20240722_184324

20240411

Narrative – 10 page limit, text only. Tables are OK to include in the narrative, but they count towards the 10-page limit. So for example if you want to put the TCP, Risk table and EPOP into the narrative, you can do so. There is no new template for PE – please use what is currently available on our SharePoint. The first page is the cover page – so the total length of the document is 11 pages. Figures – all in PowerPoint slide format – limit 10 slides + 1 executive summary slide = 11 slides total. Any type of illustration – a Gantt chart, decision tree, MoA, graphs – should all be in slide format. You can put a table into slide format if you wish – but you are still restricted to 10 slides. The font for tables should be no less than 10 pt. If you decide to put it as a slide, you may do so. You are still limited to 10 slides/10 pages no matter where you decide to put the table. References do not need to be included as a separate section, you can refer to them as a footnote, thereby saving space.

PIAS2

• Pathophysiology

In normal	PIAS2 signals to stop inflammation. (PIAS2-protein is highly expressed in the neuron)
In PD	↑ PIAS2 (Protein inhibitor of STAT2, a negative regulator of STAT and IFN-β)	loss of IFNβ or IFNAR1 ( the receptor for IFNα/β)	Inflammation persists	defect in the mitochondrial energy supply
POSTmortem PD brain	PIAS2 was upregulated in the neurons of sPD patients, particularly in the brains of patients with sPDD. (Magalhaes, 2021 #1609)			PDD
GWAS		We identified SNP variants in IFNβ-IFNAR-related genes in sPD patients (Magalhaes, 2021 #1609)
COrrection

Pipeline of PD

aSyn - Antibody

	PRX002 / RG7932 / prasinezumab	BIIB054 / cinpanemab	TAK-341 / MEDI1341	Lu AF82422	ABBV-0805	Affitope PD01A	Affitope PD03A	UB-312
Type	mAb	mAb	mAb	mAb	mAb	vaccines	vaccines	vaccines
Claimed properties	IgG1 mAb selective for aggregates (>400x)	IgG1 mAb selective for aggregates (>800x), and no binding to control brain	Aglycosylated IgG1 mAb with high selectivity for aggregates	IgG1 mAb selective for aggregates (100x)	IgG1 mAb selective for aggregates (200x)	Generates antibodies and avoids T-cell response	Generates antibodies and avoids T-cell response	Generates response selective to aggregates, B-cell and Th cell epitope; avoids T cell response
α-syn epitope	C-terminal (118-126)	N-terminal (1-10)	C-terminal (102-130)	C-terminal (112-117)	C-terminal (121-127)	C-terminal (110-130)	C-terminal	C-terminal (111-135)
Development Status / Updates	Ph2 Part 1 missed primary but met some secondary endpoints; Part 2 results presented at MDS 2021; Ph2b ongoing	Ph2 primary/ secondary endpoints not met; Program terminated	Two Ph1 studies ongoing, one in PD and one in healthy volunteers; PCD of Ph1 PD study in July 2022	Ph1 study completed; Ph2 initiated in MSA patients in Q4 2021	Halted multiple-ascending dose Ph1; single-ascending dose Ph1 ongoing; considering Ph2	Ph1 completed; Asset acquired by AC Immune; Initiation of Ph2 planned in H2 2022	Ph1 completed; No development reported	Dosing in Ph1 study Part B initiated; Data expected in H2 2022; Expected PCD in Dec 2022

