Long‐term follow‐up of patients treated with caplacizumab and safety and efficacy of repeat caplacizumab use: Post‐HERCULES study

Scully, Marie; Rubia, Javier de la; Pavenski, Katerina; Metjian, Ara; Knöbl, Paul; Peyvandi, Flora; Cataland, Spero R.; Coppo, Paul; Hovinga, Johanna A. Kremer; Edou, Jessica Minkue Mi; Sousa, R.; Callewaert, Filip; Gunawardena, Sriya; Lin, Julie

doi:10.1111/jth.15892

Cited by 18 publications

(14 citation statements)

References 36 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The safety and efficacy of treatment with caplacizumab have also been demonstrated in long-term outcomes. The post-HERCULES study was recently published (40), in which the patients of the HERCULES study were followed for three more years. The results showed that the safety profile was similar to that previously reported and was equally effective for the control of recurrent episodes of aTTP.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia

Soto-Mora,

Gómez-Espitia,

Lasalvia

et al. 2023

Int J Technol Assess Health Care

View full text Add to dashboard Cite

Objectives Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological disease whose clinical management includes caplacizumab along with plasma exchange and immunosuppression, according to international guidelines. Caplacizumab has been available in Colombia since 2022. This study seeks to determine the therapeutic classification of caplacizumab according to the methodology of the Instituto de Evaluación Tecnológica en Salud. Methods The classification was carried out through a deliberative process following the modified Delphi technique, with a panel of experts, made up of four hemato-oncologists, a pharmaceutical chemist, and a patient. The results of effectiveness and safety obtained through a systematic review, therapeutic thresholds (clinical significance), and degree of acceptability (willingness to use the technology) were used for the classification. Results Fourteen effectiveness and safety outcomes were submitted for the classification process. Caplacizumab showed clinical significance for some effectiveness outcomes, was not considered inferior in terms of safety, and displayed acceptability of use. Through consensus, the panel determined that caplacizumab plus the standard regimen is superior to the standard regimen in terms of treatment response and composite outcome, and no different for the other effectiveness and safety outcomes. Likewise, in overall terms, the panel determined that caplacizumab together with the standard regimen is superior to the standard regimen. Conclusion Treatment with caplacizumab together with the standard regimen was considered superior to the standard regimen for the treatment of patients with aTTP, as it showed clinically significant benefits in critical outcomes for decision making, and a safety profile no different to its comparator.

show abstract

Section: Discussionmentioning

confidence: 99%

Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia

Soto-Mora,

Gómez-Espitia,

Lasalvia

et al. 2023

Int J Technol Assess Health Care

View full text Add to dashboard Cite

show abstract

“…Relapses, however, were more common among caplacizumab- treated patients in both studies ( 7 , 8 ). Despite the safety and efficacy of caplacizumab, several questions remained unanswered by these randomized clinical trials and the subsequent analyses ( 9 ). Caplacizumab has also been used in pregnancy ( 10 ) and for treatment of pediatric patients ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Caplacizumab for immune thrombotic thrombocytopenic purpura: real-world multicenter data

Gavriilaki,

Nikolousis,

Koravou

et al. 2023

Front. Med.

View full text Add to dashboard Cite

Given the limited real-world data of caplacizumab, our multicenter real-world study was designed to assess the safety and efficacy of caplacizumab in immune thrombotic thrombocytopenic pupura (iTTP), compared to historic controls. We have studied 70 patients: 23 in the caplacizumab and 47 in the historic control group. Plasma exchange was applied in all episodes except for two patients that denied plasma exchange. Rituximab as first-line treatment was more common in the caplacizumab group compared to historic control. Caplacizumab (10 mg daily) was given at a median on day 7 (1–43) from initial diagnosis for 32 (6–47) dosages. In the caplacizumab group, a median of 12 (8–23) patients required plasma exchange sessions versus 14 (6–32) in the control group. Caplacizumab administration did not produce any grade 3 complications or major hemorrhagic events. After a median of 19.0 (2.6–320) months since the iTTP diagnosis, 5 deaths occurred (4 in the control group and 1 in the caplacizumab group, p = 0.310). Caplacizumab patients achieved early platelet normalization and ADAMTS13 activity normalization at the end of treatment. Relapse was observed only in 2/23 (9%) caplacizumab patients, compared to 29/47 (62%) historic controls (p < 0.001). Overall, caplacizumab is safe and effective in treating iTTP, including cases refractory to plasma exchange, re-administration, and cases without previous plasma exchange treatment. No major hemorrhagic events were observed. Cessation of dosing guided by ADAMTS13 has ensured a low relapse rate.

