Late-Stage Failures of Monoclonal Antibody Drugs: A Retrospective Case Study Analysis.

AIM: To analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor. METHODS: We review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures. RESULTS: In some cases, the failures are unavoidable due to the lack of adequate science, but in others, we characterize the causes of such failures and recommend how such failures may have been avoided. CONCLUSION: By learning from previous mistakes and adhering to the principles and recommendations provided, it is possible to avoid these common pitfalls, increasing the likelihood of success in phase III clinical trials, and thus securing regulatory approval.

Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80-1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72-1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0-9·3] months vs. 5·8 [3·7-6·6] months; HR [95% CI] = 1·59 [1·11-2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.

Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma.

B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).

The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase 3 randomized, clinical trials.

INTRODUCTION: Tabalumab is a monoclonal antibody that neutralizes membrane and soluble B-cell activating factor. Two 52-week, randomized, double-blind, placebo controlled phase 3 trials evaluated the safety and efficacy of tabalumab in systemic lupus erythematosus. METHODS: Patients with moderate to severe active systemic lupus erythematosus (without severe active lupus nephritis) were randomly assigned 1:1:1 to receive tabalumab (120 mg subcutaneously every 2 or 4 weeks) or placebo for 52 weeks. Serum creatinine concentration, estimated glomerular filtration rate, urine protein/creatinine ratio, renal flares and renal adverse events were determined monthly. Data were analyzed for the intent-to-treat population and for intent-to-treat patients with baseline urine protein/creatinine ratio >20 mg/mmol (intent-to-treat plus urine protein/creatinine ratio). RESULTS: The trials enrolled 2262 patients. At baseline, demographics, systemic lupus erythematosus disease activity, serum creatinine concentration, estimated glomerular filtration rate and urine protein/creatinine ratio were similar among the treatment arms (with the exception of disease duration). In the intent-to-treat and intent-to-treat plus urine protein/creatinine ratio populations, there were no differences between the arms in the baseline-to-endpoint change in serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates. Tabalumab resulted in a significant B-cell reduction and decreased immunoglobulin G levels at both doses. CONCLUSIONS: Compared to placebo, tabalumab did not significantly affect the serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates over 1 year in intent-to-treat or intent-to-treat plus urine protein/creatinine ratio patients. There were no significant renal safety signals.ClinicalTrials.gov identifiers: NCT01205438 and NCT01196091 Lupus (2016) 25, 1597-1601.

Pharmacokinetics and safety of single doses of tabalumab in subjects with rheumatoid arthritis or systemic lupus erythematosus.

AIMS: Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg(-1) and SLE 0.125 or 2.0 mg kg(-1) ) or placebo. In study B, subjects with RA received a single tabalumab dose i.v. (10 mg) (n = 12) or s.c. (20 mg) (n = 12). Serum tabalumab and CD20+ B cells were evaluated and safety was assessed throughout both studies. RESULTS: Tabalumab PK were non-linear across the 0.01 to 8.0 mg kg(-1) dose range. Clearance (CL) decreased from 2.9 to 0.1 l day(-1) and terminal half-life (t1/2 ) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (tmax ) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. CONCLUSION: A single tabalumab dose administered i.v. or s.c. was well tolerated and had non-linear CL over the dose range investigated in subjects with RA and SLE. The non-linearity likely reflects target-mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE.

An Enhanced Pre- and Postnatal Development Study in Cynomolgus Monkeys with Tabalumab: A Human IgG4 Monoclonal Antibody.

