Journal Club – TTP

Scully M, Antun A, Cataland SR, Coppo P, Dossier C, Biebuyck N, Hassenpflug WA, Kentouche K, Knöbl P, Kremer Hovinga JA, López-Fernández MF, Matsumoto M, Ortel TL, Windyga J, Bhattacharya I, Cronin M, Li H, Mellgård B, Patel M, Patwari P, Xiao S, Zhang P, Wang LT; cTTP Phase 3 Study Investigators. Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2024 May 2; 390(17):1584-1596.

Clinical Question

In patients with congenital thrombotic thrombocytopenic purpura (TTP), what is the efficacy and safety of routine prophylaxis or on demand treatment with recombinant ADAMTS13?

Background

Congenital TTP (cTTP) is an extremely rare condition characterized by a severe deficiency (<10% of normal activity) of ADAMTS13. The deficiency of this metalloproteinase leads to the formation of ultralarge von Willebrand factor multimers, which have a high affinity for binding platelets. Platelet microthrombi form and lodge in the microvasculature causing ischemia and an acute TTP event. The formation of platelet mirothrombi underpin the clinical presentation of acute TTP. Such symptoms include thrombocytopenia, hemolytic anemia, abdominal pain, headache and neurologic symptoms (including stroke). Pregnancy, infections and trauma all can induce acute TTP events. The standard therapy for TTP includes replenishing ADAMTS13, prophylactically or on demand through administration of fresh frozen plasma, solvent detergent plasma, or ADAMTS13 containing plasma derived factor VIII (FVIII)-von Willebrand factor (vWF) concentrates. These products rely on a donor population and are limited in their content of ADAMTS13. Additionally, they require time consuming infusions/transfusions which maybe complicated by allergic reactions.

This phase III randomized controlled cross over trail was undertaken to examine safety and efficacy in administration of recombinant ADAMTS13 (rADAMTS13) or standard therapy for prophylactic and on demand treatment of cTTP in children and adults.

Guidelines

The ISTH recommends:

• Strong: Prophylactic plasma infusion during pregnancy.
• Conditional: Plasma infusion or watchful waiting outside of pregnancy.
• Conditional: Use of plasma over FVIII-vWF concentrates due to low ADAMTS13 content in the latter.

Study Design:

• Type: Phase III, multinational, open-label, randomized, controlled, two-period crossover trial
• Sites: 34 centers in the EU, US, UK, and Japan
• Enrollment Period: October 2017 – August 2022
• Participants: n= 48:
  • Prophylactic Cohort:
    • Given either weekly or every 2 weeks, consisted of 3 periods, each lasting 6 months:
      • Periods 1 and 2: Two 6-month periods of prophylaxis with rADAMTS13 or standard therapy followed by the alternate treatment
      • Period 3: Followed by another 6 months of rADAMTS13 40 IU
  • On-demand Cohort: given for acute TTP events
  • Standard Therapy:
    • Choice of 3 pooled plasma products:
      • Fresh frozen plasma
      • Plasma treated with solvent detergent process
      • Plasma derived FVIII: vWF concentrates
  • Recombinant ADAMTS13 (rADAMTS13):
    • Dose 40 IU /kg on day 1, 20 IU /kg day 2 and 15 IU/kg daily from day 3 until 2 days after the acute TTP event had resolved.
    • After resolution of the acute TTP event, the on-demand cohort could opt to join the prophylactic cohort.
  • Recombinant ADAMTS13 then standard Therapy: n=21
  • Standard Therapy then recombinant ADATMS13: n=27
• Washout period:
  • 7 days for prophylactic infusion
  • 5 days for FVIII: VWF concentrates
• Follow-up period:
  • First pharmacokinetics (PK-1) assessment occurred after first dose rADAMTS13, or standard therapy followed by the alternate infusion.
  • Second pharmacokinetics (PK-2) assessment after Periods 1 & 2 to assess comparability of rADAMTS13 manufactured in Austria and in Singapore.
  • Third pharmacokinetics (PK-3) assessed after period 3 to assess sustained exposure to rADAMTS13.
• Analysis:
  • The trial lacked adequate power to support hypothesis testing.
  • All results were reported as point estimates and 95% confidence intervals.
• Primary outcome:
  • Experiencing an acute TTP event, defined as:
    • Decrease in the platelet count by at least 50% from baseline or to less than 100,000 per microliter, and
    • Elevation of lactate dehydrogenase (LDH) level to more than 2 times the baseline value or more than 2 times the upper limit of the normal range (ULN)
• Secondary efficacy outcomes TTP manifestations defined as:
  • Thrombocytopenia (a decrease in the platelet count by >25% from baseline or to <150,000 per microliter)
  • Elevated LDH level to >1.5 times the baseline value or >1.5 times the ULN
  • Abdominal pain
  • Neurologic symptoms
• Exploratory efficacy outcomes:
  • Composite TTP manifestations:
    • >1 TTP manifestation and subacute TTP events
    • Subacute TTP events were >2 of the following:
      • >1 laboratory measurement: a decrease in platelet count by 25% from baseline or to <150,000 per microliter, an elevated LDH level to >1.5 times the baseline value or >1.5 times the ULN
      • Or organ specific signs or symptoms of TTP
• Adverse events: Fatal or life-threatening events, resulting in prolonged hospitalization, or in persistent or clinically significant disability or a congenital anomaly

