A Phase 1, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Cyclin A/B-RxL Inhibitor CID-078 in Patients With Advanced Solid Tumor Malignancies

This is a first-in-human, multicenter, open-label, phase 1 study to evaluate safety, tolerability, and efficacy of CID-078, a Cyclin A/B-RxL inhibitor, in patients with advanced solid tumors.

Start Date14 Aug 2024

Sponsor / Collaborator

Circle Pharma, Inc.

100 Clinical Results associated with Circle Pharma, Inc.

0 Patents (Medical) associated with Circle Pharma, Inc.

Literatures (Medical) associated with Circle Pharma, Inc.

01 Dec 2023·Molecular Cancer Therapeutics

Abstract LB_C04: Novel orally bioavailable macrocycles that target cyclin A and B elicit antitumor activity in breast cancer patient-derived xenograft models

Author: Molina, Cristina ; Dias, Mariana Paes ; Wang, Evelyn W. ; Levin, Bernard ; Liu, Li-Fen ; Serra, Violeta ; Guzmán, Marta ; Rodríguez, Olga

AbstractBackground: Cyclin/cyclin-dependent kinase (CDK) complexes regulate the activity of RB1 and E2F to drive cell cycle progression while ensuring fidelity of DNA replication. The interaction between cyclins and a critical subset of their substrates, including RB1 and E2F, is mediated by a conserved short linear RxL motif. RxL peptides have been shown to inhibit substrate phosphorylation by CDK2/cyclin A (AACR 2022 poster #5379). Previously, we have shown that macrocycles that selectively inhibit RxL-mediated binding to cyclins A and B (RxL inhibitors) lead to growth inhibitory activity in multiple cancer cell lines, and result in tumor regression in small cell lung cancer (SCLC) and ovarian cancer xenograft models (AACR 2023 poster #1560). Here, we test the antitumor activity of CID-016 in patient-derived xenograft (PDX) models from breast cancer.Methods: Bioinformatic analyses using RNA sequencing (RNAseq) and whole exome sequencing (WES) data from 39 breast cancer cell lines was employed to identify biomarker profiles that associate with sensitivity to CID-016. The antiproliferative activity of CID-016 was assessed by GI50 after 4-8 days of treatment. Hallmark pathway scores were calculated by Gene Set Variation Analysis (GSVA) method using MSigDb Hallmark collection from cell lines and existing PDX models. Based on the calculated hallmark pathway score, triple negative breast cancer (TNBC) PDX models were selected to test the anti-tumor activity of CID-016. In vivo, NMRI-Foxn1nu/nu mice were implanted with tumor fragments in the lower flank and treated with vehicle or CID-016 oral formulation of 50-100 mg/kg BID or 100 mg/kg QD, respectively for at least 28 days. Tumor volume and body weight were measured biweekly. Pharmacodynamic (PD) analyses will be conducted after treatment with CID-016.Results: Treatment of the breast cancer cell line panel with CID-016 demonstrated greater potency by GI50 in TNBC compared to other breast cancer cell lines (p=0.009). Gene expression levels of CCNB1, CCNA2, CCNE1 as well as target hallmark scores for “E2F targets”, “G2M checkpoint” and “Mitotic spindle” were significantly higher in TNBC vs other breast cancer cell lines. Oral treatment with CID-016 resulted in tumor regression in at least one triple-negative breast cancer PDX model and was well tolerated with no significant body weight changes. In vivo PD analyses will be assessed after 5 days of treatment with CID-016.Conclusions: The selective cyclin A/B RxL inhibitor CID-016 exhibits potent antitumor activity in TNBC preclinical models, consistent with the proposed mechanism of RB1/E2F pathway dysregulation. Given their compelling characteristics, orally bioavailable RxL inhibitors are advancing as the only first-in-class orally bioavailable dual inhibitors of cyclins A and B into clinical development.Citation Format: Mariana Paes Dias, Li-Fen Liu, Bernard Levin, Cristina Molina, Marta Guzmán, Olga Rodríguez, Evelyn W. Wang, Violeta Serra. Novel orally bioavailable macrocycles that target cyclin A and B elicit antitumor activity in breast cancer patient-derived xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C04.

04 Apr 2023·Cancer Research

Abstract 1560: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types

Author: Bambal, Ramesh ; Nosrati, Meisam ; Sala, Roberta ; Liu, Li-Fen ; Wang, Evelyn W. ; Aggen, James ; Hamkins-Indik, Frances ; Bhatt, Chinmay ; DeMart, Megan ; Dupper, Nathan ; Metobo, Sammy ; He, Daphne ; Singh, Rajinder ; Kreatsoulas, Constantine ; Garcia, Pablo D. ; Shapiro, Justin ; Levin, Bernard ; Earp, David J. ; Yang, Kai ; Cremin, Peadar ; Leung, Siegfried ; Fraga, Breena ; Situ, Gavin ; Odeh, Ranya ; Bockus, Andrew T. ; Gleason, Catherine E.

