State of the field, third pass

Four weeks on, the ladder has not moved: one program has adult safety data and nothing more, and everything else remains upstream of a person.

Written 2026-10-05. This is the third pass; it supersedes the second pass of 2026-09-07, which stays published and unchanged in the archive. The pass is published on the four-week cadence, on time. Since the second pass, the lead program’s registry entry has flipped to recruitment complete, a sponsor disclosure from November 2025 has been added to the record, the cichlid whole-tooth-regeneration study has completed public review at eLife, and the pulp-dentin stream gained a trial registry record and an in-vitro dose-finding study. None of it is human efficacy data, and no tier moved.

Every program’s basis was re-verified this pass against the research pool, the trial registries, and the sponsor’s disclosure pages; 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. This pass re-verified that answer at the registry: the Phase I record (jRCT2051240154) now shows recruitment status Complete, with a target of 30 healthy adult males aged 30 to 65, a single intravenous dose in five ascending steps, a primary endpoint of safety, and secondary endpoints of pharmacokinetics and anti-TRG035 antibody frequency (kitano-2024-phase1). No outcome data is posted there.

On the sponsor’s side, the news since the second pass is absence. The latest disclosure remains the 17 August 2026 completion of the PMDA clinical trial notification investigation for the Phase IIa trial (toregem-2026-pmda-ctn), a procedural step that precedes a trial and reports no results; the sponsor’s next disclosed step is institutional ethics review at the participating sites. The 28 August 2026 leadership announcement (toregem-2026-leadership) is a governance item, not a field event. No enrollment, no dosing, and no results for Phase IIa have been disclosed.

One record gap is closed this pass: the sponsor disclosed on 27 November 2025 that it had received the US FDA’s response to pre-IND meetings for the US development of TRG-035 (toregem-2025-fda-preind). The disclosure predates the second pass and had not entered the record; it is regulatory preparation and contains no results. A review this window proposes USAG-1/SOSTDC1 as a candidate target for periodontal regeneration and maps the knowledge gaps (hashim-2026-usag1-periodontal); it contains no new functional data.

Tier 4 stands unchanged: human safety data exists for a single program, and nothing more. No peer-reviewed human result set is public and no efficacy endpoint has been tested in anyone.

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

One publication event this window, and it is context rather than capability. The Lake Malawi cichlid study of accelerated whole-tooth replacement passed public review at eLife and was published as the version of record on 24 September 2026 (mubeen-2026-cichlid-tooth-replacement, covered in the analysis stream). Review added a putative dental ectomesenchyme analysis and removed an unsupported marker claim, and the eLife assessment itself states the conclusions rest on computational inference without experimental validation. The quantitative core stands: plucking one jaw half accelerates one-for-one tooth replacement about threefold across three cichlid species. For this program the study is the field’s most detailed time-resolved parts list of a regenerating tooth; it offers no mammal data and no confirmed causal signal.

The mammal basis is otherwise untouched: a transplanted bioengineered tooth germ erupted, occluded, and responded to mechanical and pain stimuli in an adult mouse (2009, ikeda-2009); chemically defined culture supports mouse tooth reconstitution with BMP-driven enamel induction (zhang-2024-chemically-defined-tooth-reconstitution); and 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 (zhang-yelick-2025-decellularized-tooth-bud). The qualifying results also stand: lingual-buccal positional memory persists in dissociated and reaggregated mouse dental mesenchyme (kim-2025-dental-mesenchyme-position), and the inductive tooth-germ secretome, including small extracellular vesicles, is not sufficient to replace living mesenchyme for tooth induction in mice (birjandi-sharpe-2025-tooth-germ-secretome, with a February 2026 publisher correction, birjandi-sharpe-2026-secretome-correction, replacing Figure 7 panels D-I, conclusions unchanged per the authors). No new mammal result appeared this window. 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

No news this pass, and the absence of news is the finding: four weeks produced no new primary result for this program in the pool, the registries, or the citation record. The basis stands: human dental epithelial organoids with a stemness phenotype and in vivo assessment (hemeryck-2022) remain the tier basis, supported by a soluble Notch agonist maturing human ameloblast organoids to enamel-like mineral under the mouse kidney capsule (patni-2026-ameloblast-organoid), PITX2-positive embryonic oral epithelium induced from human pluripotent stem cells in ten days (nakashima-2025-oral-epithelium), and a biomimetic elastin-like matrix nucleating enamel-like mineral on acid-etched human enamel and dentin ex vivo (hasan-2025-biomimetic-enamel-restoration). The program sits at the organoid/model boundary, not at a replacement tooth.

