Tildrakizumab-asmn (Ilumya) is a recombinant humanized IgG1Κ monoclonal antibody that inhibits the interleukin-23 (IL-23) receptor that specifically binds to the p19 subunit of IL-23, thereby blocking the release of proinflammatory cytokines and chemokines during the inflammatory response.
Psoriasis is a chronic, immune-related disease of the skin that primarily affects adults. Plaque psoriasis is the most common form, characterized by scaling and inflammation. Individuals diagnosed with psoriasis may experience pain and itching, restricted range of motion in their joints, and emotional distress. The course of psoriasis is marked by chronic and acute phases with a wide variety in relapse and clearance rates. Disease severity and clinical response to biologics may be measured with either the Psoriasis Area and Severity Index (PASI) or the Physician Global Assessment (PGA) scale.
The treatment of psoriasis consists of controlling inflammation and preventing discomfort through methods such as light therapy, stress reduction, and medications that suppress the immune response (e.g., topical corticosteroids or nonsteroidals, oral methotrexate, retinoids, cyclosporine).
Tildrakizumab-asmn is a biologic treatment for adults with moderate-to-severe plaque psoriasis. Tildrakizumab binds specifically to IL-23p19 and binds to IL-23 molecules and prevents its interaction with the IL-23R, blocking the downstream signaling cascade. IL-23 is a naturally occurring cytokine known to be involved with multiple inflammatory pathways. This block initiates a downstream signaling cascade to induce a transcription of the inflammatory cytokines, IL-17. IL-17 activates inflammatory pathways associated with psoriasis.
PEER-REVIEWED LITERATURE
Summary
On March 20, 2018, based on results from two three-part, phase 3, randomized, placebo-controlled studies, the US Food and Drug Administration (FDA) approved tildrakizumab-asmn in the treatment of adult individuals with moderate-to severe plaque psoriasis.
ReSURFACE 1 randomly assigned 772 participants in a 2:2:1 ratio to either receive tildrakizumab 200 mg (n=308), tildrakizumab 100 mg (n=309), or placebo (n=155). The three-part series comprised two treatment assignments with re-randomization after the initial 12 weeks. The participants were re-randomized in part 2; those in the placebo group were re-randomized (1:1) to either tildrakizumab 200 mg or tildrakizumab 100 mg. Participants were then re-randomized across the dosing regimens. In part 3 of both studies (week 28), responders (PASI ≥75) and partial responders (PASI ≥50 and PASI <75) to tildrakizumab 200 mg and 100 mg were re-randomized to continue the same treatment, a different dose of tildrakizumab, or placebo. Results from reSURFACE 1 indicate that at week 12, 192 patients (62%) in the 200-mg group and 197 patients (64%) in the 100-mg group achieved PASI 75, compared with nine patients (6%) in the placebo group (P<0.0001).
In reSURFACE 2, 1039 participants were assigned to four arms in a 2:2:1:2 ratio. The comparison groups were tildrakizumab 200 mg (n=314), tildrakizumab 100 mg (n=307), placebo (n=156), or etanercept (n=313). Similarly, participants were re-randomized at week 12, and again at week 28, subjects were re-randomized based on their PASI response status (<50% improvement or partial response ≥50 <75%). All responsive participants were followed until week 52. The individuals treated with etanercept were converted into one of the tildrakizumab treatment groups and treated at weeks 28, 32, 36, and 48.
The researchers reported that the two co-primary endpoints evaluated in the trial were the proportion of participants achieving PASI 75 and a PGA response. In reSURFACE 2, results at week 12 demonstrated 206 participants (66%) in the 200-mg group, and 188 participants (61%) in the 100-mg group achieved PASI 75, compared with nine individuals (6%) in the placebo group and 151 of those (48%) in the etanercept group (P<0.0001 for comparisons of both tildrakizumab groups vs. placebo; P<0.0001 for 200 mg vs. etanercept and P=0.0010 for 100 mg vs. etanercept).&& Researchers reported on PGA response: 186 participants (59%) in the 200-mg group and 168 participants (55%) in the 100-mg group achieved a PGA response, compared with seven individuals (4%) in the placebo group and 149 of those (48%) in the etanercept arm (P<0.0001 for comparisons of both tildrakizumab groups vs. placebo; P=0.0031 for 200 mg vs. etanercept and P=0.0663 for 100 mg vs. etanercept). Results demonstrated statistical significance across all comparisons excluding 100 mg versus etanercept.
