On April 8, 2024 PDC*line Pharma, a clinical-stage biotech company developing a new class of potent and scalable active immunotherapies for cancers, reported the interim results from the last cohort of patients in its phase I/II clinical trial (PDC-LUNG-101, NCT03970746) with PDC*lung01 (Press release, PDC Line Pharma, APR 8, 2024, View Source [SID1234641919]).

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"These interim results have real potential; this is a very encouraging step for the company. We are looking forward to sharing the complete set of data when the B2 cohort is complete"

Post this
PDC*lung01 is the company’s off-the shelf therapeutic cancer vaccine candidate for Non-Small Cell Lung Cancer (NSCLC). The preliminary data on the last cohort of patients was presented today through both an oral presentation and a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024. This data revealed that the high dose PDC*lung01 combined with pembrolizumab shows an immunological activity in a majority of patients and a promising antitumor response in stage IV NSCLC with a mild safety profile.

The phase I/II trial (PDC-LUNG-101) aimed to assess the safety, tolerability, immunogenicity and preliminary clinical activity of PDC*lung01 in NSCLC patients, alone or in combination with anti-PD-1 treatment. PDC*lung01 was administered weekly through both subcutaneous and intravenous routes, in six consecutive doses. The trial was conducted across 17 clinical sites in France, Belgium, Germany, the Netherlands and Poland. PDC*lung01 was administered to a total of 67 evaluable HLA-A*02:01 positive NSCLC patients, at two dose levels and settings:

As a single agent in the adjuvant setting (cohorts A1: Low Dose, A2: High Dose)
Combined with standard of care anti-PD-1 monotherapy in first-line stage IV (metastatic) NSCLC patients with a PD-L1 tumor proportion score of ≥50% and no targetable driver mutation (cohorts B1: Low Dose, B2: High Dose)
Clinical activity parameters such as Objective Response Rate (ORR) and Progression-Free Survival (PFS) were assessed only in cohorts B1 and B2. The B2 cohort included 45 patients. PDC*Line is reporting preliminary efficacy results for 19 evaluable patients in the B2 cohort that reached the 9-month PFS mark.

Key highlights from the oral presentation
Title: Preliminary clinical results of a therapeutic cancer vaccine PDC*lung01 in combination with anti-PD-1 in patients with Stage IV NSCLC

PDC*lung01 treatment at high dose with pembrolizumab exhibited a mild safety profile
At database cut-off, 38 patients started treatment. Out of the 21 patients in the B2 cohort who started treatment and reached the 9-month follow-up, 19 received at least 5 doses of PDC*lung01 and had 1 post-baseline radiological evaluation, qualifying them as evaluable per protocol. Overall, the high dose of PDC*lung01 showed an acceptable safety profile. Most of the treatment-related AEs were consistent with AEs associated with SC/IV injections of other vaccines, or with AEs already observed in clinical trials of anti-cancer vaccines. The evaluation of the SAEs reported did not identify any safety concerns.
PDC*lung01 demonstrated biological activity in triggering an antitumor immune response in the majority of patients
A peptide-specific and effector memory CD8+ T-cell response was induced against the lung antigens of PDC*lung01 in 68.4% of patients. Immune responses with remarkable expanded anti-tumor CD8+ T-cells were observed in both Partial Response and Stable Disease patients. More immune response results will be available in the final analysis of the 45 patients in cohort B2.
PDC*lung01, in combination with pembrolizumab, is associated with a promising objective response rate and progression free survival in first line setting stage IV NSCLC patients
With the 19 evaluable patients, the median follow-up at the database lock was 12.5 months (95% CI: 9.9, 14.2). The Best Objective Response (BOR) included 12 Partial Response (63.2%) and 7 Stable Disease (36.8%) with ORR of 63.2% (80% CI 45.9 – 78.2) and a Disease Control Rate (DCR) of 94.7% (80% CI: 81, 99.4). The 9-month PFS according to the Kaplan-Meier estimate was 52.1% (80% CI 36.5 – 65.56). The median PFS was 10.9 months (95% CI 5.6 – Not Reached). The median duration of response was 9.49 months (95% CI: 4.4, -).
The safety, immunological and clinical activity results from the B2 cohort are consistent with the data from the first three cohorts of patients (A1, A2 and B1) that were presented at ESMO (Free ESMO Whitepaper) 2022 in September 2022 in Paris (France) and ESMO (Free ESMO Whitepaper)-IO in December 2022 in Geneva (Switzerland).

