Even if Humira having a more than five-year market headstart, its standard of care status is not set in stone. However, challengers need to be weary of undercover competitors in the form of off-label biologics
Need to know:
- Analysts forecast that the global hidradenitis suppurativa market may garner sales of $763.6m in 2021, with a compound annual growth rate of 4.2% up to 2023
- Moderate-to-severe patients have varying efficacy milage with Humira, underscoring the need for more biologic options
- Candidates Cosentyx and bimekizumab are possible contenders with Phase III trials underway
- Remicade, which is not approved, might be the real success bar in this chronic skin disease. It is intravenously administered, allowing for flexible dosing to reach ideal efficacy
Despite AbbVie’s Humira being the only approved biologic in moderate-to-severe hidradenitis suppurativa (HS), it is not too late for other biologics still in the development pipeline to carve out market share in this chronic skin condition, experts said.
Humira was FDA approved in September 2015, and thus has a notable head start in the market. Novartis’ Phase III asset Cosentyx and UCB’s Phase III bimekizumab have a strong shot at matching Humira’s efficacy at the very least, thus offering more options to patients and catering to those who may want to switch from the only approved biologic, experts added.
Even InflaRx’s Phase III-ready IFX-1 (vilobelimab) could be a potential player due to encouraging Phase IIb efficacy data. However, vilobelimab has a much heavier load to prove its clinical worth as it failed in its Phase IIb primary endpoint HS clinical response (HiSCR), which is the FDA-supported endpoint used in Phase III trials, experts explained added.
The real competition for any of these and future contenders may not be Humira, but instead may be off-label biologics, particularly Johnson & Johnson’s Remicade. Remicade is intravenously (IV) administered, which allows for dosing flexibility for maximum efficacy. This advantage is unlikely to be replicated by fixed-dose injections Humira, Cosentyx, and bimekizumab. Vilobelimab is an IV biologic. The companies mentioned in this article did not respond to a comment request.
Not all benefit with Humira
Humira has room for improvement, because even if symptoms improve with the biologic, not all patients improve to a point where it may be considered clinically impactful, said Dr Jarad Levin, assistant professor of dermatology, University of Oklahoma, Oklahoma City. Patients who respond to Humira still have flares or suffer from lesions, even if the frequency of these flares has declined or lesions are physically further apart, Levin explained.
Approximately 50% of patients reach HiSCR-50 and about 20% of these may reach clear to almost clear with Humira, said Dr Wayne Gulliver, professor of dermatology, Memorial University of Newfoundland, St John’s, Canada. HiSCR is defined as at least a 50% reduction in total abscess and inflammatory nodule count, with no increase in abscess and draining fistula count.
Prolonged Humira use in some patients may lead to reduced efficacy over time, said Dr Jacek Szepietowski, head of the Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland. This is due to the patient developing antibodies against the biologic, added Dr Aude Nassif, dermatologist, Institut Pasteur, Paris, France. Antibiotics can be used to supplement biologic efficacy to target the bacterial element of the skin disease, she noted.
Six months to find out if Humira works
Physicians should prescribe Humira for a minimum of six months to see if patients experience any benefits, Gulliver said. If they do not reach the 50% improvement benchmark, then they cycle back through different antibiotic regimes or enter a clinical trial with a new therapy, he added. The inconsistent efficacy of Humira among patients underscores the need for additional approved biologics to cater for more patients, Szepietowski noted.
HS severity is graded according to the Hurley system, which divides patients into three different subgroups, with the third and final subgroup typically being prescribed biologics. However, clinicians are increasingly using biologics in more severe cases of Hurley stage II patients to prevent them from progressing to stage III, Levin said. Approximately 28% of all patients are Hurley stage II and 4% are stage III, Nassif noted. Analysts forecast the global HS market may garner sales of $763.6m in 2021, with a compound annual growth rate of 4.2% up to 2023.
Noninferiority with Humira realistic
Based on clinical trial data so far, Cosentyx and bimekizumab may at least match Humira’s efficacy, which may be enough for approval, Szepietowski said. In an open-label Cosentyx trial recruiting 20 patients, including six patients who had previously taken Humira, 14 (70%) achieved the HiSCR endpoint after 24 weeks (Casseres, R., et al.  Am Acad Dermatol, 82(6), pp. 1524–1526).
Meanwhile, in the Phase II bimekizumab trial (NCT03248531), 56.9% of 44 bimekizumab patients reached the HiSCR primary endpoint, compared with 59.8% of 20 Humira patients and 23.7% of 20 placebo patients, as detailed on the trial’s EU clinical trials registry listing (2017-000892-10).
