Targeting TSLP in Asthma

Figures & data

Figure 1 TSLP Acts Across the Spectrum of Asthma Inflammation. TSLP-driven mechanisms of disease in different asthma endotypes. Epithelial alarmins, including TSLP, are released in response to triggers at the epithelium. The alarmins activate multiple innate and adaptive immune responses that participate in overlapping and distinct pathways. TSLP may also mediate structural cell effects that contribute to airway hyperresponsiveness and remodeling. Figure adapted, with permission, from Gauvreau GM et al. Expert Opin Ther Targets. 2020;24(8):777–792.^9,74–76

Abbreviations: IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cell; T2, type 2; Th, T helper; TSLP, thymic stromal lymphopoietin.

Table 1 Tezepelumab Clinical Trials in Asthma

Phase Study Name NCT Number	Design	Patient Population Key Inclusion Criteria (N)	Treatment Dose	Primary Objective
Phase 1 Proof of Concept NCT01405963	Randomized, placebo-controlled study to evaluate safety and response to allergen challenge	Adults with mild, stable atopic asthma (31)	700 mg or placebo in a 1-hour IV infusion on study days 1, 29, and 57	Assess the effect of tezepelumab on the late asthmatic response, as measured 3 to 7 hours after allergen challenge on days 42 and 84^Citation36
Phase 2 PATHWAY NCT2054130	Randomized, placebo-controlled, double-blind, multiple dose trial to evaluate safety and efficacy	Adults with severe, uncontrolled asthma and history of exacerbations during year prior to trial entry (550)	70 mg or 210 mg SC Q4W or 280 mg SC or placebo Q2W	Assess the effect of tezepelumab on asthma exacerbations at week 52^Citation39
Phase 3 NAVIGATOR NCT03347279	Randomized, placebo controlled, double-blind trial to evaluate efficacy and safety	Adults and adolescents with severe, uncontrolled asthma on medium- to high-dose ICS and ≥ 1 additional asthma controller medication with/without OCS (1059)	210 mg SC or placebo Q4W	Assess the effect of tezepelumab on asthma exacerbations at week 52^Citation40,Citation41
Phase 3 SOURCE NCT03406078	Randomized, placebo-controlled, double-blind trial to evaluate efficacy and safety	Adults with OCS- dependent asthma; stable daily dose of OCS 7.5 to 30 mg for ≥ 1 month; 35% with eosinophils ≥ 300 cells/µL (150)	210 mg SC or placebo Q4W	Assess the effect of tezepelumab in reducing the prescribed OCS maintenance dose at week 48 while not losing asthma control^Citation50,Citation51
Phase 3 DESTINATION NCT03706079 (ongoing)	Randomized, placebo controlled, double-blind extension trial to evaluate safety and tolerability	Adults and adolescents with severe, uncontrolled asthma; previously enrolled in NAVIGATOR or SOURCE trial	210 mg SC or placebo Q4W	Assess long-term safety and tolerability of tezepelumab over 104 weeks^Citation70
Phase 2 UPSTREAM NCT02698501 (independent)^a	Randomized, placebo-controlled, double-blind trial to evaluate AHR	Adults with uncontrolled asthma and AHR to inhaled mannitol despite any stable dose of ICS (40)	700 mg IV or placebo Q4W	Assess the effect of tezepelumab on airway hyperresponsiveness to mannitol at 12 weeks^Citation63
Phase 2 CASCADE NCT03688074	Randomized, placebo-controlled, double-blind trial to evaluate airway inflammation	Adults with inadequately controlled moderate-to-severe asthma on ICS and ≥1 additional asthma controller (116)	210 mg SC or placebo Q4W	Assess the effects of tezepelumab on change from baseline to week 28 in airway submucosal inflammatory cells^Citation56,Citation64
Phase 3 PATH-HOME NCT03968978	Randomized, open-label trial to evaluate at-home administration of an accessorized pre-filled syringe (APFS) and an autoinjector (AI)	Adults and adolescents with severe, uncontrolled asthma (216)	210 mg SC Q4W via APFS or AI	Assess proportion of successful administrations of tezepelumab by SC injection with an APFS or AI in the clinic and at home over 24 weeks^Citation72

Note: ^aExternally sponsored study.

Abbreviations: AHR, airway hyperresponsiveness; AI, autoinjector; APFS, accessorized prefilled syringe; ICS, inhaled corticosteroids; IV, intravenous; OCS, oral corticosteroids; Q2W, every 2 weeks; Q4W, every 4 weeks; SC, subcutaneous.

Figure 2 NAVIGATOR: Annualized Rate of Asthma Exacerbations at Week 52, According to Baseline Biomarker Status.

Note: Reproduced from The New England Journal of Medicine , Menzies-Gow A, Corren J, Bourdin A, et al, Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma, 384., 1800-1809. Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁴¹Abbreviations: AAER, annualized asthma exacerbation rate; CI, confidence interval; Eos, eosinophils; FEIA, fluorescence enzyme immunoassay; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; ppb, parts per billion; Q4W, every 4 weeks.

Figure 3 NAVIGATOR: Change from Baseline to Week 52 in Prebronchodilator FEV₁.

Note: Adapted from The New England Journal of Medicine, Menzies-Gow A, Corren J, Bourdin A, et al, Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma, 384., 1800-1809. Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁴¹

Abbreviation: FEV₁, forced expiratory volume in 1 second. I bars indicate 95% confidence intervals.

