"A small molecule (MW = 500 Da) is a promising antidepressant candidate and is currently being developed for the treatment of depression:
i) Critically discuss the pharmacological evidence that would be needed to justify clinical development. ii) Propose the incremental toxicological studies and data that would be needed to support: a. A single ascending dose in a first-in-human study b. A multiple ascending dose clinical study c. A 6-month Phase 2 study d. Two one-year Phase 3 studies e. Marketing approval iii) Propose the starting dose, and the dose escalation, including the rationale for their choice, for the first-in-human single ascending dose study. Given that the NOAEL in the most sensitive species (rat) was 3 mg/kg."
An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London
i) Critically discuss the pharmacological evidence that would be needed to justify clinical development.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) describe the aims of preclinical testing in their M3 guidance as “[The characterisation of the] toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility..[and] to characterise potential adverse effects” (ICH, 2009).
Non-clinical studies ensure that the Investigational medicinal product (IMP) pharmacokinetic (PK) and pharmacodynamic (PD) properties can be determined. Bioavailability studies, mechanisms of ADME (absorption, distribution, metabolism and elimination), safety pharmacology studies, toxicity studies and the assessment of potential genotoxicity, mutagenicity and carcinogenicity are all critical to carry out (Andrade et al., 2016).
Primary and Secondary Pharmacology Studies
The drug half-life reflects the distribution and elimination of the drug and is especially important in drugs administered orally due to first-pass metabolism by the liver. Required PK data would be maximal IMP blood-plasma concentration (Cmax), the time at which this took place (Tmax) and the area under the curve (AUC). When these data are plotted the systemic exposure of IMP can be determined. Clearance rates and volume of distribution can be calculated in order to better inform decision making when determining doses in humans. As drug metabolites may impart a pharmacological effect, the route of metabolism must be understood and characterised (Attia, 2010). If the drug is excreted by the renal pathway, it might be prudent to carry out further investigation into the impact on the kidney. As the proposed IMP will be for long-term, chronic use any detrimental impacts of metabolic or excretory organs fully elucidated.
The mass of the IMP should be sufficient to cross the blood brain barrier (BBB). As well as lipid solubility, molecular weight is critical to a substance’s ability to permeate the BBB. The literature suggests a maximal molecular weight of >500 Da (Banks, 2009). However, in order to establish that the proposed drug reaches its target (namely, the brain), a radiolabelled version of the drug can be administered, brain imaging techniques then allow for the determination of the drug or metabolite presence in the target tissue. Radioligand-binding studies of cells expressing human serotonin transporters, for example could be carried out to show IMP affinity to target receptors. (Owens et al., 1997, Owens, Knight and Nemeroff, 2001).
Affinity selection-mass spectrometry (AS-MS) and Protein binding assays can determine further binding locations of IMP to receptors and provide indicative information on the likely efficacy of the candidate compound. (Pollard, 2010, Annis et al., 2007). IMP-plasma protein binding can infer the likely distribution of the drug in the systemic circulation and provide a measure of how easily the target is reached. Binding potency can predict clinical efficacy and likely adverse effects (Ye, Nagar and Korzekwa, 2016). These studies also provide a route to determine bioavailability. Absorption mechanisms of pharmaceutical products can be similar across species. Although metabolic process such as, first-pass metabolism account for some observed differences (Voortman and Paanakker, 1995). Data from these studies are extrapolated to determine the in-vivo blood plasma concentration needed for elicit a PD effect in humans. Mechanism of action (MoA) can be further elucidated buy the use of animal models. The most commonly used will be discussed below.
In-vivo microdialysis is carried out to determine brain neurochemistry. (Tzavara et al., 2003) and is often used to determine the in-situ effect of IMP treatments.
The forced-swim test is a type behavioral despair test (Gleason et al., 2015). Immobility is used as a surrogate for depressive behavior. Post-dosing, rodent escape behaviours are measured. The specificity of this test for antidepressants has been questioned as a range of antidepressants showed no effect on rat populations (Porsolt, 1981). Further, large number of non-antidepressants which also reduce immobility (Willner, 1984). The Vogel Conflict assay (Vogel et al., 1971) is a ‘punishment-based’ test in which rats receive a mild Electroconvulsive shock (ECS), leading to suppressive behaviour. Some studies have found ECS ineffective, additionally false positives can be seen in this test from other drug classes (De Graaf et al., 1985). The tail suspension test quantifies escape oriented behaviors to provide a measure of IMP efficacy. However, tail climbing behaviors can impact on result collection and the validity of this test for some classes of antidepressants is unclear (Can et al., 2011).