show abstract

“…Because of their small size, nanobody systemic kinetics and diffusion within the brain extracellular space may be expected to be relatively fast [ 19 ], though they can be engineered to have prolonged half-lives in blood [ 18 ]. The first approved nanobody therapeutic, caplacizumab-yhdp which targets von Willebrand factor, has proven to be effective for the rapid treatment of thrombotic thrombocytopenic purpura [ 20 – 23 ]. Additional nanobody-based therapeutics approved for human use include ciltacabtagene autoleucel which targets B-cell maturation antigen for multiple myeloma [ 24 ], envafolimab which targets programmed death ligand 1 for solid tumors [ 25 ] and ozoralizumab which targets tumor necrosis factor alpha for rheumatoid arthritis [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced in vivo blood brain barrier transcytosis of macromolecular cargo using an engineered pH-sensitive mouse transferrin receptor binding nanobody

Esparza,

Su,

Francescutti

et al. 2023

Fluids Barriers CNS

View full text Add to dashboard Cite

Background The blood brain barrier limits entry of macromolecular diagnostic and therapeutic cargos. Blood brain barrier transcytosis via receptor mediated transport systems, such as the transferrin receptor, can be used to carry macromolecular cargos with variable efficiency. Transcytosis involves trafficking through acidified intracellular vesicles, but it is not known whether pH-dependent unbinding of transport shuttles can be used to improve blood brain barrier transport efficiency. Methods A mouse transferrin receptor binding nanobody, NIH-mTfR-M1, was engineered to confer greater unbinding at pH 5.5 vs 7.4 by introducing multiple histidine mutations. The histidine mutant nanobodies were coupled to neurotensin for in vivo functional blood brain barrier transcytosis testing via central neurotensin-mediated hypothermia in wild-type mice. Multi-nanobody constructs including the mutant M1R56H, P96H, Y102H and two copies of the P2X7 receptor-binding 13A7 nanobody were produced to test proof-of-concept macromolecular cargo transport in vivo using quantitatively verified capillary depleted brain lysates and in situ histology. Results The most effective histidine mutant, M1R56H, P96H, Y102H-neurotensin, caused > 8 °C hypothermia after 25 nmol/kg intravenous injection. Levels of the heterotrimeric construct M1R56H, P96H, Y102H-13A7-13A7 in capillary depleted brain lysates peaked at 1 h and were 60% retained at 8 h. A control construct with no brain targets was only 15% retained at 8 h. Addition of the albumin-binding Nb80 nanobody to make M1R56H, P96H, Y102H-13A7-13A7-Nb80 extended blood half-life from 21 min to 2.6 h. At 30–60 min, biotinylated M1R56H, P96H, Y102H-13A7-13A7-Nb80 was visualized in capillaries using in situ histochemistry, whereas at 2–16 h it was detected in diffuse hippocampal and cortical cellular structures. Levels of M1R56H, P96H, Y102H-13A7-13A7-Nb80 reached more than 3.5 percent injected dose/gram of brain tissue after 30 nmol/kg intravenous injection. However, higher injected concentrations did not result in higher brain levels, compatible with saturation and an apparent substrate inhibitory effect. Conclusion The pH-sensitive mouse transferrin receptor binding nanobody M1R56H, P96H, Y102H may be a useful tool for rapid and efficient modular transport of diagnostic and therapeutic macromolecular cargos across the blood brain barrier in mouse models. Additional development will be required to determine whether this nanobody-based shuttle system will be useful for imaging and fast-acting therapeutic applications.

show abstract

Long‐term follow‐up of patients treated with caplacizumab and safety and efficacy of repeat caplacizumab use: Post‐HERCULES study

Cited by 18 publications

References 36 publications

Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia

Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia

Caplacizumab for immune thrombotic thrombocytopenic purpura: real-world multicenter data

Enhanced in vivo blood brain barrier transcytosis of macromolecular cargo using an engineered pH-sensitive mouse transferrin receptor binding nanobody

Contact Info

Product

Resources

About