"Rapid symptom relief"…'Rhapsido' a new treatment option for CSU

Number of patients show non-responsiveness to antihistamines…unmet medical needs remain

Demonstrated to be effective from week 1 of receiving treatment…reflected in the global guideline

"Chronic spontaneous urticaria (CSU) is not simply a dermatological condition. A significant number of patients remains inadequately controlled with existing treatments. There is a significant medical need for novel therapeutic options." 

During a recent joint interview with DailyPharm, Dr. Sarbjit Saini, a professor of the Division of Allergy & Clinical Immunology at Johns Hopkins University School of Medicine, and Dr. Jeong-Hee Choi, a professor of the Department of Pulmonology and Allergy at Hallym University Dongtan Sacred Heart Hospital evaluated the unmet medical needs in CSU and the strategic significance of emerging treatments.  

The therapeutic landscape for CSU is undergoing a new shift. Patients remain highly symptomatic despite standard antihistamine treatments. Therefore, attention is drawn to domestic approval of Novartis’s Rhapsido (remibrutinib), the first oral Bruton’s tyrosine kinase (BTK) inhibitor indicated for this patient population. This drug has been demonstrated to provide rapid symptom relief.

CSU is a chronic inflammatory skin disease characterized by recurrent wheals and angioedema persisting for six weeks or longer without specific triggers. Although urticaria is commonly dismissed as a transient allergic reaction, CSU is differentiated from typical acute urticaria by its long-term recurrence and highly unpredictable patterns of exacerbation and remission.

The overall disease burden carried by patients is substantial. Recurrent pruritus and wheals frequently lead to sleep disorders and fatigue, and when accompanied by facial or lip edema, significantly compromise interpersonal relationships and social activities. The persistent anxiety surrounding sudden symptom exacerbation serves to restrict patients' daily routines. In real-world clinical practice, patients routinely complain of itching, sleep deprivation, impaired concentration, and diminished work efficiency; however, the disease itself still tends to be misperceived as a basic skin condition.

Dr. Sarbjit Saini, a professor of the Division of Allergy & Clinical Immunology at Johns Hopkins University School of Medicine, and Dr. Jeong-Hee Choi, a professor of the Department of Pulmonology and Allergy at Hallym University Dongtan Sacred Heart Hospital 

Current CSU management utilizing standard second-generation antihistamines serves as the first-line therapy, with additional interventions, such as dose escalation or the introduction of biologic agents, considered if symptom control remains insufficient. Nevertheless, more than half of the patient is reported to experience inadequate symptom control despite undergoing antihistamine therapy.

For patients who continue to present with pruritus and wheals following antihistamine dose escalation, available therapeutic options are highly restricted. Although clinical guidelines recommend a staged escalation of treatment, real-world execution is frequently hindered by a combination of low disease awareness, limited treatment access, financial constraints, and the logistical burden of frequent hospital visits.

Certain patients rely on short-term pharmacological interventions during acute flares or repeatedly cycle through treatments with heavy long-term burdens, such as systemic corticosteroids. However, medical experts point out that because CSU requires chronic management, a purely reactive approach focused on mitigating acute exacerbations is insufficient to adequately alleviate the cumulative disease burden.

Under these circumstances, Rhapsido is being evaluated as an option capable of introducing new dynamics to the established treatment paradigm. As the inaugural oral BTK inhibitor indicated for CSU, Rhapsido selectively inhibits BTK, an enzyme involved in the upstream activation pathways of mast cells and basophils, a mechanism designed to directly block the secretion of histamine and secondary co-inflammatory mediators.

While conventional antihistamines operate by blocking already secreted histamine from binding to its receptors, Rhapsido works by modulating the upstream signaling pathways of the histamine release cascade. This targeted therapeutic approach is drawing considerable interest, particularly for addressing the complex autoallergic and autoimmune pathways concurrently involved in CSU.

Dosing convenience represents another key differentiator. Administered as a twice-daily oral medication, Rhapsido offers a novel alternative for patients who feel burdened by injectable therapies like 'Xolair (omalizumab)' or face difficulties accommodating regular hospital visits. Given that the CSU patients features a high proportion of young, socially active individuals, the arrival of an oral targeted option carries substantial clinical weight.

In clinical trials, Rhapsido demonstrated rapid improvement of symptoms. In the REMIX-1 and REMIX-2 studies, Rhapsido demonstrated measurable improvements in pruritus and wheals starting from week 1 of administration, and significantly improved the weekly Urticaria Activity Score (UAS7) compared to placebo at week 12. In certain patients, a complete resolution of both itching and hives was documented alongside overall disease control.

Recently updated international urticaria guidelines establish complete symptom control as the ultimate therapeutic objective, integrating Rhapsido as a validated targeted option to be considered following antihistamine therapy. This global regulatory momentum is anticipated to influence domestic clinical guidelines during future revision processes.

However, industry specialists note that maximizing real-world clinical utility will require the accumulation of additional prescriptive experience and the securing of treatment access. As a therapeutic agent featuring a novel mechanism of action, the process of collecting localized user experiences and long-term safety data within domestic cohorts remains vital, with pricing pressures and reimbursement status serving as core variables dictating patient access.