Population:

Inclusion Criteria:

• Children and adults (ages 0-70 years) with documented diagnosis of cTTP:
  • Patients < 18 years: enrollment occurred after adult enrollment and exposure to rADAMTS13, details varied based on country.
  • Patients aged ≥16 years required to have a Karnofsky score ≥70% and patients <16 years of age required to have a Lansky score ≥80%.
  • cTTP defined as a hereditary aDAMTS13 deficiency:
    • Confirmed by molecular genetic testing and documented
    • ADAMTS13 activity <10% as measured by the FRETS-VWF73 assay
    • Patients receiving prophylactic therapy were screened immediately before their usual prophylactic infusion
  • Patients were hepatitis C virus negative as confirmed by antibody or polymerase chain reaction testing or the patient was HCV- positive if their disease was chronic but stable.
  • Females of childbearing potential had to present a negative pregnancy test (blood or urine), confirmed ≤7 days before the first administration, and use adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
  • Sexually active males had to use an accepted and effective method of contraception during treatment and for ≥16 days after the last administered dose.
  • Additional inclusion criteria for prophylactic cohort only:
    • No signs of severe TTP (platelet count <100,000/μL and elevation of lactate dehydrogenase >2× upper limit of normal [ULN]) at screening)
    • Patient currently receiving standard therapy prophylactic dosing regimen or had a documents history of ≥1 TTP event and an ability to tolerate standard therapy prophylactic dosing

Exclusion Criteria:

• Diagnosed with a TTP like disorder including acquired TTP.
• Hypersensitivity to hamster proteins.
• History or presence of functional ADAMTS13 inhibitor on screening.
• Medical history of genetic or acquired immune deficiency that interferes with the assessment of product. immunogenicity, including patients who were human immunodeficiency virus–positive with an absolute CD4 count <200/mm3 or who were receiving chronic immunosuppressive drugs.
• Having a diagnosis of severe cardiovascular disease (New York Heart Association class 3–4).
• Having end stage renal disease requiring chronic dialysis.
• Diagnosed with hepatic dysfunction (Serum alanine aminotransferase (ALT) ≥2×ULN, severe hypoalbuminemia <24 g/L, portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices)
• If the patient had another clinically significant concomitant disease that could pose additional risks to the patient
• Patient had treatment with an immunomodulatory drug, excluding topical treatment (e.g., ointments, nasal sprays), within 30 days before enrollment. *Use of corticosteroids in conjunction with administration of fresh frozen plasma to prevent allergic reactions was permitted.
• Patient was planning on receiving another investigational drug within 30 days of enrollment.
• Patient had a history of drug and/or alcohol misuse within the previous 2 years.
• Patient had a progressive fatal disease and/or life expectancy of <3 months.
• As identified by the investigator, the patient was unable or unwilling to cooperate with study procedures.
• The patient had a mental condition rendering them unable to understand the nature, scope, and consequences of the study and/or evidence of an uncooperative attitude.
• The patient was a family member or employee of the sponsor or investigator.
• The patient was pregnant or lactating at the time of enrollment.
• If there were any contraindication to standard therapy medicinal product(s) as per local prescribing information.
• Additional exclusion criteria for prophylactic cohort only:
  • Having experienced an acute TTP episode <30 days before screening.
  • Having an acute illness (e.g. influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, bronchial asthma) at the time of screening

Interventions

• Prophylactic cohort patients were randomized 1:1/ equally using a permuted block algorithm to either rADAMTS13-standard therapy or standard therapy-rADAMTS13.
• On-demand cohort patients were randomized 1:1/equally to rADAMTS13 or standard therapy using a permuted block algorithm.
• rADAMTS13 was administered as a 40 IU/kg by IV infusion at a rate of 2-4 ml per minute once weekly in patients who had previously received standard therapy once weekly or once every two weeks for all other patients.   
• Standard therapy was administered every 1 or 2 weeks or alternatively every 3 weeks. Standard therapy was determined by the investigator and defined by the treatment product and dose at the time of entry into the study.
• If an acute TTP event occurred during the prophylaxis period patients, were to receive the following dose regimen:
  • During rADAMTS13 prophylaxis:
    • Patients were to receive an initial dose of 40 IU/kg rADAMTS13.
    • Patients were to receive a subsequent dose of 20 IU/kg rADAMTS13 on Day 2.
    • Patients were to receive an additional daily dose of 15 IU/kg rADAMTS13 until 2 days after the acute TTP event was resolved (acute TTP event resolution defined as platelet count ≥150,000/μL or platelet count within 25% of baseline OR elevation of lactate dehydrogenase [LDH] ≤1.5× baseline or ≤1.5× upper limit of normal [ULN]).
    • Patients were to continue prophylactic therapy 1 week after their last acute treatment dose.
  • During standard therapy prophylaxis:
    • Patients experiencing an acute TTP event during the prophylaxis period were to receive the investigator-recommended standard treatment and dosing regimen during the acute TTP event.
    • Patients were to continue prophylaxis therapy 1 week after their last acute treatment dose.
  • Investigators could elect to treat a subacute TTP event with one or two additional daily doses of standard therapy/rADAMTS13.

