At the 2018 Annual American Academy of Dermatology (AAD) conference in sunny San Diego, many exciting developments were presented at the late-breaking clinical trials session, with topics ranging from atopic dermatitis to psoriasis. Of particular interest is the long-term efficacy results update from the VOYAGE 2 trial (NCT02207244, Accessed July 12, 2018) of guselkumab, which included a treatment arm where active therapy was withdrawn at 28 weeks. Results from this study demonstrated long-term sustained efficacy of Tremfya (Janssen) in moderate to severe psoriasis patients, both in patients who were maintained on Tremfya and in some patients who withdrew from active treatment after week 28. These results suggest that as a treatment with proven efficacy sustained over time—an attribute which was ascribed as the most important efficacy attribute by dermatologists recently surveyed by Decision Resources Group—Tremfya may be in a position to at least partially address current needs in the psoriasis market (Psoriasis | Unmet Need | US/EU, published in March 2018). The DRG US/EU Unmet Need report discusses sustained efficacy as an identified opportunity in the psoriasis market and also uses a conjoint analysis of target product profiles (TPPs) to ask whether sustained efficacy can command a premium on drug price.
Long-term efficacy: an unmet need in psoriasis
Psoriasis is a chronic inflammatory skin disease in which hyperactive T-cells trigger excessive keratinocyte proliferation. There are an estimated 16.2 million diagnosed prevalent cases of psoriasis in the major pharmaceutical markets in 2018 (Psoriasis | Epidemiology | G7, published in November 2017), and, like other inflammatory diseases such as rheumatoid arthritis and psoriatic arthritis, treatment-free remission—a cure—is not yet available for psoriasis. While topical therapies, including corticosteroids and vitamin D3 analogues, are commonly used to treat patients with mild disease, the often highly efficacious biological agents are typically given to moderate to severe patients after conventional systemic agents have been tried. Depending on the biologic used, patients may undergo 1) primary failure, in which the disease does not respond to the biologic, or 2) secondary failure, in which the patient’s disease slowly loses response to the biologic despite responding to it initially. In either case, the patient typically has to switch to an alternative therapy to maintain disease remission. Thus, it is not surprising that a therapy’s ability to offer long-term efficacy is a top concern for physicians.
Evidence of drug-free efficacy from VOYAGE 2 results
During the 2018 AAD conference late-breaking clinical trials session, Professor Kristian Reich (Dermatologikum Berlin and SCIderm Research Institute in Hamburg, Germany) presented the VOYAGE 2 study results on long-term efficacy of Tremfya, Janssen’s first-in-class IL-23 inhibitor. The featured analysis focused on patients who achieved a Psoriasis Area Severity Index (PASI) 90 response at week 28 of Tremfya treatment, who were then re-randomized to receive either placebo or continue treatment with Tremfya. Among patients who were maintained on Tremfya, 88.6% and 86.0% continued to achieve PASI 90 response at week 48 and week 72, compared to 36.8% and 11.5% of the patients in the placebo arm, respectively (Reich, 2017). While not directly comparable, this result appears to be an improvement over 1) the gold standard of care, AbbVie’s Humira; of patients who maintained PASI 75 at week 33 while treated with Humira, 79% sustained a PASI 75 response at week 52 (Gordon K, 2012), and 2) the recent Novartis’s first-in-class IL-17 inhibitor Cosentyx; of the CLEAR study patients who maintained PASI 75 at week 12 on Cosentyx, 80.5 % were able to maintain this PASI 75 into week 52 (Langley R, 2014). Thus, Tremfya continues a trend in the development of psoriasis drugs toward offering longer-term duration of efficacy.
However, the VOYAGE 2 update also provided a very interesting additional outcome with over one-third (36.8%) of the patients in the placebo arm maintaining PASI 90 response from week 28 to week 48. A more detailed examination revealed that the maintenance of PASI 90 response after drug withdrawal (placebo arm) was associated with the continued suppression of IL-17A, IL-17F, and IL-22, maintaining levels of these pro-inflammatory cytokines comparable with the levels seen in healthy patients. In response to a question from the audience about whether drug availability may merely be greater in the patients who experienced sustained efficacy, Dr. Reich responded that he did not believe drug availability explained the observed effect, a stance supported by another panel member, who pointed out other instances from their personal experience when patients maintained remission to a time point long after these patient would be likely to have any therapeutically concentration of drug remaining in their body. Since results from VOYAGE 2 show a median time to relapse of 15.2 weeks, and Tremfya has a mean half-life of approximately 15 to 18 days (Drug prescribing information, Tremfya), it is extremely likely that Tremfya-treated patients are showing sustained efficacy even though the drug level is either very low or no longer in the blood stream. This observation prompted Dr. Reich to raise the question whether Tremfya could be modifying the course of the disease.
