Natural Products Have Increased Rates of Clinical Trial Success throughout the Drug Development Process

Abstract

Natural products (NPs) or their derivatives represent a large proportion of drugs that successfully progress through clinical trials to approval. This study explores the presence of NPs in both early- and late-stage drug discovery to determine their success rate, and the factors or features of natural products that contribute to such success. As a proxy for early drug development stages, we analyzed patent applications over several decades, finding a consistent proportion of NP, NP-derived, and synthetic-compound-based patent documents, with the latter group outnumbering NP and NP-derived ones (approximately 77% vs 23%). We next assessed clinical trial data, where we observed a steady increase in NP and NP-derived compounds from clinical trial phases I to III (from approximately 35% in phase I to 45% in phase III), with an inverse trend observed in synthetics (from approximately 65% in phase I to 55% in phase III). Finally, in vitro and in silico toxicity studies revealed that NPs and their derivatives were less toxic alternatives to their synthetic counterparts. These discoveries offer valuable insights for successful NP-based drug development, highlighting the potential benefits of prioritizing NPs and their derivatives as starting points.

Figure 1

(A) Percentage of patent compounds per class (Hybrid, NP, and synthetic). (B) Percentage of patent applications of each class by year.

Figure 2

(A) Proportion of NP, synthetic, and hybrid compounds in all clinical trials compared to FDA-approved drugs. (B) Proportion of NP, synthetic, and hybrid compounds across the phases of clinical trials (data from www.ClinicalTrials.gov). Compounds are stratified by their latest phase (i.e., phase I/II are categorized as phase II and phase II/III are categorized as phase III).

Figure 3

Experimental tissue and target-specific toxicity overview across NP, synthetic, and hybrid compounds. For each of the three toxicity classes (i.e., CYP450 toxicity, hepatotoxicity, and carcinogenicity), the percentage of toxic compounds for each group (i.e., hybrids, NPs, or synthetics) is shown.

Figure 4

Proportion of toxic compounds for each of the 32 toxicity end points in FP-ADMET. The predictions are made on COCONUT and Enamine DDS for NPs and synthetics, respectively. As the figure shows, DDS (synthetic) bars (orange) are generally higher than those for COCONUT (NPs).

Figure 5

Annotation pipeline for compounds from clinical trials. Created with BioRender.com.