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Sample Case A

Sample Case A. Concept: Novel mechanism for sexual dysfunction indication. Case study: FSD-204 targets a novel mechanism for the oral treatment of female sexual dysfunction

Gabriel
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Sample Case A

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  1. Sample Case A

  2. Concept: Novel mechanism for sexual dysfunction indication. Case study: FSD-204 targets a novel mechanism for the oraltreatment of female sexual dysfunction Aim is to provide sufficient pre-clinical and clinical data to allow a regulatory decision to be made on the level of abuse potential of FSD-204 Case A FSD-204

  3. DrugDiscrimination Study in drug-abusing patients Phys. Dependenceand Withdrawal Rat Self-Administration Case A Case Overview Preclinical Phase I Phase II Phase III Phase III Pivotal Efficacy Studies Phase I FIH Phase I MDT Phase II POC/Dose-Ranging Study (n=100) Receptor binding Microdialysis Animal Pharmacology Animal PK CNS Safety Pharmacology Note: company strategy requires early “de-risking” of target Development Program 2 week rat toxicology 2 week dog toxicology Questions Early Preclinical Assessment • Are there any early “signals” of concern for Abuse? • Any additional data helpful? Clinical Assessment • Review results of Clinical Abuse study • Any further work needed? Behavioral Pharmacology • Assessment of results of SA • Overall conclusion from preclinical assessment • Is there a need for a formal clinical assessment of abuse? Behavioral Pharmacology • Design features of DD and PD&W studies Clinical Assessment • Review of AE profile from FIH study • How to design Clinical study in drug abusing patients to maximize value? Behavioral Pharmacology • Assessment of results of DD and PD&W • Design of Self-administration

  4. Case A Pharmacology & Pharmacokinetics • FSD-204 is a CNS penetrant compound with a novel MOA • FSD204 is a Receptor X agonist increasing intracellular levels of cAMP • Receptor X has a distribution restricted to DA-ergic areas in the CNS: • Nucleus Accumbens (NAcc) • Dorsal Striatum • Cortex • FSD-204 binds to no other receptors,ion channel or transporter targets typicallyassociated with abuse at 10µM(68 affinities tested) • Functional activation of receptor X in bothrat and human tissue, EC50 = 3nM • From in vivo models of sexual behaviour, predicted Ceff = 30nM • Half-life in rats = 4hrs, no active metabolites identified in any species evaluated • Microdialysis experiments showed increase in DA in pre-frontal cortex only and no effect on other neurotransmitters investigated Binding Profile ReceptorAffinity Novel X 1 nM Melatonin M1/2 65nM 5HT1A 80nM Dopamine D2 350nM FDA Comment

  5. What do we know about the drug so far? FSD-204 : Binds to a novel receptor which has a dopaminergic distribution (reward areas) Binds to D2 receptors with low affinity (Ki :350 nM) - This interaction may be relevant, depending on the therapeutic dose It does not bind to other receptors associated with abuse at high concentration Increase in DA seen only in the PFC with microdialysis may be relevant to the overall activity Preliminary effective dose and limited PK in rats What else do we need to know at this point? Knowledge of the structure activity relationship (SAR) of the drug. What do we know about the drug and other analogs? Binding profile of the main metabolites How the interaction of FSD-204 at the receptor level translates into the overall activity of the drug Pharmacology & Pharmacokinetics FDA Comment Stimulant?

  6. Case A Preclinical safety studies • Rat neurofunctional assessment (FOB): small, but significant, increase in spontaneous locomotor activity/rearing at 100 and 300nM • No effect in other safety pharmacology studies • Toxicology studies: • Dog: seizures observed following multiple dosing (at free plasma levels of 200nM) • Rodent: lethality at free concentrations of 400nM. • No other organ toxicities observed

  7. Case A Questions on preclinical pharmacology • From the preclinical data provided what, if any, concerns would be raised on the possible abuse potential of FSD204? • Are any further preclinical data required for interpretation? • Would a change in spontaneous locomotor activity alter the subsequent preclinical strategy for abuse potential assessment, and if so, how? • Are hypoactivity and hyperactivity viewed differently in terms of requirements for a subsequent preclinical AP assessment?