At the discovery frontier of psoriasis treatment
The observation of possible drug-free efficacy is not limited to only Tremfya, an IL-23 inhibitor. Just over a year ago, in March 2017, it was observed that the first-in-class IL-17 inhibitor Cosentyx could maintain efficacy after drug withdrawal. In the A2302E1 study—an extension study of two Phase III trials, the ERASURE study (NCT01365455, Accessed July 12, 2018) and the FIXTURE study (NCT01358578, Accessed July 12, 2018)—patients who achieved PASI 75 after one year of Cosentyx treatment were assigned to a 300 mg or 150 mg Cosentyx arm or placebo arm. Following one additional year, it was found that just over one in five (21%) patients in the placebo arm maintained PASI 75 (Novartis press release, March 21, 2017). Similarly, Eli Lily’s second-in-class IL-17 inhibitor Taltz’s Uncover-1 and Uncover-2 studies (NCT01474512 and NCT01597245, respectively, Accessed July 12, 2018) showed that, of the patients who achieved PASI 75 at week 12 of Taltz treatment (biweekly dose), 9% maintained PASI 75 well into week 60 when randomized to the placebo arm (Kenneth B, 2016). While the data are not comparable, the drug-free efficacy results from the Tremfya, Consentyx, and Taltz studies point toward a promising trend in prolonging sustained, drug-free efficacy. To put the drug withdrawal efficacy results of Tremfya, Cosentyx, and Taltz in context, of the patients who achieved at least PASI 75 response or more at week 12 of Humira treatment, 0 % maintained this response by week 52 while being continuously treated with Humira (AbbVie M02-538 Clinical Study Report).
Based on the results from the A2302E1 study of Cosentyx, the hypothesis that Cosentyx can modify disease is being further examined via the STEPin study (NCT03020199, Accessed July 12, 2018). The STEPin study is a Novartis-sponsored Phase IV trial conducted to assess if treating new-onset moderate to severe psoriasis patients leads to a prolonged disease-free period and to look at efficacy after drug withdrawal in patients who achieved PASI 75 after being treated with Cosentyx for one year. This study design is likely influenced by investigations in other inflammatory diseases, i.e., rheumatoid arthritis and Crohn’s disease, in which aggressive intervention earlier during the disease resulted in high levels of efficacy, with improved long-term patient outcomes (Girolimoni G, 2015).
If the STEPin trial can successfully show that Cosentyx is a disease modifying agent—where drug-free sustained efficacy can be prolonged when psoriasis is treated early—consideration for Cosentyx as first line for treatment-naïve patient will likely accelerate and adds to Cosentyx’s already growing penetration in the U.S. psoriasis market into earlier lines of therapy (Psoriasis | Treatment Algorithms | Claims Data Analysis | US | 2018). As such, one can imagine developers of Tremfya and Taltz are keeping their eyes on the outcome of the STEPin trial and may even assess these drugs for the same patient population following STEPin trial’s positive results, if not before. It may be too soon to translate the prolonged drug free efficacy into treatment interruption—so-called drug holidays—since it is established that disrupting treatment schedule will likely lead to loss of long-term response (Kenneth B, 2016, Novartis press release, March 21, 2017, AbbVie M02-538 Clinical Study Report). However, prolonged drug-free efficacy of the new generation psoriasis drugs like Cosentyx, Taltz, and Tremfya does have immediate added benefits. There will be circumstances when it is necessary to halt a treatment, such as major surgery, pregnancy, live virus vaccination, serious infection, or an adverse event with unknown cause; in these cases, retreatment of the relapsed patients with the aforementioned drugs can likely recapture the high rate of initial efficacy in most, albeit not all, of the relapsed patients. In the end, it may take future efforts in addition to drug development, exemplified by a clinical study such as the STEPin trial, to try to identify different ways to treat psoriasis in order to prolong the drug holiday and the efficacy for the same.
AbbVie M02-538 Clinical Study Report, January 5, 2006: https://www.abbvie.com/content/dam/abbvie-dotcom/clinical-trials/adalimumab_M02-538.pdf
Blauvelt A, et al. Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis. J Eur Acad Dermatol Venereol. 2017 Jun; 31(6): 1004–1013.
Drug prescribing information.
- Cosentyx: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/cosentyx.pdf
- Taltz: http://uspl.lilly.com/taltz/taltz.html#section-13.1
Girolimoni G, et al. Early intervention in psoriasis and immune-mediated inflammatory diseases: A hypothesis paper. J Dermatolog Treat. 2015 Apr;26(2):103-12.
Gordon K, et al. Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open-label extension study for patients from REVEAL. J Am Acad Dermatol. 2012 Feb;66(2):241-51.
Kenneth B, et al. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. N Engl J Med. 2016 Jul; 375:345-356.
Langley R, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38.
Novartis press release, March 21, 2017: https://www.novartis.com/news/media-releases/novartis-cosentyx-first-and-only-il-17a-inhibitor-potentially-modify-course
Reich K, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator–controlled VOYAGE 2 trial. Journal of the American Academy of Dermatology, Volume 76, Issue 6, June 2017, Pages 1226.
Sofen H, et al. Guselkumab (an IL-23–specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. Journal of Allergy and Clinical Immunology, The, 2014-04-01, Volume 133, Issue 4, Pages 1032-1040.