The final analysis of the clinical trial including the 45 patients from the B2 cohort will be conducted in Q3, 2024.

The oral presentation is available here.
The poster presentation is available here.

"PDC*lung01 in combination with anti-PD-1 showed very promising signals suggesting that this combination could offer a clinically meaningful tumor response in stage IV NSCLC patients, along with an interesting mild safety profile," said Prof Johan Vansteenkiste, emeritus professor in respiratory oncology at KU Leuven in Belgium and chair of the Data and Safety Monitoring Board (DSMB).

"These interim results have real potential; this is a very encouraging step for the company. We are looking forward to sharing the complete set of data when the B2 cohort is complete," said Dr. Beatrice De Vos, chief medical officer at PDC*line Pharma.

"We are excited to share these very favourable results for our innovative cancer vaccine. The objective response rate of 63.2% and the median progression free survival of 10.9 months along with a mild safety profile are in line with our targets. We’re also encouraged by the evidence of immune response observed in patients, which supports the mechanism of action of PDC*lung01 in relation to clinical activity," said Eric Halioua, CEO of PDC*line Pharma.

About PDC*lung01

PDC*lung01 is a cell suspension of seven active agents, made of irradiated human Plasmacytoid Dendritic Cells (PDC*line), loaded with HLA-A*02:01-restricted peptides, derived from NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A tumor antigens. PDC*line is a potent professional antigen-presenting cell that is able to prime and boost the patient’s antitumor cytotoxic CD8+ T-cells and is synergistic with anti-Programmed Death-1 (PD-1) treatment.

On April 8, 2024 Delta-fly pharma reported the protocol for the Phase I/II clinical trial of DFP-10917 combined with Venetoclax (VTX) in patients with acute myeloid leukemia (AML) with prior VTX involved one regimen, which was submitted to the FDA in US on March 8 has been approved by the FDA in US dated April 8, 2024 (Press release, Delta-Fly Pharma, APR 8, 2024, View Source [SID1234641918]). Accordingly, we can start the Phase I/II combo-study very soon.

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The aim for conducting this study is to judge if DFP-10917 combined with VTX is to show superiority to the standard chemotherapy (azacitidine combined with VTX) for AML. This combo-study shall be done by major clinical sites in US like Wake Forest University, expertise with clinical study of novel chemotherapy for AML.

The interim analysis of the Phase III trial of DFP-10917 monotherapy in patients with recurrent or refractory AML is under follow-up for a number of long-term survivors that have a significant impact on the overall survival (OS) analysis.　

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On April 8, 2024 Ferring Pharmaceuticals reported the presentation of three-year follow-up data from the Phase 3 study1 at the 39th Annual European Association of Urology (EAU) Congress demonstrating a sustained durable response of ADSTILADRIN (nadofaragene firadenovec-vncg) in two cohorts of adult patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) (Press release, Ferring Pharmaceuticals, APR 8, 2024, View Source [SID1234641917]). Follow-up data from the high-grade Ta/T1 papillary disease cohort were presented for the first time at the EAU meeting and interim data from the cohort of patients with carcinoma in situ (CIS) with or without papillary tumors were reported in November 2023. Results from both patient cohorts are available at clinicaltrials.gov/study/NCT02773849.

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ADSTILADRIN is the first and only intravesical non-replicating gene therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.