  8. FDA Comment Q1: From the preclinical data provided, what, if any, concerns would be raised on the possible abuse potential of FSD-204? • Functional Observation Battery (FOB) • More than one observation time point is recommended including that of maximum plasma concentration (Tmax) • Information on all parameters evaluated and methods used should be submitted (rearing, crouched posture, arousal, hind limb splay, handling reactivity, rotarod test, etc) • Toxicology • Seizures in dogs at 200 nM. Safety concern associated with the intake of high doses for abuse purposes FSD-204 seems to produce behaviors consistent with the actions of a stimulant.

  9. FDA Comment Q2: Are any further preclinical data required for interpretation? • Drug discrimination and self administration studies are recommended

  10. FDA Comment Q3: Would a change in spontaneous locomotor activity alter the subsequent preclinical strategy for abuse potential assessment, and if so, how? • An increase in spontaneous locomotor activity suggests a stimulant profile and the possibility of abuse potential • A decrease in spontaneous locomotor activity suggests a sedative profile and the possibility of abuse potential • Thus, a change in locomotion would suggest the necessity for animal abuse studies (such as drug discrimination or self-administration)

  11. FDA Comment Q4: Are hypoactivity and hyperactivity viewed differently in terms of requirements for a subsequent preclinical AP assessment? • Both behavioral responses indicate the need for abuse potential assessments in animals • Hypoactivity suggests activation of receptors associated with depressant drugs (GABA, opioid, etc.) • Hyperactivity suggests activation of receptors associated with stimulant drugs (dopamine reuptake inhibition, dopamine release, etc.)

  12. Case A Preclinical Pharmacology – Drug Discrimination What does the Agency see as the role of DD in AP assessments? Does it have a use beyond selecting the training drug for SA studies? • Drug discrimination studies performed in Morphine, Cocaine and Diazepam trained rats • 3 doses of FSD204 and vehicle (n≥8), with maximum dose targeting 3xCeff • Route of administration chosen based solely on achieving target exposures • Results • Partial generalization (30-40%) to cocaine and morphine In designing the study, should other factors be considered in choosing the route of administration? Is the multiple of 3xCeff sufficient? If not what criteria should be used to set the dose range? • From these resultshow should the SA training drug be chosen?

  13. FDA Comment Q5: What does the Agency see as the role of drug discrimination in abuse potential assessments? Does it have a use beyond selecting the training dose for self-administration studies? • Drug discrimination determines whether Drug X produces an interoceptive cue in an animal that is similar to the training drug. Thus, generalization by Drug X to training drug is only predictive of abuse potential if the training drug is a known drug of abuse • A negative signal in drug discrimination (even against a range of training drugs known to have abuse potential) does not inherently mean Drug X has no abuse potential. A unique mechanism of action in the brain may mean a unique abuse potential profile dissimilar to those of other drugs of abuse • Doses used in drug discrimination typically produce plasma levels similar to those produced by the therapeutic dose • Choice of training drug is difficult when Drug X acts by a novel mechanism Hmm?

  14. FDA Comment Q6: In designing the study, should other factors be considered in choosing the route of administration? • Typically, the route of administration for drug discrimination studies is intraperitoneal • The route of administration should simulate the pharmacokinetic exposure in humans

  15. FDA Comment Q7: Is the multiple of 3xCeff sufficient? If not what criteria should be used to set the dose range? • The clinically effective dose is unknown at Phase 1 • Frequently, the clinically effective dose is found to be much higher (and sometimes much lower) than initially predicted by the preclinical studies • Ideally abuse potential studies should not be conducted until Phase 2 studies are completed Animal abuse potential studies may need to be repeated if the doses used are not representative of final human therapeutic doses

