© Original production of the Innovation Drug Group of Amy Observation
Author | Sha Xiaowei
BTK inhibitors are receiving favorable news again.
On November 10, Roche announced that the first of two pivotal randomized, multicenter, placebo-controlled studies (RMS) evaluating the autoimmune BTK inhibitor finanibrutinib in patients with relapsing-remitting and progressive multiple sclerosis (MS) had met its primary endpoint.
Specifically, during the 96-week treatment period, fennerubrutinib significantly reduced the annualized relapse rate compared to teriflumide. Additionally, the pivotal Phase III FENtrepid study, which evaluated fennerubrutinib versus the CD20 monoclonal antibody ozludimab for treating patients with primary progressive multiple sclerosis, also met its primary endpoint.
While the full data from both studies remain unpublished and the drug's market approval awaits the results of the second RMS study (FENhance1) in the first half of 2026, these findings undoubtedly mark a significant advancement in the field of autoimmune BTK inhibitors.
Following the approval of BTK inhibitors by Sanofi and Novartis, Roche is now on the verge of success, heralding a comprehensive triumph for autoimmune BTK inhibitors by 2025.
01. Victory 2025
2025 is clearly a year of comprehensive success for autoimmune BTK inhibitors.
In late August, Sanofi made a breakthrough by securing FDA approval for its BTK inhibitor Rilzabrutinib to treat primary immune thrombocytopenia (ITP), becoming the first BTK inhibitor approved globally in the autoimmune field.
This approval was granted due to its groundbreaking efficacy. The approval of lizabrutinib was based on the results of the Phase 3 LUNA trial: 86 patients (65%) in the lizabrutinib group achieved a platelet response, with 31 patients meeting the prespecified treatment endpoint (compared to zero in the placebo group). Additionally, its excellent safety profile and consistent improvement in patient outcomes significantly outperformed conventional treatment regimens.
Next, Novartis stepped up with a timely boost—remibutinib tablets received FDA approval on October 1st for treating adult patients with chronic spontaneous urticaria (CSU) who still experience symptoms despite H1 antihistamines. Though Novartis arrived slightly later, it clinched the title of 'first' by becoming the first FDA-approved BTK inhibitor for CSU treatment.
Novartis's breakthrough is equally supported by robust clinical data. CSU symptoms adversely affect patients' sleep, work performance, and mental health. While antihistamines are currently the first-line treatment, more than half of patients remain uncontrolled even with increased doses. For those with poor antihistamine response, injectable therapy is an option, yet fewer than 20% of eligible patients have adopted this approach.
The Phase III REMIX-1 and REMIX-2 clinical trial results of Remibutinib Tablets demonstrated superiority over placebo in baseline changes of pruritus (ISS7), hives (HSS7), and weekly urticaria activity score (UAS7) at week 12 for patients with persistent symptoms despite second-generation H1 antihistamines.
Roche's success marks a significant step forward for autoimmune BTK inhibitors in unlocking more' first-in-class' indications—relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), which were previously unaddressed by BTK inhibitors.
Dr. Levi Garraway, Chief Medical Officer and Global Head of Product Development at Roche, stated: "Fenibrutinib has significantly reduced relapse frequency in relapsing-remitting multiple sclerosis (RMS) patients and slowed disability progression in progressive multifocal sclerosis (PPMS) patients. These groundbreaking results demonstrate that fenibrutinib is poised to become the first highly effective oral therapy for RMS or PPMS patients, positioning it among the top-tier drugs in this therapeutic domain."
With multiple drugs successively approved for market release and a series of autoimmune indications being unlocked, the previous doubts surrounding autoimmune BTK inhibitors will be completely dispelled.
02. The doubts were completely eliminated.
Historically, the autoimmune field has been the top choice for BTK inhibitors to cross therapeutic boundaries, both in terms of mechanistic continuity and market demand. However, the debate over whether BTK inhibitors are effective in treating autoimmune diseases has persisted for years.
BTK inhibitors treat tumors by inhibiting the production of new B cells, thereby halting disease progression.
However, some scholars argue that this mechanism may not apply to autoimmune diseases. The rationale is that BTK inhibitors do not suppress pre-existing B cells, whereas the presence of these B cells and other immune cells in lesions is the core factor triggering autoimmune diseases. In such cases, merely inhibiting the generation of new B cells would inevitably be seen as a "post hoc" approach, leading to the "ineffectiveness theory."