AbstractRB and E2F genes are frequently altered in cancer. Cyclin/Cdk (cyclin-dependent kinase) complexes regulate the activity of RB and E2F to drive cell cycle progression and ensure fidelity of DNA replication. A critical subset of their substrates (Rb, E2F, Cdc6, etc.) requires a short linear motif (RxL) that interacts with the hydrophobic patch on cyclins. Peptides that disrupt the cyclin/RxL interaction were found to be synthetically lethal in cancer cell lines displaying Rb-E2F dysregulation (Chen, 1999). Using structure-guided design, cell-permeable macrocycles were synthesized that selectively inhibit RxL-mediated binding to cyclins A and B. Preclinical studies with an orally bioavailable cyclin A/B RxL inhibitor show activity in cell lines with Rb-E2F pathway dysregulation, and inhibition of tumor growth and regression in xenograft models of small cell lung carcinoma (SCLC).RB-null mutations occur with high frequency in SCLC tumors (Febres-Aldana 2022). Previously we reported (AACR April 2022 Abs.#5379) sensitivity of a large proportion of SCLC cell lines to cyclin RxL inhibitors. Further studies have shown that such compounds have growth inhibitory activity in cell lines representing multiple types of solid tumors and hematological malignancies. Sensitivity of the cell lines to these macrocyclic inhibitors is associated with increased expression of genes involved in the E2F pathway, consistent with the proposed Rb/cyclin/E2F pathway synthetic lethality mechanism.Disruption of RxL binding to both cyclin A and B is required for sensitivity. Cyclin A/B RxL inhibitors disrupt the interactions of E2F and Cdc6 with cyclin A/Cdk complexes in co-immunoprecipitation studies and have EC50 values consistent with biochemical and cellular activity. Cyclin A/B RxL inhibition results in accumulation of cells in the G2/M phase of the cell cycle which leads to apoptosis both in vitro and in vivo. A separate study (Singh et al. AACR 2023) utilizing a CRISPR screen identified that genes of the spindle assembly checkpoint (SAC) are required for the synthetic lethality induced by the cyclin A/B RxL inhibitors. The inhibitors assessed in vitro for off-target activity showed negligible activity in a panel of 468 kinases and in safety panels that include GPCRs, ion channels, and transporters. In a 14-day tolerability study, neither neutropenia nor significant effects in other blood cell counts were noted. Cyclin A/B RxL inhibitors cause significant tumor regression via oral administration in SCLC xenograft models.Given their compelling characteristics, we are progressing the development of these orally bioavailable macrocyclic cyclin A/B RxL inhibitors to the clinic.Citation Format: Catherine E. Gleason, Pablo D. Garcia, Ranya Odeh, Frances Hamkins-Indik, Daphne He, Meisam Nosrati, Gavin Situ, Roberta Sala, Bernard Levin, Li-Fen Liu, Evelyn W. Wang, Siegfried Leung, Breena Fraga, Andrew T. Bockus, Justin Shapiro, Nathan Dupper, Chinmay Bhatt, Kai Yang, Megan DeMart, Sammy Metobo, James Aggen, Peadar Cremin, Ramesh Bambal, Constantine Kreatsoulas, David J. Earp, Rajinder Singh. Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1560.

04 Apr 2023·Cancer Research

Abstract 1559: Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A and B RxL macrocyclic peptide inhibitors

Author: Singh, Shilpa ; Gleason, Catherine E. ; Singh, Rajinder ; Garcia, Pablo D. ; Earp, David J. ; Wang, Evelyn W. ; Oser, Matthew G. ; Durmaz, Yavuz T.

