FDA alleges ‘manipulated’ data supported approval of Amgen’s autoimmune drug

FDA Renews Call for Amgen to Withdraw Tavneos Over Data Manipulation

The FDA has renewed its call for Amgen to withdraw its autoimmune drug Tavneos from the market, alleging that study personnel manipulated data in the pivotal clinical study to make the drug appear effective when original analyses did not support this conclusion. The regulator also cited new safety concerns, including 76 cases of liver injury and eight deaths detected through post-marketing surveillance, which it believes have a causal association with the drug. Tavneos was approved in October 2021 for severe active ANCA vasculitis, a condition for which Amgen acquired its developer, ChemoCentryx, in 2022 for $3.7 billion. Amgen maintains confidence in Tavneos' safety and efficacy, stating its perspective on the benefit-risk profile differs from the agency's.

• FDA's Allegations of Data Manipulation: The FDA's Center for Drugs Evaluation and Research (CDER) claims to have discovered new information, more than three years post-approval, indicating that unblinded study personnel manipulated results of Tavneos' pivotal clinical study. This manipulation allegedly made the drug appear effective, despite original analyses not supporting that conclusion, leading the FDA to question the validity of Tavneos' efficacy demonstration.
• Amgen's Stance and Confidence: Amgen has responded by expressing strong confidence in Tavneos as a safe and effective medicine, citing years of clinical data and real-world evidence. The company stated that its perspective on the drug's benefit-risk profile differs from the FDA's and affirmed its commitment to evaluating next steps while prioritizing patient needs and support.
• Escalating Safety Concerns and Regulatory History: This renewed call follows previous FDA actions, including an initial request for withdrawal in January due to liver toxicity issues and a March safety alert. The alert flagged 76 cases of liver injury and eight deaths in patients on Tavneos, identified through post-marketing surveillance, which the FDA considers new safety concerns with reasonable evidence of causal association.

FDA Questions Tavneos' Efficacy: The Pivotal Study Under Scrutiny

Recent clinical trials have demonstrated significant advances in ANCA-associated vasculitis treatment, with multiple studies showing improved outcomes through reduced glucocorticoid exposure and novel therapeutic approaches. These findings are reshaping treatment paradigms for severe AAV, offering patients more effective and safer therapeutic options.

• PEXIVAS Trial: Evaluated reduced-dose glucocorticoid regimens, demonstrating preserved efficacy while significantly lowering infection risk compared to high-dose protocols in severe AAV patients

• LoVAS Trial: Investigated reduced-dose glucocorticoids combined with rituximab, showing maintained therapeutic effectiveness with decreased adverse events compared to conventional high-dose regimens

• ADVOCATE Trial: Led to avacopan approval as adjunctive treatment, with 52-week treatment enabling sustained AAV remission, considerable glucocorticoid exposure reductions, and superior kidney function recovery, particularly in acute kidney injury patients

• REVEAL Cohort Study (1991-2024): Compared rituximab versus intravenous cyclophosphamide in 555 AAV patients, finding rituximab superior with significantly higher 10-year survival rates and 6-month glucocorticoid-remission rates, plus zero infection-related deaths versus 15.2% with cyclophosphamide

• Ultrarapid Glucocorticoid Withdrawal Study: Evaluated combination rituximab, low-dose cyclophosphamide, and limited glucocorticoids (median 1148mg prednisolone equivalent over 14 days) in 58 patients, achieving 88% remission at 3 months with 94% kidney survival and 93% overall survival at 3 years

• Combination Therapy Study (2011-2023): Assessed cyclophosphamide plus rituximab in 112 patients, demonstrating 96% remission rates with median time-to-remission of 77 days and only 5% relapse rate over 2.9 years follow-up

• Obinutuzumab Retrospective Study: Examined reduced-dose obinutuzumab (typically 1000mg) in 16 refractory AAV patients, achieving complete remission in 81.3% at week 76 with no severe infections and predominantly mild respiratory infections in 43.8% of patients

New Liver Injury and Fatalities Raise Tavneos Safety Alarms

Published safety and tolerability data for Tavneos (avacopan) reveals a complex profile with emerging safety signals, particularly regarding liver injury, despite generally favorable tolerability compared to standard glucocorticoid therapy. Recent real-world evidence has identified new adverse events not fully captured in initial clinical trials, raising important safety considerations for clinical practice.