While these claims are not entirely accurate, the repeated setbacks in clinical trials of BTK inhibitors for autoimmune diseases have compelled the market to exercise caution.
Security is the first "checkpoint".
In hematologic malignancy treatment, adverse events such as bleeding, infection, and cardiovascular events caused by BTK inhibitors can still be controlled through close monitoring. However, the treatment duration for autoimmune patients often spans years or even decades. Any minor adverse reaction may be magnified over long-term medication, posing potential threats to patients' health.
In clinical practice, hepatotoxicity is the most serious challenge.
Earlier, Sanofi's heavily invested BTK inhibitor tolibitinib was forced to suspend clinical trials due to hepatotoxicity concerns. Even for the already approved lizabrutinib, the FDA mandated long-term post-marketing safety monitoring, with particular focus on liver/renal function and infection risks.
Similar safety concerns have emerged in other pharmaceutical products: Merck's Evolocitabine was halted by the FDA during pivotal clinical trials for multiple sclerosis due to hepatotoxicity, while Genentech's Finanibrutinib faced trial suspension in Phase 2 MS studies after liver injury risks were identified.
The second challenge is the uncertainty of the efficacy boundary.
In early-stage clinical trials for systemic lupus erythematosus, the Phase 2 study of finanibrutinib was discontinued due to failure to meet the primary efficacy endpoint. This highlights that the disease involves multiple immune signaling pathways, and that B-cell activation suppression alone is insufficient to achieve comprehensive disease improvement.
The situation with rheumatoid arthritis is similar. Poseltinib, an oral BTK inhibitor acquired by Eli Lilly, demonstrated excellent performance in preclinical models but was discontinued in phase 2 clinical trials for moderate-to-severe RA patients due to failure to show significant efficacy.
The real challenge lies in the fact that BTK inhibitors have also failed to work effectively against Sjögren's syndrome, which is primarily characterized by B-cell activation. For instance, Bristol-Myers Squibb's BMS-986142 was prematurely discontinued during Phase 2 clinical trials for PSS due to insufficient efficacy.
The frequent clinical failures have long made the value of BTK inhibitors in autoimmune diseases a hotly debated issue within the medical community.
However, with Sanofi, Novartis, and Roche making breakthroughs, this controversy will be completely resolved. Given the vast market potential in autoimmune therapy, BTK inhibitors are bound to be a major focus.
03. A new hotspot is emerging.
Of course, this is not the end.
As a latecomer in the BTK inhibitor field, the autoimmune sector has long been crowded with formidable competitors, facing intense competition across multiple targets and indications. This also imposes higher demands on pharmaceutical companies' competitiveness.
On March 10 this year, Novartis officially launched the head-to-head Phase 3 study (RECLAIM) comparing Remibrutinib versus Pulimab in the treatment of chronic myeloid leukemia (CSU). This study highlights that in the increasingly competitive autoimmune field, BTK inhibitors must outperform the current market leaders to gain greater competitiveness.
This requires a multi-dimensional approach. Molecular design differentiation is undoubtedly the key factor. The development of BTK inhibitors has now reached the third generation, with the core design focus on enhancing selectivity and reducing long-term toxicity to meet the needs of patients with autoimmune diseases requiring prolonged medication.
Furthermore, the precise identification of therapeutic indications is pivotal to the success of BTK inhibitors. This is evidenced by the early-stage development trajectory of Rilzabrutinib.
Sanofi's Phase 3 PEGASUS trial for pemphigus, its first approved indication, was halted due to failure to meet the endpoint. Undeterred, the company redirected its R&D focus to diseases closely associated with the BTK pathway to maximize therapeutic efficacy. Through a multi-pronged strategy, it has progressively secured both IPT indications and multiple FDA orphan drug designations.
The case of Rilzabrutinib serves as a cautionary example for the industry: BTK inhibitors cannot be indiscriminately applied; they must be precisely targeted to specific disease types.
In this global race, domestic players are rapidly catching up. As a highly promising field, the competition for BTK inhibitors in autoimmune diseases is bound to remain a focal point.
Disclaimer: This article is for knowledge exchange, sharing, and educational purposes only. It does not constitute commercial promotion, medical advice, or medication recommendations. If the content infringes on any rights, please contact us for removal.
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