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9b Clinical supplies for Phase IIb Licensor (Late Phase Development Activities) Manufacture of DS/DP for the entire Phase IIb (Late Phase Development Activities) Establish scale-up and manufacturing strategy to align with clinical demand projections for Phase IIb ‐ Retain and store at -80°C a minimum of 200 mL of the G... |
10 Commercial process optimization Licensor Determine if the current cell line can enable a commercial process. ‐ Confirm cell line stability is suitable for the number of generations needed at the projected commercial scale. ‐ Perform initial process optimization experiments with the curent cell line to enable a poten... |
11 DS/DP stability for Phase I-II Licensor Intended, accelerated, and stressed storage conditions to support stability dating and excursion justifications for DS/DP. ‐ DS/DP shelf-life assignments and extensions ‐ Monitor a minimum of 1 DS and 1 DP lot on stability per campaign or year. Test stability at the intended s... |
12 Charge variant characterization study Licensor Characterize the molecular structure, post-translational modifications, ALPN-101 binding activity, and CD28-ICOS inhibition activity of acidic, basic, and main charge variants of ALPN-101 as follows: ‐ Use ion-exchange chromatography to separate and collect the charge v... |
13 pH screening study and degradants studies Licensor Conduct a more expansive formulation pH screening study (pH 5.0, 5,5, 6,0, 6,5, 7,0) to confirm observed particulate and charge isoform trends ‐ Characterize structure, post-translational modifications, CD28-ICOS binding activity, and CD28-ICOS inhibition activity o... |
14 Regulatory supporting documents Licensor Verified data and reports as needed to support IND, IMPD, BLA to be provided by Licensor to AbbVie Including, but not limited to data and reports supporting: ‐ Cell line development ‐ MCB manufacture ‐ Process development ‐ Formulation development ‐ Dosage form development ‐ ... |
and/or characterize the primary structure, secondary structure, tertiary structure, post-translational modifications, aggregates, fragments, purity, impurities, CD28-ICOS binding properties, Fc receptor binding properties, and MOA-related functional activities of ALPN-101 ‐ Reference standard preparation and qualificat... |
15 Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) Licensor Upon AbbVie's request Licensor shall perform a Manufacturing Technology Transfer, including as follows: ‐ Coordinate 3-way CDA with Licensor's manufacturing, testing, storage, and drug supply (labeling/packaging/distribution) CDMO(s) ‐... |
Phase IIb/III studies ‐ Provide AbbVie with a sufficient supply of assay critical reagents to complete test method transfer, DS/DP process transfer, comparability testing, and manufacture GMP batches to supply Phase IIb/III studies ‐ Provide AbbVie with process summary reports, master batch records, process development... |
16 Quality Tasks AbbVie/Licensor Transition plans to be approved by Joint Governance Committee ‐ If AbbVie requires Licensor to supply requirements of lead Licensed Compound, lead Licensed Product and placebos, the Parties shall establish quality agreement to enable Licensor to supply such requirements for conduct by A... |
17 Post-License Option Effective Date support at Licensor If required by AbbVie, Manufacture, test, and release sufficient quantities of Licensor clinical drug supplies to initiate and support Phase IIb/III studies until such time as AbbVie sourced drug is available for use in clinical studies ‐ Supply analytical metho... |
18 Manufacturing Preparatory Development Activities, know how transfer If Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) has not yet been initiated, prior to the Option Effective Date and as jointly agreed upon the Parties shall engage in preparing for transfer of CMC activities ‐ Licensor sha... |
NONCLINICAL ACTIVITIES |
(A living document to be discussed and approved by the Joint Governance Committee.) |
Nonclinical safety evaluation studies shall be performed. The currently available general toxicity package administered 10, 100 and 150 mg/kg/week SC doses and 150 mg/kg/week IV doses of ALPN-101 for 13-weeks (followed by a 8-weeks recovery period) in NHP, defining the 150 mg/kg/week dose as the NOAEL (both IV and SC).... |
The 26-week chronic toxicity studies shall be initiated in mature NHP, with doses and design selected based on data from the 13-week study in combination with feedback from the European Medicines Agency (EMA) (Scientific Advice) and the Food and Drug Administration (FDA) (pre-IND meeting) on the preclinical plans and t... |
A pharmacokinetic study (IV/SC single dose) in NHP shall assess the bioavailability and local tolerability of the SC formulation developed for clinical use. |
