How a Small Lab Took on One of the World’s Rarest Diseases

Securing a diagnosis for a rare disease is a marathon, not a sprint. The search for an answer can become an odyssey of medical appointments and dead ends. But doctors diagnosed FIDE MIÓN’S condition when she was just six months old. They told her family two things: Her disease was vanishingly rare, and there was no cure. This was in 1980. Over four decades later, Mirón believes she is the oldest person in Spain living with congenital erythropoietic porphyria (CEP), also known as Gunther disease.

Now, the results of years of research that unmasked the biomolecular secrets of CEP and overcame countless regulatory hurdles are coming to fruition. A team led by Óscar Milleta group leader in precision medicine and metabolism at CIC bioGUNE, have a potential therapy at the brink of approval. Researchers and patient advocates hope that a treatment for this ultrarare condition will soon be available for patients around the world.

Porphyrins: The Pigments of Life and the Problems in CEP

CEP is just one of several conditions linked to molecules called porphyrins, explained Millet. “Porphyrins are the pigments of life,” he said, paraphrasing Hans Fischerwho won the 1930 Nobel Prize in Chemistry for his work on these molecules.

Porphyrins include heme, which gives red blood cells their crimson hue. With just a few atomic substitutions, heme becomes chlorophyll, which colors grass and leaves. The body makes porphyrins through a complex series of enzymatic steps, which fold precursor proteins into new shapes, like biological origami. Any mistakes in this process can cause a porphyria.¹ CEP is one of the rarest porphyrias and has been documented in only a few hundred cases since it was identified in the early 20^th century.²

On a whiteboard that covers one wall of his office, Millet has filled the space with a dizzy maze of lines and diagrams—the metabolic pathway that leads to CEP. In Mirón’s body, the guilty party is an enzyme called uroporphyrin III synthase (UROIIIS).³ In most people, this enzyme carefully binds to proteins that eventually are converted into heme. However, in CEP, the molecule’s structure resembles a Jenga tower with too many bricks removed. Shortly after forming, it collapses, and precursor proteins accumulate throughout the body. Accumulation of these porphyrins can turn teeth purple and cause severe liver damage. Patients are anemic because their bodies are starved of heme. The pathological porphyrins are also highly reactive. In the presence of visible light, the oxygen atoms they contain become excited enough to bind to water, producing peroxide, which damages nearby tissue. This leads to blister-like skin lesions.

Life with Congenital Erythropoietic Porphyria

For people with CEP, exposure to intense light is hazardous. As Mirón spent her childhood in the sun-soaked southern Spanish city of Alicante, lesions destroyed her hands and much of the soft tissue on her face. “When I was a child, the disease advanced tremendously,” she said.

Mirón struggled with her diagnosis for years. “The messages were that I was always alone, that there were no more people in the same situation,” she said. But then she discovered the Spanish Association for Porphyria, and found she was part of a patient community. As Mirón became more active in the group, she discovered Millet’s research, and they first met in 2009.

Over a decade later, Mirón still regularly makes the journey from Alicante to Bilbao to donate blood in support of Millet’s ongoing research, which is aiming to develop a much-needed treatment for CEP. On these visits, Mirón no longer has to hide entirely from the sun. That’s because her condition stopped advancing in her teenage years. Millet explained that the disease moderates in adulthood but for reasons that aren’t fully understood. Mirón’s condition still takes a toll—her porphyrin levels have to be carefully monitored and her skin is incredibly fragile, requiring occasional surgery. “It is not stabilized. It is not cured,” she said. Mirón hopes to aid research efforts so that life will be different for the next generation of CEP patients.

NMR Helps Discover a Rare Disease Therapy

In 2018, Millet and his team made a discovery in the basement of CIC bioGUNE that could one day help people with CEP all around the world.

If someone wanted to set up a recording studio inside a research institute, it would likely resemble CIC bioGUNE’s underground nuclear magnetic resonance (NMR) chamber. A computer-studded monitoring area faces onto a room lined with perforated acoustic panels. But instead of a drumkit and synth setup, the main instruments in the platform are several gray tanks bristling with wires. While the smallest is the size of a dustbin, the largest is 15 feet tall and can only be accessed by a wooden staircase and a platform surrounding it. Tammo DiercksCIC bioGUNE’s NMR platform manager, explained the complicated mathematics that enabled these hulking machines to crack molecular secrets of CEP.

In NMR, researchers bombard a molecule with intense radiofrequency pulses that alter the rotation of nuclei in the atoms that make up the molecule. How the atoms respond to these pulses depends on their chemical environment: Hydrogen atoms bound to an oxygen atom will react differently to those linked to a carbon atom. These responses tell scientists how atoms connect to each other and thus, the structure of the molecule.

In practice, researchers place a tiny vial containing a biological sample suspended in liquid inside the top of one of the hulking tanks. After each pulse, the scientists carefully analyze the chemical data broadcast by the sample. Depending on the NMR instrument and sample, these experiments can take anywhere from minutes to days to complete.

To unpick the molecular secrets of CEP using NMR, Millet wrote a program that assessed how well a vast library of FDA-approved compounds might bind with mutated UROIIIS. He and his team showed that the antifungal drug ciclopirox acted like a molecular glue, stabilizing the fragile enzyme. “NMR is incredibly versatile,” said Diercks. Users can pick up a considerable amount of structural and chemical information.

