20240722_183150

Limitations

	xxv) Papilledema score (with 0 as best outcome and 4 as worst) improved significantly during the study with an estimated change from baseline to Month 36 of -0.88 (95% CI -1.06 to -0.70; p-value <0.0001) in the best eye and -1.05 (95% CI -1.20 to -0.89; p-value <0.0001) in the worst eye. The improvement was sustained at the Month 60 visit. xxvi) Visual acuity and peripheral vision did not improve. [joint] 좋아짐.
P3:children	NCT01576367 Age at start of extension study (years): 3.1 (1.7) Bbb안 되니 csf x	(Kuemmerle-Deschner, 2011 #1837) OL, f/u=11m, N=12 중 10명이 hearing loss, 2명: improved, 2명: worsened, 6명: stable. E311K 13 (62) 7 (58) T348M 3 (14) 3 (25) V198M
P3:children	NCT01302860 Mean age: 1.9 (1.39) Infants and toddlers (28 days-23 months): n=6 Children (2-5 years): n=11 Bbb안 되니 csf x	Seven studies also demonstrated improvement or stabilisation with anakinra in neurological outcomes (eg, migrainous headache, papilledema),45 60 62 hearing loss,30 55-57 60 62 and visual acuity.30 62
(Kuemmerle-Deschner, 2011 #1837) OL	Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA N=12, primary endpoint at d8 Remission patient proportion: 93% (at both short term and ~50m long term)	N=14 primary endpoint at d14 Remission patient proportion: 67% (short term), 75% (52m, long trem)

Outcome measures

	MWS disease activity score (MWS-DAS)	AIDAI Auto-Inflammatory Diseases Activity Index	The autoinflammatory disease damage index (ADDI)
	initially developed for clinical trials	initially developed for clinical trials	The ADDI can be used to monitor structural damage in individual patients and allows outcome analysis and comparison of results in clinical trials [121].
		CAPS disease activity at home [83],	a reliable instrument for assessing disease-related organ damage [121].
원본	순환 referencing 하면서 부재	(Piram, 2014 #1842)	(ter Haar, 2017 #1843)
Domains	xxvii) 10 domains nine domains reflect the organ involvement in MWS (fever, headache, eye involvement, hearing impairment, oral ulcers, abdominal pain, renal disease, musculoskeletal disease, and rash), and the tenth is the patient's global assessment score [100,120]. The tenth domain is the Patient Global Assessment score measured on a visual analogue scale (VAS) and categorized into 0 points for ≤1 cm, 1 point for >1 to 5 cm, and 2 points for strictly >5 to 10 cm. A		The ADDI consists of 18 items grouped into the following eight categories: reproductive, renal/amyloidosis, developmental, serosal, neurological, auditory, ocular, and musculoskeletal damage [121,122]. CAPS 에 specific 안 하지만, 많아서 괜찮은 듯.
Domain-neurologic? Scoring	Hearing only	Eye only	Neurological (MR, IICP등), hearing loss, ocular
	xxviii) 0, 1, or 2 points to each level of disease activity: xxix) 2 points for severe symptoms, xxx) 1 point for mild symptoms, and xxxi) 0 points for absence of symptoms in each domain xxxii) (maximum possible score 20). xxxiii)
	xxxiv) ≤10 points : mild activity, ≥10 points: severe activity	cut-off score ≥9 discriminated active from inactive patients

Registry

	Eurofever	Infevers
	{Papa, 2017 #1830} https://www.printo.it/eurofever/registry	(http://fmf.igh.cnrs.fr/ISSAID/infevers)
CAPS patiens	N=133 Levy 2014: age=15 (8-35)

Animal model

a. NOMID mice

a. Phenotype: {Bonar, 2012 #1373} D301N mutation in Nlrp3, corresponding to the D303N mutation in human NLRP3, linked to NOMID. NOMID mice phenocopy several features of human NOMID such as early onset systemic inflammation and growth retardation. These mice also have disorganized growth plates and low bone mass associated with exuberant osteoclastogenesis,

b. The aspartate 303 to asparagine (D303N) substitution has been identified in NOMID and severe MWS patients [10,11]. This autosomal dominant point mutation occurs near the Mg2+ binding site in the NLRP3 NACHT domain and is thought to cause a conformational change that confers ligand-independent constitutive activation of the mutated NLRP3 inflammasome. To further understand the pathological impact of this mutation, we generated knock-in mice expressing D301N NLRP3 (D303N ortholog of human NLRP3)

TM

Goal:

preventing the development of any organ damage in young patients who do not yet have organ damage at the time of treatment initiation (primary prevention).
preventing the progression of organ damage (secondary prevention)

methods

the disease outcomes and the monitoring of disease activity need to be tailored to the severity of the underlying disease

