Delving into the Latest Updates on Rimiducid with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Rimiducid (USAN/INN), AP-1903

Target

FKBP12

Mechanism

FKBP12 (FK506-binding protein 1A ligand)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

B lymphoblastic leukemia lymphoma

Inactive Indication

Congenital Bone Marrow Failure SyndromesGraft vs Host DiseaseHemoglobinopathies+ [6]

Originator Organization

ARIAD Pharmaceuticals, Inc.

Active Organization

Bellicum Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

Structure

Molecular FormulaC78H98N4O20

InChIKeyGQLCLPLEEOUJQC-ZTQDTCGGSA-N

CAS Registry195514-63-7

Vimentin is a main type 3 intermediate filament protein. It seems that abnormal expression of vimentin is contributed to the appearance of the aggressive feature of cancer cells. So that it has been reported that malignancy and epithelial-mesenchymal transition in solid tumors, and poor clinical outcomes in patients with lymphocytic leukemia and acute myelocytic leukemia have been associated with the high expression of vimentin. Vimentin is a non-caspase substrate of caspase-9 although its cleavage by caspase-9 in biological processes has not been reported. In the present study, we sought to understand whether vimentin cleavage mediated by caspase-9 could reverse the malignancy in leukemic cells. Herein, to address the issue, we investigated vimentin changes in differentiation and took advantage of the inducible caspase-9 (iC9)/AP1903 system in human leukemic NB4 cells. Following the transfection and treatment of the cells using the iC9/AP1903 system, vimentin expression, cleavage, and subsequently, the cell invasion and the relevant markers such as CD44 and MMP-9 were evaluated. Our results revealed the downregulation and cleavage of vimentin which attenuates the malignant phenotype of the NB4 cells. Considering the favorable effect of this strategy in keeping down the malignant features of the leukemic cells, the effect of the iC9/AP1903 system in combination with all-trans-retinoic acid (ATRA) treatment was evaluated. The obtained data prove that iC9/AP1903 significantly makes the leukemic cells more sensitive to ATRA.

01 May 2023·Cell proliferation

Genome editing HLA alleles for a pilot immunocompatible hESC line in a Chinese hESC bank for cell therapies.

Article

Author: Wang, Lei ; Zou, Jun ; Hu, Zheng ; Xu, Fei ; Wang, Xin ; Yang, Yong-Guang ; Xu, Ling-Xue ; Ji, Tian-Tian ; Zhang, Meng ; Niu, Rui ; Fang, Ming-Hui ; Wu, Jun ; Hao, Jie ; Li, Zhi-Kun ; Li, Wei ; Zhou, Qi ; Niu, Shuai-Shuai

Robust allogeneic immune reactions after transplantation impede the translational pace of human embryonic stem cells (hESCs)-based therapies. Selective genetic editing of human leucocyte antigen (HLA) molecules has been proposed to generate hESCs with immunocompatibility, which, however, has not been specifically designed for the Chinese population yet. Herein, we explored the possibility of customizing immunocompatible hESCs based on Chinese HLA typing characteristics. We generated an immunocompatible hESC line by disrupting HLA-B, HLA-C, and CIITA genes while retaining HLA-A*11:01 (HLA-A*11:01-retained, HLA-A11^R ), which covers ~21% of the Chinese population. The immunocompatibility of HLA-A11^R hESCs was verified by in vitro co-culture and confirmed in humanized mice with established human immunity. Moreover, we precisely knocked an inducible caspase-9 suicide cassette into HLA-A11^R hESCs (iC9-HLA-A11^R ) to promote safety. Compared with wide-type hESCs, HLA-A11^R hESC-derived endothelial cells elicited much weaker immune responses to human HLA-A11⁺ T cells, while maintaining HLA-I molecule-mediated inhibitory signals to natural killer (NK) cells. Additionally, iC9-HLA-A11^R hESCs could be induced to undergo apoptosis efficiently by AP1903. Both cell lines displayed genomic integrity and low risks of off-target effects. In conclusion, we customized a pilot immunocompatible hESC cell line based on Chinese HLA typing characteristics with safety insurance. This approach provides a basis for establishment of a universal HLA-A^R bank of hESCs covering broad populations worldwide and may speed up the clinical application of hESC-based therapies.

