Tectonic Therapeutic (NASDAQ:TECX) used a virtual key opinion leader (KOL) event to outline its strategy for hereditary hemorrhagic telangiectasia (HHT) and highlight early clinical progress for TX2100, an investigational APJ antagonist designed to treat bleeding driven by dysregulated angiogenesis.
HHT described as common, severe, and underserved
Hanny Al-Samkari, MD, a professor of medicine at Massachusetts General Hospital and head of its HHT Center of Excellence, characterized HHT as “among the greatest” unmet needs in non-malignant hematology. He cited North American prevalence estimates of roughly 1 in 3,800 people—about twice as common as hemophilia—and emphasized that most patients experience moderate to severe bleeding. Despite the clinical burden, he said there are no FDA-approved therapies for HHT and no approved therapies worldwide.
Dr. Al-Samkari also pointed to initial findings from the federally funded Comprehensive HHT Outcomes Registry of the United States (CHORUS), which he said reported intracranial hemorrhage rates of 3% and found that approximately three-quarters of patients had moderate to severe bleeding. He described HHT as costly to manage, citing a financial analysis of direct medical costs and noting that bleeding and its complications—including hospitalizations, intravenous iron, transfusions, and off-label use of expensive drugs—were key cost drivers.
Current management relies on procedures and off-label anti-angiogenic drugs
Dr. Al-Samkari said patients are often managed with iron replacement and transfusions, and that procedures such as cautery and laser treatment are still used, particularly outside centers of excellence. However, he argued that repeated mucosal procedures can worsen disease over time by provoking a wound-healing response and angiogenic activation. For mild to moderate bleeding, he said clinicians may use oral antifibrinolytics, though he described a high pill burden and moderate efficacy.
For more severe bleeding, he described off-label systemic anti-angiogenic approaches such as bevacizumab and pomalidomide. While these agents can be effective, he said they do not work for everyone and their benefits may wane over time. He also detailed toxicity concerns, including hypertension and proteinuria with bevacizumab and a range of adverse effects with pomalidomide, alongside thromboembolism risk for both.
TX2100 positioned as a selective anti-angiogenic approach
Peter McNamara, PhD, Tectonic’s chief scientific officer, presented TX2100 as a “potential first-in-class” antagonist of APJ, a G-protein-coupled receptor for the peptide hormone apelin. He argued that the anti-angiogenic concept is clinically supported because anti-angiogenic oncology drugs have improved bleeding and anemia in HHT, but their toxicity limits chronic use in a non-malignant disease.
McNamara said APJ is “endothelial-enriched” and that apelin/APJ signaling is upregulated during pathological angiogenic sprouting while largely quiescent in normal adult vasculature. He contended that this “pathology-biased” biology could offer anti-angiogenic benefit while leaving baseline vascular homeostasis intact, potentially improving chronic tolerability compared with broad VEGF pathway blockade. He also contrasted APJ antagonism with approaches that broadly inhibit signaling nodes such as AKT, which he said can affect multiple tissues and drive systemic adverse effects.
Tectonic presented TX2100 as a VHH-Fc fusion, which McNamara said is intended to provide specificity, long half-life, and infrequent dosing. He reported that, in vitro, the molecule showed low nanomolar potency at APJ and more than 1,000-fold selectivity versus a closely related GPCR, and that it blocks APJ-mediated signaling.
Preclinical efficacy and toxicology highlights
McNamara discussed mouse studies using TX1351, a potency-matched, mouse-reactive surrogate. He said APJ antagonism produced robust efficacy in two HHT models: a neonatal anti-BMP9/10 model and a severe adult inducible ALK1 knockout model. According to the presentation, APJ antagonism reduced AVM formation and bleeding and increased hemoglobin—endpoints he emphasized as clinically meaningful.
In the adult inducible ALK1 knockout model, McNamara described an early hemoglobin benefit from VEGF inhibition that waned by day 12, while APJ antagonism produced sustained hemoglobin improvement through the end of the study and reduced gastrointestinal bleeding at day 12. He also described dye perfusion imaging suggesting improved vascular architecture with APJ antagonism compared with control, and said APJ antagonism provided a more complete vascular rescue than VEGF-A antagonism in that model.
On safety, McNamara said TX2100 showed no molecule-specific or target-related findings in preclinical testing, including a 13-week GLP toxicology study in cynomolgus monkeys. He reported a NOAEL of 100 mg/kg/week—the highest dose tested—and said no test-article-related findings were identified across dose levels evaluated.
First-in-human trial initiated; additional trials planned
Chief Medical Officer Marcie Ruddy, MD, said the company has “just successfully dosed” the first two subjects in a phase I first-in-human healthy volunteer study in Australia. She said the single ascending dose trial is designed to assess safety, tolerability, and pharmacokinetics, with top-line results expected by 4Q 2026.
Ruddy also outlined planned clinical next steps:
- Phase Ib (open-label): planned in patients with severe HHT to assess safety/tolerability with multiple doses and explore effects on efficacy endpoints.
- Phase II (placebo-controlled, dose-ranging): planned in moderate to severe HHT, with a primary endpoint of change from baseline in epistaxis versus placebo and secondary endpoints including hemoglobin and hematologic support.
During the Q&A, the company said it would need pharmacokinetic data from phase I to inform dosing in the phase Ib study and intended to start phase Ib as quickly as possible once adequate PK was available. Management also said phase Ib and phase II are planned to run in parallel.
Dr. Al-Samkari told attendees that clinically meaningful improvement in epistaxis severity—frequency, duration, and intensity—would be a highly valuable outcome for patients given the quality-of-life burden of facial bleeding. He noted that changes in visceral AVMs may be difficult to detect over short double-blind periods, but could potentially be evaluated over longer durations such as open-label extension studies.
In closing remarks, CEO Alise Reicin said the company views TX2100 as a novel, subcutaneously administered approach intended to capture anti-angiogenic benefit with improved safety and suggested the mechanism could potentially extend to other bleeding disorders driven by dysregulated angiogenesis, with additional preclinical data expected to be presented at an upcoming scientific congress.
About Tectonic Therapeutic (NASDAQ:TECX)
Tectonic Therapeutic, Inc engages in discovery and development of therapeutic proteins & antibodies. The company was founded by Timothy A. Springer and Andrew Kruse in 2019 and is headquartered in Watertown, MA.