"While radical cystectomy provides excellent cancer control for NMIBC patients who no longer respond to standard therapy, most are elderly with significant comorbidities or are unwilling to undergo a life-altering procedure," said Colin P.N. Dinney, M.D., Chairman of the Department of Urology, Division of Surgery, at the University of Texas MD Anderson Cancer Center, Houston, and a lead investigator of the Phase 3 study. "Intravesical gene therapy represents an important innovative treatment option for these patients. In this follow-up analysis of the Phase 3 study, we demonstrated a sustained response to ADSTILADRIN treatment over three years, allowing more than half of the patients in the study to remain cystectomy free for at least 36 months."

Ongoing Follow-up of Patients in Phase 3 Study

The follow-up analysis is part of a Phase 3 study in which patients received ADSTILADRIN 75 mL intravesical instillation (3×1011 viral particles/mL) once every three months for up to 12 months (four doses) or until signs of toxicity or recurrent high-grade (HG) NMIBC. The trial enrolled 157 patients with BCG-unresponsive NMIBC and included two cohorts: 107 patients with CIS ±Ta/T1 (CIS cohort) and 50 patients with high-grade Ta/T1 without CIS (papillary disease [PD]). The efficacy analysis included 103 and 48 patients in the CIS and PD cohorts, respectively, who met the protocol definition of BCG-unresponsive NMIBC.

Patients who were high-grade recurrence free (HGRF) at Month 12 were allowed to continue ADSTILADRIN treatment every three months as part of an ongoing follow-up analysis. In total, 12.1% (13/107) and 20.0% (10/50) of patients in the CIS and PD cohorts, respectively, received ADSTILADRIN at three years.

Follow-up Analysis Shows Durable Response

In the CIS cohort, about 53% achieved a complete response (CR) at Month 3 in the primary analysis. By 36 months, more than 25% of these patients (14/55) remained HGRF. In the high-grade PD cohort in a secondary analysis, nearly 73% were HGRF at Month 3 and of these patients, about 31% (11/35) remained HGRF through three years.

The median duration of CR in both cohorts was nearly 10 months (9.2 – 24.0), with an approximately 34% (21.6% – 47.1%) Kaplan-Meier (KM)-estimated probability of duration of CR for at least three years. The estimated median (95% CI) duration of HGRF survival was six months (3.4 – 8.3) in the CIS cohort and about 12 months (6.7 – 20.3) in the PD cohort. The KM-estimated cystectomy-free survival (95% CI) at three years was nearly 54% (43.3 – 63.1) in the CIS cohort and nearly 64% (48.0 – 75.6) in the PD cohort, and the three-year overall survival was about 90% (82.3 – 94.9) and about 91% (78.5 – 96.7) in the CIS and PD cohorts, respectively.

"ADSTILADRIN is a novel therapy that has demonstrated its value as an effective and well-tolerated standard-of-care treatment for high-risk NMIBC patients with CIS ± Ta/T1 who have BCG-unresponsive disease," said Pierre-Yves Berclaz, M.D., PhD., Executive Vice President and Chief Science and Medical Officer, Ferring Pharmaceuticals. "This 3-year analysis provides further evidence for the durable efficacy and long-term safety of ADSTILADRIN in this on-label patient population, as well as additional data showing its therapeutic potential in a separate population of NMIBC patients with papillary disease. We look forward to continuing patient follow up as we work to redefine the treatment of NMIBC."

The treatment was well-tolerated and no new safety signals were observed during this three-year long-term follow-up analysis. Over the course of three years, only three patients discontinued treatment due to an adverse event (AE), including two in the CIS cohort because of Grade 3 bladder spasm (n=1) and Grade 2 instillation site discharge (n=1), and one in the PD cohort due to Grade 2 benign neoplasm of the bladder. No events leading to discontinuation were considered serious AEs.

About ADSTILADRIN

ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical gene-therapy for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high quantities of interferon alfa-2b protein, a naturally-occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer.

ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-grade, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).1

About Non-Muscle Invasive Bladder Cancer (NMIBC)

NMIBC is a form of bladder cancer which is present in the superficial layer of the bladder and has not invaded deeper into the bladder or spread to other parts of the body.2 In the United States, bladder cancer is the seventh most common cancer, fourth among men3-4, and it is estimated that there will be approximately 83,190 new cases of bladder cancer in the U.S. in 2024.5 Historically, 75% of bladder cancer presents as NMIBC.6 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care. However, more than 50% of patients who receive initial treatment with BCG will experience disease recurrence and progression within one year, with many developing BCG-unresponsive disease.5 Current treatment options for BCG-unresponsive patients are very limited, and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder).7

INDICATION

ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.

WARNINGS AND PRECAUTIONS:

Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.

USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.

ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).

You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.

Please click to see the full Prescribing Information.

On April 8, 2024 Alterome Therapeutics, Inc., a biopharmaceutical company pioneering the development of next generation, small molecule targeted therapies for the treatment of cancer, reported promising preclinical data from their lead pipeline candidate, ALTA-2618, a mutation-selective inhibitor for AKT1 E17K driven cancers (Press release, Alterome Therapeutics, APR 8, 2024, View Source [SID1234641916]). The data are being presented in a poster presentation on April 8th at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place in San Diego, CA on April 5-10, 2024.

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ALTA-2618 is an orally bioavailable, mutant-selective, and covalent allosteric inhibitor of AKT1 E17K. AKT1 E17K is a clinically validated oncogene that drives cancers, including breast, endometrial, and prostate cancers. This program is designed for patients with limited treatment options and is expected to begin clinical testing in the next year.

"We’re excited to present data at AACR (Free AACR Whitepaper) featuring Alterome’s lead program, ALTA-2618, the first AKT1 E17K-selective inhibitor. We believe this data provides validation of the strong dependence of certain cancers on this mutation and underscores the high impact a selective inhibitor could achieve with continuous target coverage," said Eric Murphy, Ph.D., co-founder and CEO of Alterome Therapeutics. "This work was an important step forward in Alterome’s mission to discover precise therapies that generate preclinical tumor regressions with improved safety profiles, and supports the advancement of ALTA-2618 into first-in-human clinical trials in 2024."

Key Findings:

ALTA-2618 is the first allosteric & mutant-selective drug for AKT1 E17K driven cancers.
ALTA-2618 has favorable pharmacokinetic properties across multiple preclinical species.
ALTA-2618 is well tolerated with daily oral dosing in tumor-bearing mice.
The compound demonstrated significant anti-tumor effects in clinically-relevant PDX models driven by AKT1 E17K.
No on-target toxicities (e.g., hyperglycemia) are observed with daily ALTA-2618 treatment.
Poster Presentation Details:

Title: Discovery of ALTA-2618, the first allosteric, mutant-selective targeted therapy for AKT1 E17K driven cancers
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 2
Date and Time: Monday, April 8 from 1:30 p.m. – 5:00 p.m. PT
Abstract Number: LB173 / 19
Speaker/Lead Author: Tim Sen Wang, Ph.D., Alterome Therapeutics

On April 8, 2024 Boundless Bio (Nasdaq: BOLD), a clinical-stage oncology company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable oncogene amplified cancers, reported preclinical and clinical pharmacodynamic data on its lead ecDNA-directed therapy (ecDTx), BBI-355, and research on ecDNA-mediated acquired resistance to chemotherapy at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (Press release, Boundless Bio, APR 8, 2024, View Source;Directed-Therapy-BBI-355-at-the-American-Association-for-Cancer-Research-Annual-Meeting-2024 [SID1234641915]). BBI-355 is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1) being studied in the ongoing, first-in-human, Phase 1/2 POTENTIATE clinical trial in patients with oncogene amplified cancers.

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"Extrachromosomal DNA afford unique advantages to tumors, typically rendering existing therapies ineffective and correlating with poor patient outcomes," said Chris Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. "Our first poster presented this year at AACR (Free AACR Whitepaper) demonstrated that BBI-355 overcame ecDNA-mediated targeted therapy resistance in preclinical tumor models by leveraging the enhanced reliance of ecDNA-driven tumor cells on CHK1 for survival. BBI-355 showed substantial antitumor activity, including complete and durable regressions, in preclinical oncogene amplified models.

