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ADAM randomised four men in twenty-six months, and the eligibility window is the reason
Ferring's placebo-controlled trial of follitropin delta in idiopathic male infertility closed after enrolling four of the men it needed. The endocrine data from the one treated participant show the drug worked exactly as designed.
Mechanism Risk Score
| Component | Points |
|---|---|
| Phase-weighted failure burden | 8.1 / 30 |
| Archetype severity | 2.0 / 25 |
| Temporal recency | 3.4 / 15 |
| Genetic evidence deficit | 4.2 / 15 |
| Programmatic saturation | 11.3 / 15 |
For FSHR in Male idiopathic infertility, the Mechanism Risk Score is 29/100 (yellow band). The score is a failure-burden index derived from Claidex post-mortems on this target–disease pair, not a probability of approval.
Single Phase 2 termination driven by recruitment feasibility, not biology. Score is dominated by saturation, since seven approved gonadotropins target FSHR and none is approved in the male indication.
This score does not predict whether the next trial will succeed. It flags how heavy the documented mechanistic failure record is before a new program is justified.
What was tried
Ferring ran ADAM, a randomised, double-blind, placebo-controlled Phase 2 trial of follitropin delta in men with idiopathic infertility, an unexplained reduction in semen quality. Men received 12 micrograms daily by subcutaneous injection, or placebo, for six months, then three months of observation. The primary endpoint was a vital pregnancy in the female partner within nine months of randomisation, defined as an intrauterine gestational sac with a fetal heartbeat.
The trial opened on 16 August 2022 and completed on 23 October 2024. Over 26 months it randomised four participants, one to follitropin delta and three to placebo. The registry gives the reason plainly: the probability of enrolling in a reasonable timeframe was too low, and the stop was not for safety.
Follitropin delta is ChEMBL CHEMBL5315064, a recombinant protein at maximum clinical phase 4, listed under the synonyms FE 999049 and Rekovelle, and approved for female ovarian stimulation. ADAM was an indication expansion.
The biological hypothesis
Follitropin delta is recombinant human FSH produced in a human cell line. It acts on FSHR (Ensembl ENSG00000170820), the G protein-coupled receptor for follitropin. In the testis FSHR sits on Sertoli cells, where FSH support is required for quantitatively normal spermatogenesis.
Open Targets scores the FSHR association with male infertility at 0.72135, with genetic association at 0.8444 and clinical evidence at 0.8176. The genetic arm is not incidental. FSHR is a well-studied pharmacogenetic locus, and the Thr307Ala and Asn680Ser haplotype has been examined repeatedly for its effect on receptor sensitivity and FSH response.
The rationale was that a subset of men labelled idiopathic have insufficient FSH drive at the Sertoli cell despite serum FSH inside the normal range, and that more ligand raises sperm output enough to make couples fertile. Reviews describe modest gains in sperm parameters with uncertain effects on live birth, which is why a placebo-controlled trial with a pregnancy endpoint was the right study.
What actually happened
Four men were randomised and all four completed. No pregnancies occurred, 0 of 1 on follitropin delta and 0 of 3 on placebo, with no positive partner beta-hCG tests. Two of three placebo participants met the composite responder definition, against 0 of 1 on drug.
The endocrine data from the single treated man show the drug behaved as designed. His FSH rose 2.10 IU/L, inhibin B rose 28.0 pg/mL and testosterone rose 6.25 nmol/L, against placebo medians of 0.10 IU/L, minus 4.0 pg/mL and minus 0.35 nmol/L. The inhibin B rise is a Sertoli cell response, the readout the mechanism predicts.
His semen parameters fell over the same interval. Total sperm count changed by minus 13.01 million, total motile sperm count by minus 3.74 million and concentration by minus 2.14 million per mL, against placebo medians of minus 3.75, minus 0.965 and minus 0.70. No adverse events and no anti-FSH antibodies were reported. One treated participant is an anecdote and supports no comparison.
Failure mechanism, best guess
The archetype is enrollment_collapse, and the mechanism sits in the protocol, not the biology.
ADAM required a man to sit inside a narrow laboratory window: total sperm count 5 to 39 million, motility at least 10%, semen volume at least 1.4 mL, FSH 2.0 to 12.0 IU/L, LH 1.2 to 7.5 IU/L and testosterone at least 300 ng per dL, each confirmed on two samples two weeks apart. Those windows were intersected with couple-level criteria: the man 18 to 50, the partner 18 to 38, and 12 to 60 months of infertility.
Burden compounded the funnel. The sponsor's trial site describes screening of up to 90 days, six months of daily self-injection, three months of observation, at least eight site visits, and an agreement to seek no outside fertility treatment for six months. For a couple already a year into infertility, that competes with in vitro fertilisation.
At four participants across 26 months the realised rate was 0.15 randomisations per month, one every 6.6 months. Nothing about the biology was tested. The trial never assembled a population.
How to prevent this next time
Endpoint-level data cannot support a power calculation, because a pregnancy endpoint on one treated man carries no usable variance. The levers are feasibility modelling and biomarker enrichment.
The first is a computed feasibility gate. The rate of 0.15 randomisations per month follows from two registry facts, the open interval of 799 days and the count of four. A trial powered on a pregnancy endpoint needs participants in the hundreds, which at that rate is a horizon measured in decades. A pre-specified enrollment futility rule, for example a decision point at 12 months requiring a minimum randomisation rate, converts a 26-month attrition into a 12-month answer.
The second is prospective screen-failure accounting. Each window was defensible alone, and the registry does not post how many men were screened. A pilot measuring the joint pass rate of the full criterion set against a real andrology population, before the design is locked, prices the funnel rather than discovering it.
The third is biomarker enrichment, which stays qualitative because no sourced allele frequency or effect estimate is presented here. The FSHR Thr307Ala and Asn680Ser haplotype is the obvious candidate for identifying likely responders. Genotype enrichment narrows the pool further, trading feasibility against effect size, and only pays if the design also widens the phenotypic window.
The single highest leverage change would have been running a screen-failure pilot against the full criterion set in a real andrology population, and treating the joint pass rate as a go or no-go gate before opening the randomised trial.
What this means for similar programs
FSHR is well served on the female side. Open Targets lists seven approved agents against it, including urofollitropin, menotropins and follitropin alfa. That drives the Claidex mechanism risk score for FSHR to 29 in the yellow band, with saturation contributing 11.3.
The asymmetry is the point. Seven approved gonadotropins exist and none is approved for idiopathic male infertility, despite an association score above 0.72. The gap is not molecule availability and not target validity. The male indication demands a couple-level endpoint, a long observation window and an eligibility definition built by exclusion, and no sponsor has solved the recruitment problem those three create together.
Any team planning a male reproductive endocrinology trial should read this as a warning about arithmetic rather than about FSH. The trial did not answer whether follitropin delta helps these men. That remains open.
Open questions
How many men were screened to randomise four, and which individual criterion drove the largest share of screen failures?
Does a defined subgroup, such as men with low-normal FSH plus a specific FSHR genotype, show a large enough effect to make a feasible trial possible?
Sources
ClinicalTrials.gov record and posted results, NCT05403476, retrieved 31 August 2026. https://clinicaltrials.gov/study/NCT05403476 ADAM participant information, Ferring, retrieved 31 August 2026. https://www.adamclinicaltrial.com/details Santi D, et al. Prospects for FSH Treatment of Male Infertility. J Clin Endocrinol Metab.
Simoni M, Santi D. Pharmacogenetics of FSH Action in the Male. Front Endocrinol.
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