We have previously reported that the proline-rich decapeptide from Bothrops jararaca (Bj-PRO-10c) causes potent and sustained antihypertensive and bradycardic effects in SHR. These activities are independent of ACE inhibition. In the present study, we used the Ala-scan approach to evaluate the importance of each amino acid within the sequence of Bj-PRO-10c (Pyr(1)-Asn(2)-Trp(3)-Pro(4)-His(5)-Pro(6)-Gln(7)-Ile(8)-Pro(9)-Pro(10)). The antihypertensive and bradycardic effects of the analogues Bj-PRO-10c Ala(3), Bj-PRO-10c Ala(7), Bj-PRO-10c Ala(8) were similar to those of Bj-PRO-10c, whereas the analogues Bj-PRO-10c Ala(2), Bj-PRO-10c Ala(4), Bj-PRO-10c Ala(5), Bj-PRO-10c Ala(9), and Bj-PRO-10c Ala(10) kept the antihypertensive activity and lost bradycardic activity considerably. In contrast, Bj-PRO-10c Ala(1) and Bj-PRO-10c Ala(6) were unable to provoke any cardiovascular activity. In summary, we demonstrated that (1) the Pyr(1) and Pro(6) residues are essential for both, the antihypertensive and bradycardic effects of Bj-PRO-10c; (2) Ala-scan approach allowed dissociating blood pressure reduction and bradycardic effects. Conformational properties of the peptides were examined by means of circular dichroism (CD) spectroscopy. The different Ala-scan analogues caused either an increase or decrease in the type II polyproline helix content compared to Bj-PRO-10c. The complete loss of activity of the Pro(6) → Ala(6) mutant is probably due to the fact that in the parent peptide the His(5)-Pro(6) bond can exist in the cis configuration, which could correspond to the conformation of this bond in the bound state. Current data support the Bj-PRO-10c as a promising leader prototype to develop new agents to treat cardiovascular diseases and its co-morbidities.

No abstract

e15626 Background: In 2017, biosimilar trastuzumab (Zedora) became the first biosimilar trastuzumab approved in Brazil. In 2019, biosimilar trastuzumab early data from an active postmarketing surveillance program were presented in ASCO. Now, with an extended follow up and more patients included, we present updated data from the surveillance program. Methods: This is a prospective observational study based on a patient support program. HER2 + breast cancer (BC) who received prescription for biosimilar trastuzumab were invited to participate. After agreement of informed consent, they were followed by periodical phone calls after each infusion and up to 3 months after the end of treatment. Treatment related data and adverse events (AEs) were collected. Results: A total of 76 female patients with HER2 + BC were enrolled in the program between May 2018 and December 2019. 74 patients with median age 51 (range 30 to 80) received at least one biosimilar trastuzumab infusion. Out of these, 52 (70.3%) patients reported 385 AEs all-causality (Table 1). Regarding severity and expectedness, 344 (89.4%) were non-serious AE (243 expected / 101 unexpected) and 41 (10.6%) were serious AE (29 expected / 12 unexpected). Considering all serious unexpected AEs (12), 8 were assessed as unlikely and 4 as likely. For the non-serious unexpected AEs (101) causality assessment was unlikely in 32 AEs, likely in 68 AEs and conditional in 1 AE. The three most frequently reported AEs according to SOC (System Organ Classification) were gastrointestinal disorders 59 (15.3%), general disorders and administration site conditions 57 (14.8%). The five most reported symptoms (PT - Preferential Term) were nausea 15 (3.9%), fatigue 14 (3.6%), infusion reactions 14 (3.6%), diarrhea 9 (2.3%) and insomnia 9 (2.3%). Further monitoring is continued. Conclusions: Nature of AEs for biosimilar trastuzumab are consistent with the label in female patients with HER2 + BC. The risk benefit remains consistent with the label and no new safety signals were detected. [Table: see text]

e14504 Background: In 2017, biosimilar trastuzumab (Zedora) became the first biosimilar trastuzumab approved in Brazil. In May 2018 an active postmarketing surveillance program was instituted. Data from this program was presented in ASCO in 2019 and 2020. Now, with an extended follow up (May 2018 to December 2020) and more patients included, we present updated data from the surveillance program. Methods: This is a prospective observational study to evaluate data from the patient support program. Patients who received prescription for biosimilar trastuzumab were invited to participate. After agreement of informed consent, they were followed by periodical phone calls after each infusion and up to 3 months after the end of treatment. Treatment related data and adverse events (AEs) were collected. Results: A total of 74 reports containing 656 adverse events (AEs) were received from the active postmarketing surveillance program between May 2018 and December 2020. Of the 74 reports, 73 are female patients with HER2+ breast cancer (BC) and 1 is a male patient with gastric adenocarcinoma. The patients mean age was 52 years (31 to 79 years). Regarding to AEs severity and expectedness, 588 (89.63%) were non-serious AE (413 expected / 175 unexpected) and 68 (10.37%) were serious AE (51 expected / 17 unexpected). Considering all serious unexpected AEs (17), 13 were assessed as not related to trastuzumab therapy and 4 were assessed as related to therapy. For the 175 non-serious unexpected AEs, 56 were assessed as not related to therapy and 119 were assessed as related to therapy. The three most frequently reported AEs according to SOC (System Organ Classification) were general disorders and administration site conditions 111 (16.92%), gastrointestinal disorders 98 (14.93%) and nervous system disorders 88 (13.41%). The five most commonly reported adverse events (MedDRA PT - Preferred term) were diarrhea 27 (4.11%), fatigue 24 (3.66%), nausea 22 (3.35%), weight decreased 18 (2.74%) and infusion related reaction 17 (2.59%). Further monitoring is continued. Conclusions: Nature of AEs noted in patients with breast cancer and gastric cancer treated with biosimilar trastuzumab (Zedora) were consistent with the known safety profile of Trastuzumab. The risk benefit remains consistent with the reference safety information and no new safety signals were detected.[Table: see text]