01 Sep 2022·Cancer immunology research

Design and Validation of Inducible TurboCARs with Tunable Induction and Combinatorial Cytokine Signaling

Article

Author: Park, Spencer ; Lin, Regina J. ; Sutton, Janette ; Lay, Cecilia ; Chaparro-Riggers, Javier ; Blarcom, Thomas J. Van ; Zhang, Yi ; Boldajipour, Bijan ; Sasu, Barbra J. ; Melton, Zea ; Panowski, Siler H. ; Nager, Andrew R.

Abstract:

Although cytokine support can enhance CAR T-cell function, coadministering cytokines or engineering CAR T cells to secrete cytokines can result in toxicities. To mitigate these safety risks, we engineered iTurboCAR T cells that coexpress a novel inducible Turbo (iTurbo) cytokine signaling domain. iTurbo domains consist of modular components that are customizable to a variety of activating inputs, as well as cytokine signaling outputs multiplexable for combinatorial signaling outcomes. Unlike most canonical cytokine receptors that are heterodimeric, iTurbo domains leverage a compact, homodimeric design that minimizes viral vector cargo. Using an iTurbo domain activated by the clinically validated dimerizer, AP1903, homodimeric iTurbo domains instigated signaling that mimicked the endogenous heterodimeric cytokine receptor. Different iTurbo domains programmed iTurboCAR T cells toward divergent phenotypes and resulted in improved antitumor efficacy. iTurbo domains, therefore, offer the flexibility for user-programmable signaling outputs, permitting control over cellular phenotype and function while minimizing viral cargo footprint.

18

News (Medical) associated with Rimiducid

06 Apr 2023

·www.drugs.com

CAR T Cells Targeting GD2 Feasible, Safe for Pediatric Neuroblastoma

THURSDAY, April 6, 2023 -- Chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells (GD2-CAR T cells) are feasible and safe for children with heavily pretreated neuroblastoma, according to a study published in the April 6 issue of the New England Journal of Medicine . Francesca Del Bufalo, M.D., from IRCCS Ospedale Pediatrico Bambino Gesù in Rome, and colleagues conducted a phase 1/2 clinical trial involving 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and one with a complete response at the end of first-line therapy) who received GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). The researchers observed no failure to generate GD2-CART01. In the phase 1 part of the trial, three dose levels were tested (3-, 6-, and 10x10 6 CAR-positive T cells/kg body weight), with no dose-limiting toxic effects reported. For the phase 2 part of the trial, the recommended dose was 10x10 6 CAR-positive T cells/kg. In 74 percent of patients, cytokine release syndrome occurred and was mild in all but one patient. The suicide gene was activated in one patient, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo; up to 30 months after infusion, they were detectable in peripheral blood in 26 of 27 patients. Overall response was 63 percent, with nine and eight patients having a complete and partial response, respectively. Three-year overall survival and event-free survival were 60 and 36 percent, respectively, among children receiving the recommended dose. "GD2-CART01 may induce sustained eradication of disease in a proportion of patients with relapsed or refractory neuroblastoma," the authors write. Bellicum Pharmaceuticals donated rimiducid for the trial. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted April 2023

Cell TherapyPhase 1Clinical ResultImmunotherapy

15 Mar 2023

·www.fiercebiotech.com

Bellicum’s GoCAR-Ts crash out of clinic over safety signal, sparking search for strategic alternatives