Segment 2 (embryofetal toxicity) and Segment 1 (fertility, in rats) of the reproductive toxicity program shall be completed prior to initiation of the Phase IIb study in the lowest feasible species. At this time, rabbit is anticipated to be the preferred species, assuming supportive cross-reactivity studies and alignme... |
1 26-wk GLP NHP tox Licensor is in the process of initiating a 6 mo NHP study at Alta Biosciences, the protocol for which AbbVie has had the opportunity to review. Final report available 6 months from the end of the inlife portion of the study. Report as MS Word, executed PDF versions, and SEND data sets. |
2 NHP PK Study IV vs. SC single dose PK study to assess bioavailability and local tolerability of clinical SC formulation. Minimal group size of 3, with sampling timepoints for at least 2 weeks after dosing. Assess PK, ADA and local tolerability. Report available 1 month from last sampling timepoint. |
3 Developmental Tox Studies DRF and GLP Developmental studies in NHP ± rabbit following administration of ALPN-101 to time mated animals through the defined period of gestation. Each study should contain 3 treatment and 1 control group; the high dose should be based on the results from prior GLP studies. - Study endpoi... |
fetal body weights or fetal external, visceral and skeletal examinations, PK, toxicokinetics and ADA. - Study to be conducted at an AALAC accredited, USDA and FDA inspected facility in USA or GLP certification required for EU facility; facility to have experience and robust historical control database. |
4 Fertility Tox Study (species TBD; rabbit or NHP) Fertility study in NHP or rabbit shall determine the toxic effect of ALPN-101 on female estrous cycle, tubal transport, implantation and development of pre- and post-implantation stages of the embryo, and detection of functional effects on male fertility. The high dose... |
5 BA method validation (rabbit) – if species deemed feasible Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation. Validation to be completed prior to initiation of the Developmental Tox studies Validation shall be completed before study initiation |
6 BA method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
7 ADA method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
8 nAb method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
Regulatory Affairs |
(A living plan to be discussed and approved by the Joint Governance Committee) |
Regulatory Authority submissions and consultations |
US An IND shall be opened to allow enrollment of US subjects into the Phase IIa SLE 3-month study (Study A03). An FDA (Type C meeting) shall be sought in 2021 before the start of planned Phase IIa SLE 6-month study (Study A03a) initiation. This interaction shall focus on seeking FDA feedback and agreement on the noncli... |
EU Scientific Advice (SA) from at least two (2) select national competent authorities (e.g., UK, Germany, Netherlands, or Sweden) or from EMA shall be sought in 2021 before the start of Phase IIa SLE 6-month study (Study A03a). In the EU these interactions shall focus on establishing relationships with EU regulators an... |
Pediatrics |
The strategy and timing for pediatric development shall be jointly agreed upon by the Joint Governance Committee. |
EU A Pediatric Investigation Plan (PIP), including request for waiver(s) and deferral(s) for age subgroups, shall be submitted for agreement by the Pediatric Committee (PDCO). The EU PIP planning takes into consideration the availability of results from preclinical and clinical adult data/information. It is possible to... |
US In the US, the Pediatric Study Plan (PSP) shall be developed in parallel or sequential to the EU PIP submission to ensure a global pediatric development plan. Regulatory Deliverable Activities Target Timeline |
1 Submit complete IND for ALPN-101 SLE (US) and, if needed, CTA in appropriate ex-US country(ies) Author, review, finalize IND documents and submit in IND eCTD format Prior to initiating Phase IIa 3-month SLE study |
2 Submit FDA (Type C meeting) and national competent authority/EMA Sci Advice to seek feedback on development program requirements in order to initiate Phase IIa SLE 6-month Clinical Study Author, review, finalize FDA meeting and national competent authority Sci Advice documents regarding Phase IIa SLE 6-month Clinical... |
3 Transfer responsibilities and obligations of ALPN-101 SLE IND Parties to discuss date of transfer and considering any on-going activities that may impact transfer (i.e., Clinical studies) From and after the Option Effective Date |
4 Regulatory Preparatory Development Activities Prior to the Option Effective Date Licensor may prepare Regulatory Documentation related to potential Clinical Studies following completion of the Phase IIa SLE Clinical Studies Prior to Option Effective Date |
