Studies have found Tremfya has sustained therapeutic benefits.
Research suggests fully human molecular structure of guselkumab explains long term retention rate and sustained therapeutic benefit.
The introduction of biologics, in particular interleukin-23 inhibitors, has transformed the treatment landscape for patients with psoriasis, offering more effective and safer therapeutic options with the benefits of long-term disease control and improved quality of life.
Tremfya (guselkumab) is the only fully human monoclonal antibody that targets IL-23, a cytokine involved in the pathogenesis of autoimmune diseases such as psoriasis.
The fully human molecular structure contributes to its low potential for inducing neutralising antibodies (NABs) in patients.
Studies evaluating the long-term efficacy and safety of Tremfya have shown sustained therapeutic benefits over extended treatment periods of up to five years. The lack of clinical impact of ADAs reinforces the drug’s favourable immunogenicity profile and its ability to maintain efficacy without significant interference from neutralising antibodies.
Canberra-based consultant dermatologist Dr Diana Rubel said that while ADAs were rarely measured in clinical practice it was interesting to see that guselkumab, over the course of four or five years of data collection, had been shown to produce very low levels of ADAs.
“That’s good, and it probably does correlate with a good long term retention rate that people need on the drug,” she said.
“If someone’s not doing particularly well with an agent, it could be anti-drug antibody, or it could be just a poor phenotypic fit.
“We’re probably going to discover in the next few years that some genes will help us to recognise which particular people respond better to certain drugs, whether it’s an anti-drug antibody, or some other mechanism, such as metabolism of the drug.”
Dr Rubel said she believed it was likely that ADAs would play more of a role in the secondary failure of a drug – that is where they have responded and then six to 12 months later, they lose that response. She said it was unlikely to be the case in primary failure, where patients get no response from the outset.
Research suggests that ADAs, even when they happen, don’t have a major impact on the efficacy of guselkumab.
‘SUPERIOR EFFICACY’
In a letter to the editor published in the Journal of the European Academy of Dermatology and Venereology, researchers examined the long-term data from Phase 3 trials such as VOYAGE-1 and VOYAGE-2, which they say provide valuable insights into the presence and clinical impact of ADAs to guselkumab over extended treatment durations.
“In VOYAGE-1 and VOYAGE-2, guselkumab demonstrated superior efficacy to placebo and adalimumab with a favourable safety profile in adults with moderate-to-severe plaque psoriasis,” the authors wrote.
In both studies, patients randomised to placebo or adalimumab switched to guselkumab by Week (W)76, at the latest, and continued receiving guselkumab through W252. Overall, 774 of the 837 patients in VOYAGE-1 and 947/992 in VOYAGE-2 received guselkumab.
Development of guselkumab ADA did not appear to impact clinical response, nor did titre levels. In both studies, ≥80% and ≥50% of patients achieved nearly clear skin (Psoriasis Area and Severity Index [PASI]90 or Investigator’s Global Assessment [IGA]0/1) and clear skin (PASI100 or IGA0), respectively, regardless of ADA status, the researchers said.
“The data presented here demonstrate that development of guselkumab ADA had no clinically relevant impact after up to five years of guselkumab exposure,” they wrote.
ADAs are formed when the immune system recognises the drug as a foreign substance and mounts an immune response against it. This can occur with various types of drugs, including biologics and small molecule drugs. ADAs can prevent the drug from binding to its target, or can accelerate its clearance from the body, which can lead to decreased therapeutic efficacy and treatment failure.
In addition, ADAs can contribute to adverse immune reactions and side effects, including inflammatory responses and hypersensitivity reactions.
WHY IS THE FULLY HUMAN MOLECULAR STRUCTURE OF TREMFYA IMPORTANT?
The monoclonal antibody is derived entirely from human genetic sequences, which creates a molecular structure that minimises the risk of immunogenicity and the development of neutralising antibodies in patients. Unlike other monoclonal antibody formats that contained humanised elements, fully human antibodies are less likely to be recognised as foreign by the immune system, resulting in improved tolerability and sustained efficacy.
HOW DOES IT WORK?
Tremfya targets the Interleukin-23 (IL-23) pathway, a key cytokine involved in the pathogenesis of psoriasis, and promotes the differentiation and activation of Th17 cells, which are implicated in the inflammatory processes underlying psoriasis. By inhibiting the IL-23 pathway, the drug suppresses the immune-mediated inflammation that drives the development and progression of psoriatic lesions.
In an article published in the Journal of the European Academy of Dermatology and Venereology in 2022, researchers found that while ADAs could form in psoriasis patients treated with IL-23 inhibitors, their clinical significance varies and may depend on factors such as antibody concentration and neutralising effects.
They found that the incidence of ADAs varied among different IL-23 inhibitors. For guselkumab, the incidence ranged from 4.1% to 14.7%; for risankizumab it was 14% to 31%; and for tildrakizumab it ranged from 6.51% to 18%.
Neutralising antibodies were also observed but at lower rates, for example the incidence ranged from 0.1% to 0.6% with guselkumab; 2.1% to 16% with Risankizumab; and 2.5% to 3.2% with tildrakizumab.
While the presence of ADAs alone did not seem to reduce the efficacy of psoriasis treatment, some studies reported a reduction in clinical response with high ADA titres or with the presence of neutralising antibodies. This suggested that the clinical impact of ADAs may depend on their concentration and whether they have neutralising effects, the researchers found.
“Our review demonstrates that ADAs alone do not have clinical relevance in terms of efficacy of any of the IL-23 inhibitors and there is no evidence at this time to alter treatment course based on their presence alone,” they concluded.
“However, further investigation will be valuable regarding the co-features of ADAs, such as the presence of neutralising antibodies or high titres, in evaluating clinical efficacy of IL-23 inhibitors.
“Testing for neutralising antibodies along with ADA titres may have greater clinical value in terms of guiding decision making. No serious safety concerns appear to be associated with ADA+ status, other than mild-to-moderate ISRs.”
References;
Immunogenicity and pharmacokinetics of guselkumab among patients with moderate to severe psoriasis in VOYAGE 1 and VOYAGE. J Eur Acad Dermatol Venereol. 2023;37:e1375–e1379
Norden A et al., Journal of the European Academy of Dermatology and Venereology 2022
This article was sponsored by Janssen-Cilag Pty Ltd. Please consult the full Tremfya® (guselkumab) Information, and also review the full Product Information for any other product mentioned in this review via the TGA website before prescribing.