• Liver dysfunction emerges as the most frequent adverse event in real-world studies, affecting 16.7-40.9% of Japanese patients and 38.1% of patients in a 2025 Japanese cohort, with significantly higher risk observed in Japanese versus American populations (p<0.001)

• Large-scale pharmacovigilance analysis identified 136 adverse event signals from 7,141 reported events involving 3,135 patients, including newly discovered adverse events such as alopecia, sepsis, pulmonary hemorrhage, hypertransaminasemia, deafness, and insomnia

• Mortality data from real-world use shows 225 deaths among 3,135 patients in FAERS database analysis, with higher mortality rates in patients aged 65 years and above and male patients

• Drug-induced hypersensitivity syndrome (DIHS) represents a rare but serious adverse effect, documented in a 2025 case report occurring seven weeks after treatment initiation with significant liver dysfunction, fever, generalized rash, and human herpesvirus 6 reactivation

• High discontinuation rates observed in real-world practice, with 42.9% of patients discontinuing treatment in the Japanese study, primarily due to elevated liver enzymes

• Clinical trial data demonstrates favorable safety profile compared to glucocorticoids, with meta-analysis showing substantial reduction in glucocorticoid-related adverse events (RR = 0.78; 95% CI: 0.70-0.87; p <0.0001) without significant increase in serious infections or mortality

• Serious adverse events in controlled trials remain comparable to standard care, with 37.3% in avacopan group versus 39.0% in prednisone group in the ADVOCATE trial, and no increased infectious risk demonstrated

• Long-term safety monitoring through AvacoStar study is designed to evaluate medical events of special interest including liver injury, cardiac safety, serious infections, and malignancy in up to 500 patients followed for up to 7 years

Navigating ANCA Vasculitis Treatment Amidst Regulatory Uncertainty

Current treatment approaches for severe active ANCA-associated vasculitis face significant challenges that impact both patient outcomes and quality of life. While conventional immunosuppressive therapies can achieve remission in most patients, they are associated with substantial toxicity and high relapse rates. These limitations underscore the urgent need for safer and more effective therapeutic strategies.

• High treatment toxicity burden: Cyclophosphamide and corticosteroids, despite their efficacy in inducing remission, are associated with severe adverse effects including cytotoxic side effects, drug-induced liver injury, and long-term complications such as cystitis and malignancy

• Elevated infection risk: Infections represent the most frequent cause of death, with mortality highest in the first year after diagnosis; cyclophosphamide shows infection incidence rates of 19.3 per 100 patient-years during induction compared to 11.3 per 100 patient-years with rituximab

• Frequent disease relapses: 30%-50% of patients experience relapses, with 57% of patients who achieved full remission relapsing at a median of 11.5 months after rituximab therapy, leading to increased morbidity and mortality

• Glucocorticoid-related complications: Long-term corticosteroid use causes significant morbidity, with infections and multi-comorbidity strongly associated with steroid therapy; 71% of hospital costs are attributable to patients experiencing infections

• Limited efficacy of certain biologics: Rituximab is not always effective and carries high subsequent relapse risk, particularly disappointing results in non-severe active vasculitis; etanercept has proven ineffective for maintenance of remission

• Treatment-resistant disease: A significant proportion of patients remain refractory to current therapies, with conventional agents like azathioprine and mycophenolate mofetil failing to maintain remission in some cases

• Plasma exchange limitations: Plasma exchange as adjunctive therapy shows no association with improved survival or reduced risk of end-stage kidney disease in patients with severe disease

• Uncertain optimal treatment duration: The appropriate length of immunosuppressive therapy remains unclear, complicating treatment planning and relapse prevention strategies

Tavneos Under Fire: Data Integrity and Safety Concerns

Tavneos (avacopan) emerged as a significant advancement in the management of ANCA-associated vasculitis (AAV), a severe autoimmune condition. As a selective C5a receptor antagonist, it offered a novel, targeted approach to reduce inflammation and, crucially, allowed for a substantial reduction in glucocorticoid use. Clinical trials, particularly the ADVOCATE study, demonstrated its noninferiority for remission at week 26 and superiority for sustained remission at week 52 compared to prednisone, while significantly mitigating the debilitating toxicities associated with long-term corticosteroid therapy. This steroid-sparing effect, coupled with observed improvements in renal function, positioned Tavneos as a valuable adjunct to standard care, addressing a critical unmet need for patients burdened by both their disease and treatment side effects.

However, the recent FDA action casts a long shadow over these perceived benefits. The regulator's renewed call for withdrawal, citing allegations of data manipulation in the pivotal study, strikes at the very foundation of the drug's efficacy claims. This is compounded by new post-marketing safety concerns, including 76 cases of liver injury and eight deaths, which the agency attributes to a causal association with avacopan. While real-world studies have previously noted hepatotoxicity as a safety signal, the scale and FDA's stance elevate this risk significantly.

For Amgen, the strategic implications are profound. The $3.7 billion acquisition of ChemoCentryx, largely predicated on Tavneos, now faces a substantial threat of devaluation and reputational damage. For patients with AAV, a potential withdrawal would remove a key glucocorticoid-sparing option, forcing a return to regimens with higher corticosteroid burden and associated toxicities. This situation underscores the critical importance of robust clinical trial integrity and vigilant post-marketing surveillance. The ongoing AvacoStar study, designed to gather long-term real-world safety data, becomes even more crucial in providing clarity amidst this regulatory challenge. The future of targeted complement inhibition in AAV, and indeed the broader pharmaceutical landscape, will be closely watching how this unfolds.