Tabalumab, a human IgG4 monoclonal antibody (mAb) with neutralizing activity against both soluble and membrane B-cell activating factor (BAFF), has been under development for the treatment of autoimmune diseases. The purpose of this study was to determine the potential adverse effects of maternal tabalumab exposure on pregnancy, parturition, and lactation of the mothers and on the growth, viability, and development of the offspring through postnatal day (PND) 204. Tabalumab was administered by subcutaneous injection to presumed pregnant cynomolgus monkeys (16-19 per group) every 2 weeks from gestation day (GD) 20 to 22 until parturition at doses of 0, 0.3, or 30 mg/kg. Evaluations in mothers and infants included clinical signs, body weight, toxicokinetics, blood lymphocyte phenotyping, T-cell-dependent antibody response (infants only), antitherapeutic antibody (ATA), organ weights (infants only), and gross and microscopic histopathology. Infants were also examined for external and visceral morphologic and neurobehavioral development. There were no adverse tabalumab-related effects on maternal or infant endpoints. An expected pharmacological decrease in peripheral blood B-lymphocytes occurred in adults and infants; however, B-cell recovery was evident by PND154 in adults and infants at 0.3 mg/kg and by PND204 in infants at 30 mg/kg. At 30 mg/kg, a reduced IgM antibody response to T-cell-dependent antigen keyhole limpet hemocyanin (KLH) was observed following primary immunization. Following secondary KLH immunization, all infants in both dose groups mounted anti-KLH IgM and IgG antibody responses similar to control. Placental and mammary transfer of tabalumab was demonstrated. In conclusion, the no-observed-adverse-effect level for maternal and developmental toxicity was 30 mg/kg, the highest dose tested. Exposures at 30 mg/kg provide a margin of safety of 16× the anticipated clinical exposure.

Developmental Toxicity and Fertility Assessment in Rabbits with Tabalumab: A Human IgG4 Monoclonal Antibody.

Tabalumab is a human immunoglobulin G subclass 4 monoclonal antibody that has been under development for autoimmune disorders. Tabalumab has full neutralizing activity against both soluble and membrane B-cell activating factor, a B-cell survival factor. The objectives of these studies were to assess the effects of tabalumab on embryo-fetal development and on male (M) and female (F) fertility in rabbits, a pharmacologically relevant species. Doses were administered at 0 (vehicle control), 0.3 (embryo-fetal study only), 1.0, and 30 mg/kg. In the embryo-fetal study, pregnant rabbits does were given a single dose by intravenous injection on gestation day (GD) 7. In the fertility studies, tabalumab was administered by intravenous injection every 7 days starting 2 (F) or 4 (M) weeks before mating, during cohabitation, and until necropsy (M) or through GD 18 (F). Treated animals were mated with untreated partners. Parental clinical signs, body weight, food consumption, blood lymphocyte phenotyping, organ weights, morphologic pathology, ovarian and uterine observations, sperm parameters, and fertility indices were evaluated along with conceptus viability, weight, and morphology. Exposure assessments were made in all main study animals and satellite animals. No adverse parental, reproductive, or developmental effects were observed in any study at any dose. A pharmacodynamic response consisting of dose-dependent decreases in the percent and number of total B lymphocytes and increases in the percent and/or number of total T lymphocytes was observed in parental rabbits at 1.0 and 30 mg/kg. In conclusion, no adverse reproductive or developmental effects were observed in rabbits following exposure to tabalumab at doses as high as 30 mg/kg and exposures at least 14-fold greater than human exposure levels.

Anti-B-Cell-Activating Factor (BAFF) Therapy: A Novel Addition to Autoimmune Disease Management and Potential for Immunomodulatory Therapy in Warm Autoimmune Hemolytic Anemia.

Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA. Some patients do not respond to rituximab, and relapses are common. These relapses are associated with elevated B-cell-activating factor (BAFF) levels and the presence of quiescent long-lived plasma cells (LLPCs) in the spleen. A new group of immunomodulatory drugs, B-cell-activating factor inhibitors (BAFF-i), demonstrated efficacy in multiple autoimmune diseases and have the potential to improve WAIHA treatment outcomes by targeting B-cells and LLPCs. This article reviews the role of BAFF in autoimmune disorders and the currently available literature on the use of BAFF-directed therapies in various immunologic disorders, including WAIHA. Collectively, the clinical data thus far shows robust potential for targeting BAFF in WAIHA therapy.

Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation.

