Prasugrel: A Potential Treatment for AERD?

P2Y12 inhibition evaluated as potential AERD treatment mechanism
P2Y12 inhibition evaluated as potential AERD treatment mechanism

ATLANTA, GA—At the 2017 AAAAI Annual Meeting, Tanya M. Laidlaw, MD, FAAAAI, from the Brigham and Women's Hospital, Boston, MA, presented initial findings from a double-blind, placebo-controlled trial of prasugrel, a P2Y12 inhibitor for the treatment aspirin-exacerbated respiratory disease (AERD). 

Dr. Laidlaw and coauthors investigated the approach of targeting P2Y12/platelets in treating AERD. P2Y12 is an ADP-receptor with homology to cysLT1, cysLT2, and cysLT3 (GPR99).  Based on this, the team posit that inhibiting P2Y12 may decrease platelet-leukocyte aggregates, which are increased in AERD and contribute to cysteinyl leukotriene (cysLT) production; cysLT overproduction is common in aspirin reactions. Also, P2Y12 may be required for LTE4-induced inflammation, as "blockade of P2Y12 (or P2Y12+/-) in mice prevented LTE4 from causing pulmonary inflammation/eosinophils," Dr. Laidlaw explained.  

Platelets often attach to white blood cells (WBC) and these aggregates are detected in nasal polyps, in blood and are more frequently seen in AERD. Dr. Laidlaw cited a 2012 study published in Blood comparing percentages of leukocytes with adherent platelets (CD61+) in blood of non-asthmatic controls (n=9), aspirin-tolerant controls (n=13), and in AERD (n=15). A 2003 study in Clinical Pharmacology & Therapeutics  found more monocyte-platelet aggregates in untreated patients with atherosclerosis (n=7) vs. patients receiving clopidogrel (n=12), further supporting that P2Y12 inhibition reduces formation of platelet-leukocyte aggregates.

To test this potential treatment mechanism, study authors conducted a randomized, double-blind, placebo-controlled trial of prasugrel in 50 patients with AERD. At the screening visit of Part 1, patients were initiated on montelukast treatment for 4 weeks if they were not started already. After 4 weeks, patients were randomized to receive either prasugrel or placebo. After 4 weeks, they were given the first aspirin challenge (visit 2) at doses of 40.5mg, 81mg,162mg, and 325mg as tolerated. This was followed by a 2-week washout period except montelukast and the patient's previous medications. Patients were then crossed over for 4 weeks to either placebo or prasugrel. 

The second aspirin challenge was administered (desensitization) at visit 3 with the same 4 doses. Part 2 of the trial consisted of daily high-dose aspirin (650mg twice daily) administered for 8 weeks. Researchers assessed CBC differential, total nasal symptom score (TNSS), ACT, physical exam, vital signs, and FEV1.

The primary objective of Part 1 was "to determine whether blocking P2Y12 receptors in a double-blinded placebo-controlled trial of prasugrel attenuates the severity of reactions to aspirin in individuals with AERD." The study's primary outcome was the difference in provocative dose that causes an increase in TNSS of 2 (PD2) during aspirin challenge between treatment with prasugrel vs. placebo. The data showed between visits 1 and 4, there was no change in platelet activation. Prasugrel did not appear to decrease platelet activation (CD62P) and there was no change seen in WBC-platelet adherence, added Dr. Laidlaw. Moreover, the study did not report change in any of the urinary eicosanoid levels (AA metabolites). Five patients ultimately showed no reaction while on prasugrel ("responders") whereas 35 patients did ("non-responders"). 

In conclusion, platelet CD62P and platelet-WBC adherence did not change with prasugrel therapy, aspirin challenge, and high-dose aspirin therapy. There was a rise in urinary LTE4 and PGD-M levels during aspirin reactions, and a decrease in PGE-M and TXB2 during high-dose aspirin therapy. "In [the] whole AERD population, prasugrel treatment does not attenuate severity of ASA-induced reactions (PD2)," stated Dr. Laidlaw, although a "possible subset of AERD with more platelet activation does respond to prasugrel treatment." A future responder subset analysis will explore this P2Y12 polymorphism. 

Based on the findings, study authors observed that perhaps the mechanism does not rely on P2Y12 and that a different platelet inhibitor could possibly be effective. Data on demographics, detailed clinical responses, changes in CBC differential, and comparison with aspirin-tolerant and healthy controls will be announced when the data becomes available.