Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surface of B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells. By simultaneous binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates the formation of an immunological synapse with subsequent T-cell activation and proliferation, secretion of cytokines and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.
In Study NP30179, 84% (84/100) patients were already B cell depleted (<70 cells/µL) before pretreatment with obinutuzumab. B cell depletion increased to 100% (94/94) after obinutuzumab pretreatment prior to glofitamab treatment initiation and remained low during glofitamab treatment.
During Cycle 1 (step-up dosing), transient increases in plasma IL-6 levels were observed at 6 hours post glofitamab infusion, which remained elevated at 20 hours post-infusion and returned to baseline prior to the next infusion.
In Study NP30179, 16/145 patients who were exposed to glofitamab experienced a post-baseline QTc value >450ms. One of these cases was assessed to be of clinical significance by the investigator. No patients discontinued treatment due to QTc prolongation.
Non-compartmental analyses indicate that glofitamab serum concentration reaches the maximal level (Cmax) at the end of infusion and declines in a bi-exponential fashion. Glofitamab exhibits linear and dose-proportional pharmacokinetics over the dose range studied (0.005 to 30 mg) and is independent of time.
Glofitamab is administered as an intravenous infusion. Peak concentration of glofitamab (Cmax) was reached at the end of the infusion.
Following intravenous administration, the central volume of distribution was 3.33 L, which is close to total serum volume. The peripheral volume of distribution was 2.18 L.
The metabolism of glofitamab has not been studied. Antibodies are cleared principally by catabolism.
The glofitamab serum concentration-time data are described by a population pharmacokinetic model with two compartments, and both time-independent clearance and time-varying clearance.
The time-independent clearance pathway was estimated as 0.602 L/day and the initial time-varying clearance pathway as 0.396 L/day, with an exponential decay over time (Kdes ~0.445/day). The estimated decay half-life from the initial total clearance value to the time-independent clearance only was estimated as 1.56 days.
The effective half-life in the linear phase (i.e., after the contribution of time-varying clearance has collapsed to a negligible amount) is 6.54 days (95% CI: 3.74, 9.41) based on the population pharmacokinetic analysis.
No differences in glofitamab exposure were noted in patients 65 years of age and older and those under 65 years based on population pharmacokinetic analysis.
The population pharmacokinetic analysis of glofitamab showed that creatinine clearance does not affect the pharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mild or moderate renal impairment (CrCL 30 to <90 mL/min) were similar to those in patients with normal renal function. Glofitamab has not been studied in patients with severe renal impairment.
Population pharmacokinetic analyses showed mild hepatic impairment does not affect the pharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN) were similar to those with normal hepatic functions. Glofitamab has not been studied in patients with moderate or severe hepatic impairment.
No clinically significant differences in the pharmacokinetics of glofitamab were observed based on age (21 years to 90 years), gender and body weight (31 kg to 148 kg).
No studies have been conducted to establish the carcinogenic potential and mutagenic potential of glofitamab.
No fertility assessments in animals have been performed to evaluate the effect of glofitamab.
No reproductive and developmental toxicity studies in animals have been performed to evaluate the effect of glofitamab. Based on low placental transfer of antibodies during the first trimester, the mechanism of action of glofitamab (B cell depletion, target-dependent T cell activation, and cytokine release), the available safety data with glofitamab and data on other anti-CD20 antibodies, the risk for teratogenicity is low. Prolonged B cell depletion can lead to increased risk of opportunistic infection, which may cause foetal loss. Transient CRS associated with glofitamab administration may also be harmful to the foetus.
In a study in cynomolgus monkeys, animals experiencing severe CRS after a single intravenous dose of glofitamab (0.1 mg/kg) without obinutuzumab pre-treatment had erosions in the gastrointestinal tract and inflammatory cell infiltrates in spleen and sinusoids of the liver and sporadically in some other organs. These inflammatory cell infiltrates were likely secondary to cytokine-induced immune cell activation. Pre-treatment with obinutuzumab resulted in the attenuation of glofitamab-induced cytokine release and related adverse effects by depleting B cells in peripheral blood and lymphoid tissue. This allowed at least 10 times higher doses of glofitamab (1 mg/kg) in cynomolgus monkeys resulting in a Cmax of up to 3.74 times the human Cmax at the recommended 30 mg dose.
All findings with glofitamab were considered pharmacologically mediated effects and reversible. Studies longer than 4 weeks were not performed, as glofitamab was highly immunogenic in cynomolgus monkeys and led to loss of exposure and loss of the pharmacologic effect.
As all relapsed or refractory DLBCL patients to be treated have been exposed to anti-CD20 treatment before, the majority will likely have low circulating B cell levels due to residual effects of prior antiCD20 therapy, before treatment with obinutuzumab. Therefore, the animal model without prior rituximab (or other anti-CD20) treatment may not fully reflect the clinical context.
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