to designate VAD044 as a fast track product for the treatment of HHT underscores its potential to be the first ever approved treatment for this debilitating genetic disease,” said Hanny Al-Samkari, MD, the Peggy S. Blitz endowed chair in Hematology/Oncology at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in a news release.¹

REFERENCES

1. PR Newswire. Vaderis Receives FDA Fast Track Designation for VAD044 for the Treatment of Hereditary Hemorrhagic Telangiectasia. News release. November 18, 2024. Accessed November 19, 2024. https://prnmedia.prnewswire.com/news-releases/vaderis-receives-fda-fast-track-designation-for-vad044-for-the-treatment-of-hereditary-hemorrhagic-telangiectasia-893024912.html

2. CureHHT. HHT Clinical Trials. Accessed November 19, 2024. https://curehht.org/research/participate-in-research/clinical-trials/

3. Assess Safety and Efficacy of VAD044 in HHT Patients. ClinicalTrials.gov identifier: NCT05406362. Updated May 6, 2023. Accessed November 19, 2024. https://clinicaltrials.gov/study/NCT05406362?cond=Hereditary%20Hemorrhagic%20Telangiectasia&intr=VAD044&rank=1

4. Al-Samkari H, Hessels J, Riera-Mestre A, et al. 553 A Randomized, Placebo-Controlled, Multicenter Proof-of-Concept (POC) Study to Assess the Safety and Efficacy of the Novel Allosteric AKT Inhibitor, VAD044, in Adults with Hereditary Hemorrhagic Telangiectasia (HHT). Presented at: American Society of Hematology Annual Meeting & Exposition. San Diego, California. December 7-10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper206244.html