A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of Intravenous NBF 006 in Patients With Non-Small Cell Lung, Pancreatic, or Colorectal Cancer Followed by a Dose Expansion Study in Patients With KRAS-Mutated Non-Small Cell Lung Cancer

This is an open-label, non-controlled study conducted in two parts - Part A (dose escalation) followed by Part B (dose expansion).

开始日期2019-03-18

申办/合作机构

Nitto Biopharma, Inc.

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项与 Nitto Biopharma, Inc. 相关的文献（医药）

2024-04-05·Cancer Research

Abstract CT040: First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

作者: Bazhenova, Lyudmila ; Cina, Cima ; Cohen-Arazi, Yael ; Zabludoff, Sonya ; Gabayan, Afshin ; Chiappori, Alberto ; Mamdani, Hirva ; Tolcher, Anthony ; Vandross, Andrae ; Huynh, Annie ; Albaugh, Zachary ; Spira, Alexander ; Barve, Minal ; Iams, Wade ; Gullbo, Joachim

AbstractBackgroundGlutathione S-transferase Pi (GSTP) has a role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways may lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-human dose escalation and expansion study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously. The dose escalation phase enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Final results from the dose escalation and expansion of NBF-006-001 are reported here.ResultsThirty-eight NSCLC patients, with or without KRAS mutation, received treatment at 0.3 mg/kg [n=1], 0.6 mg/kg [n=12], 1.2 mg/kg [n=14], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common NBF-006-related AEs were Grade 1 or 2 infusion related reactions (IRRs) (18 %) and nausea (11 %). IRRs (n=8 in seven patients), occurred in the first cycle and were well-managed. One patient discontinued due to recurring IRR. Cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. Linear PK (t1/2 ~41 hrs) was observed with dose proportional increases up to 1.6 mg/kg without exposure accumulation or reduction after repeat doses. GSTP mRNA knock-down in PBMCs was statistically significant at 1.2 and 1.6 mg/kg dose levels. Patients had received 1-7 prior lines of therapy (1 line [n=10], 2 lines [n=10], and ≥ 3 lines [n=16] respectively). Two patients (1.2 and 1.6 mg/kg) experienced a durable PR, 17 patients experienced SD. The disease control rate is 19/38 (59%). Patient enrichment strategies were evaluated with interesting trends observed.ConclusionNBF-006 is well tolerated up to 1.6 mg/kg dose level for over a year with early signs of efficacy in heavily pre-treated pan-KRAS mutant NSCLC patients. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted.Citation Format: Lyudmila Bazhenova, Hirva Mamdani, Alberto Chiappori, Alexander Spira, Wade Iams, Anthony Tolcher, Minal Barve, Afshin Gabayan, Andrae Vandross, Cima Cina, Yael Cohen-Arazi, Zachary Albaugh, Annie Huynh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT040.

2023-12-01·Molecular Cancer Therapeutics

Abstract C101: Preclinical and clinical pharmacokinetics (PK) of NBF-006, a novel siRNA inhibitor of glutathione-s-transferase P (GSTP) encapsulated in a lipid nanoparticle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)