α-syn sequence targeted by mAbs and vaccines

Target	mechanism		Design	results
General mechanism: antibodies against α-syn	(Lee, 2016 #1515) Extracellular aSyn 이 Ab 와 complex 상태에서는 1. (평소처럼 β1-integrin & TLR2 receptor 통하기보다는) FcY receptor 통해 microglia 입장→ ↑lysosomal delivery and degradation 2. ↓인접 neuron 입장
Nitrase's first-in-class antibody	NITROME platform	Preclinical		Targeting Nitrated Alpha Synuclein for the Treatment of Parkinson's Disease" was featured in an oral presentation at the Alzheimer's Disease and Parkinson's Disease (AD/PD) Conference taking place in Lisbon, Portugal from March 5-9, 2024. itrase's antibody demonstrated both high affinity and selectivity for nitrated synuclein, and it demonstrated the ability to significantly reduce PD progression in in vitro and in vivo PD models. ntroduction of nitrated α-synuclein in PD models induced motor dysfunction and the death of dopaminergic neurons. Nitrated synuclein is elevated in the cerebral spinal fluid of PD patients suggesting it could be the pathogenic our antibody demonstrated superiority in a preclinical efficacy evaluation against the parental antibody of prasinezumab, which targets non-nitrated α-synuclein. Nitrated α-synuclein is different from normal/non-nitrated α-synuclein because protein nitration causes changes in protein structure, function and/or aggregation state; Several studies have suggested that the insolubility of synuclein may be a result of nitration, since nitrated α-synuclein accumulates in the insoluble fraction of homogenates from PD brains. These aggregates are nitrated, and this nitration strongly induces neurodegenerative disease in models. Secreted nitrated α-synuclein, and not non-nitrated α-synuclein, is elevated in the cerebral spinal fluid of PD patients, and Nitrase has found that neutralizing secreted nitrated α-synuclein decreases the spread of pathology in models of PD. Non-nitrated α-synuclein is highly expressed in the blood stream and has been shown to act as a peripheral sink in other clinical trials. Since nitrated α-synuclein is only present at low levels in the blood stream, more of Nitrase's antibody is accessible to nitrated α-synuclein present in the brain. In preclinical studies, humanized and affinity matured antibodies were characterized for in vitro binding affinity towards nitrated α-synuclein (SPR, ELISA), selectivity towards the modification over non-modified synuclein (ELISA), target engagement (ELISA), developability/stability (AC-SINS, DSF, SEC), and in vivo PK and efficacy in mouse models of PD (IHC, ELISA). In vitro data demonstrated that the antibody has a specific nitrated α-synuclein binding affinity of <2 nM without detectable binding to non-nitrated α-synuclein or another nitrated protein. In vivo pharmacokinetic data showed that the concentration of the antibody within murine brain tissue far surpassed the half-maximal inhibitory concentration (IC50). Importantly, in a preformed fibril (PFF) induced mouse model of Parkinson's disease, Nitrase's anti-nitrated-α-synuclein antibody reduced the spread of synuclein aggregates. When evaluated against prasinezumab's murine parental antibody in this in vivo model, Nitrase's antibody demonstrated a superior ability to reduce synuclein aggregate spread. In summary, these data support the potential of Nitrase's antibody to bind strongly and selectively to its nitrated α-synuclein target and reach the brain tissue with therapeutic concentrations, producing the desired efficacy outcome of reducing PD progression.
B7853 Lu AF82422, Lundbeck	anti-α-syn mAb): Anti-alpha syn mAb, (112-117)	(Phase 1 ongoing, NCT04651153 P1 P2	healthy volunteers and patients with Parkinson's Disease Estimated enrollment: 64 Primary endpoint: Incidence of treatment-emergent adverse events Estimated enrollment: 84 (actual 74)	Phase 1 trial (NCT03611569) on-going; expected primary completion date in December 2020 — completed in July 2021 Initiation of a Phase 2 study expected in H2 2021 in MSA patients
ABBV-0805 (BioArctic/Abbvie)	Antibody, Epitope: 121-127	P1 lx) lxi) lxii)		Phase 1 (NCT04127695) study started in March 2019; In March 2020, the second portion of the study was initiated with patients with Parkinson's disease BioArctic's partner AbbVie has decided to stop recruitment for the Multiple Ascending Dose (MAD) part of the Phase 1 study of ABBV-0805 in Parkinson's disease patients. Phase 1 is continuing with the single ascending dose study A detailed plan to accelerate ABBV-0805 into a Phase 2 Proof of Concept study in Parkinson's disease patients is currently being prepared by AbbVie, Ph1 trial results presented at MDS 2021 (link) differentiated from prasinezumab in terms of unique binding profile and more selectivity for the harmful aggregates of alpha-syn rather than binding to monomers → AbbVie has withdrawn the Phase 1 due to strategic considerations Preclinical, No updates for this quarter report
PD1601, PD1602 (BioArctic/Abbvie)	(BioArctic/Abbvie) Ab? BIIB-054 Cinpanemab this human monoclonal antibody binds pathological, aggregated	Preclin P2 (POC) 'SPARK' SAD		NCT03318523 • did not met its primary or secondary endpoints." → 202102: 'discontinue' In 2015, Biogen started a Phase 1 single ascending dose study in 48 healthy people between age 40 and 65. At two U.S. sites, volunteers received infusions of either 1, 5, 15, 45, 90, or a whopping 135 mg/kg,

Uncertain Spans

• 사진의 Target/mechanism/Design/results 표는 셀 경계가 흐려 일부 행에서 mechanism, Design, results 열의 시작점이 시각적으로 명확하지 않다. 위 HTML 표는 가장 가까운 분할로 옮긴 것이며 cell 경계는 100% 확정이 아니다.
• “B7853” 행 첫 셀의 “anti-α-syn mAb):“의 좌괄호는 사진 상단 잘림으로 보이지 않으며 그대로 옮겼다.
• Nitrase 결과 셀의 첫 글자가 사진 좌측 잘림으로 일부 단어가 “ntroduction”, “itrase’s”, “modification” 등 첫 글자가 빠진 채로 보인다.
• 우하단 셀 마지막 줄 “5, 15, 45, 90, or a whopping 135 mg/kg,” 다음 내용은 사진 하단으로 잘려 있어 이어지는 문장은 보이지 않는다.