AbstractMost cancer-directed targeted therapies are developed using small molecule inhibitors that require a druggable binding pocket on the target of interest. Macrocyclic peptides can selectively block protein-protein interactions required for function and hence can be used to target previously undruggable proteins. Using a structure-guided approach, Circle Pharma developed cell-permeable macrocyclic peptides that block the ability of Cyclin A and/or Cyclin B, to bind RxL motifs on their substrates thereby inhibiting Cyclin activity. A separate study (Gleason et al. AACR 2023) revealed that cancer cell lines with RB/E2F dysregulation were highly sensitive dual Cyclin A/B peptides, which includes most small cell lung cancer (SCLC) cell lines with RB1 and TP53 inactivation. Importantly, some cancer cell lines and all non-transformed cell lines examined were insensitive to Cyclin A/B inhibitors suggesting high potential for a therapeutic window. We found that dual Cyclin A/B inhibitors blocked cellular proliferation, caused accumulation of cells in mitosis, and robustly induced apoptosis in SCLC cell lines. In contrast, selective Cyclin A or Cyclin B inhibitors had significantly lower activity than dual Cyclin A/B inhibitors demonstrating that inhibition of both Cyclin A and Cyclin B is required to induce apoptosis in sensitive cells. Using these Cyclin A/B RxL inhibitors, we performed genome-wide CRISPR/Cas9 positive selection resistance screens and subsequent rigorous validation in SCLC cells. Our screen identified Cyclin B and CDK2 as the targets of Cyclin A/B inhibitors. Our screen also showed that MAD1 and the ROD-Zwilch-Zw10 (RZZ) complex of the mitotic spindle assembly checkpoint (SAC), which is regulated by the kinase Mps1, is required for Cyclin A/B inhibitors to induce apoptosis. In line with this, chemical inhibition of Mps1 caused resistance demonstrating that SAC activation by Mps1 is required for the ability of Cyclin A/B inhibitors to induce apoptosis. Interestingly, Cyclin A/B inhibitors selectively induced DNA damage measured by phospho-H2AX accumulation and SAC activation measured by Mps1 activity in highly sensitive RB1- and TP53-deficient SCLC cell lines while having no effect on DNA damage and SAC activation in resistant RB1- and TP53-proficient cell lines. Moreover, Cyclin A/B inhibitors also significantly induced phospho-H2AX accumulation in RB1- and TP53-proficient normal RPE1 cells and A549 cells only after dual CRISPR inactivation of RB1 and TP53. In summary, we found that novel cell-permeable dual Cyclin A/B RxL macrocyclic peptides selectively induce apoptosis in RB1/TP53-deficient cancer cell lines involving a mechanism where DNA damage induces SAC activation leading to apoptosis. Our data suggests that Cyclin A/B RxL peptide inhibitors should be further explored as a therapeutic strategy in RB1/TP53-deficient cancers such as SCLC.Citation Format: Shilpa Singh, Yavuz T. Durmaz, Catherine E. Gleason, Evelyn W. Wang, Rajinder Singh, David J. Earp, Pablo D. Garcia, Matthew G. Oser. Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A and B RxL macrocyclic peptide inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1559.

News (Medical) associated with Circle Pharma, Inc.

23 Oct 2024

·www.biospace.com

Circle Pharma’s First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, CID-078, Preclinical Data Highlighted at the 36th EORTC-NCI-AACR Symposium

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- #BreastCancer --Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, today announced that preclinical data from its lead candidate, CID-078, a first-in-class oral macrocycle cyclin A/B RxL inhibitor, has been selected for a late-breaking poster presentation at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, also known as the Triple Meeting. The symposium is taking place from October 23-25, 2024, in Barcelona, Spain. Poster presentation details are below: Author: Wang et al. Title: CID-078, a First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, Demonstrates Anti-Tumor Activity in ESF-driven Cancers Abstract Number: PB-515 Session Title: Late breaking posters Date and Time: October 23, 2024 (6 a.m. EST/12 p.m. CEST) to October 25, 2024 (11 a.m. EST/5 p.m. CEST) The digital poster can be viewed here. The pre-clinical data shows CID-078 demonstrated single-agent tumor activity across tumor cell line and in vivo models with dysregulated cell cycle (CDK-RB-E2F) function. Notably, tumor regressions were observed in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC) preclinical models. Within specific indications, CID-078 single agent activity was correlated with RB1 mutation, high E2F target, or G2M checkpoint hallmark pathway scores. The cumulative pre-clinical data suggests that CID-078 holds promise as a monotherapy for patients with these cancers. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients. About CID-078 CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models. A multi-center phase 1 clinical trial ( NCT06577987 ) is currently enrolling patients. About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit . Contacts Media Contact: Roslyn Patterson 650.825.4099 roslyn.patterson@circlepharma.com

Phase 1AACR

15 Oct 2024

·pipelinereview.com

Circle Pharma Announces First Patients Dosed in Phase 1 Clinical Trial of First-in-Class Oral Cyclin A/B RxL Inhibitor CID-078 for Advanced Solid Tumors