Pipeline CAPS


Inzomelid	Inzomelid: P2 EudraCT 2020-000489-40 A confirmed Dx of CAPS Documented verification of a genetic mutation in NLRP3; and Previously experienced at least 2 typical clinical symptoms of CAPS (may include urticarial skin rash, myalgia, arthralgia, recurrent fever, fatigue/malaise, headache, conjunctivitis, and any other autoinflammatory symptom usual for a given participant); Previously had elevated levels of CRP or SAA (> 2 × ULN). Positive response to IZD174 in ex vivo whole blood LPS)+Nigericin induced IL-1β release (IC50 < 50μM). Participants must be willing to DISCONTINUE current anti-IL-1 inhibitor treatment prior to dosing if applicable. Participants must DEMONSTRATE FLARING of CAPS following DISCONTINUATION of anti-IL-1 inhibitor treatment or if newly diagnosed. Flaring is defined as IGA (investigator global assessment) score specific at the time of consultation > 5 with an elevation of CRP (> 2 × ULN). [primary endpoints] xxxv) Safey xxxvi) Efficacy endpoints: • Number of participants with no disease at Week 12 during individual IZD174 treatment (pooled). No disease is complete clinical remission, defined as complete clinical response with normal CRP or SAA levels. Complete clinical response is defined as Investigator global assessment of IGA score specific at the time of consultation of <3 and IGA general assessment of absent or minimal [secondary endpoints] Plasma PK: plasma IZD174 concentrations PD: NLRP3 inhibition in ex vivo stimulated whole blood as measured by IL-1β secretion CRP (as part of safety assessments) SAA Efficacy endpoints: - Number of participants with no disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174 - Number of participants with partially active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174.	Partially active disease is incomplete clinical remission, defined as incomplete clinical response with CRP or SAA levels improved by >50% over Baseline, but still elevated. Incomplete clinical response is defined as IGA score specific at the time of consultation of 0 3 and > 50% improvement over Baseline and IGA general assessment improvement by at least one category (e.g., moderate to mild) - Number of participants with active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174

Inzomelid

Inzomelid: P2 EudraCT 2020-000489-40
A confirmed Dx of CAPS
Documented verification of a genetic mutation in NLRP3; and
Previously experienced at least 2 typical clinical symptoms of CAPS (may include urticarial skin rash, myalgia, arthralgia, recurrent fever, fatigue/malaise, headache, conjunctivitis, and any other autoinflammatory symptom usual for a given participant);
Previously had elevated levels of CRP or SAA (> 2 × ULN).
Positive response to IZD174 in ex vivo whole blood LPS)+Nigericin induced IL-1β release (IC50 < 50μM).
Participants must be willing to DISCONTINUE current anti-IL-1 inhibitor treatment prior to dosing if applicable.
Participants must DEMONSTRATE FLARING of CAPS following DISCONTINUATION of anti-IL-1 inhibitor treatment or if newly diagnosed.
Flaring is defined as IGA (investigator global assessment) score specific at the time of consultation > 5 with an elevation of CRP (> 2 × ULN).

[primary endpoints]

xxxv) Safey
xxxvi) Efficacy endpoints:

• Number of participants with no disease at Week 12 during individual IZD174 treatment (pooled).
No disease is complete clinical remission, defined as complete clinical response with normal CRP or SAA levels.
Complete clinical response is defined as Investigator global assessment of IGA score specific at the time of consultation of <3 and IGA general assessment of absent or minimal

[secondary endpoints]

Plasma PK: plasma IZD174 concentrations
PD: NLRP3 inhibition in ex vivo stimulated whole blood as measured by IL-1β secretion
CRP (as part of safety assessments)
SAA
Efficacy endpoints:

- Number of participants with no disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174
- Number of participants with partially active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174.

Partially active disease is incomplete clinical remission, defined as incomplete clinical response with CRP or SAA levels improved by >50% over Baseline, but still elevated.
Incomplete clinical response is defined as IGA score specific at the time of consultation of 0 3 and > 50% improvement over Baseline and IGA general assessment improvement by at least one category (e.g., moderate to mild)
- Number of participants with active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174

Uncertain Spans

location	transcription	uncertainty
MWS-DAS Domains row	`categorized into 0 points for ≤1 cm, 1 point for >1 to 5 cm, and 2 points for strictly >5 to 10 cm. A`	The trailing “A” indicates the sentence is cut off; what follows is not visible on this capture.
Limitations row 1	`[joint] 좋아짐.`	The square-bracketed Korean fragment sits at the bottom of the cell; its connection to the surrounding bullets is uncertain.
Inzomelid IGA criterion	`IGA score specific at the time of consultation of 0 3 and > 50% improvement`	Source shows `0 3` likely meaning `< 3` or `≤ 3`; the comparator glyph could not be confirmed.
Limitations top row	`xxv) ... xxvi) ...`	The cell labels `xxv)` and `xxvi)` are Roman-numeral list markers from the source.

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