PNH expert Jeff Szer
Jeff Szer, MD, an expert in paroxysmal nocturnal hemoglobinuria at Australia’s Royal Melbourne Hospital, with PNH patient Belinda R., a 64-year-old dairy farmer who was in the original trial of eculizumab then further improved when put into the study with pegcetacoplan, on which she remains today. (Photo by Michael Brown)

Paroxysmal nocturnal hemoglobinuria (PNH) is not only a tongue-twister of a disease; it’s also exceedingly rare. With a prevalence of only 15.9 per million, PNH generates far less attention than better-known disorders such as hemophilia and sickle cell disease.

In fact, until 2005, there wasn’t even an organization devoted to its study. But that changed with the establishment of the International PNH Interest Group (IPIG), which is now planning its first-ever scientific symposium.

Titled “Recent Advances in Paroxysmal Nocturnal Hemoglobinuria: Hemolysis, Bone Marrow Failure & Thrombosis,” the event will take place May 18-19, 2023, at the Crown Hotel in Harrogate, England.

On its website, IPIG bills itself as “the only global professional society that focuses specifically on PNH and its treatment.” It now has more than 400 members in 55 countries, including the world’s most prominent clinicians and researchers at the forefront of patient care and research in PNH—an acquired genetic illness that destroys red blood cells and can lead to life-threatening blood clots and bone marrow failure.

IPIG’s 9-member board of directors is headed by its president, Antonio M. Risitano, MD, PhD, of AORN San Giuseppe Moscati in Avellino, Italy. The board’s 3 US-based members are Neal S. Young, MD, of the National Institutes of Health, based in Bethesda, Maryland; Charles J. Parker, MD, of the University of Utah School of Medicine in Salt Lake City; and Russell E. Ware, MD, PhD, of Ohio’s Cincinnati Children’s Hospital Medical Center.

The organization’s secretary is Jeff Szer, BMedSc, a hematology professor at Australia’s Royal Melbourne Hospital. He said IPIG was formed during Alexion’s first clinical trials of eculizumab (Soliris®) to treat PNH—a usage that won US Food and Drug Administration (FDA) approval in March 2007.

Alexion, now a unit of AstraZeneca, also developed ravulizumab-cwvz (Ultomiris®) to treat PNH. The FDA approved its use in December 2018 for adults with PNH, and in July 2021 for children and adolescents with the debilitating illness. A third drug, pegcetacoplan (Empaveli®), was developed by Apellis Pharmaceuticals and won FDA approval in May 2021.

PNH Prevalence Rises as Disease Mortality Declines

“The prevalence of PNH is going up because patients aren’t dying anymore,” said Dr. Szer, who is also past president of the World Marrow Donor Association and a noted expert on Gaucher disease.

“Natural history studies in PNH showed that [without treatment] 35% of patients were dead within 15 years of diagnosis. But that’s not happening now. Since the introduction of disease-specific therapies to treat the disease, the significant mortality in PNH has largely disappeared.”

Eight pharmaceutical manufacturers jointly fund IPIG, including Alexion, Amgen, Apellis, and Novartis, yet Dr. Szer said “we’re not beholden to industry” in any form.

“These are all companies that have a footprint or hope to have a footprint in the PNH space. But we do things in a hands-off way, from the industry point of view,” he told Rare Disease Advisor. “The funds that are used to run our organization are in the scientific community’s interest.”

Dr. Szer noted that prior to 2007, physicians could prescribe anticoagulants, analgesics, and even blood transfusions, but none of these changed the course of the disease.

“The only treatment up to that point that did influence the natural history of the disorder is allogeneic stem cell transplantation,” he said. “In fact, that’s why I got interested in this condition. I’m fundamentally a bone marrow transplant physician. It all came together at the right time for me.”

Exploring Current Thoughts and Hot Topics

The 2-day conference will cover a range of topics, including:

• The pathophysiology of PNH, focusing on biologic aspects of the glycosylphosphatidylinositol (GPI) defect in PNH, the mechanism expansion of PNH hematopoiesis, and complement biology

• Current thoughts on the treatment of PNH, including anticomplement therapies for hemolytic/thrombotic PNH and immunosuppressive treatment for bone marrow failure as well as bone marrow transplantation

• Hot topics in PNH (defining response and endpoints, breakthrough hemolysis: terminal vs proximal inhibitors, proximal inhibitors: monotherapy vs combination treatment)

• A special session dedicated to recent clinical trial data on complement inhibitors in PNH

• The worldwide impact of PNH, focusing on geographic area-specific unmet clinical needs.

IPIG Plans Global PNH Patient Registry

One of the most important items at the upcoming meeting is IPIG’s planned PNH International Registry, which will build upon the success of Alexion’s existing 15-year-old patient registry.

“This has provided a number of very important scientific advances in the understanding of this condition and has led to some regulatory changes making therapy available to more patients that need it,” Dr. Szer said. “Alexion has put a lot of time, effort, and money into the existing registry over a long period of time, and they’re to be congratulated for that.”

At its peak, this Alexion-sponsored registry had 4500 patients. Dr. Szer, who managed it, said that registry will be closed within the next several years and seamlessly merged into the new registry now being planned by IPIG.

“We now have an explosive field with 3 licensed therapies in most parts of the world for this disease, and soon we’ll have more. It would not be in anybody’s interest to have multiple competing registries, each siloed according to a treatment,” he said, estimating startup costs for the new registry will run into “many millions” of dollars.

“It’s not a cheap exercise if you want to do it properly, with appropriate, usable data,” Dr. Szer added. “Other than raw laboratory and clinical outcome data, one of the things that we’re building into this is patient-reported outcomes, because the patient voice is of great importance.”

Since its beginning, IPIG has cooperated with the American Society of Hematology to present an annual “ASH-IPIG Abstract Achievement Award” to up to 2 authors of PNH-focused abstracts in the fields of red cells and erythropoiesis or bone marrow failure.

The 2022 winners, presented during the recent 64th ASH Annual Meeting and Exposition in New Orleans, Louisiana, were Carmelo Gurnari, MD, of Italy’s University of Rome Tor Vergata, and Naomi Kawashima, MD, PhD, of Ohio’s Cleveland Clinic.

Dr. Gurnari won for his paper “Clinico-Molecular Risk Factors and Management of Thrombosis in a Large Real-Life Cohort of Patients with PNH in the New Era of Anti-Complement Inhibitors and Doacs.” Dr. Kawashima’s winning abstract was titled “Immune Checkpoint Molecules Regulate PNH Clonal Evolution.”