text stringlengths 1 5.46k |
|---|
4. Evaluation in rodent model • BBB penetration o Deliverable: Rat PK studies @ 1-2 mg/kg PO dose 0-24 h pro-drug plasma and brain levels: very low or non-detectable and similar or better active component exposures than after CAR/DCAR/DDCAR administration o Methods: ■ Detailed pharmacokinetic characterization is perfor... |
rodents orally (n=3/sampling time) in an appropriate vehicle (e.g., 5% Tween 80). ■ Terminal blood and whole brain samples after PO treatment are taken generally up to 24 hours post dose. ■ Plasma and brain homogenate samples are prepared and measured for the compound by a bioanalytical assay. ■ Following oral administ... |
5. Bio-analytical assay development to support PK/PD, and non-GLP tox studies to establish adequate LLOQ Compound integrity is confirmed in dose formulation, analytical stock solutions and plasma brain homogenate matrices of the corresponding species. |
6. Compound evaluation in higher species; this could be PK/PD (PD in the relevant target tissue and potential translational measures of activity in humans-Target engagement/ biomarker) or distribution. Cognitive post hoc analyses of cariprazine is available, therefore NHP test may not be necessary for pro-drug compound... |
b. Additional study to be considered: Rhesus monkey PK study @ 1.14 mg/kg (5% Tween 80/dw suspension via oral gavage). • A single dose of the compound is administered to male rhesus monkeys (n=6) orally in an appropriate vehicle (5% Tween 80). Serial blood samples are taken up to 24 hours. Plasma samples are prepared a... |
7. Perform off-target screening, with an acceptable window over target a. Performed at Eurofins |
8. In vitro ADME a) In vitro ADME Screens: • Metabolic stability. Generate in vitro drug metabolism data across species in liver microsomes. • In vitro drug penetration b) In vitro ADME Characterization: • Cyp enzyme induction • Cyp enzyme inhibition • Preliminary identification of enzymes involved in drug metabolism •... |
9. Safety studies: • Generate in vitro safety profile via non-GLP Ames, in vitro micronucleus, and hERG testing • In vivo safety tests, TI > 10 • Cardiovascular effects in dog (e.g. blood pressure, heart rate, QT) • Rat rotarod test – possible effects on motor coordination • Rat PTZ seizure test – possible pro-, or ant... |
10. Perform maximum tolerated dose studies with lead compound prior to IND-enabling studies. |
In rats the maximum tolerated dose is established via an in-house multi-step process. Rodent: • Irwin test in rats: (N=6 males/ dose), broad range of doses (up to 10-fold the pharmacologically active dose in rodent models) with a 7-day post treatment observation period: CNS side effects and acute toxicity • 4-day repea... |
Estimated Timelines |
• Activities ongoing as of 1Q 2022: IND enabling studies with RGH-932 is underway with anticipated completion in 1H 2022. Two back-up compounds, RGH-289 and RGH-556 have been identified, which is being characterized (estimated Q1/2022 - Q2/2023). |
AbbVie Activities |
AbbVie will provide guidance for the Lead Compound selection activities as part of the Joint Steering Committee (JSC) and relevant Working Groups. |
At the conclusion of the above activities, the team should have identified promising candidate compound(s) for advancement to GLP toxicology and other IND enabling studies. |
4 |
Discovery and preclinical activities described above are expected to yield compounds that satisfy the following Lead Compound Criteria |
Pro-Metabolite Lead Compound Criteria: |
Category |
In-vitro Pharmacology |
In-vivo Pharmacology |
Target tissue (brain) Exposure |
Preclinical Safety / Safety Pharmacology |
CMC / API |
IND Enabling Studies Plan & Budget |
Phase 1 Enabling |
Gedeon Richter Activities and Deliverables |
1. Bioanalytical method 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 a. CNS, rat b. Respiratory, rat c... |
AbbVie Activities |
1. Abbvie to perform all other safety/Tox work (sub-chronic/ chronic tox, carcinogenicity, repro tox, etc.) post IND 2. Phenotypic assessment of the DCAR pro-drug lead molecule to be evaluated in the SmartCube assay to evaluate its broad in vivo pharmacological activity. 3. AbbVie will provide guidance for Phase 1 enab... |
Estimated Timelines |