Both experts assessed that "Rhapsido is an orally accessible, novel targeted therapeutic option that offers a meaningful alternative for patients who remain uncontrolled on conventional regimens," and added, "As real-world treatment experience and clinical evidence accumulate, we anticipate significant realignments in established CSU management strategies."

Q. What specific clinical and daily challenges have been experienced by CSU patients whose symptoms were difficult to control using existing treatments alone?

Dr. Sarbjit Saini, a professor of the Division of Allergy & Clinical Immunology at Johns Hopkins University School of Medicine

[Dr. Saini] The single greatest challenge is that symptom onset and acute flares manifest in a highly unpredictable manner.

Even when baseline disease activity has decreased, a sudden, severe exacerbation of angioedema causing facial and lip swelling can induce immense panic in patients, driving an immediate demand for medical intervention. Ultimately, this creates deep anxiety that stems from the perception of being unable to self-manage the disease.

Although antihistamines are used to regulate the symptoms and overall severity of CSU patients, the practical therapeutic efficacy that could be expected has faced clear limitations.

For individuals experiencing persistent, inadequate symptom control, clinicians have ultimately had to rely on interventions like systemic corticosteroids. However, while corticosteroids deliver rapid short-term efficacy, their well-documented adverse event profile makes them a highly unfavorable maintenance option. Consequently, prior to the recent emergence of these novel therapies, the available treatment choices were exceptionally limited.

[Dr. Choi] Non-responsiveness to high-dose antihistamines has been reported in as few as 20% to as many as 50% of patients, while approximately 20% remain refractory to Xolair. In the past, various immunomodulators, including antimalarials, were attempted, and the subsequent introduction of the biologic agent Xolair established a safer and more effective therapeutic alternative. However, Xolair still carries the logistical burden of requiring patients to visit the clinic once a month for injections.

Above all, the intense pruritus associated with CSU is an exceptionally difficult symptom for patients to tolerate. When symptoms worsen, patients demand therapeutic options that offer superior convenience and rapid responsiveness. While currently developing therapeutics target complete disease control, whether these agents can fundamentally alter the long-term course of the disease requires further observation. Rhapsido carries significant potential and high expectations as a treatment option featuring a novel mechanism of action.

Q. What is the mechanistic significance of BTK inhibitors within the therapeutic management of CSU?

[Dr. Choi] The pathophysiology of urticaria is fundamentally understood to be driven by immunoglobulin E (IgE) cross-linking and mast cell activation. While Xolair directly inhibits circulating IgE molecules, BTK inhibitors differentiate themselves by blocking the downstream intracellular signaling cascades required for mast cell activation following that receptor binding event.

The pathophysiology of urticaria is fundamentally understood to be driven by immunoglobulin E (IgE) cross-linking and mast cell activation. While Xolair directly inhibits circulating IgE molecules, BTK inhibitors differentiate themselves by blocking the downstream intracellular signaling cascades required for mast cell activation following that receptor binding event.

[Dr. Saini] The BTK inhibitor Rhapsido acts directly upon mast cells and basophils, which secrete symptom-inducing inflammatory compounds like histamine, thereby directly suppressing the actual exocytosis of the inflammatory mediators responsible for triggering pruritus, swelling, and angioedema. It also modulates B-cells, which are immune cells responsible for antibody production, a pathway believed to potentially exert an effect on the underlying autoantibody responses driving CSU symptom expression.

Q. How do you evaluate the efficacy and safety data confirmed for Rhapsido in clinical studies? Which data are significant?

[Dr. Saini] From an efficacy standpoint, Rhapsido demonstrated a comparatively rapid onset of symptom relief. The Rhapsido-treated cohorts exhibited measurable symptom separation from the placebo arm at an early juncture, with tangible symptom improvements manifesting as early as week 1 of administration. This Phase III program enrolled severe patients whose disease was inadequately controlled on antihistamines, many of whom had carried a heavy disease burden for extended durations, with a mean disease duration of approximately six years. Furthermore, about one-third of the participants were patients who remained uncontrolled despite extensive prior experience with existing advanced therapies.

The initial 24 weeks of the study followed a double-blind, placebo-controlled design, after which the placebo-assigned patients crossed over to active Rhapsido therapy. Upon switching, these crossover patients likewise demonstrated rapid disease control. Moreover, the 52-week long-term analysis confirmed that this therapeutic efficacy was stably and durably maintained over extended administration.

Regarding safety, the oncology sector has already established a baseline level of experience with early-generation BTK inhibitors, and subsequent generations have continually optimized molecular selectivity. Rhapsido similarly demonstrated clinical efficacy without triggering pronounced or elevated signals for the adverse events historically associated with older BTK inhibitors.

Dr. Jeong-Hee Choi, a professor of the Department of Pulmonology and Allergy at Hallym University Dongtan Sacred Heart Hospital 

[Dr. Choi] In my opinion, the clinical trial results for Rhapsido is highly positive. Initially, there were baseline concerns within the medical community that the mechanism of BTK inhibition might induce overly broad systemic suppression of immune responses. However, Rhapsido's highly selective mechanism has been consistently demonstrated, and the actual clinical datasets continue to show highly stable outcomes.

