NDI-034858 (TAK-279) in moderate-to-severe plaque psoriasis: Results from a phase IIb trial

Tyrosine kinase 2 (TYK2) is a key component of the Janus kinase/signal transducer activator transcription (JAK/STAT) signaling pathway that regulates intracellular signaling of several cytokines, including interleukin-12/-23, as well as type I interferons, implicated in the pathophysiology of psoriasis.^1,2 Hence, selective TYK2 inhibition may be a promising therapeutic alternative in the treatment of psoriasis.^1,2

NDI-034858 (TAK-279) is a novel, investigational, oral, allosteric TYK2 inhibitor and is highly selective to TYK2 owing to a single amino acid difference from TYK2 that prevents it from binding to the allosteric pocket of JAK1.^1,2 Preliminary evidence of the effect of TAK‑279 on psoriasis has been demonstrated in a phase I trial.²

At the American Academy of Dermatology (AAD) Annual Meeting 2023, Armstrong¹ presented the efficacy and safety results of the phase IIb study (NCT04999839) of TAK-279 in patients with moderate-to-severe plaque psoriasis. Here, we summarize the key findings.

Study design¹

The phase IIb randomized, multicenter, double-blind, placebo-controlled study was designed to assess the efficacy, safety, and tolerability of TAK-279 in adult patients with moderate-to-severe plaque psoriasis. Patients were randomized (1:1:1:1:1 ratio) to receive one of four doses of TAK-279 (2 mg, 5 mg, 15 mg, or 30 mg once daily [QD]) or the placebo for 12 weeks. The detailed study design is illustrated in Figure 1.

BSA, body surface area; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment; QD, once daily.
*Adapted from Armstrong, et al.¹

Results¹

A total of 259 patients with moderate-to-severe plaque psoriasis were included in the study. The key baseline patient characteristics are shown in Table 1. Across the treatment arms, the mean age was between 45 years and 49 years and most patients (≥60%) were male.

Table 1. Demographics and baseline patient characteristics*

AA, African American; BSA, body surface area; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment; QD, once daily; SD, standard deviation. *Adapted from Armstrong, et al.1
Characteristic, mean (SD) (unless otherwise stated)	Placebo (n = 52)	TAK-279 2 mg QD (n = 50)	TAK-279 5 mg QD (n = 52)	TAK-279 15 mg QD (n = 53)	TAK-279 30 mg QD (n = 52)
Age, years	48.8 (12.7)	45.8 (14.2)	45.1 (13.6)	46.2 (13.0)	48.5 (11.4)
Male, %	59.6	76.0	78.8	64.2	63.5
White, %	84.6	86.0	76.9	86.8	80.8
Psoriasis duration, years	12.7 (10.5)	13.8 (10.8)	14.8 (10.7)	17.6 (14.6)	17.4 (11.1)
PASI score	18.3 (8.1)	18.4 (6.8)	18.6 (6.1)	15.5 (4.5)	17.6 (6.2)
PGA score	3.2 (0.4)	3.4 (0.5)	3.3 (0.5)	3.2 (0.4)	3.2 (0.4)
BSA	21.3 (13.6)	24.9 (15.5)	22.6 (12.1)	18.3 (10.3)	22.2 (14.3)
DLQI	12.4 (7.0)	10.3 (6.2)	12.8 (7.5)	11.9 (7.1)	12.5 (6.9)
Bioexperienced, %	8 (15.4)	8 (16.0)	15.4	17.0	15.4

Efficacy

The primary endpoint was met, with a significantly greater proportion of patients treated with ≥5 mg TAK-279 achieving PASI 75 versus placebo at Week 12 (Figure 2).

A significantly greater proportion of patients receiving ≥5 mg TAK-279 achieved PASI 90, PASI 100, and PGA 0/1 (almost clear skin) versus placebo. In the TAK-279 30 mg QD arm, ~33% of the patients scored PGA 0, indicating totally clear skin. There were no statistically significant differences in PASI 75, PASI 100, or PGA response rates in the TAK-279 2 mg arm compared with placebo (Figure 2).

NRI, non-responder imputation; PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment; QD, once daily.
*Adapted from Armstrong, et al.^1
†p < 0.001.
^‡p < 0.005.
^§p < 0.05.

Safety

The frequency of adverse events (AEs) was 53–62% in the treatment arms and 44% in the placebo arm (Figure 3A). Two serious AEs occurred in one patient on TAK-279 15 mg and were considered unrelated to the treatment (Figure 3B). The most common treatment-emergent AEs (TEAEs) were COVID-19, acne, acneiform dermatitis, and diarrhea. Few patients with TEAEs (1–2 per treatment group) discontinued the treatment. No deaths were reported.

AE, adverse event; QD, once daily; SAE, serious AE.
*Adapted from Armstrong, et al.^1
†AEs reported by ≥3 patients in any treatment group (events elicited by laboratory testing are not included).

The laboratory parameter changes were consistent with TYK2 inhibition. There were no adverse trends for hematologic (cell counts or creatine phosphokinase levels), hepatic and renal (liver enzymes, creatinine, or estimated glomerular filtration rate), or lipid parameters (cholesterol, high-density lipoprotein, or low-density lipoprotein levels).

Conclusion

The study achieved its primary and secondary endpoints, with a significantly greater proportion of patients receiving TAK-279 achieving PASI 75, 90, and 100 and PGA 0/1 at ≥5 mg dose groups compared with placebo at 12 weeks. The phase IIb findings support further larger studies of TAK-279 in psoriasis.