Reversal After 20 Deaths Allows New Japan Patients to Take Amgen’s Rare Disease Drug Tavneos

Japan Reverses Tavneos Restriction After New Warnings Issued

Kissei Pharmaceutical has reversed its recommendation against prescribing Amgen-shared Tavneos to new patients in Japan, following new warnings from Japan’s Ministry of Health regarding serious adverse events like liver problems and death. This reversal comes after Kissei previously linked 20 deaths to Tavneos since its 2022 launch in Japan, primarily due to vanishing bile duct syndrome. Amgen maintains Tavneos' effectiveness and favorable benefit-risk profile, noting that causality for the deaths in Japan was not determined and that over 8,500 patients have been treated there. The FDA has also previously flagged VBS cases and deaths in the U.S. and alleged manipulated data in the drug's initial approval study.

• Kissei Pharmaceutical has withdrawn its recommendation to restrict new Tavneos prescriptions in Japan. This change follows instructions from Japan’s Ministry of Health to add new warnings to the drug’s packaging, advising providers to monitor liver function due to risks of serious adverse events, including liver problems and death.
• The initial restriction by Kissei was prompted by 20 deaths linked to Tavneos in Japan since its 2022 launch, with most attributed to vanishing bile duct syndrome (VBS), a complication of drug-induced liver injury. Amgen stated that causality was not determined for these deaths among over 8,500 treated patients and affirmed its belief in Tavneos' effectiveness and favorable benefit-risk profile.
• In the U.S., the FDA previously flagged 76 cases of VBS and eight deaths associated with Tavneos, citing "reasonable evidence of causal association." Furthermore, the FDA alleged that "unblinded study personnel manipulated the results" of the pivotal clinical study, leading to a request for Amgen to pull the drug from the market, a request Amgen denied.
• Amgen acquired ChemoCentryx, the original developer of Tavneos, in 2022 for $3.7 billion. This acquisition brought Tavneos into Amgen's portfolio, placing the company at the center of the ongoing regulatory and safety discussions surrounding the drug.

Tavneos's Safety Profile: New Warnings Amidst Existing Data

Recent real-world evidence from 2026 reveals concerning safety signals for Tavneos that diverge from clinical trial data. A systematic review of 16 real-world studies demonstrated serious infection rates of 14% at 6 months, with notable heterogeneity in hepatotoxicity between populations, particularly pronounced in Japanese patients. Japanese real-world data specifically showed adverse events in 47.6% of patients, with elevated liver enzymes occurring in 38.1% of cases as the most frequent complication. This led to treatment discontinuation in 42.9% of patients, highlighting significant tolerability challenges in clinical practice.

FDA Adverse Event Reporting System data from 2026 documented 7,141 adverse events involving 3,135 patients, including 225 deaths with higher mortality rates among patients aged 65 years and above. New adverse events identified through post-marketing surveillance include alopecia, sepsis, pulmonary hemorrhage, hypertransaminasemia, deafness, and insomnia. Additionally, drug-induced hypersensitivity syndrome (DIHS) has been identified as a rare but serious adverse effect, with documented cases requiring long-term hospitalization for improvement of skin symptoms and liver function.

The controlled clinical trial data presents a more favorable safety profile compared to real-world experience. In the pivotal ADVOCATE trial, serious adverse events excluding worsening vasculitis occurred in 37.3% of avacopan patients versus 39.0% of prednisone patients at 52 weeks. The CLEAR trial showed serious adverse events in 17% of avacopan patients compared to 15% with standard-of-care alone over 12 weeks. Meta-analysis of three randomized controlled trials totaling 440 patients demonstrated that avacopan substantially decreased glucocorticoid-related adverse events with a relative risk of 0.78, particularly reducing diabetes and psychiatric complications, without significant increases in serious infections or mortality compared to traditional glucocorticoid-based regimens.

