On November 8, 2015 BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine company developing targeted and programmable therapeutics called Accurins, reported data demonstrating the efficacy and tolerability of BIND’s Accurin platform with multiple anti-cancer agents (Press release, BIND Therapeutics, NOV 8, 2015, View Source [SID:1234508103]). These data, which were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held in Boston, November 5-9, 2015, describe the ability of Accurins to control the biodistribution of therapeutic payloads across multiple active anti-cancer agents, pathways and targets, which results in either improved efficacy, tolerability or both.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The four posters presented include preclinical and clinical pharmacokinetic data from BIND’s clinical stage Accurin compound, BIND-014; data from BIND’s preclinical stage Accurin, BIND-510; and new data from a previously unannounced feasibility study with Merck, demonstrating the potential value of an Accurin formulation of Merck’s proprietary AKT inhibitor, MK-2206.
"We believe data from these posters reinforce the flexibility of the Accurin platform to incorporate multiple therapeutic payloads and target them to sites of disease while limiting exposure to healthy tissue," said Andrew Hirsch, president and chief executive officer, BIND Therapeutics. "These data also demonstrate the ability of Accurins to create potentially best-in-class therapeutics, both with our proprietary product candidates as well as those of our collaborators, as demonstrated with the Merck AKT inhibitor MK-2206."
"The ability of our Accurin platform to overcome the challenges often associated with narrow therapeutic windows of otherwise powerful drugs is reinforced by these data," said Hagop Youssoufian, M.D., chief medical officer at BIND. "BIND-014 continues to demonstrate important and potentially differentiating points from docetaxel; BIND-510 exhibits promising pharmacokinetics, tumor accumulation, tolerability and anti-tumor activity across multiple tumor types in preclinical models; and the feasibility study with an Accurin formulation of Merck’s MK-2206 further validates the applicability of our Accurin platform to drugs with diverse mechanisms of action."
Posters presented at AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper)
BIND-014
1. "Evaluation of total and encapsulated drug pharmacokinetics for BIND-014 (docetaxel nanoparticles for injectable suspension) evaluated in a phase 1 study"
BIND researchers and collaborators evaluated the pharmacokinetic (PK) profile of BIND-014 in 28 patients with advanced or metastatic cancer and determined that PK properties of BIND-014 are primarily due to retention of encapsulated docetaxel within the vascular compartment and controlled release of docetaxel. These characteristics together with PSMA targeting, potentially lead to greater tumor uptake and improved activity of BIND-014 compared to conventional solvent-based docetaxel.
BIND-014 was administered by a 60-minute intravenous infusion at doses ranging from 3.5-75 mg/m2 on Day 1 of a 21-day cycle.
Plasma concentrations of BIND-014 persisted for at least 48 hours at the higher dose levels.
Clearance was independent of the administered dose, indicating a linear dose-concentration relationship following a single intravenous administration.
The total concentration of BIND-014 found in circulation compared to the concentration of encapsulated docetaxel was similar, indicating that the majority of the circulating docetaxel was encapsulated in nanoparticles.
Results are consistent with the favorable tolerability profile of BIND-014 despite the markedly higher plasma concentrations for total BIND-014 compared to published data for docetaxel at similar doses.
BIND-014 displays a PK profile well differentiated from conventional docetaxel and consistent with retention of BIND-014 nanoparticles in the blood compartment and controlled release of docetaxel.
2. "Cardiovascular safety profile of BIND-014 (docetaxel nanoparticles for injectable suspension) evaluated in phase 1 and 2 studies"
BIND researchers determined that BIND-014, when administered on day 1 of a 21-day cycle with doses ranging from 3.5-75 mg/m2, was well tolerated at all doses studied and has the potential to become a safe antitumor agent without the cardiovascular effects typically associated with docetaxel.
For all 110 patients tested, the vast majority of ECG data collected remained in normal or clinically insignificant abnormal limits.
Vitals signs for heart rate, respiratory rate, and pulse were also within normal or clinically insignificant abnormal limits.
The incidence and severity of cardiovascular adverse events was low, with only seven patients experiencing drug-related cardiovascular adverse events ranging from grade 1-3. Patients dosed below 60 mg/m2 did not experience any drug-related cardiovascular adverse events.
BIND-510
1. "BIND-510 improves the pharmacokinetics, tolerability, tumor accumulation and tumor growth inhibition in preclinical models of cancer compared to vincristine sulfate"
BIND researchers demonstrated that BIND-510 exhibited differentiated PK, tumor accumulation, tolerability and anti-tumor activity compared to conventional vincristine (VCR). In addition, PSMA expression was demonstrated in the neovasculature in hematological cancers, further supporting the feasibility of developing BIND-510 as a targeted clinical therapy with the potential for reduced toxicity and improved anti-tumor activity compared to currently available treatments.
BIND-510 had a PK profile differentiated from VCR that results in increased accumulation of vincristine at the tumor, and increased tumor growth inhibition in multiple xenograft models.
BIND-510 accumulated in nasopharyngeal carcinoma tumors at an 8-fold higher concentration than VCR, and was shown to be more tolerable than VCR.
Single dose BIND-510 administered to mice with nasopharyngeal and breast carcinoma xenografts at the maximum tolerated dose (MTD) for VCR (1.5 mg/kg) resulted in a longer tumor growth delay compared to VCR.
Due to improved tolerability, BIND-510 was able to be administered at higher doses, resulting in complete responses in some mice, and even longer tumor growth delay than VCR or BIND-510 dosed at 1.5 mg/kg.
PSMA targeting of BIND-510 in PSMA-expressing prostate cancer tumor xenografts resulted in a tumor growth inhibition (TGI) of (79%) compared to non-targeted VCR nanoparticles which caused a 47 percent TGI at the same VCR dose level.
Non-small cell lung cancer tumor xenografts that are insensitive to VCR at MTD are sensitive to BIND-510 when administered at higher dose levels.
PSMA immunostaining was detected in the neovasculature of 27.5 percent lymphoma tumors and 35 percent of bone marrow malignancies analyzed.
MK-2206 (BIND-2206)
1. "Accurins improve the pharmacokinetics, pharmacodynamics, tolerability and anti-tumor activity of the AKT inhibitor MK-2206"
BIND researchers and collaborators at Merck demonstrated that Accurin formulations of MK-2206 (BIND-2206) developed with varying in vitro release rates had differentiated PK, increased tumor exposure, improved tolerability and a prolonged duration of target inhibition compared to the parent compound. Improving these biological attributes led to a significantly enhanced anti-tumor efficacy in an ovarian cancer model and tumor regressions in a prostate cancer model. In addition, the altered bio-distribution resulted in prolonged target engagement in tumor tissue and enhanced efficacy compared to the parent MK-2206, suggesting that Accurin formulations of the AKT inhibitor (BIND-2206) may provide improved tolerability and anti-tumor activity in a clinical setting.
BIND-2206 Accurins significantly altered the pharmacokinetic parameters of MK-2206 in female nude mice following acute administration.
Dosed at maximum feasible dose, BIND-2206 Accurins significantly enhanced tolerability measured by percent survival and prevented hyperglycemic blood glucose levels in mice following acute administration.
BIND-2206 Accurins displayed significant tumor regressions in human prostate cancer models compared to MK-2206.
BIND-2206 Accurins displayed significant anti-tumor activity in human ovarian cancer model compared to MK-2206.
BIND-2206 Accurins as a single agent did not improve efficacy in a HER2 overexpressing breast cancer model but displayed significant and prolonged inhibition of the target in the tumor. This suggests that anti-tumor efficacy is model specific and that a combination strategy in breast cancer may be advantageous.