Tildrakizumab 200-mg and 100-mg doses were given at baseline and week 4 and subsequently every 12 weeks. In reSURFACE 1, participants were given tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo subcutaneously at baseline and week 4. In part 2, tildrakizumab patients received another dose at week 16; re-randomized placebo patients received either tildrakizumab 200- or 100-mg at weeks 12 and 16. In reSURFACE 2, participants received tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (etanercept 50 mg was given twice a week). In part 2, tildrakizumab patients received their doses at week 16. Etanercept patients received one dose weekly; re-randomized placebo patients received tildrakizumab 200 mg or 100 mg (at weeks 12 and 16). In part 3 of both studies, participants received doses of tildrakizumab or placebo until week 64 (reSURFACE 1) or week 52 (reSURFACE 2).
The studies indicate that tildrakizumab significantly improved the proportion of individuals achieving PASI 75 response and a PGA score of clear or minimal compared with placebo in two randomized studies at week 12 (P<0.0001). In one of the two randomized studies, a significantly greater proportion of participants achieved PASI 75 with tildrakizumab compared with etanercept, but there was no significant difference between the tildrakizumab 100-mg dose and etanercept for PGA score of clear or minimal. The median time to loss of PASI 75 response after treatment withdrawal was 20 weeks and loss of PGA score of clear or minimal response was 16 weeks. In both studies, results for PASI 75 and PGA for both doses of tildrakizumab continued to improve to week 28. A higher proportion of participants who received either dose of tildrakizumab compared to participants who received placebo achieved the more rigorous endpoints of PASI 90 (minimal) and PASI 100 (clear) in reSURFACE 1 and reSURFACE 2 at week 12.
Based on results from two studies, tildrakizumab‑asmn (Ilumya) is approved for subcutaneous dosing in adults at 100 mg at weeks 0 and 4, then every 12 weeks.
Psoriasis of the Nail
The safety and efficacy of tildrakizumab-asmn (Ilumya) was studied in a phase 3b, randomized, multicenter, double-blind, placebo-controlled trial of adults with moderate-to-severe psoriasis of the nail (NCT03897075). Participants were considered candidates for systemic therapy, since they were inadequately controlled by topical treatments (corticosteroids), and/or phototherapy, and/or previous systemic therapy. Participants were treated with tildrakizumab 100 mg (n=51) or placebo (n=48) at Weeks 0 and 4 and 16. At baseline, these subjects had a median Modified Nail Psoriasis Severity Index (mNAPSI) score of 34 and a median PASI score of 16. The primary endpoint resulted in a larger proportion of participants who achieved at least a 75% improvement from baseline in total mNAPSI at Week 28. At Week 28, 26% (13/51) of subjects who received tildrakizumab-asmn (Ilumya) achieved at least a 75% improvement from baseline (mNAPSI score) compared with 4% (2/48) of subjects who received placebo.
Psoriasis of the Scalp
The safety and efficacy of tildrakizumab-asmn (Ilumya) was studied in a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of individuals with moderate-to-severe psoriasis of the scalp. Participants were treated with tildrakizumab 100 mg (n=117) or placebo (n=114) at Weeks 0 and 4 and every 12 weeks thereafter; for Weeks 16 to 52, participants who were randomly assigned to placebo were switched to tildrakizumab 100 mg at Weeks 16, 20, 32, and 44. At baseline, these subjects had a median affected scalp surface area (SSA) of 50%, a median PASI score of 16.7, and PGA score of 3 (“moderate”) or 4 (“severe”) in 87.1% and 12.3%, respectively. The primary endpoint resulted in a larger proportion of participants treated with tildrakizumab (49%, n=44) with Investigator Global Assessment (IGA) score for the scalp of “clear” and “almost clear” with at least two-point reduction from baseline at Week 16, compared to placebo (7%, n=6).
SAFETY
Tildrakizumab-asmn (Ilumya) should be interrupted if an individual develops a serious infection or an opportunistic infection or sepsis, until the infection resolves or is adequately controlled. Other safety concerns that require monitoring during tildrakizumab-asmn (Ilumya) therapy are individuals with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients. Avoid the use of live vaccines in patients treated with tildrakizumab.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