Table 2 Tezepelumab Effect on Patient-Reported Outcomes of Asthma Control and Patient Quality of Life

Number of Patients Evaluated LS Mean Change From Baseline (SE) LS Mean Difference From Placebo (95% CI)	Placebo	Tezepelumab 210 mg SC Q4W	p value
ACQ-6 score^a,b
At week 52 in PATHWAY^Citation39	53 −0.91 –	44 –1.20 −0.29 (−0.56, −0.01)	0.039 nominal
At week 52 in NAVIGATOR^Citation41	531 −1.22 (0.05) –	528 −1.55 (0.055) -0.33 (−0.46, −0.20)	< 0.001
At EoT in CASCADE^c,^Citation56	56 −0.66 (0.88)	54 −1.10 (0.91)	N/A
At week 48 in SOURCE^Citation51	68 −0.51 (0.12)	66 −0.87 (0.13) −0.37 (−0.71, −0.02)	N/A
AQLQ(S)+12 score^b,d
At week 52 in PATHWAY^Citation39	47 0.97	41 1.17 0.20 (−0.09, 0.48)	0.185 nominal
At week 52 in NAVIGATOR^Citation41	529 1.15 (0.049)	527 1.49 (0.048) 0.34 (0.20, 0.47)	< 0.001
At week 48 in SOURCE^Citation51	67 0.58 (0.12)	66 0.94 (0.12) 0.36 (0.01, 0.70)	N/A
ASD score^e
At week 52 in NAVIGATOR^Citation41	531 –0.59 (0.03)	528 –0.71 (0.03) −0.12 (−0.19, −0.04)	0.002
At week 48 in SOURCE^Citation51	68 −0.26 (0.07)	58 −0.36 (0.07) −0.10 (−0.29, 0.09)	N/A
SGRQ score^f,g
At week 52 in NAVIGATOR^Citation41	376 −15.86 (0.97)	389 −21.91 (0.96) −6.05 (−8.74, −3.37)	N/A
EQ-5D-5L score^h
At week 52 in NAVIGATOR^Citation41	435 11.86 (0.71)	448 14.64 (0.71) 2.78 (0.81, 4.75)	N/A

Notes: ^aACQ-6 scores range from 0 to 6, with lower scores indicating better disease control; ^bMCID is 0.5 points;^{42,73 c}Mean change from baseline (SD); ^dAQLQ(S)+12 scores range from 1 to 7, with higher scores indicating better asthma-related quality of life; ^eASD scores range from 5 to 40, with higher scores indicating more severe and frequent symptoms; ^fSGRQ (St George’s Respiratory Questionnaire) scores range from 0 to 100, with higher scores indicating more limitations; ^gMCID is 4 points;^{59 h}EQ-5D-5L is calculated on a scale of 1 to 5 in 5 dimensions, with higher scores indicating worse health.

Abbreviations: ACQ-6, Asthma Control Questionnaire-6 items; AQLQ(S)+ 12, Asthma Quality of Life Questionnaire standardized for patients 12 years or older; ASD, Asthma Symptom Diary; CI, confidence interval; EoT, end of treatment; EQ-5D-5L, 5-dimension 5-level EuroQoL questionnaire; LS, least squares; MCID minimal clinically important difference; N/A not available; SD, standard deviation; SE, standard error; SGRQ, St. George’s Respiratory Questionnaire.

Table 3 Summary of Adverse Events

	NAVIGATOR^Citation41  Phase 3		PATHWAY^Citation39  Phase 2
	Tezepelumab N=528	Placebo N=531	Tezepelumab^a N=137	Placebo N=138
Patients^b with any AE, n (%)	407 (77)	429 (81)	90 (66)	91 (66)
Patients^b with any serious AE, n (%)	52 (10)	73 (14)	13 (10)	18 (13)
Deaths, n (%)	0	2 (0.4)	0	0
Patients^b with AE leading to discontinuation, n (%)	11 (2)	19 (4)	2 (2)	1 (1)
Patients reporting TEAEs,^b n (%)
AEs of any grade in ≥5% of patients in either treatment group
Asthma	27 (5)	59 (11)	27 (20)	50 (36)
Nasopharyngitis	113 (21)	114 (22)	19 (14)	16 (12)
Upper respiratory tract infection	59 (11)	87 (16)	0	0
Headache	43 (8)	45 (9)	11 (8)	6 (4)
Bronchitis	25 (5)	33 (6)	5 (4)	7 (5)

Notes: ^aTezepelumab dose 210 mg SC Q4W; ^bPatients were counted once for each category regardless of the number of events.

Abbreviations: AE, adverse event; Q4W, every 4 weeks; SC, subcutaneous; TEAEs, treatment-emergent adverse events.

Figure 4 Summary Figure: Tezepelumab Demonstrated Efficacy in a Range of Outcomes Across a Broad Population of Patients.^{39,41,53 a}PATHWAY included three tezepelumab doses; data from the 210-mg dose only are presented; ^bNominal p value; ^cScore difference meets criteria for minimal clinically important difference. ^nsp ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001 compared with placebo group.

Abbreviations: AAER, annualized asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire-6; AQLQ(S)+12, Asthma Quality of Life Questionnaire standardized for patients 12 years or older; BD, bronchodilator; eos, eosinophils; FEV_1, forced expiratory volume in 1 second; NA, not applicable; Q4W, every 4 weeks.

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