Dr. Hassig continued, "Today we present preclinical and preliminary clinical pharmacodynamic biomarker assay data that showed detection of CHK1 inhibition-associated replication stress in both patient skin and tumor tissue following administration of BBI-355. In addition, we report a possible role for ecDNA in acquired resistance to chemotherapy observed in preclinical models, extending the potential applicability of ecDNA-directed strategies beyond targeted therapy resistance. We are encouraged by these findings as we continue to advance BBI-355 through the ongoing Phase 1/2 POTENTIATE clinical trial."

Details of the presentations are as follows:

Title: Oral CHK1 inhibitor BBI-355 allows flexibility of dose and schedule with demonstration of monotherapy and combinational antitumor activity in extrachromosomal DNA (ecDNA)-driven oncogene amplified preclinical models
Abstract Number: 613
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 1
Session Date and Time: Sunday Apr 7, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 25
Poster Board Number: 23

BBI-355 showed inhibition of CHK1 in a host of tumor cell lines and demonstrated in vivo single agent tumor growth inhibition, including complete tumor regressions, across a range of tumor models representing multiple different oncogene amplifications and tumor types. BBI-355 also demonstrated synergistic tumor growth inhibition, including durable regressions, when combined with targeted therapies across multiple oncogene amplified tumor models.

Title: Preclinical and clinical pharmacodynamic characterization of BBI-355, a novel, orally bioavailable, and selective CHK1 inhibitor being evaluated in the first-in-human Phase 1/2 POTENTIATE clinical trial of patients with cancer harboring oncogene amplifications
Number: 3631
Session Category: Clinical Research
Session Title: Biomarkers in Clinical Trials
Session Date and Time: Monday Apr 8, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 40
Poster Board Number: 9

Historically, clinical CHK1 inhibitor programs have lacked effective clinical PD biomarker assays. The findings showed that phosphorylated-CHK1 Ser345 (pCHK1-S345) is a useful pharmacodynamic (PD) biomarker for confirming clinical on-target activity of BBI-355 and could potentially inform the pharmacologically active range of BBI-355 in clinical development. In addition to preclinical data, increased pCHK1-S345 expression by immunohistochemistry in skin biopsies from patients treated with BBI-355 in the ongoing POTENTIATE clinical study were also observed, marking the first, real-time analysis of PD activity from a CHK1 inhibitor in humans.

Title: Extrachromosomal DNA (ecDNA) amplification of multi-drug resistance genes results in acquired resistance to taxane-based chemotherapy
Abstract Number: 5870
Session Category: Experimental and Molecular Therapeutics
Session Title: Mechanisms of Drug Resistance 3
Session Date and Time: Tuesday Apr 9, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 24
Poster Board Number: 14

Early insights into the role of ecDNA in driving resistance to paclitaxel, a taxane chemotherapy, are revealed and highlight the importance of ecDNA-directed therapies as a potential treatment option for many patients that have chemotherapy-resistant disease. Chemotherapy remains standard of care for many cancer patients, however, resistance to chemotherapy often develops and has been associated with the emergence of multi-drug resistance (MDR) gene amplification, such as ABCB1. These preclinical findings showed that ecDNA-enabled MDR gene amplification can cause short-and long-term resistance to paclitaxel, potentially driving resistance to chemotherapy in patients and underscoring the broad need for ecDTx for chemotherapy-resistant patient populations.

About BBI-355

Boundless Bio’s lead ecDNA-directed therapy (ecDTx), BBI-355, is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1) being studied in the ongoing, first-in-human, Phase 1/2 POTENTIATE clinical trial (NCT05827614) in patients with oncogene amplified cancers. CHK1 is a master regulator of cells’ response to replication stress (RS). RS is elevated in ecDNA-enabled oncogene amplified cancer cells and, because of this, represents a key vulnerability of those cells. BBI-355 was designed to exploit the elevated RS in ecDNA-enabled oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells.