State of the field, second pass
Six weeks on, the ladder has not moved: one program has adult safety data and
nothing else, and everything else is upstream of a person.
Written 2026-09-07. This is the second pass; it supersedes the first pass of
2026-07-28, which stays published and unchanged in the archive. The pass was due
2026-08-25 on the four-week cadence and is published thirteen days late; the
assessment is current to 2026-09-07. Since the first pass, the lead program has
cleared a Japanese regulatory step toward a Phase IIa trial and the record has
gained a surrogate-endpoint proposal and a USAG-1 review, the organoid programs
have added results to the basis, and the root-organoid program has hit a scaling
constraint. None of it is human efficacy data. No tier moved.
Every program’s basis was re-verified this pass against the research pool and
the ledger; nothing rests on an entry older than the 120-day window without a
stated reason.
Tier ladder
- Tier 5: Replicated human efficacy. Held by: nothing.
- Tier 4: Human efficacy or safety data, single program. Held by: anti-USAG-1 / TRG-035.
- Tier 3: Small or single-center human data, narrow endpoint. Held by: pulp and dentin repair.
- Tier 2: Animal result, no human protocol proposed. Held by: bioengineered tooth germ, dental epithelial organoids, tooth-root organoids.
- Tier 1: In vitro only, or mechanism without a tissue result. Held by: nothing at this pass.
Per-program assessment
Anti-USAG-1 / TRG-035 (Toregem BioPharma, Kyoto University): tier 4, held
The human program has still answered only one question: whether a single
ascending dose is tolerated in adults. Phase I at Kitano Hospital enrolled adults
with a safety primary endpoint (registry entry and trial announcement, 3 May
2024), and the sponsor’s disclosure of 19 May 2026 describes Phase I as complete
with Phase II in preparation. No peer-reviewed human result set is public and no
efficacy endpoint has been tested in anyone.
New to the basis since the first pass, and none of it data:
- The PMDA clinical trial notification investigation for the Phase IIa trial was
completed on 17 August 2026, per the sponsor’s disclosure (toregem-2026-pmda-ctn).
This is a procedural regulatory step that precedes a trial; it reports no
results and does not by itself start dosing.
- A 2026 Journal of Oral Biosciences paper from the antibody’s originators
proposes MRI/CT imaging biomarkers as surrogate endpoints for pediatric
tooth-regeneration trials, developed in animals (murashima-suginami-2026-imaging).
A proposal for how to measure an endpoint is not an endpoint.
- A February 2026 review maps USAG-1 expression to gingival fibroblast and
epithelial subsets and restates the clinical timeline (moradi-2026-usag1-review).
It cites no human trial results beyond what the sponsor has disclosed.
Like the imaging paper it predates pass 1 as a publication; both entered the
record after it.
Tier 4 stands on the same basis as the first pass: human safety data exists for
a single program, and nothing more.
What would change this assessment: an efficacy endpoint in the intended
population, children with congenital anodontia, reported with its statistical
plan rather than by press release; or a dated human image showing a tooth in a
site that was radiographically empty before treatment.
Bioengineered tooth germ: tier 2, held
No new result this pass. The basis stands: a transplanted bioengineered tooth
germ erupted, occluded, and responded to mechanical and pain stimuli in an adult
mouse (2009); chemically defined culture supports mouse tooth reconstitution
with BMP-driven enamel induction (2024); decellularized porcine tooth-bud
scaffolds seeded with dental and endothelial cells form tooth-like tissues,
including periodontal-ligament-like tissue with Sharpey’s fibers, in adult
minipigs (2025); lingual-buccal positional memory persists in dissociated and
reaggregated mouse dental mesenchyme (2025); and the inductive tooth-germ
secretome, including small extracellular vesicles, is not sufficient to replace
living mesenchyme for tooth induction in mice (2025). Human cell sourcing and
developmental control remain open; no human protocol has been proposed.
What would change this assessment: independent replication of tooth
formation in a large animal by a group with no commercial stake, or a credible
human cell-sourcing plan.
Dental epithelial organoids: tier 2, held
Three results joined the basis since the first pass, and none moves the tier
(all three were published before pass 1 and entered the record after it).
A 2026 study reports that a soluble Notch agonist matures human ameloblast
organoids and produces enamel-like mineral under the mouse kidney capsule
(patni-2026-ameloblast-organoid): the cells are human, the readout is in an
animal site, which keeps the program at tier 2 under the ladder. A 2026 protocol
induces PITX2-positive embryonic oral epithelium from human pluripotent stem
cells in ten days (nakashima-2025-oral-epithelium): in vitro, a feeder layer for
future work. A 2025 study reports that a biomimetic elastin-like matrix
nucleates enamel-like mineral on acid-etched human enamel and dentin ex vivo,
restoring stiffness, hardness, and wear resistance (hasan-2025-biomimetic-enamel-restoration):
surface repair on a section of tooth, not enamel regrowth in a mouth. The 2022
human epithelial organoid result with in vivo assessment remains the tier basis.
What would change this assessment: organoid-derived enamel tissue of native
thickness and orientation, integrated in a living jaw.
