The investigational drug TRPH-222 (previously known as CAT-02-106), a next-generation antibody-drug conjugate (ADC), is demonstrating early signs of efficacy in the interim results of a multi-center, open-label, monotherapy phase I clinical trial (NCT03682796) in heavily pre-treated patients with relapsed and/or refractory (R/R) B-cell lymphoma (non-Hodgkins lymphoma or NHL), cancer that originates in the lymphatic system. [1]
To date, the majority of antibody-drug conjugates or ADCs in the pipeline are targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
Furthermore, with eight approved drugs on the market, ADCs are emerging as a powerful class of therapeutic agents in oncology and hematology
In the ongoing two-stage phase I study of TRPH-222, which started in February 2019, the drug has been safely administered intravenously to patients at dosages of up to 7.5 mg/kg every three weeks (q3w). The trial is currently ongoing with a 10 mg/kg q3w dose cohort.
Study designDuring the first stage of the study, which was designed to determine the maximum tolerated dose of TRPH-222 as well as assessing the safety, anti-tumor activity, and pharmacokinetics of the drug, investigators observed tumor area reductions in patients with both indolent and aggressive NHL subtypes, and durable responses in follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL) patients.
Early signs of potential therapeutic benefit were seen in the dose-escalation stage of the trial. These observations were based on evaluated data from 19 heavily pre-treated NHL patients, which included five (5) patients confirmed to have had a complete response (CR) at doses of 0.6 to 4.2 mg/kg q3w.
DevelopmentTRPH-222 was originally developed by Catalent Biologics subsidiary Redwood Bioscience.
In 2016 Catalent and Triphase Accelerator signed a collaboration that gave worldwide licensing of TRPH-222 to Triphase, a private drug development company with a primary focus on oncology and with operations in Toronto and San Diego.Triphase has a strategic relationship with Celgene (now Bristol Myers Squibb) for oncology-focused drug development opportunities, including TRPH-222.
Well toleratedThroughout the trial, TRPH-222 has been well-tolerated, with an overall benign safety profile.
For example, the investigators have not observed frequent side effects typically seen with other ADCs containing microtubule-interfering payloads. Events such as elevations in liver enzymes, alterations in blood cell parameters, and peripheral neuropathies, commonly observed with ADCs, have been infrequent and have reversed in all patients.
The feedback from our investigators regarding the overall safety profile of TRPH-222 is very encouraging, noted Nancy Levin, Ph.D., Vice President of Development, Triphase Accelerator, and TRPH-222 program lead.
We find that the current and emerging clinical data provide additional support for our preclinical observations of an excellent safety profile for this molecule, she added.
These interim results indicate that TRPH-222 is a very well-tolerated novel antibody-drug conjugate in this clinical study. The unique molecular design allows a higher delivery of the cytotoxic agent in the tumor bed, and, at the current doses tested, side effects have been mild and manageable, observed Francisco Hernandez-Ilizaliturri, M.D., Chief of the Lymphoma Section at Roswell Park, and lead investigator for the TRPH-222-100 study.
Of interest, clinical activity has been observed even at the lowest dose tested, and five complete remissions have been achieved in previously treated lymphoma patients. Together, our preliminary findings support our hypothesis that TRPH-222 is an active and safe novel targeted agent in B-cell malignancies, Hernandez-Ilizaliturri concluded.
Targeting CD22TRPH-222 is composed of an anti-CD22 antibody, modified to allow site-specific conjugation of a maytansine payload via a non-cleavable linker.The molecular target of the drug, CD22, is a B cell-restricted transmembrane sialoglycoprotein expressed on more than 90% of the surface of B cells in patients with B-cell malignancies and thought to be involved in signal transduction, B cell activation, and regulation.
Because CD22 is expressed on nearly all B-cell malignancies but is essentially absent in other tissues, it is considered a good target for the treatment with targeted therapeutics, including ADCs. Furthermore, with the approval, in 2017, of inotuzumab ozogamicin (CMC-544, Besponsa; Pfizer), for the treatment of R/R CD22-positive B cell ALL and trials including pinatuzumab vedotin (Genentech/Roche) and Epratuzumab (Immunomedics and Bayer), CD22 is a clinically validated target with potential in NHL and acute lymphocytic leukemia (also known as acute lymphoblastic leukemia or ALL). [2][3]
Hematologic cancers are a complex group of diseases, with more than 60 different (sub) types of lymphomas, leukemias, or myelomas that require unique treatment options. Hence, attempts to target CD22 for the treatment of B-cell malignancies by ADCs have not always been successful. One reason for this is that these drugs have demonstrated a limited therapeutic index caused in part by dose-limiting side effects triggered by unacceptably high levels of released cytotoxic payload. As a result, a number of investigational agents could not be dosed high enough to be efficacious in B-cell lymphomas.