Outcomes (comparisons are rADAMTS13 vs standard therapy in routine prophylaxis vs on demand)

Primary outcome:

• Acute TTP events:
  • 0 events in rADAMTS13 group (N=37)
  • 1 event in standard therapy group (N=38)

Secondary efficacy outcomes:

• Most frequent TTP manifestation was thrombocytopenia (annualized event rate):
  • rADAMTS13: 0.74 (95% CI, 0.37-1.50)
  • Standard therapy:1.73 (95% CI, 0.92- 3.23)

ADAMTS13 activity post-infusion:

• Mean maximum ADAMTS13 activity measured after infusion of rADAMTS13.
• rADAMTS13: 101% of normal (95% CI, 92–109)
• Standard therapy: 19% (95% CI, 15–22)

Adverse Events

• Any adverse event: 71% (rADAMTS13) vs. 84% (standard)
• Adverse event rate related to treatment: rADAMTS13 9% (n=4) vs standard therapy 48% (n=21)
• Dose interruptions: 0 (rADAMTS13) vs. 7 (standard)
• Discontinuations: 0 (rADAMTS13) vs. 1 (standard)

Commentary:

In this study, prophylactic rADAMTS13 was found to be associated with fewer acute TTP exacerbations than standard therapy, however, the study lacked statistical power, to make a statistical conclusion and with a small sample size it is difficult to even infer clinical significance of the event rates between treatments.

The cross over design of the trial enhances internal validity by reducing inter-patient variability as each patient acts as their own control. This minimizes reliance on a large sample size which is an appropriate approach as cTTP is an exceptionally rare disease. Despite a washout period ranging from 5-7 days depending on treatment and ADAMTS13 content of the product, there is potential concern for carryover effects from the previous treatment.

The treatment groups and cohorts were not uniform. The standard therapy group did vary within itself in that patients in the standard therapy group could have received either fresh frozen plasma, plasma treated with solvent detergent or plasma derived factor VIII –von Willebrand factor concentrate. Making a specific comparison on a standard therapy to rADAMTS13 challenging. The prophylactic cohort either received prophylaxis weekly or every 2 weeks which was based on previous treatment and investigator assessment. These differences within the cohort and treatment groups make forming generalizations about them challenging.

The most common adverse events associated with rADAMTS13 were headache, migraine, nasopharyngitis, and diarrhea. The most frequently reported adverse events with rADAMTS13 in periods 1 and 2, although most events were mild. When looking at trial drug interruption or discontinuation no patients receiving rADAMTS13 experienced adverse events leading to interruption or discontinuation. While 7 patients receiving standard therapy had an adverse event leading to trial drug interruption and 1 patient had an adverse event leading to trial discontinuation.

rADAMTS13 may provide more consistent and elevated ADAMTS13 activity, however its long-term adverse events and consequences are uncertain. Of note the safety and efficacy of the drug was not assessed in the pregnant or those planning on conceiving population which warrants acknowledgement. The findings of higher ADAMTS13 activity levels, no neutralizing antibodies to ADAMTS13, shorter infusion time and fewer adverse events in those taking rADAMTS13 makes it a more appealing treatment despite the lack of statistical power. Additional studies further exploring clinical outcomes, safety and efficacy would be of great interest.

This study found with its extremely small and underpowered sample size that in those patients with cTTP taking rADAMTS13 there were no acute TTP events, fewer TTP manifestations, less adverse events, normal ADAMTS13 activity levels achieved and no neutralizing antibodies against rADAMTS13 were detected. With these findings, it is reasonable to consider prophylaxis with rADAMTS13 in specific patients, with cTTP. Additional large-scale, long-term studies are warranted to further define clinical benefits and safety.

Conclusion

Recombinant ADAMTS13 appears to be a promising alternative to plasma-based therapies in cTTP, offering more consistent enzyme activity and a favorable safety profile. While results are encouraging, broader and longer-term data are needed before widespread adoption.

References

1. Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L, Tarawneh R, Valdes J, Peyvandi F. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Oct;18(10):2496-2502. doi: 10.1111/jth.15010. Epub 2020 Sep 11. PMID: 32914526; PMCID: PMC8091490.

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