Birtamimab Demonstrated Significant Improvement in Time to All-Cause Mortality in Stage IV AL Amyloidosis

VITAL study results reveal survival advantage of birtamimab for patients with Mayo Stage IV amyloid light chain amyloidosis.

Post-hoc analysis results from the phase 3 VITAL study (NCT02312206) show that birtamimab (formerly NEOD001) achieved significant survival benefit in patients with Mayo Stage IV amyloid light chain (AL) amyloidosis at month 9, according to a presentation at the 2022 ASH Annual Meeting.1

Seventy-four percent of patients assigned to birtamimab were alive at 9 months vs 49% for those assigned to placebo (HR, 0.413; 95% CI, 0.191-0.895; P = .021). The survival benefit was consistent across all key baseline variables, including demographic factors, clinical characteristics, and laboratory parameters.

“Make no mistake, we’re not claiming this is the same as a prospective randomized phase 3 trial, but in this post-hoc analysis, there was a significant improvement in all-cause mortality at month 9, as well as improvement in the 6-minute walk test and quality of life,” said lead study author Morie A. Gertz, MD, a hematologist/oncologist and chair of General Internal Medicine at Mayo Clinic Rochester in a presentation of the data. “All we’re really saying is that this is a sufficient justification to embark on a legitimate prospective, randomized, placebo-controlled phase 3 trial that is limited to patients with stage IV cardiac amyloidosis, again, using all-cause mortality as the primary end point with multiple secondary end points.”

Investigators have initiated the confirmatory phase 3 global AFFIRM-AL trial (NCT04973137) to assess birtamimab in 150 patients with newly diagnosed, treatment-naïve Mayo stage IV AL amyloidosis. The estimated primary completion date is June 2024.

AL amyloidosis is a rare plasma cell disorder that involves the production of a misfolded amyloidogenic light chain by a plasma cell clone that deposits in various organs leading to organ failure. Traditionally, efforts have focused on eliminating the culprit plasma cell clone with autologous hematopoietic cell transplantation (AHCT) in eligible patients or with bortezomib (Velcade)-based therapy, typically in combination with cyclophosphamide and dexamethasone in AHCT-ineligible patients.

Gertz explained that these patients, particularly those with advanced disease, have an urgent need for therapies that improve survival. In patients with advanced cardiac involvement, the median survival is just 5.8 months.

“In other words, frankly, it doesn't matter how good your anti–plasma cell chemotherapy is. If you diagnose patients with advanced cardiac infiltration, it’s too late; you cannot help them because they have irreversible organ damage,” Gertz said. “As a consequence, all our plasma cell–directed chemotherapy, which may impact production of amyloid, does nothing for the amyloid that is in place at the time diagnosis is made, reflecting the unmet need of making an earlier diagnosis of cardiac amyloidosis before patients have systolic blood pressures of 80 [mmHg] and repeated hospitalizations for heart failure with preserved ejection fraction.”

Birtamimab is an investigational human IgG1 monoclonal antibody that selectively targets and clears the amyloid that accumulates and causes organ dysfunction and failure in patients with AL amyloidosis.

In the VITAL study, patients were assigned 1:1 to standard of care (SOC) plus 24 mg/kg birtamimab given every 28 days for 42 months (n = 130) or placebo plus SOC (n = 130). The primary end point was time to all-cause mortality (ACM) or cardiac hospitalization (CH). Key secondary end points were change in 6-minute walking test (6MWT) distance from baseline to month 9 and change in short form 36 version 2 physical component score (Sf-36vs PCS) from baseline to month 9.­­ Investigators also evaluated safety.

Investigators concluded that the composite end point of time to ACM or CH favored birtamimab in the overall population (n = 260), but the difference was not significant (HR, 0.826; 95% CI, 0.574-1.189; P = .303). Investigators terminated the study early following a 2018 interim futility analysis.

This post-hoc analysis included 77 patients with Mayo stage IV disease at baseline—38 in the birtamimab arm and 39 in the placebo arm. Investigators sought to determine whether birtamimab extended time to ACM at month 9 and to conduct a sensitivity analysis of time to ACM adjusted for baseline characteristics.

Patient demographics were well balanced, according to Gertz. The median age in the experimental arm was 63.6 years (range, 55.7-69.8) vs 63.7 years (range, 57.0-68.4) in the placebo arm. Men made up 65.8% and 71.8%, respectively, of the cohort and most patients were White (94.7% vs 92.3%, respectively). There were no Hispanic or Latino patients in either group. Ethnicity was unknown in 10.5% and 7.7% of patients, respectively.

Gertz noted that the confidence intervals were large because of the small sample size. Nonetheless, “all subgroups” appeared to derive a statistically significant survival benefit from birtamimab. After adjusting for key baseline demographic, clinical, and laboratory variables, the adjusted HRs for ACM at month 9 ranged from 0.336 to 0.465, with all upper bounds of the 90% confidence interval less than 1.0.

Birtamimab was associated with a difference of 4.65 points (P = .046) in SF-36v2 PCS change from baseline at month 9. “The difference was statistically significant,” Gertz said. “Quality of life declined less. It didn’t improve in most patients, but the decline in function in placebo patients was quite substantial compared to the [experimental] group, which remained relatively stable.”

Birtamimab was associated with a 36.37-meter improvement in the 6MWT compared with placebo (P = .022). “I know we're not cardiologists in this room, [but] this is a statistically significant improvement in the ability to navigate, as these patients are coached to walk as fast and as far as they can, over a 6-minute period of time,” Gertz said.

Birtamimab was well tolerated in the overall population and in the Mayo stage IV patients. Although patients in the experimental arm were more likely to experience treatment-related adverse effects (TRAEs; 31.6 vs 25.6%), those in the placebo arm experienced a greater rate of grade 3 or higher TRAEs (2.6% vs 10.3%). Incidence of serious TRAEs was 2.6% in both arms. TRAEs led to drug discontinuation in 7.9% of those in the birtamimab arm vs 5.1% of those in the placebo arm. No TRAEs resulted in death.

The 4 most common treatment-emergent AEs (TEAEs) in those who received birtamimab/SOC or placebo/SOC were peripheral edema (55.3% vs 48.7%, respectively), constipation (42.1% vs 33.3%), nausea (42.1% vs 30.8%), and dyspnea (42.1% vs 30.8%).

Infusion-associated TEAEs were experienced by 3 patients in the experimental arm and included dyspnea (n = 1), chest discomfort (n = 1), and hypoxia concurring with an infusion-related reaction (n = 1).


Gertz MA, Cohen AD, Comenzo RL, et al. Survival benefit of birtamimab in Mayo stage IV AL amyloidosis in the phase 3 VITAL study consistent after adjustment for key baseline variables. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 760