Teaching an old drug a new trick to treat an ultra-rare red-blood-cell disease

Failed sickle-cell drug learns a new trick: hereditary xerocytosis

The National Institutes of Health maintains a library of drugs, the Clinical Collection, that are safe for humans but failed in clinical trials or didn’t make it to the market for other reasons. These compounds, numbering 450 to date, are just sitting on the shelf, waiting for a researcher to identify a disease process they might treat.

Repurposing such drugs could potentially save the pharmaceutical industry time and money. Getting a new drug from R&D to market currently takes $2 to 3 billion and 13 to 15 years. In contrast, some estimate that repurposing a safe drug could cost just $300 million and take just 6.5 years.

Pfizer, one of the biggest pharma companies in the world, saw the appeal. It just launched SpringWorks Therapeutics, a mission-driven company dedicated to reviving shelved drugs to treat underserved diseases. In its pipeline are experimental therapies to treat four diseases that currently have no cure.

One of the earliest-stage candidates is senicapoc. Senicapoc was tested in the early 2000s for sickle cell anemia, which had only one approved therapy at the time (hydroxyurea, developed at Boston Children’s Hospital more than 30 years ago). Then called ICA-17043, senicapoc showed a good safety profile in a Phase 2 clinical trial. But in the Phase 3 trial, it failed to meet the primary endpoint of reducing sickle-cell crises, the painful result of sickled cells blocking blood flow and oxygenation in small blood vessels.

That could have been the end of the line for senicapoc. But it wasn’t, thanks to SpringWorks Therapeutics and Carlo Brugnara, MD, director of Boston Children’s Hematology Laboratory.

Keeping water inside red blood cells

In the early 1990s, Brugnara and his colleagues (Orah Platt, MD, chief of Laboratory Medicine and Nader Rifai, PhD, director of the Chemistry Lab at Boston Children’s; Seth Alper, MD, PhD, at Beth Israel Deaconess Medical Center; and Jose Halperin, MD, of Harvard Medical School) explored a strategy to inhibit the sickling process in red blood cells (RBCs). In a series of papers, they showed that breakdown products of the anti-fungal clotrimazole improved RBC hydration and reduced sickling.

Sickling of RBCs, caused by clumping of abnormal hemoglobin molecules, is greatly exacerbated by dehydration. The researchers showed that the clotrimazole metabolites prevent RBC dehydration and reduce sickling by blocking the Gardos channel, an ion channel through which potassium and water exit the cells.

To translate these discoveries into a drug, Boston Children’s partnered with Icagen, Inc., later acquired by Pfizer. After the Phase 3 failure, Pfizer abandoned the senicapoc program, and in 2011 deposited the drug into the NIH Clinical Collection. This move let researchers, like Brugnara, have open access to senicapoc to test it for other indications.

Repurposing senicapoc for hereditary xerocytosis

Brugnara had begun working on another disease of dehydrated RBCs: hereditary xerocytosis (HX), an ultra-rare genetic disorder in which the cells become dehydrated because they lose too much potassium and cell water. The fragility of the dehydrated RBCs can cause anemia and related complications; in some cases, it leads to severe anemia that requires frequent blood transfusions. There is no approved therapy.

HX affects an estimated one in 10,000 people, and symptoms begin shortly after birth. Most cases are caused by mutation in the PIEZO1 ion channel, which allows calcium ions to flow into the RBCs. Mutations in PIEZO1 delay closing of the channel, letting too much calcium flow into the cells. The excess intracellular calcium activates the Gardos channels to let out potassium and water, leading to the dehydrated red blood cells seen in HX patients.

However, not all patients with HX have PIEZO1 mutations.

In 2015, Brugnara, with colleagues in Italy, identified two unrelated HX families with mutations in KCNN4, the gene encoding the Gardos channel. The mutated Gardos channel is 10 times more sensitive to activation by calcium. Because Gardos is activated by PIEZO1, even normal PIEZO1 activity causes red blood cells to dehydrate when Gardos is mutated.

Brugnara quickly put two-and-two together: Since senicapoc selectively inhibits the Gardos channel, it could block the effects of the KCNN4 mutation. His group recently showed that the drug reduces dehydration of RBCs from these families ex vivo. Furthermore, Brugnara thinks that blocking this channel could also mediate the dehydration caused by the more common PIEZO1 mutation. This would provide a much-needed option to hundreds of additional patients.

Advocating for a treatment

One family carrying the KCNN4 mutation is in Massachusetts, being treated by Brugnara’s collaborator Michael Snyder, MD. Robert Smith (not his real name), whose mother was Snyder’s first HX patient, is leading the call for new options for his family and others.

Most of Smith’s family members harbor the KCNN4 mutation and struggle with various degrees of symptom severity, from mild lethargy to debilitating anemia. Many have had to gallbladders removed because of gallstones, a result of the liver and gallbladder having to process an increased number of dead RBCs. Smith had his gallbladder removed at age 25 and one son had his removed at the age of 7 at Boston Children’s.

“We just want to get this drug to improve our children’s and grandchildren’s lives,” he says.

Brugnara applauds Smith’s outspoken perseverance.

“This family, like many other families affected by rare diseases that we see at Boston Children’s, is exceptionally committed to and supportive of research leading to potential new treatments,” says Brugnara. “They provide voices, faces and personal histories that motivate us to overcome obstacles and find new solutions.”

SpringWorks Therapeutics, Brugnara’s team and patient advocacy groups are in conversations to assess a path toward a new round of clinical trials for senicapoc in HX. This work may give senicapoc a second chance at becoming a bona fide drug — for patients who lack any other option.

Hereditary xerocytosis is treated in the Rare Anemias and Iron Disorders Program at Dana-Farber Boston Children’s Cancer and Blood Disorders Center.