25 research outputs found
An idealized view of the opportunity provided by a comparative and integrated oncology drug development path.
<p>This is a theoretical illustration of 100 preclinical agents that may be evaluated by either a conventional or an integrated and comparative drug development path. Data for transition rates and costs of Phase I, II, and III trials are based on published cost estimates <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi2" target="_blank">[3]</a> and reported clinical phase transition probabilities for investigational oncology compounds from the 20 largest firms (by pharmaceutical sales in 2005) from 1993 to 2002 <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Roberts1" target="_blank">[4]</a>. Estimates used to derive a vision of the benefit of an integrated approach to drug development are based, in part, on estimates of transition and approval rates for non-oncology therapeutic areas where informative preclinical models exist <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>. Relative to the conventional development path, the integrated development path is characterized by improved success early in clinical development and a reduction in drug failures late in clinical development. Conventional oncology drug development results in approximately 40% of eligible agents transitioning from preclinical to Phase I, 75% from Phase I to II, 60% from Phase II to III, and 55% from Phase III to approval <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>. Therefore, for every 100 preclinical candidates, only ten new drugs will reach the clinic. Of most significance are failures that occur late in the development path (i.e., after Phase II or Phase III evaluation). With an integrated approach, more toxic and ineffective agents may be eliminated prior to Phase I (estimate 30 agents now entering Phase I trials versus 40 in the conventional pipeline). Attrition in Phase I may be minimized (estimated 87.5% success rate) and an additional 30% of drugs may be removed from development prior to Phase II based on comparative studies that demonstrate poor pharmacokinetics, pharmacodynamics, or activity (estimate 18 agents now entering Phase II trials versus 30 in the conventional pipeline). Deprioritization (from above) of these drugs will improve the Phase II success rate (estimate 90%). Data from comparative studies will result in the removal of 20% of remaining drugs prior to Phase III based on lack of efficacy in the adjuvant setting, thereby improving success in Phase III and leading to 90% of Phase III agents receiving FDA approval (compared to 55% in the conventional pipeline). In this model, 12 new drugs out of every 100 preclinical candidates will reach the clinic. Using estimates for Phase I, II, and III trials of US23.5 million, and US86.3 million per trial respectively [3], the total clinical trial expenditures for developing 100 preclinical agents is US2.87 billion using conventional methods. Using the hypothetical improvements described above that result from the integrated approach the clinical costs for development will be US2.03 billion [3]. Factoring in additional costs for comparative studies with this approach of US150,000 for studies conducted in the preclinical setting, US1 million for studies conducted before Phases II–III studies, the total cost of development is estimated at US290 million to US$173 million <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>.</p
Canine and human iUC samples cluster together.
<p>A list of genes that are commonly annotated and significantly expressed (between normal and iUC, p<0.05, FC2) in dogs and humans, was generated. Hierarchical clustering was performed on these genes (n = 436) using Euclidean distance metrix. Figure illustrates that canine and human normal controls cluster together and these cluster separately from canine and human iUC samples. The iUC samples from dogs and humans clustered together. The color codes are: (1) red bar denoting canine normal bladder, (2) brown bar denoting normal human bladder, (3) blue bar denoting canine iUC samples, and (4) grey bar denoting human iUC samples.</p
Immunohistochemical detection of EGFR expression in normal and iUC canine tissues.
<p>Photomicrographs of canine normal bladder (A and B) and canine iUC samples (C and D) demonstrating immunoreactivity to EGFR. Paired negative controls were used for each specimen (B and D). Please note membrane immunostaining of tumor cells (C) and normal urothelium (A).</p
Analyses of canine iUC samples reveal enrichment for basal and luminal subtypes and also for genes in <i>P53</i> pathways.
<p>A list of genes representing basal and luminal subtypes and those involved in <i>P53</i> pathways was manually generated from published human iUC dataset (Cancer Genome Atlas Research Network. 2014a; Choi et al 2014a and Damrauer et al 2014). A second list was generated, using these genes as a reference, which were also significantly expressed in canine iUC samples and hierarchical clustering was performed using Euclidean distance metrix. Heat maps indicate genes enriched for basal (A) and luminal (B) subtypes of breast cancer in the canine iUC samples and also indicate enriched genes in the <i>P53</i> pathways (C). Red and blue bars above the heat map indicate the clean separation of samples into the previously observed groups. There was no clear segregation of basal and luminal genes.</p
Flow chart and summary of cross-species analyses.
<p>Step-wise depiction of sample processing and cross-species analyses that were performed.</p
Principal Component Analyses (PCA) plot of normal canine bladder and iUC samples.
<p>A PCA plot was generated using normalized data. The PCA plot shows clear separation between normal samples and canine iUC samples. In addition, the PCA plot also demonstrates clear segregation of the canine iUC samples into two groups i.e., group I and group II.</p
Canine iUC samples cluster as two distinct groups.
<p>Hierarchical clustering illustrates the differential expression of genes (p<0.05, FC2) between canine iUC samples vs. normal canine bladder. Furthermore, the canine iUC samples clustered in two distinct groups.</p
No significant changes in circulating T- or B-cell populations were seen after treatment with NHS-IL12.
<p>Relative numbers of T- and B-cell populations were quantified in PBMCs by flow cytometric analysis on days 1, 2, 3, and 8 after treatment with NHS-IL12. Immune cell determination was based on labeling: B cells, CD21<sup>+</sup>MHCII<sup>+</sup> (A),T cells, CD4<sup>+</sup> (B) or CD8<sup>+</sup> (C); regulatory T cells, CD4<sup>+</sup>Foxp3<sup>+</sup> (D);. CD4<sup>+</sup> T cells trended downward at day 8 compared to their baseline measurements (B). Other differences were not evident over the time points evaluated.</p
Serum IL-10 levels increased following treatment with NHS-IL12.
<p>Each line represents a different dog, with individual colors representing different treatment groups. Serum IL-10 levels at 48 and 192 hours were significantly different from time points 0–8 hours (Kruskal-Wallis test followed by Dunn’s multiple comparison test) when data from all dogs was pooled. There was no difference in IL-10 levels at 48 hours between any of the treatment groups (Kruskal-Wallis test, p = .06, the 0.4 mg/m2 group was not included because it was a single dog).</p
Serial serum pharmacokinetics and IFN-γ/cytokine panel collections.
<p>IFN: interferon.</p><p>Serial serum pharmacokinetics and IFN-γ/cytokine panel collections.</p