  16. FDA Comment Q8:From these results how should the self-administration training drug be chosen? • Doses are typically lower than therapeutic doses to prevent overdose in animals when the drug is self-administered repeatedly • However, a range of doses should be tested in self-administration to ensure that potentially rewarding plasma levels are achieved during the trial

  17. Case A Preclinical Pharmacology - Physical Dependence & Withdrawal • Design • Male rats (n=8) dosed once daily (p.o., clinical route) for two weeks • Dose at Cmax of 3xCeff in humans • Plasma levels measured at 24 hr post-dose are below predicted Ceff but above Ki for Receptor X • Cocaine as positive control (FSD shows mild stimulant profile) and vehicle group • Endpoints measured before, during and up to 4 days following drug discontinuation (8, 24, 32, 48, 72 and 96 hr): • Body weight and food consumption • Behavioral scoring of discontinuation signs and symptoms, including presence/absence of: salivation, jumping, wet dog shakes, head shakes, paw shakes, abnormal posture, abdominal constriction, teeth chattering, tremors, genital licking, rearing, hyperactivity, retropulsion, sniffing, stretching, scratching, burying, grooming, pilo-erection

  18. Case A Preclinical Pharmacology - Physical Dependence & Withdrawal • Result • No tolerance or withdrawal signs observed after discontinuation of FSD204 • Cocaine showed tolerance to behavioural effects and significant weight loss following discontinuation FDA Comment

  19. FDA Comment Preclinical Pharmacology - Physical Dependence & Withdrawal • Animals • If the indication is for females only, studies should include female animals • Observation times • Observation times should be based on the PK parameters of the drug for the species used and should be of a long enough duration to detect behaviors • All behaviors should be noted and not limited to a set list of behaviors of interest. Unexpected results may alter the understanding of the drug’s actions • Video recording of animals during the study might be helpful More frequent observations within the first 8 hours following drug discontinuation are recommended • Tolerance is not directly related to physical dependence

  20. Case A Questions on PD&W study design • Is cocaine the appropriate positive control? • Are the endpoints sufficient to assess PD&W? If not,how should appropriate endpoints be selected? • Should both a positive and negative control group beincluded if in-house data is available to show validation of the cocaine PD&W model? • Is dosing for 14 days by the clinical route adequatefor the non-clinical assessment of PD&W? • What other factors should be considered when selecting the route of drug administration for a PD&W study? • Is there a need to target sustained pharmacologicalexposures, or is it sufficient to achieve this transiently?

  21. FDA Comment Q9: Is cocaine the appropriate positive control? • FSD-204 is reported to be a “mild stimulant”, so methylphenidate may have been a better positive control than cocaine in dependence and withdrawal studies • The Sponsor can propose any drug as a positive control, but must justify the selection

  22. FDA Comment Q10:Are the endpoints sufficient to assess physical dependence and withdrawal? If not, how should appropriate endpoints be selected? • Withdrawal behaviors known to be associated with the drug class should be observed during discontinuation • For a drug with novel mechanism of action, a number of withdrawal behavior checklists derived for various classes of drugs may be useful in establishing which behaviors to look for during Drug X discontinuation • The presence of physical dependence (withdrawal behaviors following drug discontinuation) is not sufficient to indicate abuse potential • However, full characterization of a drug’s abuse potential does require assessment of physical dependence

  23. FDA Comment Q11: Should both a positive control and a negative control group be included if in-house data is available to show validation of the cocaine physical dependence and withdrawal model? • The data reported for cocaine did not show any weight loss during the drug administration phase. Given that stimulants are known to reduce feeding and to reduce body weight, this suggests that the dose of cocaine used was not high enough • A positive control is used to validate the study. A placebo is the only necessary negative control

  24. FDA Comment Q12: Is dosing for 14 days by clinical route adequate for the non-clinical assessment of physical dependence and withdrawal? • Duration of exposure needed depends on the PK of the drug • Appropriate duration of drug administration prior to assessing withdrawal is based on elimination half-life • For most drugs, a 14-day duration of drug administration should be sufficient. However, for drugs with half-lives that are relatively long, additional drug dosing may be necessary prior to discontinuation