Other models include the observation of the ‘reward system’ such as the sucrose intake take can also be used to determine the efficacy of potential anti-depressant drug candidates. Reduced preference for sucrose can be reversed by treatment with antidepressants. However, sucrose intake has also been shown to be unreliable as the observations are thought to be inconsistent over time (Kurre Nielsen, Arnt and Sánchez, 2000) Intracranial self-stimulation (ICSS) is another reward-system model. Depressive behaviour presents as a reduced preference for self-stimulation and again, IMP efficacy is determined by reversal of this aversion. Other models have also been developed to induce depressive-like states in rodents. Namely the stress models. In these cases, rodents are exhibited to a set of conditioning experiments in order to mimic- depressive states in humans. The most widely used of these is the Learned Helplessness model. Animals are exposed to unpredictable and uncontrollable stressors such as, electrical shocks, cold water immersion and inversion of daylight cycles. ‘Open field activity’ is then observed as an indicator of depressive states (Overmier and Seligman, 1967).
Separation models are often considered the most demonstrative and are carried out in non-human primates. This is because the separation-response of these animals is most similar to humans. However, even this model’s validity is questioned and is described as “tenuous” Willner, P. (1984).
Animal models cannot entirely mimic human diseases (Seok et al., 2013). Multiple examples of efficacy failure in clinical studies and unexpected toxic events exist. Further, the lack of animal models for mood disorders (Savitz, Rauch and Drevets, 2013) further complicates matters and may, in part be as a result of lack of understanding in human brain and central nervous system (CNS) structures. Animal models can only ever be indicative of potential efficacy in the clinical setting. However, they do provide essential information in the selection of IMPs. Willner (1984) established criteria with which to assess animal models of depression as: Predictive validity, Face validity and Construct validity. In this review only four out of the eighteen models reviews were considered to be ‘good’ in that they exhibited each of the validity measures. These were Forced Swim test, Chronic Stress, Separation and Self-stimulation. Although other frameworks have been suggested (Belzung and Lemoine, 2011) a review into which animal models would be considered most efficacious under this new framework has not yet been carried out.
Safety Pharmacology
Safety Pharmacology studies are a battery of nonclinical tests used to characterise adverse PD effects, toxicological effects and to determine the mechanism of these (ICH, 2000). They are required in order to progress a drug’s development into the clinical setting.
The genotoxic potential of the IMP and its impurities are required to be studied in a battery of in-vitro and in-vivo assays for determining mutations and chromosomal damage. It may be the case that there are significant toxicology effects which prevent the IMP as being a viable drug candidate. Some of these investigations are not required until later stages of the trial process namely, in-vitro cytotoxicity, immunotoxicity and metabolic stability. However, single-dose toxicology, repeat-dose toxicity and genotoxicity must be carried out prior to administration in humans (ICH, 1998).
Carcinogenicity testing will be required for this IMP, especially as it will be used for chronic treatment, however this does not need to take place in the preclinical stage. Reproductive toxicity and teratogenicity must also be determined and these are permitted to be carried out after phase I (ICH, 2008). ICH (2000, 2005a) outline the ‘core battery’ of tests that must be carried out all new drug entities prior to entry into humans, to investigate the effects of the IMP on vital functions. They are focused around the Cardiovascular system (CVS), Central nervous system (CNS) and Respiratory System (RS). CNS tests can either be the Functional Observational Battery (FOB) (Moser, 1997) or, more commonly, the adapted Irwin Profile for rats (Esteve, Farré and Roser, 1988). While the Irwin Profile tests predate the FOB tests, they allow for faster screening. Under the Irwin Profile of tests, the first set of tests determine the drug action on the autonomic, neuromuscular, sensorimotor nervous system, while another set of tests determine behavioural effects. Given the IMP is a candidate in the treatment of depression, FOB, as well as the Irwin tests, should really be carried out in order to provide in-depth assessment of this drug. CV tests include the monitoring of Blood pressure, heart rate and the measurement of QT interval and hERG potency. These are required under ICH guidelines (2005a, 2005b) This is an important as QT interval is a measure of the overall ventricular cell action potential duration and a prolonged QT interval can be detrimental to cardiac health. RS Tests are carried out to determine respiratory rate, tidal volume, minute volume and resistance/compliance and is often carried out through whole body plethysmograph. If signals are identified during the ‘core battery’ of tests then further investigations in CNS, CVS and RS impact may be needed. For example, EEG, vascular resistance or pulmonary hemodynamics.
As the IMP is an antidepressant in nature, further studies should be carried out in order to determine the impact on cognition and dependence. Agency guidelines do not specify studies on cognitive functions as part of safety pharmacology. However, the following tests are often used to determine the cognitive impact of IMP: Passive avoidance test, social recognition test and water maze test (Hernier, Froger-Colléaux and Castagné, 2016). FDA draft guidance suggests the use of specific tests to determine dependence and abuse potential: Self-administration, Condition place preference, drug discrimination, psychomotor tests and dependence potential tests. However, these are not suggested to take place before the end of phase II (FDA 2017).
