Q&A: PORT-77 Phase 2a Results in Adults with EPP and XLP

Erythropoietic protoporphyria (EPP) has no approved disease-modifying treatment. The only US Food and Drug Administration (FDA)-approved therapy for the condition, afamelanotide, increases pain-free light exposure by boosting skin pigmentation, but it does not address the underlying protoporphyrin IX buildup driving the disease.²

More than 25,000 patients in the US and EU live with EPP or the related X-linked protoporphyria (XLP), and up to 5% progress to acute liver failure requiring transplantation.¹ Investigational agent PORT-77, an oral ABCG2 transporter inhibitor, blocks the efflux of protoporphyrin IX from red blood cells into plasma.

In the phase 2a GATEWAY trial, a placebo-controlled crossover study in 19 adults with EPP, the drug produced mean plasma PPIX reductions of 79% at the higher dose and 63% at the lower dose.¹ These effects appeared within hours of dosing and showed no rebound after treatment stopped.¹ No serious adverse events or treatment discontinuations occurred, and the data were presented at the European Hematology Association 2026 Congress in Stockholm.¹

If confirmed in the planned phase 2b/3 PATHWAY trial, these reductions could translate into fewer phototoxic episodes and meaningful gains in quality of life. Robert Sarkany, MD, FRCP, is a consultant dermatologist and senior photodermatology consultant at St John's Institute of Dermatology, Guy's and St Thomas' Hospital, London. He has treated and researched EPP for more than 3 decades. In the following Q&A interview with HCPLive, Sarkany discusses the significance of the phase 2a data:

HCPLive: What was your initial reaction to the phase 2a PORT-77 data showing rapid reductions in plasma PPIX in patients with EPP?

Sarkany: They're exciting findings, there's no question about it, and this is an exciting time in EPP. I've been involved with patients and research into EPP for over half of my life, since the early 1990s. I'd say this is a very exciting period of drug development in EPP, and PORT-77 is a very exciting part of that.

HCPLive: Why is reducing plasma PPIX considered such an important therapeutic target, and how could this translate into clinical benefit?

Sarkany: Patients with EPP have one of two different genes that cause it, but it's the same underlying problem: a defect in the production of heme. The biosynthetic pathway of heme is disrupted either at the beginning or at the end, and the result is an accumulation of one of the intermediates, called protoporphyrin. This accumulates in patients who have a deficiency of ferrochelatase, or a dominantly inherited increased-activity mutation in ALAS2, another enzyme in the pathway. The end result is high levels of protoporphyrin in erythroblasts, reticulocytes, and red blood cells in the red cell series, because that's where 80% of heme is made, since most heme is used for hemoglobin.

Protoporphyrin has two types of toxicity in the body. One is that it's chemically toxic when there's light, essentially blue or violet light, producing various free radical activated oxygen species. That matters in the skin because protoporphyrin is in blood vessels not far below the surface, a millimeter or two down, and those blood vessels, carrying red cells full of protoporphyrin, may be vulnerable to endothelial damage. That causes bouts of severe pain when there's endothelial necrosis from the phototoxicity. The other toxicity is in the liver: protoporphyrin is excreted into the bile because it's hydrophobic, so the concentrations in the liver are quite high, and despite there being no light there, through a different mechanism, the high concentrations are toxic to liver cells, particularly bile canalicular cells.

What this means is that 100% of patients with EPP suffer from severe bouts of 3- to 4-day-long burning pain, severe enough to prevent sleep and unresponsive to conventional analgesia, mainly on the hands and face, and that's lifelong for everybody. About 3% of patients also develop progressive cirrhotic liver disease, fibrosis, and bile canalicular damage, eventually presenting with liver failure and cholestasis that usually requires liver transplantation.

What PORT-77 does is prevent the protoporphyrin that has accumulated within the red cell series from leaving the red cell and leaking into plasma. Until this work, I thought it was just passive diffusion out of red cells into the plasma, but it turns out there's a specific transporter involved, called ABCG2. Its old name is the breast cancer resistance protein; it's an ATP-binding cassette transporter that pumps xenobiotics and various biochemicals and vitamins out of cells in the body. It was found to be involved in breast cancer cells pumping out cytotoxics, but it also functions in red blood cells and erythroblasts or reticulocytes, pumping protoporphyrin out from the red cell into the plasma.

