20240722_184327

(patent) epitope 4-15 이라는 것 같음. Specifically, these antibodies bind an epitope within amino acids 4-15 of SEQ ID NO				Some participants complained of headache, dizziness, or pain related to the infusion, and one developed a skin rash at the infusion site. The pharmacokinetic profile was as expected, with a half-life of 28 days and a CSF/serum ratio of 0.2 percent at all doses. The maximum concentration in blood was proportional to the antibody dose given. The researchers are still analyzing what happens to plasma α-syn, Brys noted. This trial is ongoing, aiming to enroll 66 people, but based on the preliminary data, the researchers are already planning to take BIIB054 into Phase 2, Brys said.
		In vitro	In Vienna, Andreas Weihofen of Biogen, Cambridge, Massachusetts, presented preclinical findings. In cell culture, BIIB054 reduced spreading of aggregated α-syn between neurons, and in mice injected with α-syn fibrils, BIIB054 slowed down pathology and improved motor function,
		In vivo	(Weihofen 2019 #2236) pff mouse model
Prothena (Roche) ↓ Free (unbound) aSyn CSF? the amount of monomeric α-syn in CSF did not change	Prasinezumab (PRX002/RG7935) a humanized monoclonal antibody, higher affinity for aggregates and oligomers of syn, It binds aggregated forms of α-syn 400 times more strongly than monomeric forms,	P2b, ath434 n=575 NCT04777331 Early PD: Dx at least 3m – 3y	Iv, Early Parkinson's Disease (PD) who are on stable symptomatic PD medication (low dose L-DOPA) Estimated study start date: May 31, 2021 Estimated primary completion date: November 13, 2023 Number of Arms: 2 Experimental Arm: Participants will receive an IV infusion of prasinezumab (Q4W) Comparator Arm: Participants will receive placebo as an IV infusion Q4W Primary outcome measure: Time to meaningful progression on motor signs of the disease, as assessed by ≥ 5 points increase in MDS-UPDRS Part III score from baseline (Time frame: From baseline until 28 days after final dose of study treatment) Ages eligible for study: 50 years to 85 years they did not include DATscan in PADOVA because he think one needs more time (2 years) to see an effect, although he would consider the use of PET DAT or VMAT2) due to their higher sensitivity to detect change.
	용액에는 fibril 이 존재 못 하므로 (insoluble이므로) (monomer 대비) affinity 비교가 불가하고, 그냥 aggregate 라고 표현하고 있는 듯 (이건 대부분 oligomer 지칭하는 것이겠지) 조직염색에서만 fibril 에 대한 결합을 non-quantitavely 볼 듯 Epitope: (patent) epitope 110-130 이라는 것 같음. Epitope: 118-126 (aSyn propagation suppressor slide) Epitope: (Oliveira 2021) 115-126	P2 = PASADENA NCT03100149	(design) 80% power and a one-sided alpha of 0.10 to detect a 37.5% relative change between group reduction from baseline to week 52 on the primary endpoint (i.e., MDS-UPDRS) total score vs placebo in Part 1 of the study), Part 1 is a randomized, double-blind, placebo-controlled, three-arm study that enrolled 316 patients to evaluate the efficacy and safety of prasinezumab in patients over 52 weeks. In Part 1, patients were randomized on a 1:1:1 basis to receive one of two active doses (1500 mg or 4500/3500 mg, depending on body weight) of prasinezumab or placebo via intravenous infusion once every 4 weeks. Eligible patients were not on dopaminergic therapy (MAO-B inhibitors 허용) and were not expected to require dopaminergic therapy for at least 52 weeks. Part 2 of the study, which is ongoing, is a 52-week blinded extension phase in which patients from the placebo arm of the study have been re-randomized onto one of two active doses on a 1:1 basis, so that all participants are on active treatment. Patients who were originally randomized to an active dose will continue at that dose level for the additional 52 weeks. In Part 2, patients are allowed to start dopaminergic therapy. Any patient who medically required initiation of dopaminergic therapy during Part 1 have had their subsequent data censored for the primary endpoint analysis. Key secondary endpoints include safety, and DaT-SPECT imaging.	(results) did not meet the primary objective (MDS-UPDRS total score), but showed signals of efficacy (MDS-UPDRS, Part III) 2020 MDS에서 발표함: MDS-UPDRS에서 다소 좋은 듯함. DIGITAL ENDPOINTS & TIME TO WORSENING OF MOTOR SYMPTOMS 도 이 signal of efficacy를 support함. Low & high dose 간에는 차이 없어 보임 DaTScan changes showed no differences (밑에 MAD 등에서 보면 aSyn 줄이는 것 확실할텐데도 Datscan 과 연결 안 되는 point!) between groups there was limited progression (11%) in placebo & treated participants. Genaro Pagano (Pasadena/Padova Roche GCL), claims that in the Pasadena population (which was denovo + MAOi) those under MAOi showed the biggest response. Roche tool kit (digital bm) Mao-b ↓