While many safety pharmacology studies do not need to comply with Good Clinical Practice (GLP) regulations, repeated dose toxicity, genotoxicity and safety pharmacology must be carried out under GLP (Andrade et al., 2016).
ii) Propose the incremental toxicological studies and data that would be needed to support: a. A single ascending dose in a first-in-human study b. A multiple ascending dose clinical study c. A 6-month Phase 2 study d. Two one-year Phase 3 studies e. Marketing approval.
Clinical trials begin by monitoring low systemic exposure of the IMP in few subjects. This exposure increases as the trials progress but should only ever be extended once adequate clinical and nonclinical safety information becomes available ICH (1997, 2009).
a. A single ascending dose in a first-in-human study
ICH (S7B) suggests that “delayed ventricular repolarization and QT interval prolongation” should be determined prior to First Time In Human (FTIH) dosing. Toxicokinetic testing guidelines are provided by ICH (1994a). The role of these tests are to determine the systemic exposure (AUC and Cmax) of the drug. In order to further inform FTIH dosing. There are clear inadequacies in the data as a result of physiological differences in animal models and humans, as outlined in the previous section.
Single ascending dose (SAD) in a first-time-in-human (FTIH) study are typically conducted in healthy volunteers in order to identify the maximum tolerated dose and pharmacologically active dose ranges. EMA guidelines (2017) state that the maximum exposure of healthy volunteers (HV) should be within the estimated PD range, higher exposures can only be investigated with clear rationale. There is disagreement in industry about this as it is often critical for the FTIH study to define PK and tolerability outside the therapeutic range (DeGeorge et al., 2017). FDA (2005) that safe starting doses for human are calculated from the ‘The No Observed Adverse Effect Level’ (NOAEL). Single-dose and repeat-dose toxicology should have been carried out in the nonclinical phase and are required prior to entry in humans (ICH, 1994a, 1994b). A single gene-mutation assay is described as being sufficient for single-dose studies (ICH, 2009).
b. A multiple ascending dose clinical study
The estimated dose range and toxicity level of IMP should be determined from SAD studies. Any adverse events must be analysed and discussed. IMP accumulation must be determined and half-life data in the preclinical phase is compared to the PK data collected in the SAD phase to inform the multiple ascending dosing (MAD) schedules.
The EMA guidance states that previous Maximum Tolerated Dose (MTD) and the predicted Cmax and AUC0-tau should have been assessed during the previous SAD study and are not to be exceeded (EMA 2017). Which limits the determination of the MTD in FTIH trials.
The MAD study attempts to elucidate the required dosage to maintain steady-state blood plasma concentrations and to understand how the long-term exposure of the drug impacts on the body. Further genotoxicology studies are required for multiple dosing studies in order to determine chromosomal damage in mammal systems (ICH, 2009).
c. A 6-month Phase 2 study
Any adverse events from Phase I studies must be analysed and discussed. The Maximum Tolerated Dose (MSD) or, alternatively, the maximum feasible dose (MFD) should be determined in the previous phase. Pharmacologically active dose range (PAD) can be used to aid in determination of dose escalations for the Phase II study. Treatment durations are usually determined by the animal toxicology data provided by the nonclinical phase. In this case, data should be being collected for at least 6 months in a rodent and 9 months in non-rodent (ICH 1994, ICH 1998). Surrogate biomarkers or surrogate clinical end-points should be determined in advance of the commencement of Phase II trials.
The Phase II study represents a Proof of Concept (PoC) analysis and should ensure that the clinical target have been successfully engaged and that end points observed are consistent with the predictions made during the nonclinical phase. Preclinical data supporting a therapeutic effect for example, receptor occupancy is used to suggest human dosages of the IMP. This therapeutic effect can be determined by imaging studies from radiolabeled products among other methods. (Wong, Tauscher and Gründer, 2009). Biomarkers are described by Temple (1995) as “indirect measures of clinically meaningful endpoints” and must be identified to determine likely efficacy of the IMP. The Minimum effective dose (MINED) and dose range should also be determined. MINED is defined by ICH (1994c) as “The smallest dose with a discernible useful effect”.
As the proposed Phase II study is over 3 months, the EU and Japan would require Embryo-foetal development (EFD), Organogenesis studies to be carried out. The complete battery of Genotoxicity studies, looking at chromosomal damage must also be carried out prior to entry into Phase II studies (ICH 2011, ICH 2009).
d. Two one-year Phase 3 studies
Adverse event analysis from Phase II must be thoroughly investigated and examined. The recommended dose ranged should also be determined by data collected a Phase II. Phase II studies should have resulted in identification and validation of biomarkers to be sued as measures of clinical end-points (Fleming and Powers, 2012). Drug-drug interaction (DDI) studies should also have been carried out during the Phase II period and these will need to be interpreted in order to progress into Phase III clinical trial. If drug impurities had been identified earlier as warranting further investigation, this should take place prior to Phase III (ICH, 2009). The FDA state that “dose-limiting toxicity should be identified..[from the[ 50-fold [exposure margin]” and where this has not happened, additional studies must be carried out at whichever is lowest from: MFD, MTD or 1g/kg dosages.
