Amgen’s Tavneos troubles continue as NEJM retracts pivotal publication

NEJM Retracts Pivotal Tavneos Publication Amid Data Manipulation Claims

The New England Journal of Medicine has retracted a pivotal publication for Amgen's rare disease drug, Tavneos, following an ongoing FDA investigation into allegedly manipulated data. Two study authors requested the retraction after discovering the primary endpoint assessments for nine patients were readjudicated post-database lock and trial unblinding without their knowledge, a conduct inconsistent with proper research. This adds to Amgen's challenges, which include the FDA's earlier request to withdraw the drug due to efficacy data issues and the attribution of over 70 cases of drug-induced liver injury, including eight deaths, to Tavneos. Amgen maintains confidence in the drug's safety and efficacy and has requested an FDA hearing, initiating an independent re-adjudication of the data.

• Pivotal Publication Retraction: The New England Journal of Medicine retracted a key paper supporting Amgen's Tavneos approval. This action was prompted by two study authors who revealed that the primary endpoint data for nine patients was readjudicated after the trial was unblinded and the database locked, a critical breach of research integrity that was not disclosed in the original article.
• FDA's Ongoing Scrutiny: The FDA has been in a months-long dispute with Amgen regarding Tavneos, initially requesting its withdrawal in January due to concerns over re-adjudicated efficacy data. The agency later attributed over 70 cases of drug-induced liver injury (DILI), including eight deaths, to the drug, and stated it could no longer conclude that Tavneos is effective due to manipulated study results.
• Amgen's Response and Defense: Amgen has consistently defended Tavneos, refusing the FDA's request to withdraw the drug and asserting its confidence in the medicine's safety and efficacy, backed by clinical and real-world evidence. The company has requested a hearing with the FDA and commissioned the Duke Clinical Research Institute to conduct an independent, blinded re-adjudication of the pivotal study data to address the integrity concerns.

Pivotal Tavneos Data Retracted Amidst Manipulation Allegations

Several landmark and recent studies have shaped the treatment landscape for severe active ANCA-associated vasculitis (AAV). The ADVOCATE Trial evaluated avacopan — a selective oral C5a receptor 1 (C5aR1) antagonist — as adjunctive therapy over 52 weeks and demonstrated non-inferior remission rates at week 26 and significantly higher sustained remission rates at week 52 compared to conventional glucocorticoid-containing regimens. Notably, avacopan enabled considerable reductions in glucocorticoid exposure and greater recovery of kidney function, particularly in patients presenting with acute kidney injury, ultimately supporting its regulatory approval. Complementing this, a 2025 systematic review and meta-analysis pooling 9 studies and 2,080 patients confirmed these findings, reporting non-inferior remission rates at week 26 (RR = 1.02, 95% CI: 0.88–1.19), significantly higher sustained remission at week 52, reduced glucocorticoid toxicity, fewer adverse events, and improved quality-of-life scores, with low heterogeneity (I² = 5.4%). A 2025 retrospective study of 66 patients further supported avacopan's clinical utility, demonstrating comparable remission rates and BVAS reductions versus non-avacopan regimens, a significantly smaller increase in Vasculitis Damage Index (VDI) score, and meaningfully lower daily glucocorticoid doses and glucocorticoid-related adverse event rates at 1, 3, and 6 months.

The REVEAL multicenter cohort study (1991–2024) compared rituximab (RTX) versus intravenous cyclophosphamide (IVCY) in 178 patients with severe microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). RTX was associated with significantly higher 10-year survival rates (p = 0.04) and higher glucocorticoid-remission rates at 6 months (p = 0.017), while ESRD progression and relapse rates were comparable between groups. Critically, 15.2% of patients in the IVCY group died due to severe infections versus none in the RTX group (p = 0.007), underscoring RTX's superior safety profile. A separate 2025 retrospective observational cohort study of 112 patients (median age 67 years; 85% with kidney involvement; baseline eGFR 24 mL/min/1.73 m²) treated with combination cyclophosphamide and rituximab alongside a rapidly tapering oral-only glucocorticoid regimen reported a 96% remission rate, with median time-to-remission of 77 days (IQR: 64–92) and a disease relapse rate of only 5% over 2.9 years. Patients receiving glucocorticoids for ≤12 weeks showed a trend toward fewer serious infections compared to those treated beyond 12 weeks (7% vs. 21%; P = 0.06), with no significant differences in remission or relapse rates.