B cell-activating factor (BAFF) can bind with specific receptors to activate signalling pathways associated with the B cell activation. Belimumab and tabalumab are anti-BAFF (B cell depleting) monoclonal antibodies, with therapeutic efficacy demonstrated for the treatment of autoimmune disorders, while belimumab was approved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and exhibited better clinical outcome than tabalumab. In this investigation, the combination modes of BAFF-belimumab and BAFF-tabalumab complexes were simulated in silico to better understand the reason for the comparative inhibitory difference between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed through homology modelling. The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, while that of BAFF-tabalumab complex was analyzed by protein-protein docking following the molecular dynamics simulation. Both belimumab and tabalumab were bound with BAFF at the same hydrophobic center to which the natural receptors of BAFF bind as well. Belimumab heavy chain components I51, F54, K58, D100, D101, L102, L103, and P105 and R27, Y30, K49, and S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly via hydrogen bonds, salt bridges, and hydrophobic interactions. More importantly, belimumab could bind to L83 of BAFF and produce steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Therefore, our results indicated that belimumab has a better clinical outcome compared with tabalumab mainly because belimumab could bind to L83 of BAFF and interfere the formation of a BAFF 60-mer, besides mediating inhibition of the interaction of BAFF with its receptors.

Inhibition of B cell activating factor (BAFF) in the management of systemic lupus erythematosus (SLE).

INTRODUCTION: The anti-BAFF monoclonal antibody, belimumab, was approved 5+ years ago by the US Food and Drug Administration for the treatment of adult SLE patients. Although BAFF is now a proven therapeutic target in SLE, the limited clinical efficacy both in the clinical trials setting and in 'real-life' experience begs for further therapeutic improvement. Areas covered: In addition to belimumab, three other BAFF antagonists (atacicept, blisibimod, tabalumab) that biologically differ from belimumab are being or have been evaluated in SLE late-stage clinical trials. Literature search was performed using the search words/phrases, 'BAFF', 'BLyS', 'APRIL', 'BCMA', 'TACI', 'BR3', 'belimumab', 'atacicept', 'blisibimod', 'tabalumab', 'lupus clinical trial' along with papers from the author's personal library. Expert commentary: The reasons underlying current lack of enthusiasm among clinicians for BAFF antagonism are discussed, and speculation if offered regarding the use of a BAFF antagonist as part of sequential therapy and regarding the utility of individual or pairs of BAFF receptors as therapeutic targets.

Fully human anti-BAFF inhibitory monoclonal antibody tabalumab does not adversely affect T-dependent antibody responses in cynomolgus monkey (Macaca fasicularis): A summary of three pre-clinical immunotoxicology evaluations.

The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. Study 1, a 4-week pilot study, evaluated biweekly intravenous (IV) control, and 0.3, 1.0, 5.0, and 15.0 mg/kg tabalumab doses. Study 2 evaluated IV control, and 0.1, 1.0, and 30.0 mg/kg tabalumab doses biweekly for 6 weeks. Study 3 evaluated IV control and 0.1, 1.0, 30.0 mg/kg, and subcutaneous (SC) 30.0 mg/kg tabalumab biweekly for 6 months, with recovery (16 weeks) to monitor standard immunotoxicity endpoints. T-cell dependent primary and secondary antibody responses to tetanus toxoid antigen challenge (4-week and 6-week studies) or keyhole limpet hemocyanin (KLH; 6-week and 6-month studies) were evaluated as a measure of immunocompetence, together with quantitation of T- and B-cell subsets. In addition, anti-tabalumab antibody formation (6-week and 6-month studies) was assessed. The results indicated that, despite expected decreases in circulating B-cell populations, no changes in follicle histopathology or organ weights, except decreases in spleen weight (after 6-months of 30 mg/kg IV/SC treatment only), were attributed to tabalumab. Non-adverse microscopic decreases in size or number of germinal centers in spleen, mesenteric, and mandibular lymph nodes occurred, but without an effect on antibody responses to KLH or tetanus. At 16-weeks recovery, microscopic compound-related changes observed after 6 months of treatment were completely reversed (0.1 mg/kg group) and partially reversed (1.0 and 30.0 mg/kg groups), while peripheral blood B cells remained 66-72% reduced from baseline. Despite reduced germinal centres in lymphoid organs, and reductions in circulating B cells, T-cell-dependent humoral immunity was maintained following tabalumab administration in three safety studies in cynomolgus monkeys.