March 2016 – Page 12 – 1stOncology™: Cancer Intelligence Service

Regulatory considerations in oncologic biosimilar drug development.

Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice.

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!

Antitubercular agent delamanid and metabolites as substrates and inhibitors of ABC and SLC transporters.

Delamanid (Deltyba; OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as substrates and inhibitors of various transporters were evaluated in vitro. Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion transporting polypeptides or organic cation transporter 1. Similarly, metabolite M1 was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP and the bile salt export pump (BSEP, ABCB11), SLC transporters or organic anion transporters. Metabolites M1 and M2 inhibited P-gp- and BCRP-mediated transport, but only at IC50values (M1: 4.65 and 5.71 μmol/L; M2: 7.80 and 6.02 μmol/L), well above corresponding Cmaxvalues observed following multiple dosing in clinical trials. Metabolites M3 and M4 did not affect the activities of any transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide.

Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.

Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection.

Patients with resectable gastrointestinal stromal tumors (GISTs) might not receive the recommended duration of adjuvant therapy if their risk of recurrence is underestimated, which can have an impact on their recurrence-free survival (RFS).
To determine the extent of physician underestimation of risk of recurrence after complete primary GIST resection, the impact of underestimation on planned adjuvant treatment duration, and the association among high-risk patients of planned adjuvant treatment duration and RFS.
This was a retrospective observational medical record review reported by participating oncologists in 2013. US patients with complete primary GIST resection after 2010 were grouped as underestimated or not if their oncologists’ charted risk assessments were lower than assessments based on the Revised National Institutes of Health Consensus Criteria or not. Patients were followed by general community oncologists until death or the end of follow-up.
Fisher exact tests compared planned adjuvant treatment duration between groups. Cox proportional-hazards models estimated the impact of planned adjuvant treatment duration on RFS.
A total of 109 oncologists reported information on 506 patients with GIST after primary resection (65.8% were high-risk and 8.7% were intermediate-risk). Physicians underestimated risk for 190 patients (37.5%); 30.1% of tumors with an intermediate-level mitotic count (6-10 per 50 high-powered fields) and an intermediate tumor size (6-10 cm) were correctly recognized as high-risk, as were 7.5% of nongastric tumors with an intermediate-level mitotic count and a tumor size of 2 to 5 cm. A smaller proportion of high-risk patients in the underestimated vs not-underestimated groups had at least 3 years of planned adjuvant therapy (36.1% vs 65.9%; P &lt; .001). Planned adjuvant treatment of at least 3 years vs less than 3 years among high-risk patients conferred a lower hazard of recurrence and/or death (adjusted hazard ratio, 0.29; P &lt; .001; 95% CI, 0.14-0.59).
Overall, physicians tended to underestimate the risk of recurrence for many patients with GIST, especially for patients with tumors of intermediate size, intermediate-level mitotic count, and nongastric location, which had an impact on planned adjuvant therapy duration. Patients with at least 3 years of planned adjuvant treatment had longer RFS. Improved education on postresection risk assessment and risk reduction is needed.

Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient.

Data reported directly by patients about how they feel and function are rarely included in oncology drug labeling in the United States, in contrast to Europe and to nononcology labeling in the United States, where this practice is more common. Multiple barriers exist, including challenges unique to oncology trials, and industry’s concerns regarding cost, logistical complexities, and the Food and Drug Administration’s (FDA’s) rigorous application of its 2009 guidance on the use of patient-reported outcome (PRO) measures. A panel consisting of representatives of industry, FDA, the PRO Consortium, clinicians, and patients was assembled at a 2014 workshop cosponsored by FDA to identify practical recommendations for overcoming these barriers. Key recommendations included increasing proactive encouragement by FDA to clinical trial sponsors for including PROs in drug development programs; provision of comprehensive PRO plans by sponsors to FDA early in drug development; promotion of an oncology-specific PRO research agenda; development of an approach to existing (&quot;legacy&quot;) PRO measures, when appropriate (focused initially on symptoms and functional status); and increased FDA and industry training in PRO methodology. FDA has begun implementing several of these recommendations.

1stOncology is recognized as a
Top 10 Global Pharma Analytic Provider

Continue your journey with 1stOncology by accessing our Free Leading Cancer Conference Whitepapers, signing up for our Free Weekly Newsletter and requesting a Free Demo to see how we can help you be 1st in Oncology!

Month: March 2016

Regulatory considerations in oncologic biosimilar drug development.

Antitubercular agent delamanid and metabolites as substrates and inhibitors of ABC and SLC transporters.

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide.

Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection.

Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient.