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• Target engagement: Ex vivo occupancy (rat): In vivo target engagement of compounds determined from brain regions expressing mainly D3R (cerebellum L9-10) and D2R (striatum) |
• Efficacy studies (rodents): The following studies are being considered for in vivo profiling of compounds o Partial agonists (assays available at Richter): - Efficacy – Reversal of positive symptoms: apomorphine-induced climbing, amphetamine or PCP-induced hypermotility - Efficacy – Improvement of cognitive symptoms: continuous performance task (CPT, touchscreen) - Side effects: spontaneous locomotor activity, spontaneous catalepsy, passive avoidance |
o Antagonists (assays being considered, minimal acceptable threshold is for efficacy in at least one of the assays listed for each group below): - Efficacy – Improvement of cognitive behavior: Reversal of Morris water maze deficit (impairment induced by acute pharmacological intervention with proven memory disrupting effect or neonatal PCP + social isolation). Target validation ongoing: Touchscreen CPT and IntelliCage (reversal learning). - Efficacy – Improvement of negative symptoms: Social recognition (impairment induced by PCP), - Selectivity: D2/D3 agonist-induced hypothermia (high dose)-validation ongoing in mice, rat assay under establishment - Pharmacodynamic tests for D3R function: Rat/mouse: D3R agonist-induced hypomotility; Mouse: hypermotility in adapted animals. |
• Bio-analytical assay development to support PK/PD, and non-GLP toxicity studies to establish adequate LLOQ • Compound integrity is confirmed in dose formulation, analytical stock solutions and plasma brain homogenate matrices of the corresponding species |
• Evaluation in non-rodent species: • Detailed pharmacokinetic characterisation of promising compounds is performed in dogs and/or NHP • Single dose of the compound is administered to male and female dogs intravenously or orally in an appropriate vehicle and bioavailability is determined • Serial blood samples are collected for up to 24 hours • Plasma samples are prepared, and the compound detected with a bioanalytical assay • Primary pharmacokinetic parameters (volume of distribution, systemic clearance, terminal half-life) are defined after iv dosing • Following oral administration maximum concentration (Cmax), time of occurrence of Cmax (Tmax), area under the concentration versus time curve (AUC), apparent terminal half-life (T1/2) are derived from the concentration-time data • Selection of tox species for select compound(s), typically dog or monkey |
• D3R antagonists are reported in the literature to affect performance in behavioral assays requiring cognitive flexibility and intact executive function: assays are available to test PD in NHP (final assay TBD; located at Richter's NHP facility or CRO). |
• Perform off-target screening, with an acceptable selectivity window over hD3R • Performed at Eurofins, similarly to CAR: 8.1. Initially compounds are evaluated in the in-house assays as for example: o hERG, hNav1.5 and h5-HT2B receptor agonist functional assays. o Profiling receptor assays: h5-HT2A receptor binding and functional assays hH1 receptor binding adrenergic ra1 receptor binding muscarinic rM receptor binding 8.2. This is followed by a custom selected set of target binding assays at a CRO: h5-HT1A, 2B,2C, 6, 7. hD1,4, 5 hH2, 3 hM1 SERT 8.3. Candidate compounds are further evaluated in a broad panel (e.g. SafetyScreen87 Panel, Panlabs) • Additional profiling (as needed) – For example, h5-HT1A partial agonism and h5-HT2A receptor antagonism, 5-HT2B could be acceptable if antagonistic • Other off targets >100-fold selectivity |
• Metabolic stability. Generate in vitro drug metabolism data across species in liver microsomes. In vitro ADME Screens: • Penetrability/efflux liability o Pappin-out/Efflux ratio/Recovery% in VB-Caco-2 and/or MDR1-transfected MDCK cell lines • Metabolic stability o Intrinsic Clearance CLint (µL/min/mg protein) o In drug relevant tissues e.g., microsomes/ hepatocytes of human and pharmacological/ toxicological species (mouse/rat/dog/NHP) In vitro ADME Characterization: • Enzyme induction o CYP1A2/2B6/3A4 mRNA level fold changes over untreated controls o human hepatocytes (CRO or Gedeon Richter) |
• Enzyme inhibition - direct- and preincubation dependent IC50 and % Inhibition toward CYP1A2/ 2B6/ 2C8/ 2C9/ 2C19/ 2D6/ 3A4/5 human liver microsomes • Tissue binding - plasma protein, - brain tissue, - microsomal fu in plasma samples of human/pharmacological /toxicological species, rat brain tissue, human liver microsomes • Reaction phenotyping - preliminary identification of enzymes involved in drug metabolism (clearance) • Preliminary determination of in vitro metabolite profile(s) with selected compounds (CRO)- cross species comparison. • In vitro identification of potential reactive metabolites |
• Generate in vitro safety profile via non-GLP Ames, in vitro micronucleus, and hERG assessment |
AbbVie Activities |
AbbVie will provide guidance for the Lead Compound selection activities as part of the JSC. This will include input on the acceptability criteria for the candidates. |
Estimated Time- lines |
Goal is to identify at least one (1) Lead Compound and (1) Backup Lead Compound with respect to the D3R discovery program |
Projected timeline estimates: Activities ongoing as of 1Q 2022. Projected timeline is Q3 2022 for completion of activities with the D3R modulator (antagonist) compound For estimates of timelines with the current D3R compound, 70024303, see Figure 1. Activities ongoing as of 1Q 2022. Projected timeline is Q4 2023 for completion of activities with the back-up D3R modulator (e.g. antagonist or partial agonist) compounds. |
Selection & Characterization of Lead Compounds for Candidate Nomination |
Gedeon Richter Activities and Deliverables |
• With selected candidate compound(s), perform Maximum Tolerated Dose study with lead candidate compounds prior to IND-enabling studies. Rodent: • Irwin test in rats: (N=6 males/group) broad dose (up to ~10X the pharmacologically active dose in rodent models) with a 7-day post treatment observation period; CNS side effects AND acute toxicity • 4-day repeat-dose toxicology and toxicokinetic study in rats: (Ctrl, low, intermediate, or low and high intermediate, and high dose) with target top dose in the range of overt toxicity. (N=5 males/ group) • 14-day repeat-dose toxicity and toxicokinetic study in rats (N=5/sex/ group) is conducted to find doses for a GLP 4-week toxicity and TK study. Standard repeat-dose toxicity endpoints, including haematology, clinical chemistry, histopathology, prolactin level, and toxicokinetics, without urinalysis. |
Non-rodent: dogs or other species • MTD study design, dose escalation phase on 2 animals per sex • MTD 14-day fix-dose phase with two groups of 2 animals per sex one serving as vehicle control, the other receiving the maximum tolerated dose established in the dose escalation phase. Standard repeat-dose toxicity endpoints, including haematology, clinical chemistry, histopathology, prolactin level, and toxicokinetics, without urinalysis. |
Further in vivo safety tests (non-GLP), TI > 10 • Cardiovascular effects in dog (e.g. blood pressure, heart rate, QT, plasma exposures) • Rat locomotor activity test – possible effects on spontaneous locomotion • Rat rotarod test – possible effects on motor coordination • Rat grip strength test – possible effects on muscle strength • Rat seizure threshold test – possible pro- or anti-convulsant effects • Rat plethysmography test – possible effects on respiratory parameters |
AbbVie Activities |
AbbVie will provide guidance for the Lead Compound selection activities as part of the JSC. This will include input on the acceptability criteria for the candidates. |
Estimated Timelines |
Projected timeline estimates (activities ongoing as of 1Q2022) Projected timeline for completion is Q3 2022 with the D3R modulator (antagonist) compound. For estimates of timelines with the current D3 compound 70024303, please see Figure 1. Projected timeline for completion is Q4 2023 with back-up D3R modulator (e.g. antagonist or partial agonist) compounds. |
Discovery and preclinical activities described above are expected to yield compounds that satisfy the following Lead Compound Criteria |
Table I. Lead Compound Criteria |
Category |
In-vitro Pharmacology |
In-vivo Pharmacology |
Target tissue (brain) penetration |
Preclinical Safety / Safety Pharmacology |
CMC / DS |
IND-Enabling Studies Plan and Budget |
Phase 1 enabling studies |
Gedeon Richter Activities and Deliverables |
1. Bioanalytical method development validation for GLP tox studies (including stable label internal standard) 2. GLP compliant genotoxicity studies: a. Bacterial reverse mutation (Ames test) b. In vitro human micronucleus c. Rat micronucleus (in vivo) 3. ICHS7-compliant safety pharmacology package (GLP compliant) a. CNS, rat b. Respiratory, rat c. CV, non-rodent (NHP/dog) d. hERG (Human Ether-a-go-go-related Gene), in vitro 4. GLP 1-month systemic Toxicity (2-species with recovery) a. rat b. NHP/dog 5. Human Pharmacokinetic predictions including DDI assessments. |
AbbVie Activities |
AbbVie will provide guidance for the Phase 1 enabling activities as part of the JSC. This will include oversight on the acceptability of safety margins for the candidates. |
Estimated Timelines |
Projected timeline estimates Projected timeline of Phase 1 enabling studies is Q4 2023 for completion of studies with D3R modulator (antagonist); For estimates of timelines with the current D3R compound 70024303, See Figure 1. Projected timeline of Phase 1 enabling studies is Q1 2025 for completion of studies with backup D3R modulator (e.g. antagonist or partial agonist). |
IND-Enabling Studies Criteria (for development candidate): The IND Enabling Studies Plan and Budget is expected to generate data sets to determine whether a Lead Compound should further progress to clinical studies as a development candidate. |
The overall goal of the IND-Enabling Studies Plan and Budget with the Lead Compound is to develop a data package that meets the general criteria outlined below and acceptable to regulatory authorities to authorize initiation of first-in-human (FIH) clinical studies. |
IND-Enabling Studies (Development Candidate): General Criteria |
Category |
In-vitro Pharmacology |
In-vivo Pharmacology |
Target tissue (brain) penetration |
Preclinical Safety / Secondary Pharmacology |
PK-ADME |
GLP toxicology Studies |
API |
IP |
Budget for the IND-Enabling Activities |
Activities |
Preclinical characterization |
IND enabling preclinical GLP studies |
Materials for Pre IND meeting(s) / IND ready documents |
* 1 employee working full day (8h / day) in the given period; ** including but not limited to: study monitoring activity, TK method development and TK measurements, data evaluation, reporting |
Figure 1. |
Current Status for Preclinical Activities with D3 Compound – 70024303 |
[THIS APPEARS TO BE A FIGURE/CHART THAT IS NOT FULLY REPRESENTED IN TEXT FORMAT] |
Schedule 1.106 |
Identified Indications |
• Bipolar Mania / Mixed |
• Bipolar Depression |
• Major Depressive Disorder (Adjunct or Monotherapy) |
• Autism Spectrum Disorder (irritability, core symptoms) |
• Agitation or Psychosis associated with Alzheimer's Disease, Parkinson's Disease, or Frontotemporal Dementia |
• General Anxiety Disorder (Adjunct or Monotherapy) |
• Posttraumatic stress disorder |
• Schizophrenia Negative Symptoms; Cognitive Impairment Associated with Schizophrenia |
• Cognitive impairment associated with MDD, Bipolar Disorder, Alzheimer's Disease or Parkinson's Disease |
• Obsessive Compulsive Disorder |
• Attention deficit hyperactivity disorder |
Schedule 1.134 |
Manufacturing Costs |
For purposes of the Agreement, "Manufacturing Costs" means: |
(a) with respect to a Licensed Compound Manufactured by Richter, Richter's internal and external costs, calculated by Richter in a manner that is consistent with the Accounting Standards used by Richter to determine the manufacturing cost (direct manufacturing and manufacturing support costs) of other compounds manufactured by Richter at its facilities, incurred in manufacturing, acquiring, packaging, transporting or storing such Licensed Compound (including the costs of direct materials, direct labour, factory overhead, quality control and quality assurance costs, regulatory compliance and other support costs in relation to Manufacturing), in each case, to the extent directly related and allocable to the Licensed Compound supplied to AbbVie hereunder. Manufacturing Costs shall not include any underutilized capacity at any manufacturing site or facility where the Licensed Compound is Manufactured or any cost attributable to general corporate activities, including, by way of example, executive management, investor relations, business development, legal affairs and finance; and |
(b) with respect to Licensed Product Manufactured by AbbVie, AbbVie's internal and external costs, calculated by AbbVie in a manner that is consistent with the Accounting Standards used by AbbVie to determine the manufacturing cost (direct manufacturing and manufacturing support costs) of other products manufactured by AbbVie at its facilities, incurred in manufacturing, acquiring, packaging, transporting or storing such Licensed Product (including the costs of direct materials, direct labour, factory overhead, quality control and quality assurance costs, regulatory compliance and other support costs in relation to Manufacturing), in each case, to the extent directly related and allocable to the Licensed Product supplied to Richter hereunder. Manufacturing Costs shall not include any underutilized capacity at any manufacturing site or facility where the Licensed Product is Manufactured or any cost attributable to general corporate activities, including, by way of example, executive management, investor relations, business development, legal affairs and finance. |
Schedule 1.167 |
Pro-metabolite Discovery Program Plan |
Program Overview and Objectives |
Cariprazine (Vraylar®), a D3R preferring compound, is thought to confer a distinct and unique clinical profile vs. other atypical antipsychotic agents. In particular, the higher D3R vs. D2R occupancy seen at lower doses (≤ 3 mg/d) may underlie clinical efficacy in unipolar depression, both poles of bipolar disorder, negative symptoms of schizophrenia, anxiety and improvements of cognitive tasks. These benefits are not typically seen at higher doses where the preferential binding to D3R is lost or there may be excessive D2R antagonism interfering with D3R effects. Since cariprazine's active metabolites (desmethyl-cariprazine, DCAR and didesmethyl-cariprazine, DDCAR) have a relatively higher D3R/D2R selectivity, the goal of the Pro-metabolite Discovery Program is to develop compounds that are directly converted to DCAR or DDCAR without the formation of cariprazine. |
The goal of the Pro-metabolite Discovery Program is to identify molecules that are rapidly converted in vivo to DCAR and/or DDCAR. Pro-metabolite compounds are expected to satisfy the criteria outlined below: |
