The discovery and development of new drugs is a long process which faces different challenges, having as a final goal the identification of a molecule that meets multiple criteria. In the last few decades, different guidelines focussing on structural and physicochemical properties improved ADME and toxicology profiles leading to a reduction of attrition in the drug development process. However, the overall failure still remains quite high with only 4% of the candidates reaching the market, with several suboptimal compounds entering costly clinical trials, some of which should not have been made in the first instance!
The following paper published in Nature Review Drug Discovery (Nat Rev Drug Design 2015, 14, 475-486) reports a new analysis on the drug development attrition faced by four major pharmaceutical companies (Astra Zeneca, Eli Lilly, GlaxoSmithKline and Pfizer). Would this analysis finally reveal medicinal chemists how to reduce attrition in drug discovery program?
This study evaluated 812 small molecule drug candidates developed in the decade 2000-2010 analysing physicochemical properties, target class, broad disease area and reasons for failures. Unfortunately, certain specific characteristics such as chemical structures, pharmacological targets etc., were not provided due to confidentiality issues.
The table below summarises the primary cause of failure for the compounds analysed, reporting also the difference between compounds developed in 2000-2005 and those developed in 2006-2010. Non-clinical toxicology was found to be the major cause for compounds termination (40%), followed by “the less noble” rationalization of company portfolio (21%), then clinical safety (11%), efficacy (9%), etc. Interestingly, comparing the first five years of the decade with the last five, a decrease in failure has been observed for the majority of categories, with the exception of the rationalization of company portfolio which showed a whopping 20% increase!
The major cause of failure for each individual class was: non-clinical toxicology for the preclinical phase (59%), clinical safety for phase I (25%), lack of efficacy and clinical safety for phase II (35% and 25% respectively). The failure due to reorganization of company portfolio was constant for the three phases (20%)
An analysis of the physicochemical properties of the considered compounds showed that 75% of compounds fall within the desirable range of properties and the distribution overlap with the standard deviation values of the marketed drugs considered, with only 7.6% of compounds breaking two Lipinski’s Ro5 (molecular weight >500 and CLogP >5). However, looking at these properties in more details significant differences were noticed. The mean molecular weight was found to be 10% higher for the drug candidates compared to the approved drugs, and both calculated logP and logD were 0.5 log units higher for the drug candidate compared to the approved ones’. In addition, differences were also observed for the ratio of sp3 atoms and the mean aromatic ring count. This result indicates the tendency to design and select more lipophilic and planar clinical candidates, a lesson not yet learnt?
Controversial findings were observed when comparing physicochemical properties with non-clinical toxicology and clinical safety failure. In fact, while no correlation between non-clinical toxicology failure and physicochemical properties was identified, in the case of clinical safety a statistically relevant correlation was observed with regards to the lipophilicity of the compounds. Compounds failing due to clinical safety issues were more lipophilic compared to the ones progressing (CLogP= 3.8±1.6 versus 3.1±2.1 respectively). Although the results are very close and within the desired range, these findings were found to be statistically significant. Similarly, this trend was observed for calculated logD but was not statistically relevant.
Despite the progress made, human pharmacokinetics remains the third cause of failure (16%) in phase 1. From the analysis no correlation between physicochemical properties and failure or progression to the next phase was observed. However, it was noticed that almost as twice as acidic compounds failed compared to basic/neutral compounds, which may be attributed to poor predictive results from preclinical data.
This analysis points out, as also described in one of our recent blog, the necessity to consider with caution the calculated physicochemical properties of the compounds considered as the results obtained may be misleading. In general, it reinforces the current guidelines used in drug design and in particular the need to move away from the extremes of the drug like properties and to use them with more care. In particular, it supports the notion that more lipophilic and planar compounds have an increased chance of failing during development.
Blog written by Marco Derudas