Bellicum was running phase 1/2 clinical trials of two GoCAR-T candidates. Bellicum Pharmaceuticals’ GoCAR-T cell therapies have skidded out, with the biotech halting trials of the two candidates over dose-limiting toxicities. The evaporation of Bellicum’s pipeline prompted the CAR-T cell therapy specialist to start an evaluation of strategic alternatives. Houston-based Bellicum was running phase 1/2 clinical trials of two CAR-T candidates, namely the PSCA prospect BPX-601 and the HER2 candidate BPX-603. Both assets use the biotech’s GoCAR-T technology. BPX-601 expresses a rimiducid-inducible co-activation switch to enhance T cell potency and persistence. And BPX-603 features both the co-activation switch and a CaspaCIDe safety switch. Bellicum pitched the switches as ways to boost effector cell proliferation, enhance functional persistence and empower physicians to wipe out the CAR-T cells in the event of a serious side effect such as cytokine release syndrome. Yet, the early data on the candidates have discouraged Bellicum. The most recent metastatic castration-resistant prostate cancer patient to receive BPX-601 experienced serious immune-mediated adverse events including grade 4 cytokine release syndrome. The adverse events marked the second time Bellicum has seen a dose-limiting toxicity in that dose escalation cohort. In response, the biotech paused enrollment and reviewed the data. The review showed four of the nine prostate cancer patients experienced a 90% or greater reduction in the PSA biomarker. But also revealed the need to optimize either the clinical dose and schedule of BPX-601 and the activating agent rimiducid, or the design of the BPX-601 cell construct to make the benefits outweigh the risks. Bellicum, which ended September with $28.8 million to its name, lacks the cash to pull off the BPX-601 rescue mission, leading it to stop clinical trials of the candidate and its other pipeline prospect BPX-603. With all clinical development winding down, the biotech is now evaluating strategic alternatives. The initiation of the evaluation suggests Bellicum’s drawn-out demise is now nearing the end. Back in 2014, the biotech was one of three CAR-T cell therapy developers to arrive on Nasdaq. The other two cell therapy developers—Kite Pharma and Juno Therapeutics—went on to land multi-billion dollar buyouts and deliver commercial products. Bellicum has looked unlikely to follow in the footsteps of the other members of the CAR-T class of 2014 for several years. In 2020, the company laid off 79% of its employees after BPX-601 delivered lackluster safety and efficacy data.

Cell TherapyImmunotherapyClinical Study

15 Mar 2023

·pipelinereview.com

Bellicum Discontinues Phase 1/2 Trials and Initiates Evaluation of Strategic Alternatives

HOUSTON, TX, USA I March 14, 2023 I Bellicum Pharmaceuticals, Inc. (Nasdaq: BLCM), today announced its decision to discontinue its ongoing Phase 1/2 clinical trials evaluating the safety and preliminary efficacy of its GoCAR-T cell product candidates in combination with rimiducid in heavily pre-treated cancer patients. The trials for BPX-601 and BPX-603 are being discontinued following the Company’s assessment of the risk/benefit profile of BPX-601 in combination with rimiducid. The most recent patient treated in the Phase 1/2 trial of BPX-601 in metastatic castration-resistant prostate cancer (mCRPC) experienced serious immune-mediated adverse events including Grade 4 cytokine release syndrome (CRS), the second dose-limiting toxicity observed in this cohort of dose escalation. The company paused enrollment in its clinical studies and conducted a thorough review of the risk/benefit observed to date. While clinically meaningful efficacy has been observed—including 5 of 9 mCRPC patients treated achieving PSA50 response, 4 of whom achieved PSA90 response—the Company believes it does not have the necessary resources to optimize either the clinical dose and schedule of BPX-601 cells and the activating agent rimiducid, or the design of the BPX-601 cell construct to achieve a favorable risk/benefit profile. The Company is communicating with clinical trial sites and regulatory agencies regarding its decision to discontinue its trials, and an evaluation of the Company’s strategic alternatives is underway. More information about Bellicum can be found at www.bellicum.com . SOURCE: Bellicum Pharmaceuticals

