Intact PTH rises in 34% of patients on revumenib, and hyperparathyroidism is on the label
also called revumenib PTH · menin inhibitor hyperparathyroidism · REVUFORJ parathyroid signal
The approved label for revumenib reports that the parathyroid hormone level went up in about a third of treated patients, and lists hyperparathyroidism as a side effect. That is the same hormone that goes wrong first in people born with a faulty menin gene.
The same thing, for a scientist
The US prescribing information for REVUFORJ reports intact parathyroid hormone increased in 34% of the pooled safety population (N=241; lab denominators 139-240), lists it among the most common adverse reactions at 20% or more, and separately lists **hyperparathyroidism** under *Endocrine disorders* among clinically relevant adverse reactions occurring in under 20% of patients [E1]. This is the single most important correction to the framing that has been used in this graph: the claim that no endocrine parameter is measured in menin-inhibitor development is **false for the FDA label**, although it remains true for the trial registries and for the pivotal publication, which report neither PTH nor hyperparathyroidism anywhere [E2]. The finding matters because primary hyperparathyroidism is the first and commonest manifestation of MEN1, reaching roughly 90% penetrance in carriers [E3].
What the label actually says, verbatim1 deeper
From section 6.1 of the REVUFORJ full prescribing information, read directly from DailyMed on 2026-09-18 1:
- Among the most common (>= 20%) adverse reactions including laboratory abnormalities: "...potassium decreased, parathyroid hormone intact increased, alkaline phosphatase increased..."
- Under Clinically relevant adverse reactions in less than 20% of patients who received REVUFORJ include: ... "Endocrine disorders : Hyperparathyroidism"
- Table 8, Selected New or Worsening Laboratory Abnormalities, denominator 139-240:
| Laboratory abnormality | Grades 1-4 | Grades 3-4 |
|---|---|---|
| Phosphate increased | 51% | - |
| Potassium decreased | 34% | 12% |
| Parathyroid hormone, intact increased | 34% | - |
| Alkaline phosphatase increased | 33% | <1% |
| Phosphate decreased | 25% | - |
| Calcium corrected increased | 15% | 0% |
Safety population: 241 patients, 207 adults and 34 children, including 25 infants under 2 years, 78 children aged 2 to under 12 and 29 adolescents. Median duration of exposure 2.5 months (range <1 to 40 months); 10% exposed beyond 6 months 1.
What it does not say
The label gives no grade 3-4 rate for PTH, no magnitude of the rise, no time course, no attribution of causality, and no statement of whether PTH normalised after discontinuation. It does not report vitamin D status or ionised calcium. It does not say how many of the 34 paediatric patients were among those with raised PTH. Every one of these omissions is answerable from data that already exist in the sponsor's database.
The competing explanations, which are not weak
A raised intact PTH in this population is not diagnostic of a menin effect. At least four ordinary explanations are live and are supported by numbers on the same label 1:
- Renal. Creatinine increased in 38%, and renal impairment is listed among reactions under 20%. Reduced GFR raises PTH by a well-understood route.
- Phosphate. Phosphate increased in 51% - the single commonest laboratory abnormality on the label - and a rising phosphate raises PTH directly. This is the most parsimonious explanation of the whole cluster and is discussed in
risk-revumenib-mineral-axis-phosphate-calcium. - Vitamin D. Not measured; deficiency is near-universal in heavily pretreated inpatients and raises PTH.
- Ascertainment. PTH was in the trial laboratory panel, so it was measured; parameters that are measured generate abnormalities.
What cuts the other way is the direction of the calcium. Corrected calcium increased in 15% with 0% grade 3-4. Secondary hyperparathyroidism from renal impairment, phosphate retention or vitamin D deficiency should push calcium down, not up. A co-occurring rise in PTH and in calcium is the signature of primary hyperparathyroidism - the MEN1 pattern. The label does not report how often the two rose in the same patient, and that single cross-tabulation would go a long way to settling this.
Why this is a finding and not an alarm
Nothing here shows harm. No case of persistent hyperparathyroidism after stopping a menin inhibitor has been published. Grade 3-4 hypercalcaemia was 0%. The exposures are short. The drug produces remissions in children with relapsed KMT2A-rearranged leukaemia, for whom the alternative outcome is usually death.