Pasadena trial design (Part 1 / Part 2 / Part 3)

Part 1* (2019–2020) 52-week double-blind treatment (placebo controlled)	Part 2 (2020–2021) 52-week extension (active treatment, blinded to dose)	Part 3 (2021 onwards) Up to 60 months active treatment, open-label extension
Placebo IV Q4W	Prasinezumab IV Q4W Low dose (1500 mg) Prasinezumab IV Q4W High dose (4500 mg)‡	Prasinezumab IV Q4W Low dose (1500 mg) All eligible patients
Prasinezumab IV Q4W Low dose (1500 mg)	Prasinezumab IV Q4W Low dose (1500 mg)
Prasinezumab IV Q4W High dose (4500 mg)‡	Prasinezumab IV Q4W High dose (4500 mg)‡

N = 316. Randomize (1:1:1). Screening: Up to 8 weeks. DaT-SPECT anchors at Screening / start of Part 1 / start of Part 2 / start of Part 3 (12-week follow-up treatment free).

Signal-detection study designed to include ~100 patients/arm, resulting in 80% power and two-sided alpha of 0.20, to detect a 37.5% relative change in MDS-UPDRS Total score between groups from baseline to Week 52.

*COVID-19 did not affect assessments during PASADENA Part 1 as these were completed before the pandemic. ‡High dose = 4500 mg for ≥65 kg; 3500 mg for <65 kg. ‡Digital biomarkers (smartphone and wrist-worn wearable assessments). COVID-19, coronavirus disease 2019; DaT-SPECT, dopamine transporter imaging with single-photon emission computed tomography; IV, intravenous; MDS-UPDRS, Movement Disorder Society Unified PD Rating Scale; PD, Parkinson’s disease; Q4W, every month. ClinicalTrials.gov, NCT03100149. (Accessed February 2021).

The mentioned compounds and their use are investigational and have not yet received regulatory approval in any country.

P1 MAD, m-to-m PD, iv, monthly dosing, six doses: 0.3, 1, 3, 10, 30, or 60 mg/kg, 12w F/U	In June 2014, an eight-center, multiple-ascending-dose trial began comparing a six-month course of PRX002 to placebo in what was to be 64 people with idiopathic PD. The trial evaluated safety and pharmacokinetic parameters, included exploratory CSF, imaging, and clinical markers, and was completed in September 2016. At the 2017 AD/PD conference, the trial was reported to have enrolled 84 people with mild to moderate PD and to have been safe, without anti-PRX002 antibodies or serious adverse events. Side effects included gastrointestinal complaints, infusion site rash, headaches, and peripheral edema. PRX002 half-life was 14 days, and the CSF/serum ratio was 0.3 percent for all dose groups at week 9. Unbound serum α-syn dropped by up to 97 percent at the highest dose, indicating peripheral target engagement. Antibody levels rose dose-dependently in CSF, but the amount of monomeric α-syn in CSF did not change. At the time, Prothena had no assay to measure the concentration of α-syn aggregates in CSF before and after treatment. To see improvement on MDS-UPDRS, see May 2017 conference news. These data were subsequently published, and the half-life estimate was revised to 10.2 days (Jankovic et al., 2018). Notably, this trial explored the use of smartphone measures to monitor clinical changes, showing that they closely correlate with the MDS-UPDRS but may be more sensitive (May 2017 conference story).
P1 SAD	40 healthy adults younger than 66 to compare the safety and pharmacokinetics of a single infusion of 0.3, 1, 3, 10, or 30 mg/kg to placebo. This trial assessed peripheral target engagement (May 2015 news story, company press release). At the 2015 AD/PD conference, Prothena reported that the antibody was safe, well-tolerated, and dose-dependently reduced the concentration of free α-syn in the blood down to 4 percent; data were subsequently published (Schenk et al., 2017).
preclinical	In aSyn TG mice, the murine version of prasinezumab, reduced the appearance of α-syn pathology, protected synapses and halted the worsening of behavioral phenotypes. Prothena researchers have found that antibodies can mop up intracellular pathology as well (https://www.alzforum.org/news/conference-coverage/syn-antibodies-enter-phase-2-sans-…), composed of an anti-alpha-syn antibody and Grabody-B, a BBB-penetrating shuttle targeting insulin-like growth factor 1 receptor (IGF1R)
ABL301 (Sanofi, ABL Bio)	anti-α-syn bispecific mAb, In preclinical studies, ABL301' showed robust recognition of pathological aggregates with high affinity and with minimal affinity to monomeric aS
preclinical	By utilizing the Grabody-B platform, ABL301 is proven to enter the cerebrospinal fluid (CSF) of rodents and non-human primates more than an alpha-syn monoclonal antibody According to ABL Bio, ABL301 have demonstrated superior BBB-penetrating capability and better efficacy to reduce brain aggregated alpha-syn in both PD and MSA mouse models, vs. monoclonal a-syn binding antibody (link)

