Late stage clinical development

Teriflunomide is the active metabolite of leflunomide (vide infra). It is in late-stage clinical development as potentially the first oral agent for multiple sclerosis. 

In summary, rivaroxaban 1 is an oral direct factor Xa inhibitor and is the first approved factor Xa inhibitor on the European and Canadian market. This class of inhibitors is expected to expand, with new members currently in late-stage clinical development. Rivaroxaban is indicated for the prevention of venous thromboembolic events in patients who have undergone elective total hip or total knee replacement surgery. Rivarobaxan was underwent extensive clinical program that included three Phase III trials of rivaroxaban involving a total of nearly 12,000 patients. The results from these three studies demonstrated the superior efficacy of the factor Xa inhibitor, both in head-to-head comparisons with enoxaparin and when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin. In all three... 

Vancomycin, a natural product that was first approved in 1955, is still the prototype for structural variations with the same mechanism of action the binding to the terminal L-Lys-D-Ala-D-Ala tripeptide in Gram-positive cell wall biosynthesis. The compounds below are semi-synthetic modifications of the same basic structural class (glycopeptides) as the prototype vancomycin, thus following in the chemical footsteps of the (1-lactams currently, there are three semi-synthetic glycopeptides, oritavancin 39, telavancin 40 and dalba-vancin 41, in late stage clinical development. 

A Snapshot of Natural Product-Derived Compounds in Late Stage Clinical Development at the End of 2008... 

Everolimus 8 is also in late stage clinical development by Novartis as RAD001 for the treatment of various cancers. 

Table 11.2 Natural product derived drugs in late stage clinical development (NDA or equivalent and Phase III), lead source with year structure determined and disease area (current 31 December 2008). ... 

Compound, IC50 — 1- p-g/niL Table 15 16 Anttobesity Drugs in Late-Stage Clinical Development... 

If you go back 5 or 7 years, explains Dr David Brown, all the big pharma companies were trying to in-license Phase III or Phase II compounds, which are close to market. And of course they d still prefer to do that, overall. But there are a limited number of compounds in late-stage clinical development and buying them is very expensive. So companies search now more often for Phase Ila or Phase Ilb compounds. Everybody s competing for those. There s now even a trend growing to in-license Phase I and lead-optimization compounds and much competition there. ... 

The recombinant, humanized anti-IgE MAb (rhuMAb-E25) is in late-stage clinical development for patients with allergic rhinitis. This anti-IgE MAb was been tested in two different models of seasonal pollinosis ragweed in the central United States and birch in several Scandinavian countries. 

Drug development is a long and cost-intensive business. Only after years of lead identification, chemical optimization, in vitro and animal testing can the first clinical trials be conducted. Unfortunately, many projects still fail in this late stage of development after a considerable amount of money has been spent. According to estimates, preapproval costs for a new drug exceed US 800 million [1]. 

Late Stage Clinical Drug Development—Phase Three... 

The primary purpose of evaluating chugs as inhibitors of CYP enzymes in vitro is to determine their perpetrator or precipitant potential before advancing a candidate dmg to a late stage of development. However, identifying a dmg as an in vitro inhibitor of a given CYP enzyme does not imply that the dmg will necessarily cause clinically relevant dmg interactions. The clinical relevance of the inhibition must be considered in the following context ... 

De Ridder, F. Predicting the outcome of phase III trials using phase II data a case study of clinical trial simulation in late stage drug development. Basic Clin Pharmacol Toxicol 2005, 96 235-241. 

At the end of 2008, there were five NP-derived compounds in the New Drug Application (NDA) development phase in the USA and/or Market Authorisation Application (MAA) in Europe and thirty-one NP-derived compounds undergoing Phase III clinical trials (Table 11.2). Details of late stage clinical trials, mechanism of action and derivation of each compound are described in this section. 

The late stage NP-derived compounds discussed in this chapter originate from research undertaken at least ten years ago. This is demonstrated by Tufts CSDD data, which shows there is an average time of 8.5 years from the start of clinical testing to FDA approval with a 21.5% success rate.267 As a consequence, late stage clinical compounds represent a window into the past and certainly do not reflect the current state of NP-derived drug development. 

We promised to return to the earlier statement that a healthy development pipeline of natural product derived candidates implies that natural products will still have a role to play in modern day drug discovery. In fact, this is far from reality. Firstly, these late-stage clinical candidates reflect the output from research activities undertaken at least 10 years ago and certainly not the current situation. Secondly, there is a lack of truly novel chemical templates in the pipeline and thirdly, it is clear that very few pharmaceutical companies remain engaged, at least internally, in natural product drug discovery activities. 

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