The Role of ADAMTS13 Activity Levels on Disease Exacerbation or Relapse in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura: Post Hoc Analysis of the Phase 3 HERCULES and Post-HERCULES Studies

Introduction: The management of exacerbations and disease relapse is an important aspect of treatment and follow-up of patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), also known as acquired TTP. Severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency during clinical remission is associated with risk of relapse and may guide prophylactic immune-modulatory therapy. We further evaluated ADAMTS13 activity as a potential biomarker of exacerbation or relapse risk in the HERCULES and post-HERCULES studies, which assessed the efficacy and safety of caplacizumab in patients with iTTP.

Methods: This is a post hoc analysis of integrated data from the HERCULES and post-HERCULES studies. The Phase 3 HERCULES study (NCT02553317) was a double-blind, randomized controlled trial comparing the efficacy and safety of caplacizumab versus placebo, both administered in conjunction with standard-of-care (therapeutic plasma exchange [TPE] and immunosuppressive therapy), in patients with iTTP. ADAMTS13 activity levels were determined at baseline, weekly during the treatment period starting with the first day after end of TPE, and twice during follow-up. Post-HERCULES (NCT02878603) was a 3-year follow-up study of patients who completed the HERCULES study per protocol. Patients in the modified intention-to-treat (mITT) population from HERCULES were included in the analysis (all patients who received at least 1 dose of caplacizumab or placebo) and were followed until the end of HERCULES or post-HERCULES for patients who did not or did enroll in post-HERCULES, respectively. Risk of recurrence (including exacerbations and relapses) was assessed according to ADAMTS13 activity at baseline or end of study drug treatment. Recurrence was defined based on adverse event codes of "thrombotic thrombocytopenic purpura.” For events during HERCULES, exacerbations were defined as recurrences during the double-blind treatment period post-TPE, and relapses as recurrences after the double-blind treatment period. For events during post-HERCULES, exacerbations were defined as recurrences occurring ≤30 days after end of study treatment, and relapses occurring >30 days after end of study treatment. Cox models were performed to test associations between ADAMTS13 levels and time to first recurrence.

Results: Of 144 patients in the HERCULES mITT population, 49 (34%) had a recurrence during HERCULES or post-HERCULES. Baseline ADAMTS13 activity was <10% in 91.8% (45/49) of patients who had a recurrence, and in 83.2% (79/95) of patients without recurrence (P=0.206). There was a trend for reduced risk of first recurrence corresponding to a 10% increase in screening/baseline ADAMTS13 activity, with a hazard ratio (HR) of 0.695 (95% CI: 0.447, 1.081).

In the HERCULES mITT population 140/144 patients had follow-up data after end of HERCULES study drug treatment. Of these patients, 39 (28%) had a recurrence in HERCULES or post-HERCULES after the end of treatment and their mean (SD) ADAMTS13 activity was 20.5% (28.7) compared with 54.0% (34.9) in patients without recurrence (P<0.0001). The proportion of patients with an ADAMTS13 activity <20% at end of treatment was 69.2% (27/39) and 27.1% (26/96) among those with and without recurrence, respectively (P<0.0001). Higher ADAMTS13 activity at end of study drug treatment was associated with a reduced risk of subsequent recurrence, with an HR of 0.772 (95% CI: 0.690, 0.864) corresponding to a 10% increase in ADAMTS13 activity level. Similarly, evaluating time to first exacerbation and relapse separately yielded HRs (95% CI) of 0.726 (0.623, 0.847) and 0.831 (0.706, 0.979), respectively. Risk of first recurrence was also significantly greater in patients with an ADAMTS13 activity of <20% vs ≥20% (HR 4.429 [95% CI: 2.238, 8.765]; P<0.0001) at end of treatment. Similar trends were observed across both the caplacizumab and placebo treatment groups, with lower mean ADAMTS13 activity associated with risk of recurrence (Table).

Conclusion: Regardless of the treatment received (caplacizumab or placebo), lower ADAMTS13 activity levels at end of treatment were associated with a higher risk of recurrence in the HERCULES and post-HERCULES studies. These data highlight the predictive value of ADAMTS13 levels on the risk of recurrence and may assist clinical decision making in the treatment of iTTP.

Kremer Hovinga Strebel:Ablynx/Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Baxter, now part of Takeda: Research Funding; CSL Behring: Honoraria; Roche: Honoraria. de la Rubia:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Ablynx/Sanofi: Honoraria; GSK: Honoraria. Pavenski:Pfizer: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria, Other: Participated in studies; Alexion: Consultancy, Honoraria, Other: Participated in studies; Bioverativ/Sanofi: Consultancy, Honoraria, Other: Participated in studies; Ablynx/Sanofi: Consultancy, Honoraria, Other: Participated in studies. Metjian:Shire/Takeda: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ablynx/Sanofi Aventis: Consultancy, Research Funding. Knoebl:Biotest: Honoraria; Alexion: Honoraria; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Shire/Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ablynx/Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Peyvandi:Grifols: Honoraria; BioMarin: Honoraria; Roche: Honoraria; Takeda: Honoraria; Sobi: Honoraria; Sanofi: Honoraria. Cataland:Takeda: Consultancy; Alexion: Consultancy; Sanofi: Consultancy. Coppo:SANOFI ALEXION TAKEDA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khan:Seattle Children's Hospital: Ended employment in the past 24 months; Sanofi: Current Employment, Current equity holder in private company. Menapace:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Marques:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Gunawardena:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Scully:Shire: Research Funding; Novartis: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Ablynx/Sanofi: Consultancy, Honoraria.