Cell TherapyClinical StudyClinical Result

100 Deals associated with Rimiducid

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External Link

KEGG	Wiki	ATC	Drug Bank
D11195	-	-	DB04974

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Graft vs Host Disease	Phase 2	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
Leukemia	Phase 2	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
Multiple Myeloma	Phase 2	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
Myelodysplastic Syndromes	Phase 2	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
B lymphoblastic leukemia lymphoma	Phase 2	US	Bellicum Pharmaceuticals, Inc.	-
Congenital Bone Marrow Failure Syndromes	Phase 1	US	Bellicum Pharmaceuticals, Inc.	01 Feb 2015
Hemoglobinopathies	Phase 1	US	Bellicum Pharmaceuticals, Inc.	01 Feb 2015
Lymphohistiocytosis, Hemophagocytic	Phase 1	US	Bellicum Pharmaceuticals, Inc.	01 Feb 2015
Metabolic Diseases	Phase 1	US	Bellicum Pharmaceuticals, Inc.	01 Feb 2015
Primary Immunodeficiency Diseases	Phase 1	US	Bellicum Pharmaceuticals, Inc.	01 Feb 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02231710 (CTgov)	Phase 1	Graft vs Host Disease \| Lymphohistiocytosis, Hemophagocytic \| Metabolic Diseases ... View more	1	Rimiducid+BPX-501	nemcbsjymm(rhcoumexpz) = xbzdklfiwo ofwjnucynt (curyqodnes, vapvyzxlfp - okiktxpqgd) View more	-	25 Mar 2024
NCT02743611 (CTgov)	Phase 1/2	Acute Myeloid Leukemia \| Uveal Melanoma \| Myelodysplastic Syndromes	4	BPX-701 (DLT Population)	xinxpcdrfk(nfneukvdye) = kvovtmddis zijjspkqdk (msrvodksyw, ehbiifivtj - qhxeyqbdjg)	-	05 Oct 2023
NCT02743611 (CTgov)	Phase 1/2		4	BPX-701 T cells+rimiducid+BPX-701 (Arm 1 Part 1: Dose Escalation)	qcwlrraufi(bgypnobzfu) = pihgvytzih ssluvdzzfp (sgnndrhzpq, fpcppwucnx - feksoezjrx) View more	-	05 Oct 2023
NCT02744287 (ASCO_GU2023) Manual	Phase 1	Metastatic castration-resistant prostate cancer Third line	7	BPX-601 5 x 106 cells/kg+rimiducid 0.4 mg/kg	rhcssrwlgw(jmykwujbdd) = tdcrlmpokd folckryqhu (ukhegjnnyc ) View more	Positive	21 Feb 2023
NCT03958656 (CTgov)	Phase 1	Multiple Myeloma	13	Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) - Chimeric antigen receptor (CAR) + T cells (LEVEL 1 - 0.66x10^6 Per Kilogram (kg))	tncqcilpsj(oyenkeavuw) = vbiocqycue oxqnlgzsym (dkoqshcujc, gynhjshuah - ydhdvtlszk) View more	-	09 Sep 2021
NCT03958656 (CTgov)	Phase 1	Multiple Myeloma	13	Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) - Chimeric antigen receptor (CAR) + T cells (LEVEL 2 - 2.0x10^6 Per kg)	tncqcilpsj(oyenkeavuw) = tqkkczqqlb oxqnlgzsym (dkoqshcujc, jizbhjmdiw - jfcbwmwkog) View more	-	09 Sep 2021
NCT02065869 (BP-004, Corporate Publications) Manual	Phase 2	Hematopoietic stem cell transplantation	-	Rivogenlecleucel+rimiducid	cmusvpypge(occtutjqml) = jmzihpohty rxqwzzmkkn (yshuxdlfpl, 84.8 ~ 94.6)	Positive	08 Jul 2019