What has changed is the epistemic status of the risk. It is no longer a mechanistic inference from a crystal structure with no clinical counterpart. There is a measured, on-label, high-frequency disturbance in exactly the hormonal axis that MEN1 hits first, in a drug that occupies the MEN1 protein's peptide pocket. FDA reached the same view and mandated a study - see reg-fda-pmr-endocrine-chronic-menin-inhibition.
| kind | toxicity |
|---|---|
| severity | laboratory abnormality of unknown clinical significance; grade 3-4 hypercalcaemia 0% |
| hyperparathyroidism listed | true |
| label section | 6.1 Adverse Reactions, Table 8 and the Endocrine disorders line |
| mitigation | paired intact PTH, corrected and ionised calcium, phosphate, 25-OH vitamin D and creatinine at baseline, monthly on treatment and at 3, 6 and 12 months after discontinuation; the label already requires monthly electrolytes |
| reported in pivotal publication | false |
| corrects prior graph claim | the assertion that no endocrine parameter appears in menin-inhibitor safety reporting is false for the FDA label and true only for the trial registries and the pivotal publication |
affects
[ "drug-revumenib" ]
measured rates
{
"intact_pth_increased_pct": 34,
"corrected_calcium_increased_pct": 15,
"phosphate_increased_pct": 51,
"phosphate_decreased_pct": 25,
"alkaline_phosphatase_increased_pct": 33,
"creatinine_increased_pct": 38,
"n_safety_population": 241,
"lab_denominator_range": "139-240",
"median_exposure_months": 2.5
}- The counter-argument at full strength: this is a laboratory abnormality in an uncontrolled single-arm population of heavily pretreated leukaemia patients with a 38% rate of rising creatinine and a 51% rate of rising phosphate, either of which raises PTH by ordinary physiology. Zero grade 3-4 hypercalcaemia and no reported clinical sequelae. Attributing it to menin's tumour-suppressor role is an inference, not an observation.
- The co-occurring rise in corrected calcium is what keeps the menin explanation alive, because renal and phosphate-driven secondary hyperparathyroidism should lower calcium. But 15% versus 34% is compatible with two separate, unlinked populations of patients, and the label does not cross-tabulate them.
- Even if the effect is entirely on-target, a reversible biochemical shift over 2.5 months is not MEN1 syndrome, and treating it as though it were would be a serious misreading that could cost children a drug that works.
- How often did intact PTH and corrected calcium rise in the same patient? A single cross-tabulation from the sponsor database would separate primary from secondary hyperparathyroidism and is the highest-value unanswered question in this beat.
- Did PTH normalise after discontinuation, and on what timescale? No off-treatment values are published for any menin inhibitor.
- Is the PTH rise dose- or exposure-dependent? The programme has AUC data on every patient and a twofold dose difference between the CYP3A4-inhibitor and non-inhibitor arms, which makes this directly answerable.
- What were the rates in the 34 paediatric patients, and in the 25 infants under 2 specifically?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The US prescribing information for REVUFORJ (revumenib) reports intact parathyroid hormone increased in 34% of patients, phosphate increased in 51%, phosphate decreased in 25%, corrected calcium increased in 15% (0% grade 3-4) and alkaline phosphatase increased in 33%, in a pooled safety population of 241 patients (207 adult, 34 paediatric including 25 infants under 2 years) with a median exposure of 2.5 months; hyperparathyroidism is listed under Endocrine disorders among clinically relevant adverse reactions in less than 20% of patients.
REVUFORJ (revumenib) tablets, for oral use - US full prescribing information (NDA 218944) · Syndax Pharmaceuticals / US FDA · DailyMed / Drugs@FDA (NDA 218944) 2025What this evidence cannot show
Read verbatim from the DailyMed full prescribing information (setid 6eb3cdbc-0e74-477d-82d6-3bb172d3f63f) on 2026-09-18; every figure above was confirmed in the retrieved document text, not from memory or a summary. Single-arm, uncontrolled data with no comparator, so background rates in an equivalently pretreated leukaemia population are unknown. Laboratory denominators vary 139-240. No causality assessment, no time course, no reversibility data, no paediatric subgroup breakdown.