  25. FDA Comment Q13: What other factors should be considered when selection of the route of drug administration for a physical dependence and withdrawal study? • Half-life determines duration of the drug discontinuation observation period • The observation period should extend to at least 3-7 days, or longer if the drug is known to be eliminated slowly

  26. FDA Comment Q14:Is there a need to target sustained pharmacological exposures, or is it sufficient to achieve this transiently? • Drug exposure should parallel exposure in clinical populations • This may depend on the intended use of the drug and the PK parameters of a drug. For instance, a drug may be intended for chronic use if steady state levels of drug are needed for optimal clinical benefit • If the drug product is controlled- or sustained-release, then a mini-pump may be an appropriate method for delivering drug to an animal in the physical dependence study • If the drug produces pharmacokinetics that peak and trough across the day, then the animal drug administration should attempt to produce a PK profile that is as similar as possible

  27. Case A Preclinical Pharmacology –I.V. Self-administration • Rats (n≥8) trained to respond for cocaine under FR3 • Responding extinguished until stable and <50% of cocaine infusion rates • Test FSD-204 (3 doses & vehicle with highest dose targeting 3xCeff) • Each dose available for minimum of 3 days until responding stable • Randomized order within animal design

  28. Cocaine Vehicle FSD-204 high dose **p<0.01 compared to vehicle Case A Preclinical Pharmacology –I.V. Self-administration • Data: FDA Comment

  29. FDA Comment Preclinical Self-Administration • Animal self-administration studies measure two related aspects of abuse potential: • Reward: If the drug produces a positive measured effect in a self-administration study for a limited time period, this may suggest that the drug can be abused by a human on a single occasion • Reinforcement over time: If the drug maintains a positive measured effect in a self-administration over extended periods of time, this may suggest a drug can be abused by a human on multiple, closely-spaced occasions • If a drug produces self-administration in early trials (showing that it has rewarding properties), this may suggest that the drug can be used successfully by humans on an acute basis to produce a “high” and that the drug may have human abuse potential

  30. FDA Comment Preclinical Self-Administration • The inability of a drug to produce reinforcement following initial indication of reward does not negate the abuse potential signal. In terms of public health, non-chronic use of an abusable drug might be relevant • Typically a FR10 schedule of reinforcement is used • Doses should proceed from low to high. If animals are exposed to high doses first, they may not self-administer the low doses as readily A negative result in self-administration studies does not always indicate lack of abuse potential Animals typically do not self-administer 5-HT2 agonist hallucinogens, cannabinoids, NMDA antagonists, and other drugs that produce effects broadly characterized as “psychedelic”

  31. Case A Preclinical Pharmacology –Self-administration • Design • Are rats an appropriate species for self administration studies? • Are there specific criteria which must be met to justify the use of the rat for abuse potential assessments? • Data • When rats are given the opportunity to self-administer FSD-204, they respond for 2-3 days in a burst extinction pattern for the high dose only. How is this viewed? Is there a minimum number of sessions that each dose of the test drug should be available for? • When responding stabilizes, no increase in infusion rates above vehicle is observed. Does this change the interpretation? • It is normal practice to present rat data as grouped means. Does the Agency agree that this is sufficient for such data?

