TB Antibiotic Shows Promise in Mice with Erythropoietic Protoporphyria, but Researchers say More Human Studies are Needed

Isoniazid, an antibiotic to treat tuberculosis, produces promising results in mice with erythropoietic protoporphyria (EPP), but the standard dose is not high enough to have an effect in humans, a pilot study finds.

The study, “Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria,” was published in the journal Molecular Genetics and Metabolism.

Isoniazid, which is sold in the U.S. with the brand name Laniazid, is an antibiotic that is mostly used to treat tuberculosis infections. This compound can also bind to a human protein called aminolevulinic acid synthase 2 (ALAS2), in addition to its bacteria-killing properties.

ALAS2’s job is to make protoporphyrin IX (PPIX), which is an important precursor compound of hemoglobin production. Some people taking isoniazid develop a particular type of anemia (sideroblastic anemia) that’s characterized by reduced levels of hemoglobin or red blood cells, which is triggered by the inhibition of ALAS2.

PPIX builds up in the tissues of people who have EPP — the most common porphyria of childhood and the third most common porphyria of adulthood — ultimately causing the disease symptoms. As isoniazid binds to ALAS2, it can block the production of PPIX — potentially a useful strategy to treat people with EPP.

To explore the therapeutic activity of isoniazid for EPP, American and French researchers started by testing the compound in a mouse model of EPP. After a month, the treatment was found to lower the levels of PPIX in the blood of these mice to nearly the levels found in healthy mice. PPIX liver levels were also approximately 60% lower than before the treatment, but these levels were still higher than those in the control mice.

The team then performed a small pilot study in which 15 people (47% female) with EPP were treated with isoniazid for two months at dosages up to 300 mg, which is the standard regimen to treat tuberculosis. The researchers collected blood samples to measure PPIX levels during this two-month treatment period and the following month.

The treatment was found to have no significant impact on PPIX levels in this small group of patients. Overall, none of the results suggested a beneficial effect on EPP-related symptoms or markers of disease activity.

These disappointing results in humans may be due to the dosage used, which may be effective to treat tuberculosis but it may not be high enough to change PPIX levels, the researchers said.

“Higher doses of [isoniazid] may be efficacious and development of novel agents that specifically target ALAS2 are warranted to address the absence of effective treatments for the erythropoietic porphyrias,” the researchers wrote. “Although these are rare diseases that are uncommonly fatal, the debilitating impact that they inflict upon individual patients is life-altering and life-long.”