Safety and Early Hints of Benefit Seen in Phase 1b Trial of PF-04447943

Sickle cell disease (SCD) patients were safely treated with a phosphodiesterase 9A (PDE9) inhibitor therapy called PF-04447943 with no serious side effects reported and possible evidence of fewer vaso-occlusion pain crises, a Phase 1b clinical trial reports.

Safety and early signs of possible efficacy — including a drop in biomarkers linked to vaso-occlusion — were seen regardless of whether patients given PF-0444794 3 were also taking hydroxyurea.

The study, “PF-04447943, a phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study” was published in the journal, Clinical and Translation Science.

Sickle cell disease, caused by an inherited alteration in a gene that instructs the making of the beta-globin subunit of hemoglobin, the protein responsible for carrying oxygen in the blood, leads to sickle hemoglobin production and sickle-shaped red blood cells. These cells are prone to bind and stick to blood vessel walls and other blood cells, like leukocytes — increasing the risk of vaso-occlusion, or blocked blood vessels.

A vaso-occlusion crisis, or a sickle cell crisis, is a common and very painful complication of this disease, often leading to hospitalizations, and the risk of strokes and severe organ damage. It is a cause of mortality in patients.

Hydroxyurea (available under the brand name Siklos), marketed by Addmedica, is an FDA-approved therapy for SCD. Siklos is also widely approved across Europe.

The therapy blocks the sickle hemoglobin formation, and promotes the production of cyclic guanosine monophosphate (cGMP), which regulates cell adhesion in SCD, minimizing vaso-occlusion.

PDE9 has been shown to regulate cGMP, and in testing in animal models, PF-04447943 — being developed by Pfizer — showed an ability to lower cellular aggregates and adhesion markers.

A randomized, double-blinded, Phase 1b trial (NCT02114203) at 18 centers in the U.S. and Europe evaluated the safety and tolerability of PF-04447943 over 29 days in people with stable SCD.  Researchers also noted possible biomarkers for use in future SCD studies, as the disease now has no validated biomarkers to measure efficacy.

A total of 30 patients (12 men and 18 women, ages 18 to 65), were enrolled. Stable disease was defined as no “significant complications” at least one month before the study’s start. Twenty-eight people completed the study, and 15 were already taking hydroxyurea and allowed to continue.

Patients were broken into three groups — two given PF-04447943, one at a 5 mg (seven patients) and another at 25 mg dose (15 patients) orally twice a day, with the final group on placebo (seven patients).

The most common adverse effects reported were: headache, dizziness and fatigue, with a higher incidence (13-27%) on the 25 mg dose group.  Fatigue (29%) was highest in the placebo group.

Four patients experienced a sickle cell, or vaso-occlusion, pain crisis — one on the 5 mg dose, two who took 25 mg, and one in the placebo group.

No severe adverse effects “were considered related to the study drug by the investigators,” the researchers noted, adding that no patients reduced or temporarily stopped treatment. One on 25 mg, however, left the study after eight days due to a pain crisis and pneumonia.

The team also explored biomarkers in the patients’ blood, verifying that the number and size of circulating blood cells (monocyte-platelets and neutrophils) aggregates and the levels of soluble adhesion molecule — E-selectin — were significantly lower in those on the higher dose of PF-04447943, compared to levels recorded at the trial’s beginning. This held whether or not these patients were taking hydroxyurea.

These findings point to PF-04447943’s potential to ease vaso-occlusion and provide benefit.   

Overall, “multiple doses of PF-04447943, with or without hydroxyurea, administered to patients with SCD were generally well tolerated and showed pharmacodynamics [what medicine does to the body] effects suggestive of a protective effect against vaso-occlusion,” the study concluded.