For patients with refractory disease, a 2025 single-center retrospective chart review evaluated reduced-dose obinutuzumab (most commonly 1,000 mg for induction) in 16 consecutive patients with active AAV who had failed cyclophosphamide and/or rituximab, or who presented with severe treatment-naïve multiorgan failure. Complete remission was achieved in 50% of patients (8/16) at week 24, rising to 81.3% (13/16) at week 76, with accompanying peripheral B-cell depletion, ANCA negativization, and improvement in renal and pulmonary outcomes. No severe infections occurred, though 43.8% of patients developed treatment-emergent infections, predominantly respiratory. Additionally, the PEXIVAS and LoVAS trials both demonstrated that reduced-dose glucocorticoid regimens preserve efficacy while significantly lowering infection risk in severe AAV, providing the clinical rationale underpinning current steroid-minimization strategies across induction regimens.

FDA Links Tavneos to DILI and Patient Deaths

Clinical trials in ANCA-associated vasculitis (AAV) have consistently identified serious infections and glucocorticoid-related toxicity as the dominant safety concerns across treatment regimens. The adverse event profile is strongly shaped by glucocorticoid dose intensity, with reduced-dose strategies demonstrating meaningfully improved safety outcomes without compromising efficacy.

• Serious adverse events (SAEs) are substantially higher with high-dose glucocorticoid regimens: In a 140-patient randomized trial, SAEs occurred in 36.9% of patients receiving high-dose prednisolone (1 mg/kg/day) plus rituximab versus 18.8% in the reduced-dose group (0.5 mg/kg/day) at 6 months (difference −18.1%, 95% CI −33.0% to −3.2%, P = 0.02), with the gap persisting at 24 months (46.2% vs. 27.5%, P = 0.025).

• Serious infections represent a major and independently prognostic safety signal: Infection rates at 1, 2, and 5 years reached 51%, 58%, and 65%, respectively, with pulmonary and upper respiratory infections most prevalent. Patients sustaining severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0–8.7; P = 0.001), and all-cause 12-month mortality scaled with infection burden (0 infections: 3%; 1–2 infections: 10%; ≥3 infections: 13%; P = 0.002).

• High-dose intravenous methylprednisolone carries compounding risks: Pulse methylprednisolone (1.5 g) was associated with higher infection risk during the first 3 months (HR 2.7, 95% CI 1.4–5.3) and a markedly elevated incidence of new-onset diabetes (HR 6.33, 95% CI 1.94–20.63) versus low-dose IV methylprednisolone (250 mg), with more deaths in the high-dose group (26.5% vs. 6.5%, P = 0.05), though this did not reach significance on multivariable analysis.

• Rituximab is associated with late-onset neutropenia and IgM reduction: Across 65 patients in a refractory AAV cohort, 46 SAEs were recorded, with 2 episodes of late-onset neutropenia directly attributed to rituximab; IgM levels declined while IgG remained stable. Rituximab did not significantly reduce or increase the overall frequency of serious adverse events versus cyclophosphamide (SAE rate 42% vs. 36%, P = 0.77; mortality 18% vs. 18%, P = 1.00).

• Avacopan (C5a receptor inhibitor) demonstrates a favorable safety profile relative to standard glucocorticoid taper: In rituximab-treated patients, SAEs occurred in 34.6% of the avacopan arm versus 39.3% in the prednisone taper arm. A meta-analysis of 2,080 patients confirmed avacopan was associated with significantly reduced glucocorticoid toxicity, fewer adverse events, and improved quality-of-life scores, while maintaining comparable disease control.

• Mortality risk varies substantially by regimen and disease severity: Reported mortality ranges from 2.8% (reduced-dose glucocorticoid arm at 24 months) to 26.5% (high-dose IV methylprednisolone), with severe infections, respiratory failure, and heart failure identified as the principal causes of death in long-term follow-up cohorts.

