Our Science: Communications
Abstract selected for oral communication O-288
IGX12, an FSH-potentiating innovative therapeutic antibody for use in male and female infertility, showed good tolerability in a first-in-human, single ascending dose study
E. Bestel (1), E. Kara (1), T. Ziegler (1), D. Coquoz (1), R. Frydman (2), M. C. Maurel (1)
(1) Igyxos S.A., Research & Development, Nouzilly-, France
(2) Hôpital FOCH, Service de Gynécologie Obstétrique, Suresnes, France
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Study question: Are increasing doses of single, subcutaneous (s.c.) injections of IGX12 safe for use in male and female healthy volunteers?​​
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Summary answer: In a single ascending dose (SAD) study, IGX12 demonstrated a tolerability comparable to placebo in 16 male and 16 female healthy volunteers.
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What is known already: Follicle stimulating hormone (FSH) regulates gametogenesis by acting on granulosa cells and Sertoli cells. IGX12 exerts its pharmacological action by binding to FSH and potentiating its activity, thereby improving gametogenesis.
In vivo studies in female cynomolgus monkeys treated with IGX12 demonstrated a three-time higher ovarian stimulation output. In a model of male hypogonadotropic hypogonadism in rats, IGX12, added to hormonal treatment with FSH/LH and hCG, increased motile sperm count. In male hypogonadal mice, the addition of IGX12 to FSH/hCG treatment led to a ~6-fold increase in motile sperm count.
There were no obvious signs of toxicity in any species tested.
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Study design, size, duration: This double-blind study followed recommendations
for a First-in-Human study with sequential dose escalation after
thorough safety review of each cohort, and a sentinel, staggered approach
within cohorts, allowing investigation of the safety and tolerability of IGX12.
No formal hypothesis was defined.
Subjects received IGX12 or placebo and were followed in hospital for 6 days, followed by up to 11 outpatient visits. The study lasted 16 weeks from the start of treatment.
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Participants/materials, setting, methods: 32 healthy volunteers (16 men and 16 women) were planned to be treated in 4 cohorts testing 5, 10, 20 and 40 µg/kg IGX12. Within each cohort, gender-wise randomization to IGX12 or placebo at a ratio of 3:1 was performed. To facilitate treatment start in female participants, contraception was used to synchronize menstrual cycles.
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Main results and the role of chance: 32 participants aged from 21 to 49 years were treated and completed the study.
Exposure in terms of Cmax and AUC0-tlast increased with increasing doses.
IGX12 was slowly absorbed with a median tmax of 12 to 16 days and slowly eliminated with a half-life of approximately 43 days. There was limited occurrence of anti-drug antibodies, all with low titers, and no observable impact
on IGX12 pharmacokinetics.
In women, no negative effects on ovarian stimulation or hormone levels were observed and increase in ovarian volume and endometrial thickness were within expected ranges.
In men, no effects on testis morphology or hormones were observed.
Sperm counts showed a high intraindividual variability, but values were always
within normal ranges.
Overall, 24 (75%) participants reported a treatment-emergent adverse event (TEAE), with 12 (37.5%) participants reporting TEAEs considered related to IGX12. The frequency of TEAEs was similar across active and placebo.
No severe TEAEs, TEAEs leading to discontinuation or serious TEAEs were reported.
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Limitations, reasons for caution: The study was designed to assess the safety of IGX12. This clean safety profile is to be confirmed in the multiple ascending dose study that is still ongoing in healthy male volunteers.
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Wider implications of the findings: IGX12 is an FSH-potentiating monoclonal
antibody that has been shown to have the potential to change the treatment paradigm for infertility. Its long half-life may allow bi-weekly or monthly dosing. The results of this study will allow further testing and setting up of Phase 2 trials.
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Trial registration number: Yes
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