Projected timeline is approx. 12 months to complete IND enabling studies and reports required for the regulatory submission for RGH-932 As of 1Q 2022: IND enabling studies with RGH-932 is underway with anticipated completion of studies by 1H 2022. |
Two back-up compounds, RGH-289 and RGH-556 have been identified, which is also being characterized towards IND enabling studies (estimated Q1/2022 - Q2/2023). |
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. |
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 (for development candidate): General Criteria |
Category |
In-vitro Pharmacology |
In-vivo Pharmacology |
Preclinical Safety / Secondary Pharmacology |
Target tissue (brain) exposure |
PK-ADME |
GLP toxicology studies |
API |
IP |
Estimated Budget for the IND-Enabling Activities for RGH-932 (Richter internal & CRO) |
Activities |
IND enabling preclinical studies |
Materials for Pre IND meeting(s) / IND ready documents |
13w GLP Tox and reprotox |
Chronic Tox, Carcinogenicity |
* including but not limited to: study monitoring activity, TK method development and TK measurements, data evaluation, reporting etc. ** = 1 employee working full day (8h / day) in the given period |
Estimated Budget for the IND-Enabling Activities for RGH-932 back-up compounds |
Activities |
IND enabling preclinical studies |
* including but not limited to: study monitoring activity, TK method development and TK measurements, data evaluation, reporting etc. ** = 1 employee working full day (8h / day) in the given period |
Figure 2: Structures of RGH-932 |
(and potential back-up compounds RGH-289 and RGH-556) |
RGH-932 (70023351) |
[CHEMICAL STRUCTURE IMAGE] |
RGH-289 (70023528) |
[CHEMICAL STRUCTURE IMAGE] |
RGH-556 (70024948) |
[CHEMICAL STRUCTURE IMAGE] |
Schedule 1.197 |
Richter Territory |
• Albania • Andorra • Armenia • Austria • Azerbaijan • Belarus • Belgium • Bosnia and Herzegovina • Bulgaria • Croatia • Cyprus • Czechia • Denmark • Estonia • Finland • France • Georgia • Germany • Greece • Hungary • Iceland • Ireland |
• Italy • Kazakhstan • Kyrgyzstan • Latvia • Lithuania • Luxembourg • Malta • Monaco • Montenegro • Netherlands • North Macedonia • Norway • Poland • Portugal • Republic of Moldova • Romania • Russian Federation • San Marino • Serbia • Slovakia • Slovenia • Spain • Sweden • Switzerland |
• Tajikistan • Turkmenistan • Ukraine • United Kingdom of Great Britain and Northern Ireland • Uzbekistan • Vietnam |
Schedule 3.6.1 |
Draft Development Manufacturing Plan |
GENERAL CONSIDERATIONS This draft document is a general guide to the Development Manufacturing Plan – for both IND API Development & API supply and for Late-Stage API Development & API Supply. Specifics will be finalized by JSC during the collaboration phase depending on the profile of Lead Compound and Back-up Compoun... |
Should there be a need to support activities by Gedeon Richter, AbbVie will provide relevant drug product regulatory submission documents, as appropriate. |
IND API Development & API Supply AbbVie will provide guidance and technical / scientific input for the API Development activities as part of the Joint Steering Committee (JSC) and associated working team meetings. As part of the collaboration, there will be designated individuals for API and API supply-related support ... |
This IND-Enabling Studies Plan and Budget (INDPB) summarizes the anticipated IND-enabling studies that will be conducted once the JSC nominates a Lead Compound (LC). The goal of the INDBP will be to robustly characterize the safety profile of the nominated LC in accordance with the regulatory guidelines provided by FDA... |
This document is meant to serve as a high-level guideline of standard IND-enabling studies. The actual studies run once a LC is nominated will be agreed upon by the JSC, with AbbVie providing input on strategic study decisions, study protocol review and study report review. For clarity, initial drug substance and tox f... |
The first step to conducting IND enabling studies is the robust characterization of the LC including solubility (salt, polymorph, etc.) screening, process familiarization, analytical method development. Following initial studies, it is expected that batches of both non-GMP and GMP will be produced and characterized. |