Amgen Defends Tavneos Amidst Regulatory Scrutiny

Across clinical trial settings, avacopan (Tavneos) has demonstrated a broadly acceptable safety profile relative to standard corticosteroid-based regimens for ANCA-associated vasculitis (AAV). In the 12-week Phase 2 CLEAR trial, serious adverse events occurred in 17% of avacopan-treated patients versus 15% in the standard-of-care-only arm, indicating comparable tolerability at both the 10 mg and 30 mg twice-daily doses. The pivotal Phase 3 ADVOCATE trial (n=331) further established that serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the avacopan arm versus 39.0% in the prednisone taper arm — with avacopan demonstrating non-inferiority at week 26 and superiority in sustaining remission at week 52. A meta-analysis pooling data from three pivotal randomised controlled trials (CLASSIC, CLEAR, and ADVOCATE; total n=440) confirmed that avacopan substantially reduced glucocorticoid-related adverse events (RR=0.78; 95% CI: 0.70–0.87; p<0.0001), with particular reductions in diabetes, psychiatric complications, and general glucocorticoid toxicity, without any significant increase in serious infections, mortality, or treatment discontinuations.

Real-world data from early access programmes in France and Spain have largely corroborated the clinical trial findings, while surfacing some important signals. In the French programme (n=31; median age 72 years), 81% of patients achieved a favourable outcome; however, two patients experienced severe adverse events leading to avacopan withdrawal — specifically hepatitis and age-related macular degeneration. The Spanish programme (n=29; median follow-up ~457 days) reported a remission rate of 86.2%, with two drug-related adverse events (severe neutropenia and gastrointestinal affectation), 13 infections, and one death. ADVOCATE subgroup analyses indicate the greatest clinical benefit in patients with renal impairment, pulmonary manifestations, and relapsing disease — populations in which the glucocorticoid-sparing effect of avacopan is particularly consequential.

More recent post-marketing data have introduced additional nuance to the safety picture. A 2026 systematic review of real-world studies reported a serious infection rate of 14% (95% CI: 0.10–0.18), and identified notable hepatotoxicity heterogeneity across populations — most pronounced in Japanese cohorts, where a single-centre study (n=21) reported elevated liver enzymes in 38.1% of patients and avacopan discontinuation in 42.9%. An FDA Adverse Event Reporting System analysis covering Q3 2021 to Q4 2024 captured 7,141 avacopan-related adverse events across 3,135 patients, with 225 deaths — disproportionately among male patients aged 65 and above. Newly identified signals include alopecia, sepsis, pulmonary haemorrhage, hypertransaminasaemia, deafness, and insomnia. The ongoing AvacoStar study — a prospective European real-world evidence study enrolling up to 500 patients across Germany and the United Kingdom, with follow-up through 2031 — is designed to provide long-term clarity on events of special interest including liver injury, cardiac safety, serious infections, and malignancy.

Tavneos Retraction: Unraveling Trust in ANCA-Associated Vasculitis Therapy

The recent retraction of a pivotal publication for Amgen's Tavneos (avacopan) in the New England Journal of Medicine marks a critical juncture for the drug and the broader treatment landscape for ANCA-associated vasculitis (AAV). Tavneos, an oral C5a receptor antagonist, was heralded as a significant advance, offering a glucocorticoid-sparing strategy to reduce the severe toxicities associated with long-term steroid use in AAV patients, while also demonstrating benefits in renal outcomes. The alleged manipulation of primary endpoint data, specifically the post-database lock readjudication for nine patients, fundamentally compromises the scientific integrity of the trial and the reliability of its reported findings.

This development exacerbates existing challenges for Tavneos, including prior FDA concerns regarding efficacy data and the attribution of over 70 cases of drug-induced liver injury, including eight deaths. While real-world evidence and subgroup analyses have generally supported avacopan's efficacy in reducing glucocorticoid exposure and improving outcomes in various AAV patient populations, including those with severe kidney involvement or receiving rituximab/cyclophosphamide, the data integrity breach casts a shadow over all reported benefits.

For Amgen, the strategic implications are severe, ranging from potential market withdrawal to significant reputational damage that could impact future drug development. Clinicians and patients now face heightened uncertainty regarding the drug's true benefit-risk profile. The risks to consider extend beyond the immediate efficacy concerns to the long-term safety profile, which includes known signals for hepatobiliary disorders, serious infections, and rare but severe events like drug-induced hypersensitivity syndrome. The need for robust, transparent, and long-term real-world safety data, as aimed for by studies like AvacoStar, becomes even more critical. This event underscores the paramount importance of data integrity in clinical research and will undoubtedly influence regulatory scrutiny and prescribing practices for novel therapies in complex autoimmune diseases.