Schedule 4.2 |
Option Exercise Disclosure Schedule |
To be attached following the Option Exercise Data Package Trigger Event. |
Schedule 6.6.3(c) |
Special Offset |
1. Offsets Regarding Identified Patent. Notwithstanding Section 6.6.3(c) (Reductions) or Section 6.6.4 (Mechanics of Adjustments to Royalties), in the event that (a) AbbVie or its Affiliate enters into an agreement with a Third Party owning or controlling any issued patent that claims priority from WO 2012/142515 (the ... |
2. Mechanics of Adjustments to Royalties. Notwithstanding Section 6.6.4 (Mechanics of Adjustments to Royalties), any reductions made pursuant to paragraph 1 above, collectively with the other reductions set forth in Section 6.6.3 (Reductions), shall not reduce the royalties that would otherwise be owed under Section 6.... |
3. Right to Challenge. Notwithstanding Section 7.6 (Third Party Licenses and Patents), Licensor shall have the right, but not the obligation, and in close consultation with AbbVie, to challenge the patentability, validity or enforceability of the Identified Patent in any court of competent jurisdiction or before any su... |
Schedule 7.2 |
Licensor Prosecution Countries |
Family No. 003 ICOS LIGAND VARIANT IMMUNOMODULATORY PROTEINS AND USES THEREOF |
Country Atty. Ref. Application No. (Country Filing Date) Publication No. (Publication Date) Status and Comments |
AU 20003.41 2017250358 (9/26/2018) AU-A-2017250358 (10/18/2018) Pending |
BR 20003.42 BR 11 2018 070934 4 (10/10/2018) BR1120180709344 (2/26/2019) Pending |
CA 20003.43 3,019,199 (9/26/2018) CA 3019199 (10/04/2018) Pending |
CN 20003.44 201780036984.0 (12/13/2018) CN 110088126 (08/02/2019) Pending |
EA 20003.45 201892336 (11/14/2018) EA 201892336 (06/28/2019) Pending |
EP 20003.46 17733114.7 (9/28/2018) EP 3442999 (02/20/2019) Pending |
IL 20003.47 262365 (10/14/2018) IL 262365 (11/29/2018) Pending |
IN 20003.48 201817041129 (10/31/2018) IN 201817041129 (03/01/2019) Pending |
JP 20003.49 2018-554101 (12/10/2018) JP 2019514361 (06/06/2019) Pending |
KR 20003.50 10-2018-7033049 (11/14/2018) KR 20190005879 (01/16/2019) Pending |
MX 20003.51 MX/a/2018/012472 (10/11/2018) MX/a/2018/012472 (09/06/2019) Pending |
NZ 20003.52 746741 (9/26/2018) NZ 746741 A1 (09/28/2019) Pending |
SG 20003.53 11201808457P (9/27/2018) SG 11201808457P (10/30/2018) Pending |
HK (EP) 20003.54 19121707.4 (4/1/2019) HK 1261801 (1/3/2020) Pending |
HK (CN) 20003.55 19128847.1 (8/28/2019) Not yet published Pending |
US 20003.00 15/488409 (04/14/2017) US 2017/0320959 (11/9/2017) Pending |
Family No. 022 VARIANT ICOS LIGAND IMMUNOMODULATORY PROTEINS AND RELATED COMPOSITIONS AND METHODS |
Country Atty. Ref. Application No. (Country Filing Date) Publication No. (Publication Date) Status and Comments |
AR 20022.41 20180103041 (10/18/2018) None Pending |
AU 20022.43 2018351000 (4/9/2020) Not yet published Pending |
BR 20022.44 BR 11 2020 007542 6 (4/16/2020) Not yet published Pending |
CA 20022.45 3,078,517 (4/3/2020) Not yet published Pending |
CN 20022.46 Not yet available Not yet published Pending |
EA 20022.47 Not yet available Not yet published Pending |
EP 20022.48 18803814.5 (4/1/2020) Not yet published Pending |
IL 20022.49 273726 (3/31/2020) Not yet published Pending |
IN 20022.50 20201701941 (5/7/2020) Not yet published Pending |
JP 20022.51 2020-521877 (4/17/2020) Not yet published Pending |
KR 20022.52 Not yet available Not yet published Pending |
MX 20022.53 MX/a/2020/004540 (4/30/2020) Not yet published Pending |
NZ 20022.54 763426 (4/9/2020) Not yet published Pending |
SG 20022.55 11202003078V (4/2/2020) Not yet published Pending |
UAE 20022.56 P6000549/20 (4/15/2020) Not yet published Pending |
BH 20022.57 20200069 (4/16/2020) Not yet published Pending |
MY 20022.60 PI2020001960 (4/18/2020) Not yet published Pending |
PH 20022.62 Not yet available Not yet published Pending |
QA 20022.63 QA/202004/00202 (4/15/2020) Not yet published Pending |
SA 20022.64 520411779 (4/16/2020) Not yet published Pending |
TW 20022.42 107136610 (10/17/2018) 201925223 (07/01/2019) Pending |
UA 20022.66 Not yet available Not yet published Pending |
ZA 20022.67 Not yet available Not yet published Pending |
US 20022.00 16/757,344 (4/17/2020) Not yet published Pending |
Family No. 032 METHODS AND USES OF VARIANT ICOS LIGAND (ICOSL) FUSION PROTEINS |
Country Atty. Ref. Application No. (Country Filing Date) Publication No. (Publication Date) Status and Comments |
PCT 20032.40 PCT/US2020/028601 (4/16/2020) Not published yet Pending |
For any other Licensor Product Patent families: AU, BR, CA, CN, EA, EP, IL, IN, JP, KR, MX, NZ, SG, HK and US; and validation in the following EP countries: BE, CH, DE, DK, ES, FR, GB, IE, IT, LU, NL, NO, PL and SW |
Schedule 9.5 |
Press Release |
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