SOUTH SAN FRANCISCO, CA, USA I October 15, 2024 I Circle Pharma, Inc., a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, announced today that the first patient cohort has been dosed in the phase 1 trial of CID-078, the company’s first-in-class oral cyclin A/B RxL inhibitor. The trial will evaluate CID-078 in patients with advanced solid tumors, including tumors with elevated E2F transcription factor activity, such as small cell lung cancer, triple negative breast cancer and ER+ HER-2- breast cancer following CDK 4/6-inhibitor therapy. “We are thrilled that the IND for CID-078 was cleared at the end of the 30-day regulatory review period and that CID-078 has now moved into human dosing at a consortium of world class cancer centers. This will allow our investigators to generate clinical proof-of-concept data which will inform CID-078’s potential impact in settings of high unmet medical need as well as validate Circle Pharma’s proprietary MXMO™ macrocycle platform for difficult-to-drug targets in cancer and other serious diseases,” said David J. Earp, JD, Ph.D., CEO of Circle Pharma. CID-078 is designed to selectively inhibit key protein-to-protein interactions involving cyclins A and B, both of which have been implicated in the proliferation and survival of cancer cells. The research program builds on work performed in the laboratory of Nobel Laureate and Circle Pharma’s Scientific Advisory Board Chair, William G. Kaelin Jr., MD, who demonstrated synthetic lethality through the disruption of these cyclins in settings of dysregulated cell cycle control and elevated E2F activity. Geoffrey Shapiro, MD, Ph.D., senior vice president, Development Therapeutics at Dana-Farber Cancer Institute and professor of medicine at Harvard University, stated, “Disrupting the ability of E2F-driven cancer cells to turn off E2F at the appropriate time in the cell cycle has been shown to selectively induce apoptosis. Until now there hasn’t been a selective therapeutic agent to exploit this observation and so I am extremely excited to see Circle Pharma’s cyclin A/B RxL inhibitor move into the clinic.” All patients in the cohort are enrolled at The START Center for Cancer Research, Midwest, Grand Rapids, MI. Other clinical sites currently open include The START Center for Cancer Research, West Valley City, UT, and NEXT Oncology in San Antonio, TX. Additional clinical sites are planned to open soon. Circle Pharma’s Phase 1 clinical trial (NCT06577987) is an open label, multi-center dose escalation and expansion study that is expected to enroll up to 100 patients. The study will evaluate the safety, pharmacokinetics and pharmacodynamics of CID-078 as well as preliminary anti-tumor activity in solid tumors. Circle Pharma anticipates reporting preliminary safety and anti-tumor data from the Phase 1 study in 2025. About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program CID-078 is an investigational orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s investigational cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple xenograft models. Based on these findings CID-078 has progressed to a Phase 1 clinical study (NCT06577987). About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit www.circlepharma.com . SOURCE: Circle Pharma

Phase 1

15 Oct 2024

·www.pharmaceutical-technology.com

Boehringer partners WHO Foundation to advance healthcare access

Boehringer Ingelheim partners with the WHO Foundation to financially support WHO’s Fourteenth General Programme of Work (2025 to 2028). Credit: PeopleImages.com – Yuri A/Shutterstock. Boehringer Ingelheim , in partnership with the WHO Foundation [an organisation set up to support the World Health Organization and its global network of partners by mobilising new funding] has committed $5m to enhance healthcare access for debilitated people in the Americas, particularly those at higher risk of suicide. The partnership will allow the company to provide financial support to WHO’s Fourteenth General Program of Work, covering 2025 to 2028, as part of WHO’s investment round. Boehringer Ingelheim and the WHO Foundation jointly seek to underscore the importance of funding equitable healthcare services globally, with a particular emphasis on mental health. WHO Foundation CEO Anil Soni stated: “WHO’s mission of Health for All can only be achieved with the combined commitment of the public and private sectors. Boehringer Ingelheim recognises this and is meeting WHO’s call to action by making a pledge of predictable and flexible resources. “Moreover, by donating to WHO for the first time, Boehringer Ingelheim is broadening the base of WHO’s supporters, affirming WHO’s essential role to global public health.” See Also: Evergreen Theragnostics Radiopharmaceutical Manufacturing Facility, New Jersey, US Merck Biotech Development Center, Corsier-sur-Vevey, Switzerland The collaboration aims to support evidence-based interventions that promote equitable healthcare access and prevent suicide in the Americas. Boehringer Ingelheim’s support extends to private initiatives including the Friendship Bench, a programme in Zimbabwe, which utilises grandmothers as participant therapists to deliver mental health support. Boehringer Ingelheim corporate affairs global head Médard Schoenmaeckers stated: “Limited or no access to help for patients is alarming, especially in underserved communities. We truly look forward to our collaboration with the WHO Foundation and its partners as we want to increase access to life-saving healthcare services.” Both the WHO Foundation and Boehringer Ingelheim are dedicated to deploying additional resources to enhance equitable mental health access. Boehringer Ingelheim and Circle Pharma recently entered a research partnership and licence agreement to develop a new precision cancer treatment.

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The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Drug(Targets)	Indications	Global Highest Phase

CID-078 ( CCNB1 x cyclin-A )	Triple Negative Breast Cancer More	Phase 1
CXCR7 modulator (Circle Pharma) ( ACKR3 )	-	Preclinical
CID-016 ( CCNB1 x cyclin-A )	Triple Negative Breast Cancer More	Preclinical
Cyclin E inhibitor (Circle) ( CCNE1 )	Neoplasms More	Preclinical
Macrocyclic peptides targeting p53(Circle Pharma) ( p53 )	Neoplasms More	Discovery

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