Evidence that argues against this (1)
- The pivotal peer-reviewed publication of the same programme reports no parathyroid, calcium or phosphate abnormality anywhere. Its adverse-reaction table lists only hypokalaemia (27.7%) among electrolyte events, and its prespecified adverse events of special interest were differentiation syndrome, QTc prolongation and peripheral neuropathy. So the endocrine signal is visible in the regulatory document and invisible in the literature a clinician would read. Issa GC et al. 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
The phase II registration publication of AUGMENT-101 (94 patients, median treatment duration 10 weeks) reports adverse events of special interest as differentiation syndrome, QTc prolongation and peripheral neuropathy, and its table of adverse events occurring in 20% or more of patients contains no parathyroid, calcium or phosphate entry; hypokalaemia (27.7%) is the only electrolyte abnormality listed.
Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). · Issa GC, Aldoss I, Thirman MJ, DiPersio J, Arellano M, Blachly JS, et al., Stein EM · J Clin Oncol 43:75-84 2024What this evidence cannot show
Read in full text via PubMed Central. The absence is of reporting, not necessarily of measurement: the paper does not state which laboratory parameters were collected, and the FDA label shows PTH was collected in at least 139 patients across the programme. This is therefore evidence about what the literature communicates, not about what the trial measured.
Evidence that argues against this (1)
- The adverse events of special interest being differentiation syndrome, QTc prolongation and peripheral neuropathy is the point AGAINST inferring anything about PTH from this trial in either direction. With no endocrine or calcium endpoint prespecified, a PTH elevation would be captured only if it became clinically apparent and was reported, and the median treatment duration was 10 weeks. This publication is therefore not evidence that PTH elevation is absent, and should not be cited as reassurance. Journal of Clinical Oncology 2025
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Parathyroid hyperplasia and adenoma developed in 77% of 258 systematically screened MEN1 germline mutation carriers, reaching a maximum age-related penetrance of approximately 90%, roughly twice the rate of enteropancreatic and pituitary tumours.
Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. · Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F, Dralle H · Clin Endocrinol (Oxf) 67:613-22 2007What this evidence cannot show
Read as abstract. Establishes that the parathyroid is the first and commonest MEN1 target, which is why a parathyroid signal on a menin-pocket ligand is the one worth taking seriously. It says nothing about drug exposure.
Evidence that argues against this (1)
- Parathyroid penetrance near 90% in germline carriers explains why the parathyroid is the first place to look and provides no expected magnitude for a pharmacological effect. The observed human finding is a 34% rate of raised intact PTH over a median ten weeks, which is a different quantity from a decades-long two-hit penetrance and should not be read as its early phase. Clinical Endocrinology 2007
intact PTH increased in 34%; hyperparathyroidism listed under Endocrine disorders on the label
- related to →Primary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin
the same hormonal axis that MEN1 disrupts first
- supports →The same pocket suppresses JUND: menin inhibition's unmeasured endocrine liability in infants
upgrades the risk from a structural inference to a measured on-label signal in the predicted axis
the pocket the drug occupies is the MEN1 protein's peptide pocket
the PTH rise sits inside a wider mineral-axis disturbance that has a mundane renal explanation
the regulator classified elevated parathyroid hormone as a signal of serious risk requiring a clinical trial
zero endocrine reports across 904 revumenib exposures - but the labelled 34% PTH finding also generated zero reports, so the channel is blind
proposes the discriminating measurements that separate on-target from renal explanations
the minimum panel that discriminates on-target parathyroid effect from renal or vitamin-D secondary hyperparathyroidism
Makes the on-target reading of the labelled 34% intact-PTH elevation mechanistically specific rather than asserted
Would discriminate the on-target reading of the labelled 34% PTH elevation from the renal secondary-hyperparathyroidism null
Three models on data that already exists: exposure-response adjusted for creatinine and phosphate, paediatric stratification, and post-discontinuation trajectory