The Bial 10-2474 Phase 1 Study-A Drug Development Perspective and Recommendations for Future First-in-Human Trials

Abstract

BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses. After only 5-6 days of multiple-dose administration of 50 mg daily in the MAD phase, several subjects became quite ill with central nervous system symptoms. One subject progressed to brain death within several days of symptom onset. Magnetic resonance imaging scans demonstrated signal abnormalities consistent with microbleeds affecting the hippocampus and pons, suggestive of possible cytotoxic or vasogenic edema compatible with a toxic/metabolic process. There were no findings at lower MAD doses or during the SAD phase. The toxicology program carried out in 4 preclinical species (mouse, rat, dog, and monkey) did not demonstrate significant neurotoxicity. The probable mechanism of neurologic toxicity demonstrated in humans at the 50-mg daily dose was inhibition of off-target cerebral receptors or through another mechanism. Additional recommendations have been proposed for future first-in-human studies to maximize subject safety. However, one must also accept the basic premise that, in general, first-in-human phase 1 studies are remarkably safe, and these rare events are not 100% avoidable during the drug development process.

Reply to Letter: The Use of IC50 for Potency and MTD as Objective in Study BIA 10‐2474, by Mattheus van Iersel, MD

“…1 I have pointed out previously that additional clinical signs were noted in the monkeys at this dose consisting of weakness, incoordination and tremor. 3 This underscores my original concern that the 100 mg/kg dose is an overestimate of the true NOAEL in monkeys. In addition, cerebral damage was noted in the hippocampus in several rodents, with gliosis and inflammatory cell reaction at high doses in the rat (150 mg/kg) and in mice (500 mg/kg), but these doses translate to very high human equivalent doses.…”

“…2 Despite some of the limitations in calculating IC50 for potency determination of a covalently bound drug such as BIA 10-2474, it is still well known that it is considerably less potent as an inhibitor of FAAH vs other FAAH inhibitor drugs in development (potency in the micromolar range vs nanomolar range for the other drugs). [1][2][3] Dr van Iersel raises additional points regarding the safety and ethics of defining the maximum tolerated dose (MTD) in subjects if there are irreversible toxicities observed in preclinical toxicology studies that are not easily monitored in man. In previous publications, I have stated that pushing the dose to MTD may not be warranted in this situation, and one should consider using pharmacokinetic exposures based on toxicokinetic data and/or pharmacodynamic markers to curtail dose escalation in a FIH study to avoid placing subjects at risk.…”

“…In previous publications, I have stated that pushing the dose to MTD may not be warranted in this situation, and one should consider using pharmacokinetic exposures based on toxicokinetic data and/or pharmacodynamic markers to curtail dose escalation in a FIH study to avoid placing subjects at risk. 3,4 This may apply to drugs with delayed toxicities or with a narrow therapeutic index. I agree with Dr van Iersel that, depending on the therapeutic index of the drug, one might limit the maximum exposure to a sufficient supratherapeutic dose without aiming to determine dose-limiting toxicities (DLT) and MTD.…”

“…In addition, cerebral damage was noted in the hippocampus in several rodents, with gliosis and inflammatory cell reaction at high doses in the rat (150 mg/kg) and in mice (500 mg/kg), but these doses translate to very high human equivalent doses. 1,3 Importantly, at the NOAEL dose of 10 mg/kg in the rat, the most sensitive animal toxicology species, there were no irreversible central nervous system (CNS) findings, and this was the dose on which human dose calculations were made to determine starting dose and maximal dose administered in man. However, one must recognize that the safety margin was only in the range of 1.4 to 1.5 when the area under the drug concentration-time curve in rat at the 10 mg/kg NOAEL toxicology dose was compared with the estimated steady-state area under the curve in man at the highest dose cohort of 50 mg/day.…”

“…However, one must recognize that the safety margin was only in the range of 1.4 to 1.5 when the area under the drug concentration-time curve in rat at the 10 mg/kg NOAEL toxicology dose was compared with the estimated steady-state area under the curve in man at the highest dose cohort of 50 mg/day. 3 At the sponsor stated NOAEL dose of 100 mg/kg in monkeys which produced axonal dystrophy in the medulla, the safety margin was >10 (3). The safety margin would have been less had the sponsor correctly identified the NOAEL in this species.…”