Prometabolite Compound Criteria: |
• In vitro dopamine D3/D2 receptor binding, with D3 preference for the pro-drug • Rapid in vivo bioconversion to DCAR and / or DDCAR, with little to no detectable cariprazine • Acceptable brain exposure of DCAR and/or DDCAR to achieve efficacy in relevant preclinical models within the range of that observed with cariprazine after oral dosing • The bioconversion to DCAR and/or DDCAR should be species independent • Total brain and plasma exposure (DCAR and/or DDCAR) should be similar to or higher than dosing with equimolar cariprazine. • Dose-independent conversion in wide dose range • Safety/ tolerability profile should be equivalent to or better than cariprazine. |
Program Status |
To date, this program has generated several chemical analogues (listed in Schedule 1.164) that are rapidly converted to DCAR and/or DDCAR after oral administration, without significant transformation to cariprazine. These chemical analogues include leads from the hemiaminal-ether, dipeptide, cyclic carbamide and sulfenamide series (see Figure 1). Compounds from these series were screened via in vitro and in vivo models to determine their D3R/D2R selectivity and metabolic profile. From the set of analogs thus far synthesized, 70023351 (also known as RGH-932), a hemiaminal-ether DCAR derivative has emerged as a promising compound that is being further characterized and advanced as the current Lead. In addition, two compounds, RGH-289 and RGH-556 are being evaluated as potential back-up compounds (see Figure 2). |
Studies have shown that RGH-932 preferentially binds to the D3R versus D2R, is stable at neutral pH, readily converts to DCAR at acidic pH and is subsequently metabolized to DDCAR. Pharmacokinetic investigations in rats (po, iv, ip, or sc), dogs (po) and rhesus monkeys (po) have revealed that both DCAR and DDCAR were present in blood after dosing with RGH-932, while little to no transformation of RGH-932 to cariprazine has been detected, based on initial evaluation. Behavioral studies in rodents, have also shown efficacy in rodent models of acute psychosis after dosing with RGH-932. Additional characterization including behavioral, toxicology and cardiovascular studies are ongoing. |
Due to the low number of functional groups, only two sites appear to be available for chemical modification; the urea site which can be modified in several ways at both the nitrogen and oxygen atom and the more nucleophilic tertiary alkyl N-atom of the piperazine which can also be quaternarized. Thus far, several additional chemical analogues have been identified, including 70023586 and 70023604 from the hemiaminal-ether series, 70024113 and 70024948 from the sulfonamide series, 70023182 from the peptide series and 70023528 from the cyclic carbamide series. These compounds will be characterized by additional preclinical activities described in this Research Program Plan as potential back-up compounds. |
The research plan for the Pro-metabolite Discovery Program comprises the following key activities: 1. Compound screening and evaluation 2. Preclinical characterization of selected compounds 3. Selection and characterization of Lead Compound and Backup compound for Candidate Nomination 4. IND enabling studies |
Figure 1. Example Structures of Diverse Chemical Series |
[THIS APPEARS TO BE A FIGURE THAT IS NOT FULLY REPRESENTED IN TEXT FORMAT] |
Studies conducted to support this Pro-metabolite Discovery Program will be conducted at Gedeon Richter labs or with AbbVie's prior written consent (not to be reasonably withheld, delayed or conditioned) at mutually-agreed-upon vendors, service providers, CROs or CMOs. Gedeon Richter will be responsible for managing day-to-day project management with contracted service providers in accordance with the terms and conditions of the Agreement. |
Compound Screening and Evaluation |
Gedeon Richter Activities and Deliverables |
1. Screening to identify hits a. in vitro pH dependent stability, pH range: Simulated Gastrointestinal Fluid (SGF) pH=6.8, 7.4 b. Pilot rat PK study @ 10 mg/kg PO, 1-4 hours Pro-drug plasma levels: very low or non-detectable (concentration determination by LC-MS/MS after protein precipitation) c. hD3 receptor binding inhibition (%) |
2. In vitro screen of identified leads for each target in hD3R, hD2LR -binding selectivity |
3. In vitro studies in target primary cells, ex vivo organ culture; etc. a. agonism for βarrestin translocation at human D3 receptors b. agonism at cAMP readout in HEK 293 cells co-expressing human D3 receptor and AC 5 c. antagonism at cAMP readout in HEK 293 cells co-expressing human D3 receptor and AC 5 d. agonism at human 5-HT2A receptors using Ca2+ readout in CHO-K1 cells e. agonism at human D2 receptors in cAMP readout in CHO-K1 cells f. antagonism at human D2 receptors in cAMP readout in CHO-K1 cells |
Preclinical Characterization of Selected Compounds |
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