In the clinical perspective, attention is drawn to the speed of symptom improvement. Xolair often shows varying response times across distinct patient subsets, and parameters such as baseline IgE levels are sometimes used to predict treatment responsiveness. In contrast, Rhapsido's capacity to induce rapid improvements in pruritus and urticarial lesions independent of these biological variables was highly impressive.

The current lack of extensive comparative trials against Xolair limits direct cross-trial conclusions. Nonetheless, evaluating the data package compiled to date suggests that this oral small molecule can deliver efficacy comparable to that of established standard-of-care biologic agents.

Q. Given Rhapsido's rapid symptom improvement, which specific patient subpopulations do you anticipate will benefit most in real-world clinical practice?

[Dr. Choi] The primary candidates will be patients who require advanced step-up interventions due to inadequate disease control on optimized antihistamine regimens. Additionally, the option can be strategically considered during the treatment selection process for patients who cannot tolerate continuous high-dose antihistamines due to side effects, individuals facing logistical hurdles that restrict regular clinic visits for injections, and patients harboring a strong aversion or resistance to injectable therapies.

[Dr. Saini] Priority consideration can be given to patients maintaining high baseline disease activity despite cycling through multiple antihistamines and various advanced therapies mandated by prior tiers of established clinical guidelines.

It can also deliver distinct benefits in clinical scenarios requiring rapid stabilization, such as patients with severe edema or angioedema who frequently present to emergency departments. Furthermore, it represents a viable alternative for individuals currently dependent on oral corticosteroids due to a lack of alternative options, patients experiencing dose-limiting toxicities such as somnolence from legacy antihistamine choices, and individuals undergoing immunosuppressive therapies like cyclosporine that necessitate rigorous, ongoing laboratory safety monitoring.

Q. Despite its recent regulatory clearance, Rhapsido was swiftly integrated into international guidelines. How do you evaluate this rapid academic adoption?

[Dr. Saini] The relatively rapid inclusion of Rhapsido into global guidelines indicates that international medical societies, steering committees, and researchers concluded that the product's clinical value had been robustly validated through its clinical data package.

To date, approximately six to seven months of commercial real-world user experience has been compiled in the United States, alongside a broader experience across diverse patient cohorts via clinical trial extensions. Our perspective on this real-world clinical feedback is highly positive.

The rapid onset of symptom relief documented in controlled trials is being directly mirrored in clinical practice, with clinicians frequently recording instances where patients explicitly report rapid, tangible improvements. For patients, directly experiencing this rapid therapeutic validation serves as a powerful driver that reinforces long-term treatment adherence and persistence.

[Dr. Choi] Its prompt integration as a primary scond-line therapy within international consensus guidelines carries significant weight. While the domestic medical community will naturally look to expand its localized clinical experience, this international endorsement provides a solid foundation of clinical confidence for South Korean prescribers.

Because Korean experts had already established expectations and early familiarity through participation in global clinical programs, the broader medical community is viewing this rapid guideline integration with substantial optimism.

Q. How do you project the long-term evolution of the CSU commercial and clinical landscape moving forward?

[Dr. Choi] When Xolair initially entered the marketplace, there was a baseline level of clinical hesitation toward adopting a novel mechanism, which gradually dissolved as extensive real-world safety registries expanded. Today, it stands as a trusted, routine intervention, and I anticipate Rhapsido will chart a highly identical trajectory of market assimilation.

There is currently strong consensus within the medical community on the need to update South Korea's localized CSU clinical consensus guidelines. The revision process is slated to commence late this year with completion targeted for next year, during which Rhapsido's positioning will be evaluated in depth.

From a policy and structural standpoint, bolstering market access and affordability remains imperative, as refractory chronic urticaria continues to receive insufficient public health attention relative to its severe daily disease burden. Nevertheless, the ongoing diversification of the advanced therapeutic arsenal marks a clearly meaningful shift for patient care.

In the future, we must collaborate to establish an ecosystem that supports sustained, optimized treatment pathways, necessitating synchronized public health advocacy and pricing policy discussions.

[Dr. Saini] I anticipate robust, expansive prescription adoption of Rhapsido globally. The product addresses a critical commercial white space by offering patient-centric dosing convenience while drastically shortening the time-to-resolution, fundamentally elevating the standard of care for patients suffering from refractory CSU.

Beyond urticaria, the asset possesses significant pipeline expansion potential across broader allergic indications. Early-stage data packages in food allergy have already demonstrated promising outcomes, where the molecule rapidly attenuated hypersensitivity reactions in peanut- and tree-nut-sensitive cohorts, signaling its utility in mitigating anaphylactic risks during accidental allergen exposures.

The mechanism could similarly be utilized within the drug allergy sector. In clinical scenarios where a patient presents with a known allergy to an indispensable, non-substitutable therapeutic agent, co-administration of a highly selective BTK inhibitor could, in theory, provide a vital protective buffer, opening new avenues for safe desensitization protocols.