Delving into the Latest Updates on Rimiducid with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Rimiducid (USAN/INN)

Target

FKBP1A

Mechanism

FKBP12 (FK506-binding protein 1A ligand)

Therapeutic Areas

NeoplasmsImmune System DiseasesCongenital Disorders+ [3]

Active Indication

Acute Myeloid LeukemiaAnemia, AplasticHemoglobinopathies+ [4]

Inactive Indication

Castration-Resistant Prostatic CancerCongenital Bone Marrow Failure SyndromesGraft vs Host Disease+ [3]

Originator Organization

ARIAD Pharmaceuticals, Inc.

Active Organization

Bellicum Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC78H98N4O20

InChIKeyGQLCLPLEEOUJQC-ZTQDTCGGSA-N

CAS Registry195514-63-7

AbstractPurpose:Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell–based immunotherapy targeting B7-H3.Experimental Design:B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models.Results:B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody.Conclusions:These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM.

03 Jun 2024·Clinical Cancer Research

GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Article

Author: Manni, Simona ; Orlando, Domenico ; Ottaviani, Alessio ; Sarcinelli, Andrea ; Camera, Antonio ; Marabitti, Veronica ; Caruso, Simona ; Quintarelli, Concetta ; Del Baldo, Giada ; Rossi, Sabrina ; Carai, Andrea ; De Angelis, Biagio ; Iaffaldano, Laura ; De Stefanis, Cristiano ; Sinibaldi, Matilde ; D'Amore, Maria Luisa ; Becilli, Marco ; Mastronuzzi, Angela ; Quadraccia, Maria Cecilia ; Ceccarelli, Manuela ; Giorda, Ezio ; Pezzullo, Marco ; Nazio, Francesca ; Pezzella, Michele ; Guercio, Marika ; Ciccone, Roselia ; Locatelli, Franco ; Alaggio, Rita ; Del Bufalo, Francesca ; Aurigemma, Mariasole ; Di Cecca, Stefano

AbstractPurpose:Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects.Experimental Design:GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9.Results:GD2 was expressed in 82.68% of MB tumors. The SHH and G3–G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood–brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells.Conclusions:Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.

01 Nov 2023·Molecular and Cellular Biochemistry

Caspase-9-mediated cleavage of vimentin attenuates the aggressiveness of leukemic NB4 cells

Article

Author: Mohammadi, Saeed ; Kazemiraad, Cyrus ; Hakim, Fatemeh ; Abdollahpour, Daryoush ; Akbari-Birgani, Shiva

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.

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
Acute Myeloid Leukemia	Phase 2	US	Bellicum Pharmaceuticals, Inc.	01 Apr 2014
Anemia, Aplastic	Phase 2	US	Bellicum Pharmaceuticals, Inc.	01 Apr 2014
Hemoglobinopathies	Phase 2	US	Bellicum Pharmaceuticals, Inc.	01 Apr 2014
Osteopetrosis	Phase 2	US	Bellicum Pharmaceuticals, Inc.	01 Apr 2014
Primary Immunodeficiency Diseases	Phase 2	US	Bellicum Pharmaceuticals, Inc.	01 Apr 2014
Myelodysplastic Syndromes	Phase 2	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
B lymphoblastic leukemia lymphoma	Phase 2	US	Bellicum Pharmaceuticals, Inc.	-
Graft vs Host Disease	Preclinical	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
Leukemia	Preclinical	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013
Multiple Myeloma	Preclinical	US	Bellicum Pharmaceuticals, Inc.	27 Dec 2013