At the initiation of IND enabling studies, it is expected that Gedeon Richter will manufacture a suitable quantity (~50g) of non-GMP API for use in salt and polymorph screening, tox formulation and analytical development. [Given that some of the analytical method development may already be in progress, it is expected t... |
Coincident with the above, it is expected that Gedeon Richter will initiate a process development effort for larger-scale synthesis of the chosen API, and a non-GMP demonstration batch of sufficient quantity to support GLP tox and formulation/process development studies. The non-GMP batch will be analyzed for impuritie... |
At a time determined by the JSC, Gedeon Richter will initiate production of a cGMP batch of sufficient quantity to support early-phase clinical studies, and the resulting API will be formulated into a first-in-human study ready drug product by AbbVie. A second stability study will be initiated on the cGMP API with time... |
In summary, API synthesis, formulation to support GLP toxicology / other IND enabling studies and preliminary pharmaceutics studies for the LC will be conducted by Gedeon Richter. |
API |
• API manufacturing including procurement of raw materials • API process development activities • Conduct polymorphic and salt screening to discover solid-state landscape and to choose optimal solid form for development • Long term and accelerated ICH stability studies for drug substance in solid-state • Conduct physic... |
Analytical: Development of phase-appropriate analytical methods and validation |
GLP/Tox Formulation Development: Develop and manufacture a suitable GLP tox formulation and conduct supportive analytical testing |
Reports: Prepare required reports and documents to support Pre-IND Meeting and submission of IND |
API IND Reports Reports anticipated to be required by AbbVie for an IND include but are not limited to the following documents. |
● Properties of the API: optical isomerism, physical state/description, melting point, pKa, solubility (specify conditions - temp./pH), hygroscopicity, polymorphism ● Names and addresses of sites performing API manufacture and testing (release and stability) ● API batch records which should include any testing done in-... |
● Documentation on how the GLP tox batch was manufactured (e.g., synthetic scheme or development report) so that a high-level comparison can be made with the GMP batch ● Confirmation of structure: information associated with mass spec, IR, NMR (H1 and C13), X-ray, UV (including spectra) ● PMI assessment reports; summar... |
Late-Stage API Development & API Supply It is expected that Gedeon Richter will continue API development of a larger-scale process suitable for late-phase clinical supplies and intended commercialization and provide support of ongoing and initiation of future clinical studies by manufacturing GMP API in support of Phas... |
• Deliveries o API for Ph 1b, 2 and 3 clinical studies and carcinogenicity studies (using the proposed commercial process) o Others as needed – API reference standard, impurity (enantiomer, regio-isomers, etc.) standards, stable labeled API, radiolabeled API • API process development o Commercial route assessment – ass... |
Schedule 3.9.5 |
FTE Rates |
With respect to activities performed under this Agreement in the United States, the FTE Rate shall be $375,000 per one full FTE per full 12-month Calendar Year, which rate includes all direct and indirect costs of the performing Party's FTE, including personnel and travel expenses. Such rate is subject to adjustment pu... |
With respect to activities performed under this Agreement outside the United States, the FTE Rate shall be $255,000 per one full FTE per full 12-month Calendar Year, which rate includes all direct and indirect costs of the performing Party's FTE, including personnel and travel expenses. Such rate is subject to adjustme... |
Schedule 4.9.1(a) |
Principal Terms of Richter Supply Agreement |
1. Purpose and Scope of the Supply Agreement |
Richter will Manufacture, sell, and deliver to AbbVie, and AbbVie will purchase and take delivery of, such quantities of Licensed Compounds for use in the Manufacture of Licensed Products as may be ordered by AbbVie in accordance with the Richter Supply Agreement. |
Each Party is and will be solely liable for all of its own fees, costs, and other expenses in conjunction with preparation of the Richter Supply Agreement. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.