If you can keep the plasma protoporphyrin concentration lower, that matters because it's the plasma that's in contact with vascular endothelium in epidermal blood vessels in the skin, where the damage causing severe photosensitivity occurs, and it's also the plasma in contact with bile canalicular cells and hepatocytes. So the theory is, if you can keep the concentration in the plasma down, whatever it's doing in the red blood cell, you may be able to protect against the skin and liver toxicity. It looks as though that's the case.

HCPLive: Given the favorable safety profile and rapid PPIX reductions, what are your biggest reasons for optimism, and what questions remain unanswered?

Sarkany: The biggest reasons for optimism are that with the higher dose used in this trial, about 19 or 20 patients with EPP were dosed with placebo and then with drug at different doses, a higher dose and a lower dose, without knowing the order. There was single blinding in terms of whether they were on placebo during that period, a couple of weeks, maybe 10 days or so, and during that period they didn't know whether they were on placebo or active drug. The endpoint was a fairly objective one: plasma protoporphyrin concentration.

In the people on the higher dose, the minimum fell within about 6 hours, and within 4 days there was a full decrease: the lowest fall was 57%, the average was 79%, and the highest was virtually no plasma protoporphyrin at all, something like 98% or 99%. These are quite big falls, there were no patients without a significant fall, and the effect appeared dose dependent, which is a positive thing.

That's the data we've got from patients, along with a much bigger group of phase 1 healthy volunteers showing minimal, if any, side effects. What reassures me is that blocking the ABCG2 transporter isn't something one would predict to be very toxic. One could argue there might be completely unrelated side effects, but about 1 in 2,000 people in Japan have a homozygous knockout mutation in ABCG2, and they're well, aside from a slightly increased uric acid concentration in their plasma; I don't think there are any other known ill effects. ABCG2-null mice also seem fine, and ABCG2-null mice that also have EPP seem fine as well. In fact, they're much better off than mice with the transporter protein still working, and their survival is longer, because their liver seems to do better.

So from the phase 1 and phase 2a data, it's looking pretty safe, and it's looking promising in terms of plasma levels; the mouse work suggests it will have clinical implications, and theory would support that. What we now need is the full trials, to see not only whether we can decrease plasma protoporphyrin in these patients, but whether we indeed end up with significantly less photosensitivity, as we would expect.

HCPLive: As PORT-77 moves into the phase 2b/3 trial, what outcomes and endpoints will you be watching most closely?

Sarkany: Ideally, you look at liver as well as skin. Skin photosensitivity is the big endpoint, since it's part of the disease in almost everybody who has it. You would hope not only to replicate these very significant and fast reductions in plasma levels of protoporphyrin in patients in the phase 2b/phase 3 trial, but you'd also want to measure how many phototoxic episodes, how many painful episodes of photosensitivity lasting 3 or 4 days, happen during [UNCLEAR — please review] compared to normal. Are there changes in well-being data and quality of life data, that sort of thing, and as many clinical correlates as we can use for reductions in photosensitivity?

You can also get a general idea as to whether anything is happening with the liver, but the problem is one can't really trial for that specifically, which would be interesting and nice, because it's a rare complication that happens in a small number of people, at one point in their lives, developing over a few years. So that's not going to be trialable, because most patients aren't having that complication. So the clinical outcomes that matter most are about pain on sun exposure.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. GondolaBio. GondolaBio announces positive phase 2a results demonstrating 79% plasma protoporphyrin IX reduction and disease-modifying potential of PORT-77 for erythropoietic protoporphyria. Published June 22, 2026. Accessed August 12, 2026. https://gondolabio.com/gondolabio-announces-positive-phase-2a-results-demonstrating-79-plasma-protoporphyrin-ix-reduction-and-disease-modifying-potential-of-port-77-for-erythropoietic-protoporphyria/.

2. HCPLive. FDA approves afamelanotide to treat erythropoietic protoporphyria. Published October 2019. Accessed August 12, 2026. https://www.hcplive.com/view/fda-afamelanotide-erythropoietic-protoporphyria.