“We use NMR for everything,” said Millet. He added that he preferred the tool over other molecular characterization methods like mass spectrometry because of NMR’s more robust quantification. While mass spectrometry is more sensitive, this wasn’t an issue for Millet because of how clearly he and his team could pick up ciclopirox’s signal.

After identifying ciclopirox, the team put it through its paces in preclinical trials. Mouse models of CEP recapitulated many of the same symptoms of human patients. In these trials, CEP mice given the drug had healthier spleens and lower porphyrin levels.⁴

To develop ciclopirox as a drug for CEP and steer it through complicated regulatory hoops, Millet’s team founded a small company, Atlas Molecular Pharma. In 2022, the FDA and European Medicines Agency awarded orphan drug designation to the treatment, signaling that it is a potential therapy for a rare disease.

Over these years of research, Mirón has closely collaborated with the CIC bioGUNE team and raised awareness of the research through her active social media presence. She is now the president of the Spanish Association of Porphyria. Mirón said that a highlight of her work was meeting Spain’s Queen Letizia, who has been vocal in her support for rare diseases, earlier this year.

Taking Ciclopirox Out of the Lab and Into the Clinic

As ciclopirox, now designated ATL-001, moved into clinical trials, Millet has juggled the roles of both academic and drug developer. In a short presentation summarizing ATL-001’s journey, there is just a single slide dedicated to the results of a Phase 1 studywhich confirmed the drug’s safety in a group of 40 healthy volunteers. The biggest shock for Millet about the drug development process has been the bureaucracy. “The paperwork is probably more than 10,000 pages sent to the FDA, just for that slide,” he sighed. However, his opinion of the regulator is very high—he complimented their fast turnaround time and their decision to allow the follow-up Phase 2b trial to adopt an unorthodox format. That trial will have just six participants, all of whom are American CEP patients. Pathology varies significantly between patients, so the trial participants will act as their own controls. The team will record their disease course for six months to set a baseline measurement, and then for a further year while taking the drug.

One obstacle that has dogged the Atlas team has been choosing a clinical endpoint. FDA trials require a yardstick by which to assess a drug’s effect on a patient’s symptoms. But choosing a symptom to measure for a variable disease like CEP is not straightforward. Millet said that the team has decided to use the number of bullous skin lesions as a final measure. He remains hopeful that the regulator will accept the reduction in patients’ porphyrin levels as a surrogate biomarker of progress, as evidence suggests that this will lead to downstream benefits for patients’ health.

Other discussions have shifted from molecular insights to entirely practical matters. Will the patients be able to fit all the vials of medication they are sent in their fridge? How can they safely dispose of excess medication? These are concerns all drug developers have to reckon with. However, most of these companies are behemoths that can deploy an army of logistical specialists to wargame these issues. In contrast, an all-hands Atlas meeting has just a handful of attendees. Millet said the most significant obstacles are the restrictive processes that force all pharma companies, large or small, to use external consultants to prepare and submit data. This might simply involve formatting some results into a new file type, but Millet said that Atlas pays tens of thousands of Euros each time they need to submit data to regulators. Ultimately, he estimated that developing the drug will cost between €5 million and €10 million, a cost that he saw as artificially inflated. This state of affairs, he said, benefits big pharma, as it crowds out smaller players from the market. “For Glaxo (SmithKline, the tenth largest pharmaceutical company), what is five million? Nothing. For Atlas, what is five million? Life or death,” he said.

The Stars and the Sun: What’s Needed to Cure a Rare Disease?

Beside the whiteboard in Millet’s office sits a framed print by Belgian cartoonist François Schuiten. Millet’s late father was a bookbinder, and the print was a gift from one of his publishers. The print depicts three Enlightenment-era astronomers—“all male, of course,” noted Millet drolly—gathered around a giant telescope. Despite bright, shining stars glinting down on them, the trio is distracted by a primitive camera obscura. This predecessor of the modern camera projects upside-down images through a pinhole onto a screen. The camera obscura became an aid to astronomers who wanted to observe the sun.

Modern drug development needs both a telescope and a camera obscura. High-powered technology, like the NMR chambers below Millet’s office, can crack the code of life, but without simpler, softer, and more earthly skills, like the knowledge required to run a clinical trial, those insights may never see the light of the sun. Millet is a rare researcher who wants to see his molecular discovery through to the final endpoint in clinical use. “If you start from the beginning, and then you stop in the publication where you say that (the solution) is possible, it’s rather void to me,” he said. “You may go home and say, ‘Look, I published this paper. I cured this disease.’ It’s not true. Curing a disease is a much more complex thing outside science.”

For now, Atlas, Millet, and Mirón are all waiting to see the results of the Phase 2 trial. Despite the damage that CEP has caused to her, Mirón’s spirit is unbroken, and she recognizes that if the disease finds a treatment, it will be part of a small minority of rare diseases with available therapies. “The message that we want to convey is that there must be more investment in research, more support in research, ensuring that the research is long-term and that we find treatment for the diseases that we suffer from,” she said.