Immunotoxicity testing should have been carried out in the nonclinical phase. If the “weight-of-evidence” assessment gives any indications then, additional immunotoxicology must be carried out prior to Phase III (ICH, 2005c). Carcinogenicity and reproductive studies are also be required prior to Phase III. Male and female fertility studies are necessary for Phase III trials (ICH, 2009). Chronic toxicology studies to determine long-term exposure effect should be carried out prior to administration in human individuals (ICH, 1998).
e. Marketing approval
Discontinuation rates and adverse events, as well as analyses of impact on organs systems, and ECGs must be conducted prior to marketing approval. In addition, real-term clinical end points must be measured. These are ultimately the only acceptable measure of efficacy in IMPs. In the case of anti-depressants these are likely to be an assessment of suicide-related behavior and ideations, Hamilton depression rating scale scores (Munkholm, Paludan-Müller and Boesen, 2019). Pre- and postnatal development studies must have been carried out prior to market approval (ICH, 2009).
iii) Propose the starting dose, and the dose escalation, including the rationale for their choice, for the first-in-human single ascending dose study. Given that the NOAEL in the most sensitive species (rat) was 3 mg/kg.
Whilst EMA guidelines emphasise ‘exposures’ as being more important that dosages, The FDA explain that NOAEL is most often, the safety benchmark used. These regulations are from 2005 and the EMA have since provided updated guidance suggesting that Minimum Anticipated Biological Effect Level (MABEL) is a preferred starting point for calculations of Human Equivalent Doses (HED). This update has come from landmark studies where significant adverse effects were seen from doses calculated by the NOAEL route, namely the TGN1412 disaster. (EMA, 2017). In most cases, the FTIH dosage will be below PAD. Van Gerven and Bonelli (2018) further suggest the determination of the anticipated therapeutic dose (ATD) to aid FTIH dose estimation. ICH (2005b) describe the potential for QT interval prolongation if doses above PAD range are used, especially in individuals with renal or hepatic impairment. (EMA, 2015).
Without being provided a MABEL figure, we must establish the Maximum Starting Dose (MSD) in Humans through the FDA’s NOAEL method.
In this case the following calculation can be applied:
· A NOAEL in rats of 3mg/kg is multiplied by 0.162 in order to establish an HED of 0.486mg/kg.
· A fixed HED is calculated by using the FDA reference mass of a human as 60kg.
· This provides a fixed HED of 29.16mg.
A safety factor is then applied, which is most commonly 10 (unless there are specific indication this should be raised).
· This therefore establishes an MSD for Humans at 2.916mg. (FDA, 2005).
This dose may exceed the pharmacologically active dose (PAD) or the MABEL (Cohen et al., 2015). EMA guidance therefore suggests that MABEL and the PAD should be considered alongside the MSD calculated from NOAEL and whichever is the lowest figure should be used as the starting point for consideration in FTIH trials. Best practice would then assess the MSD (2.916mg) and clinicians would most often select an actual starting dose well below this figure.
There is not specific guidance available on this assessment so, for the purposes of this assignment, I propose an actual starting dose for FTIH SAD study as being 1mg.
Dose Escalation Scheme
The EMA provide guidance on the dose escalation scheme. They describe how PD factors measured at the preclinical stage such as, the dose-response should be used to inform the dose escalation. (EMA 2017).
They suggest that the dose escalation should also be guided by the dose-toxicity and dose-effect relationships. The steeper these curves, the smaller the dose increment should be. They go on to say that there should be an assessment of PD and adverse effects in order to further inform this escalation scheme. Prior to each dose escalation, there should be a meeting of all practitioners to analyse collected data and determine whether the proposed next dose should be altered. Previous experience with similar compounds and MoA should be used in this determination. In lieu of this information and for the purposes of proposing a dose escalation scheme a sequential dose escalation is suggested. One individual receives a dose and a second individual does not receive their dose until the health of the first individual can be safeguarded. Suggested dose escalations will be fixed intervals on a linear scale as this will provide further opportunities to determine adverse effects on this new drug.
EMA (2017) guidelines states that dose escalation criteria should be based on clinical exposure in individual subjects. If after dosing there are no symptoms nor, safety signals from vital signs or laboratory tests, and AUC and Cmax scaled to NOAEL or MABEL, have not been achieved, then the dose escalation protocol is followed. FDA guidance suggests that dose escalation should continue until MTD can be determined unless adverse signals are generated from QTc or QRS prolongation or other safety pharmacology assessments. (FDA, 2013).
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An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London