Background: Current treatment options (eg, hydroxyurea, chronic blood infusions, and bone marrow or stem cell transplantation) for the prevention of sickle cell disease (SCD) complications vary in effectiveness and are associated with safety risks/tolerability issues. PF-04447943, a selective inhibitor of the cyclic guanosine monophosphate−specific phosphodiesterase-9A enzyme, is being developed for prophylactic therapy to reduce the incidence and/or severity of vaso-occlusive crises in patients with SCD. Herein, we report on the safety and tolerability of PF-04447943, based on a large data set from the clinical trial program.

Methods: The PF-04447943 safety database includes data from 8 phase 1 studies in healthy adult and elderly subjects, a phase 2 study in patients with Alzheimer's disease (AD) from a previous development program, and a phase 1b study in stable SCD patients. Study durations ranged from 1 day to 3 months. Data are presented descriptively.

Results: Safety data for 277 patients receiving PF-04447943 were available. Frequently reported treatment-emergent adverse events (TEAEs) were headache, diarrhea, and nausea, which were generally mild in severity. In the phase 1 thorough QTc (TQT) study (N=44; study duration, 28 days), at therapeutic and supratherapeutic doses, PF-04447943 was not associated with QTc interval prolongation that met the threshold of clinical concern, based on ICH E14 criteria. In the phase 2 study of the AD development program (PF-04447943, n=91; placebo, n=100; study duration 12 weeks), the incidence of TEAEs was 63.7% with PF-04447943 and 58.0% with placebo. Incidence of all-causality AEs in the gastrointestinal disorders class (including abdominal pain, diarrhea, dry mouth, dyspepsia, gastroesophageal reflux disease, intestinal obstruction, nausea, and upper gastrointestinal hemorrhage) was higher with PF-04447943 (19.8%) vs placebo (5.0%); no other notable differences were observed. In the phase 1b study in SCD patients (safety analysis set: PF-04447943, n=22; placebo, n=7; study duration, 29 days plus 28 days follow-up), nervous system disorder TEAEs (eg, headache) occurred more frequently with PF-04447943 (25 mg BID, 60.0%; 5 mg BID, 57.1%) vs placebo (28.69%). In total, 6 serious AEs (sickle cell anemia with crisis, n=4 [one patient had 3 crises, of which 2 occurred during the follow-up period]; pneumonia, n=1; biliary colic, n=1) occurred in 3 patients receiving PF-04447943; all were consistent with the course of SCD and were not considered to be treatment related.

Conclusion: Review of the safety database for PF-04447943, which includes 277 patients who received the study drug, indicates that PF-04447943 is generally well tolerated, with no major safety signals. Planned long-term, phase 2 and 3 studies of PF-04447943 in patients with SCD will provide additional safety data in this population.


Charnigo: Pfizer: Employment. Tan: Pfizer Inc: Employment. Rybin: Pfizer: Employment. Pittman: Pfizer: Employment. Sivamurthy: Pfizer Inc: Employment. Beidler: Pfizer: Employment. Clarke: Pfizer Inc: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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