作者: Hall, Michael ; Zabludoff, Sonya ; O'Brien, Zhihong

AbstractBackground: GSTP has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple key oncogenic pathways such as KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a drug product comprised of GSTP siRNA encapsulated within a novel LNP. It is designed to deliver siRNA to localized and metastatic lung tumors. Unlike other well-established drug modalities, there is a general need for increased understanding of the PK of RNA therapeutics. For NBF-006, we present preclinical PK data in healthy mice and monkeys, prediction of human doses, and phase 1 clinical PK data.Methods: Preclinical PK studies were performed by intravenous bolus injection of NBF-006 once weekly for 1 month at 5, 20, and 40 mg/kg in mice and 6, 12, and 18 mg/kg in cynomolgus monkeys. Human drug exposures were predicted based upon simple allometry. For the phase 1 clinical study, a total of 48 advanced NSCLC, pancreatic, or colorectal cancer patients received 4 weekly doses of NBF-006 by infusion at 0.15, 0.3, 0.6, 1.2 or 1.6 mg/kg followed by a 2-week rest period. In all studies, serial blood samples were collected at weeks 1 and 4. Plasma concentrations of siRNA were determined by a hybridization ELISA. Non-compartmental PK analysis (NCA) was performed with the resulting concentration-time data. Results: In mice, terminal elimination half-life (t1/2) of plasma siRNA ranged between 3.69 to 9.04 hr, clearance (CL) ranged between 3.61 and 5.81 mL/hr/kg, and volume of distribution (Vd) ranged between 23.5 and 57.4 mL/kg. In cynomolgus monkeys, t1/2 ranged between 8.22 and 28.2 hr, CL ranged between 1.38 and 3.97 mL/hr/kg, and Vd ranged between 31.7 to 83.3 mL/kg. Exposure (maximal plasma concentration, Cmax, and area under the curve, AUC) increased with increasing dose in both species and was generally dose proportional. Following weekly administration of NBF-006, no apparent accumulation or reduction of siRNA exposure was observed. Human PK exposures were well-predicted within 2-fold accuracy at clinically studied doses. Clinically, NCA demonstrated consistent slow CL and low Vd with a mean t1/2 of 41 (± 13) hours. Exposure showed dose proportionality from 0.15 to 1.2 mg/kg. At 1.6 mg/kg, exposure was not statistically different than that of 1.2 mg/kg. No accumulation risk potential was identified following the current dosing regimen. Moreover, exposure was not reduced after repeat dosing in any dose group.Conclusions: Preclinical PK profiling enabled initial characterization of the in vivo disposition of NBF-006 and prediction of human PK and doses. In patients, repeated administration of NBF-006 was well-tolerated up to 1.6 mg/kg. Exposure appeared to be dose proportional through 1.2 mg/kg. Neither exposure reduction nor accumulation was observed.Citation Format: Michael Hall, Zhihong O'Brien, Sonya Zabludoff. Preclinical and clinical pharmacokinetics (PK) of NBF-006, a novel siRNA inhibitor of glutathione-s-transferase P (GSTP) encapsulated in a lipid nanoparticle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC) [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 C101.

2023-12-01·Molecular Cancer Therapeutics

Abstract PR013: First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

作者: Zabludoff, Sonya ; Chiappori, Alberto ; Gabayan, Eli ; Cohen-Arazi, Yael ; Bazhenova, Lyudmila ; Mamdani, Hirva ; Huynh, Annie ; Tolcher, Anthony W ; Gullbo, Joachim ; Vandross, Andrae ; Barve, Minal ; Albaugh, Zachary ; Spira, Alexander ; Iams, Wade

AbstractBackground Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-man dose escalation (Part A) and expansion (Part B) study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously over 70 minutes, QW4 followed by a 2-week rest period. Part A of the study enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Results from advanced KRAS-mutated NSCLC patients enrolled in NBF-006-001 are reported here.Results Thirty-four KRAS-mutated NSCLC patients received treatment at 0.6 mg/kg [n=12], 1.2 mg/kg [n=11], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common (>10 % of patients) NBF-006-related AEs were Grade 1 or 2 infusion related reactions (low grade IRRs) (20.6 %) and nausea (11.8 %). There was no dose relationship in the number of AEs or any observed AEs. Low grade IRRs (n=8 in seven patients), occurred in the first cycle of therapy and were generally well-managed. Only one patient discontinued study therapy due to recurring IRR. Substantial cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. PK analysis indicated a mean terminal half-life of 41 (± 13) hours with no accumulation. Cmax and AUC demonstrated dose-proportionality up to 1.2 mg/kg and no apparent increase in exposure at 1.6 mg/kg. Patients had received 1-7 prior lines of therapy (average 2.6; 1 line [n=10], 2 lines [n=9], and ≥ 3 lines [n=15] respectively). Two patients (treated at 1.2 and 1.6 mg/kg) experienced a durable PR, 14 patients experienced SD. One patient with PR and one patient with a mixed response stayed on study for >12 months.Conclusion The expansion part of the NBF-006-001 study confirmed the favorable safety profile of NBF-006 and demonstrated early signs of antitumor activity in KRAS-mutated NSCLC. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted.Citation Format: Hirva Mamdani, Alberto Chiappori, Lyudmila Bazhenova, Alexander Spira, Wade Iams, Minal Barve, Anthony W Tolcher, Eli Gabayan, Andrae Vandross, Annie Huynh, Yael Cohen-Arazi, Zachary Albaugh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [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 PR013.