  32. FDA Comment Q15: Are rats an appropriate species for self-administration studies? • Rats are an appropriate species for self-administration studies. Rats might be advantageous when a large number of animals are required, or in studies where drug naïve animals are necessary • Some researchers may justify conducting self-administration studies in non-human primates, based on their scientific expertise and the type of drug being studied (examples : ethylketazocine, modafinil)

  33. FDA Comment Q16: Are there specific criteria which must be met to justify the use of the rat for abuse potential assessments? • The drug must cross the blood-brain barrier of the rat • If the drug produces a high degree of vomiting in humans, rodents may be an inappropriate species because they do not have an emetic response

  34. FDA Comment Q17: When rats are given the opportunity to self-administer FSD-204, they respond for 2-3 days in a burst-extinction pattern for the high dose only. How is this viewed? Is there a minimum number of sessions that each dose of the testdrug should be available for? • If animals fail to maintain initially high levels of self-administration for a drug despite continued access, this can be interpreted in a variety of ways: • development of tolerance • the drug has long-lasting effects and the preferred level of effect does not require further self-administration • inhibition of metabolism, which can also lead to prolongation of the rewarding effects • development of negative effects • A “burst-extinction pattern” may indicate that the drug has rewarding properties on an acute basis, which is suggestive of human abuse potential • Duration of exposure should be at least 3-5 days

  35. Q18: When responding stabilizes, no increase in the infusion rates above vehicle is observed. Does this change the interpretation? The drug appears to have rewarding properties on an acute basis FDA Comment

  36. FDA Comment Q19: It is normal practice to present rat data as grouped means? Does the Agency agree that this is sufficient for such data? • Group means with SEM bars is adequate. However, data may also be presented as scattergrams or other methods of representing individual data in conjunction with the overall mean

  37. Case A Preclinical summary • Overall, no positive signals were observed in the drug discrimination, physical dependence and withdrawal, or self-administration studies. • Does the Agency agree with this assessment given the non-clinical data supplied?

  38. FDA Comment Q20: Does the Agency agree with the assessment [that no positive signals were observed in the drug discrimination, physical dependence and withdrawal or self-administration studies] given the non-clinical data supplied? • Under the conditions of the study, self-administration data show that the drug may produce rewarding effects on an acute basis, which is suggestive of human abuse potential • Interpretation of data from animal abuse potential studies requires review of full protocols and full individual and mean datasets

  39. Case A Proposed Safety Monitoring in Clinical Program • All clinical trials will include routine collection of AEs, with special attention to CNS effects FDA Comment

  40. Proactive collection of CNS AEs is necessary Points to consider for collecting AE data of specific interest: Correlate AEs with known or suspected mechanism of action Thoroughly review the literature for drugs with similar mechanisms of action or targets Probing questions should be considered when evaluating adverse events that are spontaneously reported (The terms on the following slides should be considered) More frequent/longer evaluations of AEs should be included until the PK is more fully characterized Prospective questionnaires should be used in later phases of development FDA Comment Proposed Safety Monitoring in Clinical Program

  41. FDA Comment Abuse-Related Adverse Event Terms • This compilation of terms is based on our experience to date and is not intended to be inclusive of all possible abuse-related MedDRA terms. Also, not all groups of terms will apply to every drug under development • Most terms are listed under General, Neurological, and Psychiatric Disorders High Level Groupings • The list includes: • Specific terms that are in the MedDRA dictionary • Frequently used verbatim terms, words or phrases

  42. FDA Comment Euphoria-related terms: • Euphoric mood: euphoria, euphoric, exaggerated well-being, excitement excessive, feeling high, felt high **, high**, high ** feeling, laughter • Elevated mood: mood elevated, elation • Feeling abnormal: cotton wool in head, feeling dazed, feeling floating, feeling strange, feeling weightless, felt like a zombie, floating feeling, foggy feeling in head, funny episode, fuzzy, fuzzy head, muzzy head, spaced out, unstable feeling, weird feeling, spacey • Feeling drunk: drunkenness feeling of, drunk-like effect, intoxicated, stoned, drugged ** Exclude terms that clearly are not pertinent or relevant such as “high blood pressure,” “respiratory depression,” etc.