Tooth-root organoids: tier 2, held
New since the first pass: a 2026 scaling study from the originators’ group finds
that smaller root-organoid constructs lose the layered mineral pattern, pointing
to a minimum cell mass for proper dentin, pulp, cementum, and ligament
patterning (calabrese-2026-root-organoid-scaling), the only new primary result
among the tracked programs this window. This is a constraint on the
route to a larger construct, not a new capability. The 2024 self-assembly result
from postnatal human dental stem cells, including in vivo assessment, remains
the tier basis. Eruption, crown formation, innervation, and periodontal
integration are still unresolved, and nothing has been placed in an animal jaw.
What would change this assessment: eruption, crown formation, innervation,
and periodontal integration of an organoid-derived construct in an animal jaw.
Pulp and dentin repair: tier 3, held
The basis stands and no new human evidence beyond the pulp space appeared this
pass. The tier rests on the randomized trial of autologous deciduous-tooth pulp
stem cell implantation in immature permanent incisors: 26 patients evaluated
with 24-month imaging, regenerated pulp tissue with vessels and nerves
(xuan-2018), plus a 2026 small randomized trial of platelet-rich fibrin versus
mineral trioxide aggregate for direct pulp capping in 20 adult molars, reporting
a borderline larger dentin-bridge volume with PRF at six months and clinical
outcomes indistinguishable from MTA (asthana-2026-prf-mta-pulp-capping).
Tideglusib dentin repair remains preclinical (neves-2017). The research pool gained further
pulp-dentin repair studies in this window, on exosomes, small molecules, and
platelet derivatives; all are incremental preclinical or small-clinical work,
and none is controlled human evidence that repair extends beyond the pulp space.
What would change this assessment: controlled human evidence that repair
extends beyond the pulp space, or true enamel regrowth rather than surface
remineralization.
Myth vs record
- Claim: a tooth-regrowth drug will be available in 2030. Verdict:
unsupported. Still no filing, guidance, or trial schedule in the record
adopts a date. The 17 August 2026 PMDA notification step concerns trial
preparation and carries no availability date.
- Claim: the Phase I trial enrolled children aged 2 to 6. Verdict:
misstated. Phase I enrolled adults with a safety primary endpoint. Children
with congenital anodontia remain the planned later population, and no
pediatric dosing has begun.
- Claim: the antibody works by blocking both BMP and Wnt. Verdict:
misstated. The 2021 proof-of-concept paper reports field-selective BMP
action; the Wnt half is an inference carried forward from reviews. The 2026
Moradi review discusses both pathways and reports no new functional data
settling the question (moradi-2026-usag1-review).
- Claim: the tooth-regrowth drug has been approved in Japan, or Phase IIa
is already running. Verdict: misstated. Completion of the PMDA clinical
trial notification investigation is a procedural prerequisite for starting
a trial. The sponsor has disclosed no enrollment, no dosing, and no results
for Phase IIa (toregem-2026-pmda-ctn).
- Claim: humans can be made to grow a third set of teeth. Verdict: not
established. Established in mice and ferrets. In humans, only tolerability
in adults has been tested, and no human has grown a tooth in the record.
What would change the field-level assessment
- A dated human image showing a tooth in a site that was radiographically empty
before treatment.
- An efficacy endpoint, in children, reported with its statistical plan rather
than by press release.
- Independent replication of tooth formation in a large animal by a group with
no commercial stake.
Corrections applied this pass
None. No correction has been logged since the first pass.
Cited here
- kitano-2024-phase1: first-in-human Phase I announcement, single ascending dose, adults.
- toregem-2026-financing: Phase I complete and Phase II preparation disclosure, 19 May 2026.
- toregem-2026-pmda-ctn: PMDA CTN investigation completed for Phase IIa, 17 August 2026.
- murashima-suginami-2021: anti-USAG-1 rescues tooth agenesis in mice and ferrets.
- murashima-suginami-2026-imaging: imaging biomarkers proposed as surrogate endpoints.
- moradi-2026-usag1-review: USAG-1 expression map and clinical-timeline review.
- ikeda-2009: bioengineered tooth germ functional in an adult mouse.
- zhang-2024-chemically-defined-tooth-reconstitution: chemically defined mouse tooth reconstitution.
- zhang-yelick-2025-decellularized-tooth-bud: decellularized scaffolds in minipigs.
- kim-2025-dental-mesenchyme-position: positional memory in dental mesenchyme.
- birjandi-sharpe-2025-tooth-germ-secretome: secretome does not replace living mesenchyme.
- hemeryck-2022: human dental epithelial organoids with in vivo assessment.
- patni-2026-ameloblast-organoid: Notch-agonist-matured ameloblast organoids, enamel-like mineral in mice.
- nakashima-2025-oral-epithelium: PITX2-positive oral epithelium from human pluripotent stem cells.
- hasan-2025-biomimetic-enamel-restoration: biomimetic enamel-like mineral ex vivo.
- calabrese-2024: self-assembled tooth root organoids from human dental stem cells.
- calabrese-2026-root-organoid-scaling: size scaling disrupts the layered mineral pattern.
- xuan-2018: randomized autologous pulp stem cell trial, 26 patients, 24-month imaging.
- asthana-2026-prf-mta-pulp-capping: PRF versus MTA direct pulp capping randomized trial.
- neves-2017: tideglusib promotes reparative dentin in mice.
Every entry dated and cited · corrections logged, never silently edited ·
pass archive