GondolaBio Reports Positive Data from Phase IIa Trial of PORT-77

GondolaBio's PORT-77 Shows Positive Phase IIa Data in EPP/XLP

GondolaBio announced positive results from its Phase IIa GATEWAY study of PORT-77, an oral ABCG2 inhibitor, for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). The trial, involving 19 participants, demonstrated that PORT-77 was well tolerated with no serious adverse events. Key findings showed a mean 79% decrease in plasma protoporphyrin IX (PPIX) for the 300mg BID dose and 63% for the 180mg QD dose, with rapid reductions observed within hours. These results support the drug's potential as a disease-modifying therapy.

• The GATEWAY study revealed significant reductions in plasma protoporphyrin IX (PPIX) levels, a critical biomarker for EPP and XLP. Participants receiving 300mg BID of PORT-77 experienced a mean 79% decrease in PPIX, while those on 180mg QD saw a mean 63% reduction. These rapid and profound decreases, observed within hours of dosing and without rebound, highlight PORT-77's potential to address the underlying pathology of these conditions.
• PORT-77 demonstrated a favorable safety profile in the Phase IIa trial. The drug was well tolerated by all 19 participants, with no serious adverse events reported and no treatment discontinuations. This strong safety data, combined with the observed efficacy, supports further clinical development and suggests a positive risk-benefit profile for patients suffering from EPP and XLP.
• Following these positive Phase IIa results and discussions with the FDA, GondolaBio plans to initiate the global Phase IIb/III PATHWAY trial of PORT-77 in EPP and XLP in the third quarter of 2026. This progression underscores the company's confidence in PORT-77's potential as a disease-modifying therapy that could significantly improve the quality of life for patients by reducing photosensitivity and liver complications.

PORT-77's Positive Phase IIa Efficacy and Safety in EPP

The BEACON Study, a Phase II randomized, open-label, parallel-arm trial, evaluated oral once-daily bitopertin at two doses — 20 mg (n=14) and 60 mg (n=12) — over 24 weeks in adult and adolescent participants with EPP or XLP (26 participants total). The primary efficacy endpoint was met, with significant, dose-dependent reductions in whole-blood protoporphyrin IX (PPIX) levels compared to baseline: −31.7% ± 7.0% (P < 0.001) at 20 mg and −57.7% ± 7.4% (P < 0.001) at 60 mg. Consistent improvements were observed across multiple measures of light tolerance and quality of life, with comparable efficacy between adult and adolescent populations. From a safety standpoint, no serious adverse events were reported; the most common adverse event was dizziness, occurring in 55% of the 20 mg group and 64% of the 60 mg group, with the majority of events being mild to moderate in severity. Notably, bitopertin targets the underlying disease pathophysiology by directly reducing PPIX levels.

A prospective single-center cohort study assessed the adjunctive use of Polypodium leucotomos extract (PLE) in eight adults with confirmed EPP or XLP who continued to experience symptoms despite regular afamelanotide implants administered every two months. Participants received 480 mg oral PLE daily for four months, with six completing the full study. Statistically significant improvements in quality of life were observed at Day 60 (p = 0.014), though this effect was not sustained at Day 120 (p = 0.152). Half of the participants reported a reduction in phototoxic reaction severity. PLE was well tolerated with no adverse events reported, suggesting a potential role as a short-term adjunctive option for patients with incomplete symptom control on afamelanotide monotherapy.

A clinical trial conducted between January 2023 and August 2024 evaluated an oral therapy to improve sunlight tolerance in adults with EPP or XLP, with a specific focus on validating two patient-reported outcome measures (PROMs): the Sunlight Exposure Diary and the EPP Impact Questionnaire (EPIQ). The analysis included 65 participants (mean age 45; 51% male; mean whole-blood metal-free PPIX levels of 9,335.5 µg/L). Exploratory Factor Analysis identified three underlying factors in the EPIQ — Duration of Full Reaction, Overall Change, and Overall Severity and Impact — all demonstrating acceptable to strong psychometric properties across reliability (internal consistency and test-retest), validity (construct and known groups), and responsiveness domains. The Sunlight Exposure Diary yielded one factor (Tingling/Itching) with less consistent psychometric performance. Ranges for meaningful change were established using both anchor- and distribution-based approaches, supporting the utility of these PROMs in future EPP/XLP clinical research.

Designing GATEWAY: PORT-77's Phase IIa Trial and Next Steps

Clinical trials in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) have increasingly centered on patient-reported outcomes (PROs) to capture the subjective burden of phototoxicity, with endpoints spanning pain-free sunlight exposure, symptom severity, and health-related quality of life (HRQoL). Two key trials — a 2010 afamelanotide study and a more recent 2023–2024 oral therapy trial — illustrate the evolution of endpoint design and measurement methodology in this rare disease setting.

Addressing Significant Unmet Needs in EPP and XLP Patients

Despite the availability of afamelanotide, significant therapeutic gaps persist in the management of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Both conditions are rare genetic disorders characterized by accumulation of protoporphyrin IX (PPIX), painful phototoxic reactions, and hepatobiliary disease — all of which continue to impose a substantial burden on patients' health-related quality of life (HRQoL).

• Absence of disease-modifying therapies: No disease-modifying treatments are currently approved for EPP or XLP. Afamelanotide, the only approved therapy, effectively prevents pain and prolongs sunlight tolerance but does not address the underlying disease mechanism — leaving the pathophysiological drivers of PPIX accumulation and associated organ complications unresolved.

• Unmet need in pediatric and adolescent populations: Afamelanotide is approved for adult patients only, leaving children and adolescents without any approved treatment option. This represents a critical population gap, particularly given the early-onset nature of these disorders.

• Prevention of hepatobiliary complications: Therapeutic intervention to prevent or mitigate hepatobiliary disease associated with PPIX accumulation remains an active unmet need, as no approved agent currently addresses this disease complication.

• Lack of validated, disease-specific patient-reported outcome measures (PROMs): There is a recognized need for reliable and validated PROMs that comprehensively capture the full symptom burden of EPP/XLP — including the duration, severity, and impact of early warning symptoms and full phototoxic reactions — as well as broader impacts on well-being and HRQoL. The Sunlight Exposure Diary and EPP Impact Questionnaire (EPIQ), validated in a clinical trial conducted between January 2023 and August 2024 (n = 65; mean age 45; 51% male), represent recent progress in this area, with the EPIQ demonstrating acceptable to strong psychometric properties across reliability, validity, and responsiveness domains.

• Investigational therapies targeting residual unmet needs: Bitopertin and dersimelagon are under investigation as agents that could address several of these gaps. In the BEACON phase II study, bitopertin demonstrated dose-dependent reductions in whole-blood PPIX levels (−31.7% ± 7.0% at 20 mg and −57.7% ± 7.4% at 60 mg; both P < 0.001 vs. baseline), with consistent improvements in light tolerance and HRQoL measures, tolerability across adult and adolescent populations, and no serious adverse events reported. Dersimelagon has shown treatment effects versus placebo in EPP, though further characterization of its safety, efficacy, and comparative profile relative to afamelanotide is needed.