Atossa Therapeutics wins FDA Rare Pediatric Disease designation for Z-endoxifen in McCune-Albright Syndrome

Edited by Robert McTiernan··3 min read

Atossa Therapeutics (Nasdaq: ATOS) announced receipt of an FDA Rare Pediatric Disease (RPD) designation for (Z)-endoxifen in the treatment of McCune-Albright Syndrome (MAS) in females, extending the Seattle-based company’s development program for the molecule beyond its oncology origins into a rare pediatric endocrine disorder.

The RPD designation, granted by the US FDA, applies to drug candidates intended to treat serious or life-threatening diseases primarily affecting individuals from birth to 18 years of age that meet the definition of a rare disease or condition under Section 526 of the Federal Food, Drug & Cosmetic Act (FD&C Act). The designation may provide development incentives and, upon approval of a qualifying New Drug Application (NDA) or Biologics License Application (BLA) — provided all statutory criteria are met — may make Atossa eligible to receive a Priority Review Voucher (PRV).

(Z)-Endoxifen is a small molecule Selective Estrogen Receptor Modulator/Degrader (SERM/D) originally identified through pharmacogenomic research at the Mayo Clinic, which characterized it as the primary pharmacologically active metabolite of tamoxifen. Atossa licensed exclusive worldwide rights to the molecule from Mayo Clinic in 2018. The company’s proprietary oral formulation is described as pharmacologically distinct from tamoxifen, with mechanisms that include estrogen receptor-targeted modulation and degradation as well as protein kinase C (PKC) inhibition.

MAS is caused by activating somatic mutations in the GNAS gene, resulting in mosaic endocrine dysregulation. The condition presents with a triad of features: polyostotic fibrous dysplasia, in which normal bone is replaced by fibrous tissue leading to fractures and skeletal deformity; café-au-lait skin patches; and hyperfunctioning endocrinopathies, most commonly gonadotropin-independent precocious puberty. In affected females, precocious puberty can begin as early as age two, leading to accelerated growth, premature epiphyseal closure, and reduced adult height. Additional endocrine complications may include thyroid dysfunction and growth hormone excess. The condition is rare enough that diagnosis is frequently delayed, and there are currently no broadly approved pharmacological treatments targeting the underlying hormonal dysregulation in pediatric patients.

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The scientific rationale for evaluating (Z)-endoxifen in MAS centers on the molecule’s capacity to modulate estrogen-driven disease manifestations. In MAS, constitutive activation of the GNAS-encoded G-protein alpha subunit leads to downstream hormonal dysregulation, with estrogen excess driving the precocious puberty phenotype in females. As a SERM/D, (Z)-endoxifen acts at the estrogen receptor to attenuate estrogenic signaling, which positions it mechanistically as a candidate for addressing this component of the disease. The additional PKC inhibitory activity of the molecule may be relevant given the role of PKC signaling pathways downstream of G-protein coupled receptor activation, though the clinical significance of this mechanism in MAS has not yet been established in published trial data.

Atossa noted its participation in the Fibrous Dysplasia, McCune-Albright Syndrome Alliance (FD/MAS Alliance) Research Priorities Workshop at Children’s Hospital of Philadelphia, a forum convening clinicians, researchers, patients, caregivers, and patient advocacy organizations to define the research agenda for MAS and identify gaps in treatment options. The company characterized its engagement there as part of its approach to developing the clinical pathway for (Z)-endoxifen in this indication.

This is the second RPD designation Atossa has received for (Z)-endoxifen. The company previously received both an Orphan Drug Designation and an RPD designation from the FDA for (Z)-endoxifen in Duchenne Muscular Dystrophy (DMD).

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