Phase efficacy data

Safety and quality aspects are the main topics that must be addressed from a regulatory perspective at the pre-clinical phase of drug development. Indicative efficacy data will also be obtained, but authoritative data can be obtained only from clinical studies conducted with humans. Safety and preliminary efficacy indications... 

Samples of blood and excreta are taken for laboratory analysis. It is expected that, at the end of this phase, you will have a preliminary estimate of the maximum dose that may be safely tolerated in humans, and also a basic profile of the drug s pharmacokinetic behaviour. Depending on the availability of appropriate analytical indicators, pharmacodynamic and indicative efficacy data may also be generated. The data acquired must be carefully analysed and assessed so that, based on the findings, appropriate Phase II trials can be planned. 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Many participants expressed that there is more willingness to stratify on the basis of pharmacogenetics and pharmacogenomics for safety than for efficacy. For example, it was felt that for a CYP2D6 substrate (confirmed by in vitro and Phase I data), a stratified... 

Phase I clinical evaluation of BMS 599626 is ongoing [79,80] however, no efficacy data have been reported to date. Dose escalation has proceeded to 660 mg/day and is ongoing since a MTD has not been reached. The pharmacokinetic profile in both healthy volunteers and cancer patients supports once-daily dosing with a half-life of ca. 20 h. An area under the curve of ca. 2.4 xgh/ml with a maximum concentration of ca. 0.18 xg/ml was achieved at steady state after 100-mg dosing in patients. In mice at a dose that resulted in modest antitumor activity (ca. 50% TGI), significantly higher plasma levels were achieved (AUC ca. 14.5 xgh/ml and Cmax ca. 5.0 xg/ml) [76]. 

Phase I data were presented at the 95th AACR meeting, March 2004. Normal healthy male volunteers were subjected to bone marrow aspirations prior to and 4 h following a single 25 mg oral dose of the compound or placebo. L21649 achieved plasma concentrations of 103.4 nM at 4 h post-dose. In July 2004, similar clinical data were presented at the 29th National Medicinal Chemistry symposium. The PK/PD correlated well, and at that time, it was believed that the plasma levels should be closer to the EC90 levels for maximal efficacy. 

There is a phase 1 trial (trials that examine the toxicity of the proposed treatment and determine an appropriate dose of the treatment) of an intramuscularly delivered O x-antitryp sin gene in a modified adeno-associated virus vector. It will be some time before efficacy data are available ... 

Ruboxistaurin (LY333531) 41 (Eli Lilly) is being evaluated in a Phase III trial for the treatment of diabetic macular oedema.224 Lilly had submitted an NDA in February 2006 to the FDA for the treatment of diabetic retinopathy and received an Approvable Letter in September 2006 that requested another Phase III trial for additional efficacy data. The EMEA also required further clinical data and, as a consequence, Lilly withdrew its European MAA. Ruboxistaurin 41225 228 competitively inhibits adenosine triphosphate (ATP) binding to PKC/i and is a synthetic analogue of staurosporine 42. 

It is possible to develop ways to ascertain in Phase I some efficacy data in endocrinological indications, antibiotics, antivirals, and certain cardiovascular indications. Even in CNS disease, for example in Alzheimer disease one can look for changes in attention span in older healthy volunteers in Phase I as an indicator of possible efficacy. 

On the contrary, the new formulation might be deliberately designed not to be bioequivalent. Slow-release formulations are, by definition, not bioequivalent but often associated with therapeutic superiority due to reduced probability of C -related adverse events and better compliance because of reduced dosage frequency. In this case, efficacy data will normally be required of the scale and rigor of the earlier phase III program. 

Medical Affairs departments design valuable and often extremely creative trials that provide important later phase information about clinical research conducted with soon-to-be-marketed or already marketed drugs in regard to their relative efficacy compared to others of its class, new information concerning efficacy in related indications and additional safety and efficacy data that supplement the core data which led to original approval. Because the type of research conducted in this later phase is often in response to residual questions about safety as part of phase IV commitments agreed to upon original approval,... 

Overall, it appeared that the population response reached a plateau at approximately 30mg therefore, administration of doses greater than 30mg did not provide additional benefit. This conclusion was consistent with the findings resulting from the efficacy data reported in the Phase 3 trials. 

---