Humira was approved based on data from two Phase III trials. In the first Phase III (NCT01468207) investigating Humira monotherapy recruiting 307 patients, the biologic reached 41.8% in the HiSCR endpoint at week 12, versus 26% with placebo (Kimball, A. B., et al.  N Engl J Med, 375(5), pp. 422–434). The second Phase III Humira trial, which showed a 58.9% treatment response rate versus 27.6% with placebo, allowed antibiotic use.
Higher bar needed to edge Humira
To clearly demonstrate superiority over Humira, any of the biologic challengers need to demonstrate 75% of patients reaching a 75% reduction in the total abscess and inflammatory module count of the HiSCR endpoint, Gulliver and Szepietowski said.
While Cosentyx and bimekizumab both target interleukin (IL)-17, bimekizumab may have an advantage as it targets both IL-17A and IL-17F, while Cosentyx only targets IL-17A, noted Dr Rita Pichardo, dermatologist, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
While bimekizumab is yet to be approved in any indication, experts did not flag any highly concerning side effects, which would have made it stand out from other biologics. Fellow anti-IL-17 Cosentyx does not have a boxed warning, while Humira does, flagging a risk of tuberculosis, bacterial sepsis, and invasive fungal infections, among others. Decisions on which of the three would be used would be a holistic decision between clinicians and patients, Szepietowski added.
The ClinicalTrials.gov listing of two Phase III Cosentyx trials in HS, SUNRISE (NCT03713632) and SUNSHINE (NCT03713619), were updated to “active, not recruiting” status this month. Bimekizumab’s Phase III trials BE HEARD I and II (NCT04242446, NCT04242498) are still enrolling patients.
Vilobelimab carries large burden
A third contender, vilobelimab, failed to reach its 16-week HiSCR primary endpoint in the Phase IIb SHINE trial (NCT03487276). The lowest dose of 800mg every four weeks delivered the best results, with a 51.5% response rate. However, a 47.1% response rate was reported with placebo administered every two weeks, as per a June 2019 media release.
While the Phase IIb failed, improvements have been seen in further analysis of the Phase IIb data, Gulliver and Szepietowski noted. Since then, InflaRx has subsequently released additional SHINE data showing vilobelimab can reduce draining fistulas and maintained response through to week 40, among others. These efficacy signals mean the next step might be finding the right HS subgroup that would benefit from the biologic, Szepietowski said.
Vilobelimab’s mechanism as an anticomplement C5a aims to downregulate HS’ inflammatory cascade, with experts noting Phase IIb data do not raise significant side effect issues. The most common treatment-emergent adverse events were HS exacerbation and nasopharyngitis.
However, the issue with targeting the complement system is how it is important in fighting infections, and HS has a bacterial element to its pathology, Nassif said. Downregulating the complement system may also reduce the ability of the immune system to combat HS-relevant bacteria, she explained. Vilobelimab’s Phase III trial design is still being finalised with the FDA.
Biologics to find niche
Nevertheless, if any of the aforementioned biologics are to be approved, they will likely find a subset of patients capable of responding, Gulliver said. It will be challenging to pinpoint the defining characteristics of these subgroups as some are rarer than others, Nassif added. There may be an overlap in symptoms between subgroups that can only be determined via mutation differences, she explained.
That said, if the patient needs to switch from an anti-IL-17 biologic to bolster efficacy, the switch would not be to another IL-17-targeting biologic but one with a different target altogether, Szepietowski noted.
Remicade covert challenger to Humira
For real-world relevance, the HS contenders may have to underscore their value against both Humira and off-label options. Humira’s approval opened the door to HS off-label use of Remicade, which also targets tumour necrosis factor (TNF)-alpha like Humira, said Levin and Pichardo.
While Remicade is administered via IV, it is an advantage to the biologic because the dose and its frequency can be easily adjusted until the desired effect is reached, Pichardo noted. This contrasts with Humira, which is a fixed-dose injection, Levin explained. Cosentyx and bimekizumab are also fixed-dose injections, while vilobelimab is an IV.
Even with Remicade’s advantages, Humira is still the first choice as it is approved, Pichardo said. However, if there is a signal of improvement and higher or more frequent dosing might be needed to garner better efficacy, then a case could be made to insurance providers, she added.
A patient’s weight and lifestyle factors such as smoking are among the reasons why a patient may have HS flares even with Humira, and thus a higher dose might be needed, she noted. Just like Humira, Remicade also has a boxed warning flagging similar, potentially serious side effects.
Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.