  43. FDA Comment Euphoria-related terms (cont.) • Feeling of relaxation: Feeling of relaxation, feeling relaxed, relaxation, relaxed, increased well-being, excessive happiness • Dizziness: dizziness and giddiness, felt giddy, giddiness, light headedness, light-headed, light-headed feeling, lightheadedness, swaying feeling, wooziness, woozy • Thinking abnormal: abnormal thinking, thinking irrational, wandering thoughts • Hallucination: (auditory, visual, and all hallucination types), illusions, flashbacks, floating, rush, and feeling addicted

  44. FDA Comment Terms associated with drugs of abuse related to mood, impaired attention, psychomotor events cognition: • Somnolence: groggy, groggy and sluggish, groggy on awakening, stupor • Mood disorders and disturbances: mental disturbance, depersonalization, psychomotor stimulation, mood disorders, emotional and mood disturbances, deliria, delirious, mood altered, mood alterations, mood instability, mood swings, emotional lability, emotional disorder, emotional distress, personality disorder, impatience, abnormal behavior, delusional disorder, irritability • Mental impairment disorders: memory loss (exclude dementia), amnesia, memory impairment, decreased memory, cognition and attention disorders and disturbances, decreased concentration, cognitive disorder, disturbance in attention, mental impairment, mental slowing, mental disorders • Drug tolerance, Habituation, Drug withdrawal syndrome, Substance-related disorders

  45. FDA Comment Dissociative/Psychotic Terms • Psychosis: psychotic episode or disorder • Aggressive: hostility, anger, paranoia • Confusion and disorientation: confusional state, disoriented, disorientation, confusion, disconnected, derealization, dissociation, detached, fear symptoms, depersonalization, perceptual disturbances, thinking disturbances, thought blocking, sensation of distance from one's environment, blank stare, muscle rigidity, non-communicative, sensory distortions, slow slurred speech, agitation, excitement, increased pain threshold, loss of a sense of personal identity

  46. Case A Clinical Evaluation • If there is agreement that FSD-204 is not self-administered by rats and no withdrawal signs have been observed, are there circumstances under which a Clinical Abuse Potential study in drug abusing subjects would not be required? • Are there thresholds for requiring a Clinical Abuse Potential study?

  47. FDA Comment Q21: If there is agreement that FSD-204 is not self-administered by rats and no withdrawal signs have been observed, are there circumstances under which a Clinical Abuse Potential study in drug abusing subjects would not be required? • The self-administration data show that the drug may produce rewarding effects on an acute basis, suggestive of human abuse potential • Data regarding behaviors observed during the drug discontinuation period is needed to conclude that no withdrawal signs have been observed • A clinical abuse potential study would not be necessary if: • The NME is not CNS active • A narrow safety margin is determined • No signals suggestive of abuse potential are identified in Phase I and II studies

  48. FDA Comment Q22:Are there thresholds for requiring a Clinical Abuse Potential study? • NMEs that are CNS-acting require a human abuse potential study if there are positive signals from the preclinical data or the clinical AE profile in Phase 1 and 2 signals abuse potential • For known drugs of abuse that are already scheduled under the CSA, a novel formulation may require additional abuse potential studies, depending on the adverse event profile observed during clinical efficacy trials • Sponsors may plan to conduct clinical abuse potential studies when moving into Phase 3 studies. This approach will allow for selection of appropriate comparator drug(s), subject population, dose selection, and timing/duration of assessments

  49. Case A AE Profile of FSD-204 following FIH studyEscalating doses (3, 10, 25, 50, 100mg) • Treatment emergent Adverse Events (8 subjects/FSD group) FDA Comment

  50. FDA Comment AE Profile of FSD-204 following FIH Study • Given the non-existence of hallucinations in the placebo group, the rate of hallucination (n=1 of 40) in FSD-204 treated subjects is concerning when extrapolated to the clinical population or to a drug-abusing population who may use supratherapeutic doses • Hallucinations should be actively monitored in all further clinical studies to determine whether this AE has clinical relevance • Terms such as dizziness and somnolence are somewhat vague and do not always capture the ‘true experience’ of the adverse event. Occasionally the verbatim term does not directly map to a preferred term. Attempts should be made to accurately capture all adverse events

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