20240722_183311

Reactome

NLRP3	HSP90AB1
	SUGT1
	HSP90
	TXNIP
	HMOX1
	Thioredoxin
	2Xhc-TNX

Safety

General

	📊 safety tracking spreadsheet
TSR	2) 📊 Target Safety Review (TSR) link
In vitro	📊 NLRP3 Representative Backup Compounds Safety.pptx in vitro Safety data files for the backup programs – primarily TSD series, but also some TSHO if we ran in vitro assays in US. Recent results have come in from the latest, around the end of Sep.
	TR06693098 (front runner) - CN candidate
In vitro	ü Toward CN for TR098, the results of GSH trapping with human LM, Ames and MNT would be generated. Of these, the timing of the MNT results is the latest, around the end of Sep. ü As BU compounds, team need to find the compounds that avoid the toxicity identified in tox studies of TR443, TR993 and TR098. There is no effective in vitro assessment to mitigate PLsis-related finding. The strategy for PLsis is to move away from CAD-like structures (pKa of the piperidine is reduced to ~6.7) and to lower the lipophilicity in Series 5. ü In Series 6, hERG liability and cytotoxicity would be improved by reduction of basicity of the LHS. Other than Series 5 and 6, the optimization of pyrazole amide, macrocyclization type and amide series is ongoing for BU series.

Non-GLP Tox studies

[098]

		Doses (exp margin)	Results
Rat	3 day minitox study
Rat	2Week DRF Study (TKD BCS 01692, CRL #00691234)	30 (x3.7), 100 (x16.5), 600 (x40.1) No abnormal clinical observations were noted in both 30mg/kg and 100mg/kg groups until Day 8	20230104: 600mpk lost due to deaths. → MTD is 100mpk: Anticipated exposure (AUC 0 24) 1,252,400ng*h/mL, Safety margin: 16.5X (=1,252,400/76,100) (all 30 mg/kg and 100 mg/kg rats survived to scheduled necropsy. No TR098 related abnormal clinical observations, no changes in body weight/gainandfood intake, or body temperature observed in either the 30 mg/kg or 100 mg/kg groups.) Tolerated up to 900mg/kg •Slight to full body tremors were observed as early as 1 h post-dose in female dogs at ≥300mg/kg •Less than dose proportional increase in Cmax and AUC •NOAEL 900mg/kg/d males AUC 0 24 (D1) = 511,500 h*ng/mL (6.7x margin) •NOAEL 900mg/kg/d females AUC 0 24 (D1) = 59x h*ng/mL (7.8x margin)
Dog	Dog Acute Escalating Dose Toxicity and Toxicokinetic Study (TKD BCS 01694, CRL Study #00691236) Is this Dog SAD study?	30, 100, 300, 600, 900
Dog	2w DRF Study (TKD BCS 01696, CRL #00691238)	30 (x1.2-1.6), 700 (x7.9)(700 못 버티면, 시간있으면 200 mpk (x4.2)로 전환 계획이었는데..) Given high variability in the dog TK profile from the dog SAD study, the formulation needs to be optimized. Ideally we'd want to assess two different formulations	20230104: 700mpk lost due to deaths. → MTD is 30mpk, Anticipated exposure (AUC0-24): 88,354 ng*h/mL in males; 120,270 ng*h/mL in females, •Safety margin: 1.2X in males; 1.6X in females (note: 10mpk might have x3.6-4.8) (all 30 mg/kg dogs survived to scheduled necropsy. No TR098 related abnormal clinical observations, no changes in body weight/gain and food intake, or body temperature were noted in 30 mg/kg group.) 200mpk showed reversible generalized tremors, emesis, soft feces. → to be seen
Dog CV	Dosage Selection: Dog CV Safety Pharmacology Study (TKDBCS 01851, CRL#006903026), single dose	30 (x0.6-0.8), 200 (x1.6, 1.9), 700 (x2.7, 2.8)

The objective of formulation (for high exposure OR reducing variability) will be discussed after obtaining the results of rat/dog TK results.

[660]

Study	Study #	Initiation	Study Design	API Estimate
Rat 2-week DRF	00691235 (CRL Ashland)	30 Mar 2023	30, 100, 600mg/kg oral gavage once daily x 14d (N=6/sex/group), Necropsy on Day 15	57g
Dog SAD	00691237 (CRL Ashland)	28 Mar 2023	30, 100, 300, 600, 900mg/kg oral gavage single ascending dose (N=2/sex/group for two dosing groups receiving three different, ascending doses of the TA, with the 72-hr observation period in between the doses)	121g
Dog CV	6903027 (CRL Montreal)	26 Jul 2023	30, 100, 300, 900mg/kg oral gavage single dose (N=4 males with 1-week washout between doses)	83g
Dog 2-week DRF	00691239 (CRL Ashland)	Late Jul 2023	30, 300, 900mg/kg oral gavage once daily x 14d (N=3/sex/group), Necropsy on day 14	1.24kg (20% overage) 1.35kg (30% overage)