TRPH-222, which combines a humanized antibody optimized for site-specific protein-modification conjugation to a cytotoxic payload using Hydrazino-Pictet-Spengler (HIPS) chemistry and a proprietary linker, is based on Catalents proprietary aldehyde tag SMARTag technology. [4][5]
This technology employs natural co-translational modifications found in human cells to create one or more attachment sites at designated positions on protein molecules. These chemical handles are then stably conjugated to payloads (e.g., cytotoxic or effector) to prevent their systemic release.
The SMARTag platform provides precise payload positioning, stable, site-specific conjugation, and defined stoichiometry of drugto-antibody ratios. The control afforded by the technology enables the identification of superior drugs from libraries of differentially designed conjugates.
Preclinical data have suggested that this optimization of payload placement and linker composition, combined with the stability afforded by HIPS chemistry, may lead to better tolerability, efficacy, and expanded therapeutic index as compared to standard maytansine-based ADCs. [1][6][7]
MilestoneAlthough advances in combination chemotherapy, stem cell transplantation, and the advent of rituximab have, over the last 20 years, improved the cure rates for patients with indolent and aggressive NHL, nearly 50% to 60% of patients diagnosed will ultimately fail therapy. As a result, there is a major unmet medical need.
TRPH-222 may offer a potential therapeutic alternative in these heavily pretreated patients if the interim results are confirmed in subsequent clinical studies.
Given the fact that heavily pretreated patients are not usually treated with monotherapy, the observed responses together with the demonstrated safety profile make us feel very excited about the molecule and the SMARTag technology, added Mathias Schmidt, Ph.D., Executive Vice President and Head of Research & Development of Triphase Accelerator.
This is an important interim milestone for the program, and the data are important not only in the context of TRPH-222 but also because they signal broader opportunities for the general application of SMARTag technology to improve ADC tolerability and expand its therapeutic index, said Penelope Drake, Ph.D., Director, Research & Development at Catalent Biologics.Webinar
Experts from Triphase Accelerator and Catalent Biologics plan to present further details in a webinar on Tuesday, May 26, 2020, at 2:00 p.m. EDT (11.00 a.m. PDT) in the ongoing investigational trial and underlying SMARTag technology platform.
Clinical trialsStudy of TRPH-222 in Patients With Relapsed and/or Refractory B-Cell Lymphoma NCT03682796.
Reference[1] TRPH-222 / CD22-4AP. Drug Description ADC Review, Journal of Antibody-drug Conjugates. Online. Last accessed on May 17, 2020[2] Lanza F, Maffini E, Rondoni M, Massari E, Faini AC, Malavasi F. CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults. Cancers (Basel). 2020;12(2):303. Published 2020 Jan 28. doi:10.3390/cancers12020303[3] Advani RH, Lebovic D, Chen A, et al. Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2017;23(5):11671176. doi:10.1158/1078-0432.CCR-16-0772[4] Agarwal P, Kudirka R, Albers AE, et al. Hydrazino-Pictet-Spengler ligation as a biocompatible method for the generation of stable protein conjugates. Bioconjug Chem. 2013;24(6):846851. doi:10.1021/bc400042a[5] Rabuka D, Rush JS, deHart GW, Wu P, Bertozzi CR. Site-specific chemical protein conjugation using genetically encoded aldehyde tags. Nat Protoc. 2012;7(6):10521067. Published 2012 May 10. doi:10.1038/nprot.2012.045[6] Maclaren AP, Levin N, Lowman H. TRPH-222, a novel anti-CD22 antibody-drug conjugate (ADC), has significant anti-tumor activity in NHL xenografts and reduces B cells in monkeys [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl): Abstract nr# 835.[7] Drake PM, Carlson A, McFarland JM, et al. CAT-02-106, a Site-Specifically Conjugated Anti-CD22 Antibody Bearing an MDR1-Resistant Maytansine Payload Yields Excellent Efficacy and Safety in Preclinical Models. Mol Cancer Ther. 2018;17(1):161168. doi:10.1158/1535-7163.MCT-17-0776
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Interim Results of Phase I Study Confirms Safety with Early Signs of Efficacy for TRPH-222 in NHL - OncoZine