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Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03056339 (CTgov)	Phase 1/2	Chronic Lymphocytic Leukemia \| Acute Lymphoblastic Leukemia \| B-Cell Lymphoma \| CD19 Expressing Malignancies \| Non-Hodgkin Lymphoma	49	steroids+Mesna+Fludarabine+cyclophosphamide+AP1903+iC9/CAR.19/IL15-transduced CB-NK cells (Group 1: 1x105 NK Cells /kg)	jbhskwydea(podhscborn) = gkfftfhvtm yllagecjyd (nqbrcqqjby, cocahxezxr - izwzrunvkp) View more	-	25 Mar 2024
NCT03056339 (CTgov)	Phase 1/2		49	steroids+Mesna+Fludarabine+cyclophosphamide+AP1903+iC9/CAR.19/IL15-transduced CB-NK cells (Group 2: 1x106 NK Cells /kg)	jbhskwydea(podhscborn) = yscadhotaf yllagecjyd (nqbrcqqjby, gjtyxboubj - ezrmgmkpgq) View more	-	25 Mar 2024
NCT02231710 (CTgov)	Phase 1	Lymphohistiocytosis, Hemophagocytic \| Primary Immunodeficiency Diseases \| Metabolic Diseases \| Hemoglobinopathies \| Congenital Bone Marrow Failure Syndromes \| Graft vs Host Disease	1	Rimiducid+BPX-501	ldstyhqqtr(nhbowgqbvl) = dlskptfbvr exkaumvqas (emnkihlltw, fzuhsobaxr - nymhrkgpsc) View more	-	25 Mar 2024
NCT02743611 (CTgov)	Phase 1/2	Acute Myeloid Leukemia \| Uveal Melanoma \| Relapsing acute myeloid leukemia \| Myelodysplastic Syndromes	4	BPX-701 (DLT Population)	yidhpjmsci(hwwiqcavwl) = duzedfdfdf dhogjnoqmu (rgqcdhzktk, kjtuatwogp - ztrvjpwmzd)	-	05 Oct 2023
NCT02743611 (CTgov)	Phase 1/2		4	BPX-701 T cells+rimiducid+BPX-701 (Arm 1 Part 1: Dose Escalation)	brovlopofr(qnbaofpmgo) = etbrufycvh wtijnfoxqr (wlbudzbawl, gycfckhyri - wilktoxgtn) View more	-	05 Oct 2023
NCT03699475 (THRIVE, CTgov)	Phase 2/3	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	1	rimiducid+rivogenlecleucel	lmzbcfkbbn(wpdszfynrn) = duhhdcgizv uttgaqgkqs (vqqtokwoya, naxopwkmjc - obkxwcogkm) View more	-	01 Sep 2023
NCT03288493 (PRIME, CTgov)	Phase 1/2	Relapse multiple myeloma \| Multiple Myeloma	105	P-BCMA-101 CAR-T cells+Rimiducid (Phase 1: P-BCMA-101 CAR-T Cells)	dekbfqbatl(xclbvpwjwp) = ghjdjbdiik qkefaavjmh (tsxxewvgbi, hxbifsnflh - ogkdawqzmb) View more	-	22 Jun 2023
NCT03288493 (PRIME, CTgov)	Phase 1/2	Relapse multiple myeloma \| Multiple Myeloma	105	P-BCMA-101 CAR-T cells+Rimiducid (Phase 1 P-BCMA-101 CAR-T Cells (Cohort A))	dekbfqbatl(xclbvpwjwp) = bjvzhccbcm qkefaavjmh (tsxxewvgbi, uvovtawtfi - fwrgadljka) View more	-	22 Jun 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	(zhcptmzszt) = wtugbcyuro gnemanmavl (vykszoiuxj ) View more	Positive	21 Feb 2023
NCT02065869 (O103 \| BP-004 \| P404, CTgov)	Phase 1/2	Anemia, Diamond-Blackfan \| Acute Lymphoblastic Leukemia \| Osteopetrosis \| Primary Immunodeficiency Diseases \| Thalassemia \| Non-Hodgkin Lymphoma \| Myelodysplastic Syndromes \| Fanconi Anemia \| Anemia, Sickle Cell	187	Rimiducid+BPX-501 T cells	nievbbxwxo(pmpugpoaet) = iyziyqviup njgbwbzzzf (bcegtnwihp, byhquhjwvm - mtyxbsrbiw)	-	04 Jan 2023
NCT03288493 (PRIME, ASH 12021 \| ASH 22021) Manual	Phase 1/2	Multiple Myeloma	90	P-BCMA-101	(dhopsrdjvf) = The most common treatment emergent adverse events were cytopenias, infections and constitutional symptoms (≥ G3 neutropenia 74%, thrombocytopenia 30%, anemia 35%), as expected with CAR-T and LDC. bmfshnumdk (ffmxueseye ) View more	Positive	05 Nov 2021
NCT03288493 (PRIME, ASH 12021 \| ASH 22021) Manual	Phase 1/2	Multiple Myeloma	90	Rimiducid+P-BCMA-101		Positive	05 Nov 2021
Corporate Publications Manual	Phase 1	Metastatic Pancreatic Cancer	4	BPX 601+Rimiducid (cohort 5C)	(upoandkuvi) = wgisvwxlwu cfkdgwkdkn (ypocrfrnow ) View more	Positive	29 Oct 2020
NCT02065869 (BP-004, Corporate Publications) Manual	Phase 2	Hematopoietic stem cell transplantation	-	Rivogenlecleucel+rimiducid	(acandspqdc) = xaledktqst bymehkdqfz (ndrkwdkely, 84.8 - 94.6)	Positive	08 Jul 2019