NOAEL	the highest level of exposure to the drug at which there are no biologically significant increases in the severity or frequency of AE between the treated animal group and the appropriate control group; some effects which are not considered adverse may be produced at this level. -the highest dose which will not cause any adverse effect -The highest dose tested in animal species that does not produce a significant increase in adverse effects compared to control group
MTD	the dose of a drug that produces an acceptable level of toxicity or the highest dose of a drug that does not cause unacceptable side effects.(30mpk 까지 acceptable 이고, 50mpk 부터 unacceptable 30mpk 가 MTD 됨) -The MTD is expected to produce noticeable changes in the animal, such as weight loss -the highest dose of a drug that does not cause unacceptable side effects or overt toxicity in a specific period of time -In clinical trial: the dose one level below the dose with dose-limiting toxicity (투약이 중도 중단 되는 군),
TI	Therapeutic index, MTD/Predicted exposure required for clinical efficacy (eg. MaxED)
Safety margin	NOAEL (AUC)/ Predicted exposure required for clinical efficacy (inset plot: Plasma Concentration vs Dose with bands Overt Toxicity (Lethality) / Max Tolerated Dose (MTD) / NOAEL / Highest Dose Causing No Serious Adverse Effects / Safety Margin / Intended Therapeutic Range) For benign indications, 100-fold margin may be appropriate For terminal conditions, much lower margin may be acceptable To account for differences between humans and laboratory species, a safety margin is established based on the NOAEL in the 'most sensitive' of the tested species. Dahea: in short term study, >30x is minimum, >50x is desirable
Exposure margin	분자 Day 14 AUC0-24 분모 AUCeff 098 New Human efficacious exposure (23,828 nM*h or 8,947 ng*h/mL) predicted using in vitro potency data in human iPSC-derived microglia and in vivo exposure in AAV1/2-hA53T-aSyn mice at efficacious dose of 10 mg/kg 098 old (=76,100 ng*h/mL ) AUCeff: AUC(0-24) in AAV1/2--hA53T-aSyn mice 30mg/kg/day TR06693098 for 21 days (=76,100 ng*h/mL) 660 New AUCeff is the human efficacious exposure (16,589 nM*h or 6,178 ng*h/mL) predicted using in vivo data in human iPSC-derived microglia and in vivo exposure in AAV1/2-hA53T-aSyn mice at the dose of 30mg/kg
Starting dose	SPINRAZA® (nusinersen): only one dose, safety margin of 1. -TAK341: The HED derived from the NOAEL was calculated as 24 mg/kg when derived from rat and 48 mg/kg when derived from cynomolgus monkey toxicology studies. Application of the recommended 10-fold safety factor suggests a higher starting dose based on HED from both non-clinical species, in the range of 2.4-4.8 mg/kg (144 to 288 mg for a 60 kg human).
Maximum exposure	EMA guidance in which the maximum exposure in healthy volunteers should be within the estimated human pharmacodynamic range as an MTD approach is not appropriate in healthy volunteers it is important to understand the therapeutic dose range and target saturation, Trial design using MTD is not appropriate for healthy volunteers (FDA) FDA M3(R2)-Nonclinical-Safety-Studies-for-the-Conduct-of-Human-Clinical-Trials-and-Marketing-Authorization-for-Pharmaceuticals.pdf 에 table3 에 상세 scenario CKD-504: to ensure that planned doses will not be expected to exceed exposures established as the NOAEL in the 28-day dog toxicology study. -TAK341 SAD PROtocol: Maximum exposure will not exceed an AUC0-t of 5100 ug*day/mL or a Cmax of 1940 ug/mL. - note) TAK341: Within the planned human dose range of 70 to 4200 mg, it is not anticipated that the maximum exposure will exceed a Cmax of 2800 ug/mL or an AUC∞ of 4100 ug•day/mL, the exposure achieved at the NOAEL in cynomolgus monkeys (Section 4.3.2.2) (1B)

Uncertain Spans

location	transcription	uncertainty
Reactome mini-table	”2Xhc-TNX” final entry	The label appears as “2Xhc-TNX” but the leading “2X” is small; preserved as legible.
Rat 2Week DRF result row	”(=1,252,400/76,100)” division and “16.5X” margin	Numeric quotient is partially blurred, preserved as best-effort.
Dog DRF row “30 (x1.2-1.6), 700 (x7.9)“	margin multipliers	Some margin multipliers are partially obscured by red Korean annotation; preserved as legible.
Safety margin inset plot	x-axis label “Dose” and curve labels	Inset plot kept as evidence; curve slopes/values not transcribed.