mAbs summary

mAbs	Company	Type	Epitope	Stage	Next milestone
Prasinezumab (PRX-002/RG-7935/RO7046015/9E4)	Roche/Prothena	Passive	118-126, fibril	Ph2 (early PD)	Dec 2019
BIIB-054 (NI202.12F4)	Biogen	Passive	1-10, fibril	Ph2 (PD)	Mar 2021
Lu AF82422	Lundbeck/Genmab	Passive	C-terminus (112-117?)	Ph1 (PD)	Oct 2019
ABBV-0805 (BAN0805)	abbvie/BioArctic	Passive	Oligomer/protofibril	Ready to Ph1	N/A
TAK-341 (MEDI1341/Aslo452ngl-3)	AstraZeneca/Takeda	Passive	102-130	Ph1 (PD)	Nov 2019
UB-312	United	Active	126-135	Ready to Ph1	N/A

aSyn - Small molecules

target	mechanism		Design	results
T100-18 A (small molecule)	interacts with the C-term α-syn, ↓ oligomerization and its accumulation in neurons in vitro			↑ motor deficits in α-syn transgenic mice and ↓ synaptic accumulation very rapidly (Wrasidlo et al., 2016)
200-11, 30599 (313), zasolmin /norvatis	↓ misfolding of aSyn monomer at the lipid membrane → → ↓ oligomerization of α-syn small molecule inhibitor of α-syn misfolding	P2 (NCT04658186) 'ORCHESTRA'	A double-blind, placebo-controlled, randomized, 18-month Phase 2a study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of Oral UCB0599 in study participants with early Parkinson's Disease	Estimated enrollment: 300 participants Estimated study start date: December 2020 Arms: Arm 1: placebo (n=150) Arm 2: UCB0599 high dose (n=150) Arm 2: UCB0599 low dose (n=150) Primary endpoint: MDS-UPDRS) Parts I-III sum score (Time frame: from baseline up to 18 months)

Uncertain Spans

location	transcription	uncertainty
Top continuation row — In vivo cell	(Weihofen 2019 #2236) pff mouse model	The full citation closing characters are clipped at the right edge of the cell; only pff mouse model is fully legible after the citation.
Pasadena trial design footnote	‡High dose = 4500 mg for ≥65 kg; 3500 mg for <65 kg	The footnote glyph is reproduced from the source’s ‡ mark over the High-dose arm; readability is borderline at the print resolution.
ABL301 cell — ABL301’ apostrophe	ABL301'	The trailing prime/apostrophe after ABL301 is small; the source visual shows a curved tick mark.
200-11, 30599 (313), zasolmin /norvatis	drug-name token list	The line concatenates internal codes (NPT200-11, 30599, 313) and shorthand zasolmin /norvatis; based on context the row refers to minzasolmin (UCB0599) developed with Novartis, but the visible source text reads as transcribed.