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

No news this pass. The basis stands: self-assembled tooth root organoids from postnatal human dental stem cells organize dentin-, pulp-, cementum-, and ligament-like tissue with in vivo assessment (calabrese-2024), and the 2026 scaling result still constrains the route to a larger construct: smaller root-organoid constructs lose the layered mineral pattern, pointing to a minimum cell mass for proper patterning (calabrese-2026-root-organoid-scaling). Eruption, crown formation, innervation, and periodontal integration remain 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 tier basis stands and this window’s additions qualify it rather than strengthen it. The tier still 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), supported by a 2026 small randomized trial of platelet-rich fibrin versus mineral trioxide aggregate for direct pulp capping in 20 adult molars, with borderline dentin-bridge volume difference and indistinguishable clinical outcomes (asthana-2026-prf-mta-pulp-capping), and qualified by the best available human histology after a regenerative endodontic procedure: dentin-like tissue without an organized odontoblast layer, sparse neurovascular ingrowth, apical osteoid, a single case with a contralateral control (yang-2026-rep-histology-human). Tideglusib dentin repair remains preclinical (neves-2017).

New this window, both short of the ladder’s human bar: a registered randomized trial of sodium hexametaphosphate versus MTA in necrotic immature permanent teeth in children, on the strength of a three-dog split-mouth study, has seen both estimated completion dates pass with no results posted and no registry update since July 2025 (covered in the analysis stream); and an in-vitro dose-finding study pairs low-intensity focused ultrasound with tideglusib in human dental pulp stem cells, a dish result one step upstream of the mouse injury model that already anchors the preclinical tier. Neither 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

1. Claim: TRG035 entered Phase IIa trials in August 2026. Verdict: misstated. What completed on 17 August 2026 was the PMDA investigation of the clinical trial notification, a procedural prerequisite for starting a trial (toregem-2026-pmda-ctn). The sponsor has disclosed no enrollment, no dosing, and no results for Phase IIa; its own next disclosed step is institutional ethics review.
2. Claim: the Phase I trial reported a 68% success rate, with results in March 2026. Verdict: unsupported. No efficacy endpoint existed in the trial: the registry lists safety as the primary endpoint and pharmacokinetics and anti-drug antibody frequency as secondary (kitano-2024-phase1). No result set, peer-reviewed or otherwise, is public. The figure circulates in video and social media with no source.
3. Claim: Phase I proved the drug is safe. Verdict: not established. The sponsor disclosed completion of dosing, not outcomes; no peer-reviewed safety result set is public (kitano-2024-phase1). Tolerability in 30 adults is a real but unpublished dataset, and the record says only that it exists.
4. Claim: a tooth-regrowth drug will be available in 2030. Verdict: unsupported. No filing, guidance, or trial schedule in the record adopts a date; the 2030 figure is carried by clinics and press, not by any disclosed development plan.
5. Claim: the trial enrolled children aged 2 to 6. Verdict: misstated. The registry entry specifies healthy adult males aged 30 to 65 (kitano-2024-phase1). Children with congenital anodontia remain the planned later population, and no pediatric dosing has begun.

What would change the field-level assessment

1. A dated human image showing a tooth in a site that was radiographically empty before treatment.
2. An efficacy endpoint, in children, reported with its statistical plan rather than by press release.
3. Independent replication of tooth formation in a large animal by a group with no commercial stake.

Corrections applied this pass

• 2026-09-30 (logged): a duplicate analysis of the same source (doi:10.1021/acsami.6c04380) had been published twice by concurrent daily runs on 2026-09-30. Was: two live pieces (“goqd-vesicles-inflamed-pulp-glycolysis” and “goqd-vesicles-inflamed-pulp-homing”). Now: one piece stands (glycolysis); the duplicate was retired to the inbox and its URL returns 404. Why: the dedup contract is one candidate, one piece, and corrections are logged, never silent. Analysis-stream correction only; no tier, pass, or program basis was affected.

Cited here

• kitano-2024-phase1: first-in-human Phase I announcement and registry record, single ascending dose, adults; registry re-verified this pass.
• 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.
• toregem-2025-fda-preind: sponsor disclosure of FDA response to pre-IND meetings, 27 November 2025.
• toregem-2026-leadership: sponsor disclosure of new executive leadership structure, 28 August 2026.
• amed-2025-orphan: Japanese orphan drug designation for severe congenital partial anodontia.
• 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.
• hashim-2026-usag1-periodontal: USAG-1 as a candidate target for periodontal regeneration, 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.
• birjandi-sharpe-2026-secretome-correction: publisher correction to that study.
• mubeen-2026-cichlid-tooth-replacement: cichlid whole-tooth regeneration, eLife version of record.
• 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.
• yang-2026-rep-histology-human: human histology after a regenerative endodontic procedure.
• neves-2017: tideglusib promotes reparative dentin in mice.