The Pivotal Trial Design Under FDA Scrutiny

Several pivotal trials have established the evidence base for ANCA-associated vasculitis treatment, with study designs focused on remission induction, maintenance strategies, and glucocorticoid-sparing approaches. These trials have employed rigorous randomized controlled designs with standardized endpoints to evaluate both efficacy and safety outcomes.

Addressing Unmet Needs in ANCA-Associated Vasculitis Treatment

Current ANCA-associated vasculitis treatments face significant challenges that limit their effectiveness and impact patient outcomes. Despite therapeutic advances, many patients continue to experience frequent relapses, progressive tissue damage, and chronic impairments in quality of life. These limitations underscore the urgent need for more effective and safer therapeutic approaches.

• High relapse rates persist despite treatment advances - 30-50% of patients still experience relapse, with 50% relapsing within 5 years and relapse occurring in up to 64% of patients in some cohorts, leading to increased morbidity and mortality

• Treatment-related toxicity contributes significantly to patient burden - Current immunosuppressive therapies are associated with considerable morbidity and mortality, with infection being the greatest cause of early mortality rather than uncontrolled vasculitis itself

• Glucocorticoid dependence creates substantial morbidity - While glucocorticoids remain a mainstay of treatment, their long-term use is associated with significant toxic effects, infections, and multi-comorbidity, with 71% of healthcare costs attributable to patients experiencing infections

• Current remission definitions inadequately capture disease activity - Existing definitions of remission underestimate ongoing disease activity and impact, making interpretation of residual symptoms challenging, especially in the absence of overt inflammation

• Treatment resistance affects a significant subset of patients - Approximately 10-15% of patients demonstrate treatment resistance, and many current therapies fail to achieve durable remission due to cumulative toxicity limitations

• Broad-spectrum immunosuppression increases infection vulnerability - Current treatments often leave patients susceptible to serious infections, with patients receiving prolonged glucocorticoid therapy showing trends toward higher infection rates (21% vs 7% for >12 weeks vs ≤12 weeks treatment)

• Incomplete understanding of optimal treatment duration and individualization - The optimal duration of immunosuppressive therapy remains uncertain, and robust predictors of individual clinical courses are lacking to enable personalized treatment approaches

Tavneos's Path: Balancing Efficacy with Emerging Real-World Safety

The recent decision by Kissei Pharmaceutical to reverse its recommendation against prescribing Tavneos (avacopan) to new patients in Japan, despite new warnings from the Ministry of Health regarding serious adverse events, marks a pivotal moment for the treatment of ANCA-associated vasculitis (AAV). Avacopan has been a significant therapeutic advance, offering a steroid-sparing approach that reduces the substantial glucocorticoid toxicity associated with traditional AAV regimens, while demonstrating non-inferiority in inducing remission and superiority in sustaining it, alongside improved renal function. This benefit is recognized in updated clinical guidelines, which now incorporate avacopan as an alternative to high-dose glucocorticoids.

However, the event underscores a critical tension between established clinical trial efficacy and emerging real-world safety signals. While pivotal trials showed comparable serious adverse events to prednisone, post-marketing surveillance and real-world data, particularly from Japanese cohorts, have highlighted a higher incidence of elevated liver enzymes and frequent early discontinuations due to adverse events. A specific and concerning risk is vanishing bile duct syndrome (VBS), a severe form of hepatotoxicity, which has been linked to avacopan in case reports and contributed to reported deaths. FAERS analyses further corroborate hepatobiliary disorders as prominent adverse events, with Japanese patients exhibiting a higher risk of liver dysfunction.

For clinical teams, this means a continued commitment to avacopan's use, but with heightened vigilance. Close monitoring of hepatic function is paramount, especially given the observed population-specific risks. For strategic pharma teams, the situation emphasizes the ongoing need for robust pharmacovigilance and investment in large-scale, long-term real-world evidence studies, such as the ongoing AvacoStar, to fully characterize the drug's safety profile across diverse patient populations and identify optimal usage strategies. Navigating these safety concerns transparently, while leveraging avacopan's undeniable clinical benefits, will be crucial for maintaining physician confidence and ensuring equitable patient access to this important therapy.