FDA puts Atavistik’s AKT1 inhibitor on Fast Track for rare hematology disease

Edited by Robert McTiernan··4 min read

Cambridge, Massachusetts-based Atavistik Bio announced that the US FDA has cleared its investigational new drug (IND) application for ATV-1601 and granted the compound Fast Track Designation for the treatment of moderate to severe hereditary hemorrhagic telangiectasia (HHT). ATV-1601 is an oral, selective allosteric AKT1 inhibitor. The simultaneous IND clearance and designation award allows Atavistik to enter directly into a randomized Phase I/II study, bypassing a standalone dose-escalation cohort by drawing on existing human safety and pharmacokinetic data generated in a separate oncology program.

Fast Track Designation enables more frequent FDA interactions and rolling New Drug Application review, and may confer eligibility for Priority Review or Accelerated Approval if relevant criteria are met at the time of submission. No prior expedited designations for ATV-1601 have been disclosed.

The cleared study, Harmony-HHT (NCT07601425), is a Phase I/II randomized, double-blind, multicenter, placebo-controlled trial evaluating three oral dosing regimens of ATV-1601 over a 16-week treatment period in adults with moderate to severe HHT. Participants completing Part 1 may enroll in an open-label extension (Part 2). No human HHT-specific efficacy or safety data for ATV-1601 have been publicly released. The evidentiary basis for the IND rests on preclinical HHT model data and cross-indication human data from an ongoing oncology Phase I trial (NCT07038369), in which the first patient was dosed in August 2025. That study evaluates ATV-1601 as monotherapy and in combination with fulvestrant in adults with AKT1 E17K-mutant advanced solid tumors. No interim efficacy or safety figures from that trial have been publicly disclosed.

Preclinical data presented at EORTC-NCI-AACR 2024 indicated greater than 100-fold selectivity for AKT1 E17K over wild-type AKT1, with tumor regressions reported in multiple patient-derived xenograft models, though exact regression percentages and p-values were not publicly disclosed in the abstract. In HHT-specific preclinical models carrying ENG, ALK1, and SMAD4 mutations, ATV-1601 reduced arteriovenous malformation (AVM) formation across all three genotypes; numeric detail from those experiments has not been disclosed in any public forum as of June 2026.

In HHT, loss-of-function mutations in ENG, ALK1, or SMAD4 impair regulation of endothelial cell growth and vascular branching, leading to hyperactivation of the AKT1 pathway and subsequent AVM formation. AVMs can rupture or produce abnormal blood flow, causing chronic bleeding, anemia, organ damage, and in some patients, life-threatening complications. ATV-1601’s allosteric, non-ATP-competitive mechanism of AKT1 inhibition is designed to act downstream of all three driver mutations, giving it theoretical applicability across the full HHT patient population regardless of genotype.

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Research context

HHT is the second most prevalent inherited bleeding disorder, affecting more than 80,000 people in the US and approximately 1.6 million globally, with no approved therapies. Current management is limited to supportive care and invasive interventions such as embolization and cauterization.

The most clinically advanced investigational approach in HHT to date has involved anti-angiogenic agents targeting the VEGF pathway, reflecting the vascular dysregulation underlying the disease. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody marketed by Roche, has been evaluated in HHT in investigator-initiated studies and is used off-label in some centers, but carries an intravenous administration burden and a well-characterized systemic toxicity profile. Pazopanib, an oral multi-kinase VEGF receptor inhibitor, has also been explored in small HHT studies. Neither has secured regulatory approval in HHT. ATV-1601 is mechanistically distinct from both: rather than targeting VEGF ligand or receptor, it inhibits AKT1 allosterically, addressing the intracellular signaling node common to all three HHT driver mutations. The allosteric binding mode is also differentiated from ATP-competitive AKT inhibitors such as capivasertib (Truqap), which received FDA approval in November 2023 for hormone receptor-positive, HER2-negative breast cancer, and which inhibits all three AKT isoforms rather than AKT1 selectively.

For Atavistik, ATV-1601 is the lead asset in a pipeline explicitly focused on rare hematology, alongside an earlier-stage JAK2 V617F mutant-selective inhibitor program for myeloproliferative neoplasms. The decision to pursue HHT alongside the oncology AKT1 E17K program reflects a strategy of leveraging the same allosteric AKT1 inhibitor platform across genetically defined patient populations — a model that allows the company to extract clinical safety data from the oncology program to de-risk and accelerate the HHT IND, as the Harmony-HHT study design demonstrates. Whether the tolerability profile observed in AKT1 E17K-mutant oncology patients translates to the chronic dosing context required in a non-oncology rare disease population remains to be established in the randomized trial.

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