Introducing new drugs into the clinic! Flashcards
Phases of preclinical discovery listed?
Target discovery; target validation; hit identification; hit validation; lead identification and lead optimisation.
Target discovery/identification phase?
Demonstrate that potential molecular target is present in human tumours and presence is correlated with clinical outcomes! Must be druggable e.g. GPCR. Can use genetic associations, mRNA/protein levels, phage display (phenotypic screening).
Target validation?
Proof-of-principle that modulation of the target in tumor cells has required effect on tumour biology i.e. the use of siRNA or ASO, or transgenic animals to prevent expression. Can use in vitro through to whole animal models. mAbs often better validation tools because more specific than SMIs, but obviously limited to cell surface and secreted proteins.
Hit identification/discovery?
Identify small molecule with activity against the target. Several approaches are available such as fragment-based screen, focused screens, high throughput screening uses assays assuming no prior knowledge of likely hits. For monoclonal antibodies, this may involve use of phage display technology. Can also used structural aided drug design (crystals used) or virtual screens.
Hit validation i.e. hit-to-lead?
Demonstrate that hit could be modified to be clinically viable. Activity confirmed using IC50 (concentration needed to inhibit response by half) below certain dosage, structure-activity relationship predictions made. Must demonstrate specificity and selectivity, and predict ADME early stages.
Lead identification?
One compound or series of compounds that have confirmed potential. Requirements now based on more stringent requirements of hit validation i.e. ADME modelled and assessed, SAR, IC50 more strict, selectivity. Clear intellectual property situation established.
Lead optimisation?
Two in vivo models at clinical exposure levels demonstrating efficacy, one rodent and one non rodent, PK/PD assessment clear. Patent applied for to clarify IP position. File IMP. Toxicity profile established and dosage for Phase 1. Need to demonstrate viable synthetic route for mass synthesis and also, crucially, the development of biomarkers.
NOAEL?
Non-observed adverse effect dose level relative to weight; crucial to know this in preclinical.
IMP exposure?
Like NOAEL, shows concentration in blood over 24 hours and key to know this before clinical.
LD10 in preclinical?
Particularly for cytotoxics, this is the dose that killed 10% of mice; use 1/10 of this conventionally for starting dose in humans.
Things to find in Phase I?
DLT, therefore MTD and accordingly R2PD. Also study biomarkers and PK data i.e. exposure, max concentration, half life and clearance
Grading for DLT?
Use CTCAE (common terminology criteria for adverse events)
Facilitated regulatory pathways?
FRPs; contentious
Pembrolizumab FRP?
2011; Phase I trial (PDL-1 mAB) i.e. immune checkpoint inhibitor. Showed impressive durable RR in melanoma and NSCLC and so cohorts added in these to find and evaluate dosing regimens. Was approved for melanoma 3 years later on the back of this in trial that eventually included 1,200 patients.
Crizotinib FRP?
Kinase inhibitor that works on the fusion gene between EML4 and ALK (anaplastic lymphoma kinase). This mutation is present in 4% of NSLC. On the back of a relatively small Phase III study of just 347 patients versus pemtrexed or docetaxel; showed impressive responses and led to accelerated approval. Shaw, 2013. Did not show OS benefit but PFS better.