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2023-04-17

·BioSpace

10 Biopharma Companies Hiring AI/ML Talent Now

Pictured: a scientist working on machine learning models/gorodenkoff/iStock As the number of employees laid off in the tech industry continues to grow, biopharma companies are increasingly recruiting talent who wish to transfer their skills to the life sciences. Specifically, those with skills in artificial intelligence (AI) and machine learning (ML) are in high demand across the industry. And as long as life sciences companies continue investing in AI and ML, this demand will likely continue. Biopharma Companies Hiring AI/ML Talent Now Here are 10 biopharma companies hiring AI/ML talent now, along with duties and qualifications for each role. Eli Lilly and Co. Eli Lilly is looking for an AI/ML data scientist to join its genetic medicine team in Indianapolis. The job, posted April 14, would be best for someone with a Ph.D. or someone with a master’s degree in computer science, computer engineering or a related field with four years of related work experience. See more jobs at Eli Lilly and Co. AbbVie AbbVie is hiring a senior machine learning engineer, I/II to join its Convergence AI and Data Analytics group in Lake County, Ill. The role is best for a Python developer with previous experience in machine learning, including graphical models and network analysis. See more jobs at AbbVie. Gilead Sciences Gilead Sciences is hiring a Sr Manager, Lead Integration Architect to lead the integration of software systems for its Enterprise Data and Analytics organization in Raleigh, NC. The role is best for someone with a bachelor's degree in computer science or a related field, at least eight years of industry experience and at least five years of experience working with cloud and web-based technology. See more jobs at Gilead. Regeneron Pharmaceuticals Regeneron Pharmaceuticals is hiring an associate director and machine learning scientist to work in its Sleepy Hollow, NY office. A qualified candidate will have a Ph.D. or master's degree in computer science or a related field and at least three years of work experience in the life sciences. See more jobs at Regeneron. D.E. Shaw Research D.E. Shaw Research is hiring machine learning researchers and engineers to work on its drug discovery and computational biochemistry teams in New York City. Candidates with any level of experience are encouraged to apply. See more jobs at D.E. Shaw Research. Recursion Recursion is hiring two senior machine learning product managers in its offices in Milpitas, Calif. and Salt Lake City. The ideal candidate has at least three years of experience with machine learning products and experience in product management or similar practices. See more jobs at Recursion. BigHat Biosciences BigHat Biosciences is hiring a remote machine learning scientist to advance its iterative antibody optimization platform. To qualify, a candidate should have a Ph.D. or master's degree with at least two years of experience in a relevant domain, three years of experience developing AI/ML statistical models and a strong competency in Python. See more jobs at BigHat Biosciences. Nitto BioPharma Nitto BioPharma is hiring a data scientist for its AI/ML drug discovery team in San Diego. The ideal candidate is proficient in Python and Linux bash scripting and has an M.S. in data science, machine learning, bioinformatics, cheminformatics or another related field. See more jobs at Nitto BioPharma. Sage Therapeutics Sage Therapeutics is hiring a machine learning and analytics platform architecture director to work remotely. The ideal candidate has a bachelor's degree, at least eight years of experience building data products, and at least five years of experience building large-scale analytics platforms. See more jobs at Sage Therapeutics. InVitro Cell Research InVitro Cell Research is hiring machine learning engineers in its Fort Lee, NJ offices. The ideal candidates have expertise in predictive statistics, analytics and modeling and a background in biomedical sciences is ideal. Experience working with Bayesian methods is also highly desirable. See more jobs at InVitro Cell Research. Rosemary Scott is a content editor at BioSpace, focusing on the job market and career development for professionals in the life sciences. You can reach her at rosemary.scott@biospace.com and on LinkedIn:

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