Cell Therapy TG-C Misses Primary Endpoints in Phase 3 Knee Osteoarthritis Trial

Kolon TissueGene announced topline results from ACTiVION-II (NCT03291470), the first of two US phase 3 trials evaluating TG-C (TissueGene-C), an allogeneic cell and gene therapy for knee osteoarthritis.¹ The randomized, double-blind, placebo-controlled trial missed both co-primary endpoints, change from baseline in VAS pain and WOMAC total score at month 12, and none of the key secondary endpoints were met.

"While we are disappointed by the results from the first of two Phase 3 clinical trials of TG-C, we remain committed to advancing cell and gene therapy innovation targeting osteoarthritis of the knee,” Moon Jong Noh, PhD, co-CEO of Kolon TissueGene, said in a statement.¹ Co-CEO Seng Ho Jeon added, “We are deeply grateful to the study participants, investigators and clinical trial sites for their contributions to the ACTiVION-II study over the last several years.”

Treatment-emergent adverse events were comparable between arms in incidence, severity, and pattern, with most events grade 1 or 2 and no new safety signals identified.²

Trial design

TG-C consists of a 3:1 mixture of non-transduced allogeneic human chondrocytes and chondrocytes retrovirally transduced to overexpress transforming growth factor beta 1 (TGF-β1), delivered via a single ultrasound-guided intra-articular injection.³

ACTiVION-II enrolled adults aged 40 and older with a BMI of 18.5-40, KL grade 2 or 3 knee OA, and OARSI grade 1 or 2 medial joint space narrowing, with efficacy assessed via VAS, WOMAC, and SF-12, alongside joint space width and whole-organ MRI evaluation, and safety followed for 24 months. The trial was designed with the goal of supporting a disease-modifying osteoarthritis drug designation, which no therapy has yet received from the FDA for this indication.

A trial delayed by a manufacturing scandal

ACTiVION-II's timeline reflects a difficult regulatory history. TG-C had been approved in South Korea in 2017 as Invossa, but Korean regulators revoked that license in 2019 after discovering that the second cell component of the product had been mislabeled: it was actually derived from kidney cells (GP2-293) rather than cartilage-derived chondrocytes as disclosed in the original filing. The FDA placed a clinical hold on the US phase 3 program in May 2019 in response, following which Kolon TissueGene's shares were suspended from trading in Korea for more than three years and company executives faced criminal indictment over the licensing dispute.^4,5

The FDA lifted the hold in April 2020 after Kolon TissueGene submitted additional characterization data on the cell components, but broader trial recruitment did not resume until November 2021.^5,6 Dosing across both ACTiVION-I and ACTiVION-II was ultimately completed in July 2024, roughly six years after the trials first began enrolling patients in October 2018.⁶

Prior phase 2 evidence

Earlier randomized phase 2 data had shown a more favorable picture. In a 102-patient, multicenter, double-blind, placebo-controlled trial of adults with KL grade 3 knee OA randomized 2:1 to TG-C or placebo between 2011 and 2012, TG-C produced significant improvements in IKDC and VAS scores relative to placebo through 24 months, along with less frequent and severe pain and fewer patients showing MRI-based progression of cartilage damage; the therapy was generally well tolerated with only minor adverse events.⁷

A separate, smaller phase 2 cohort had also shown a significantly greater IKDC improvement with TG-C than placebo at final follow-up (16 points vs 8 points; P = .03).⁸ Whether the larger, more rigorously controlled ACTiVION-II population and 12-month primary timepoint account for the divergence from these earlier signals is not addressed in the topline release.

What's next

Kolon TissueGene says it will continue analyzing the complete ACTiVION-II dataset for additional insights and expects to report topline results from ACTiVION-I in October 2026, after which the company will determine next steps for the program.¹

REFERENCES
1. Kolon TissueGene Reports Topline ACTiVION-II Phase 3 Clinical Trial Results for TissueGene-C (TG-C) Targeting Osteoarthritis (OA) of the Knee. News release. Kolon TissueGene, Inc. July 20, 2026. Accessed July 23, 2026. https://www.globenewswire.com/news-release/2026/07/20/3329671/0/en/Kolon-TissueGene-Reports-Topline-ACTiVION-II-Phase-3-Clinical-Trial-Results-for-TissueGene-C-TG-C-Targeting-Osteoarthritis-OA-of-the-Knee.html
2. Kolon TissueGene's TG-C misses endpoints in pivotal knee osteoarthritis trial. TissueGene-C Phase III Fails in Knee Osteoarthritis. AllSci. July 22, 2026. Accessed July 23, 2026. https://allsci.com/news/clinical-trials/kolons-tg-c-phase-iii-failure-slows-cell-therapy-push-into-knee-osteoarthritis/
3. A Study to Determine the Safety and Efficacy of TG-C in Subjects With Kellgren and Lawrence Grade 2 or 3 OA of the Knee. ClinicalTrials.gov identifier: NCT03203330. Updated 2026. Accessed July 23, 2026. https://clinicaltrials.gov/study/NCT03203330
4. Delays in court rulings raise business risks for South Korean companies. KED Global. February 2, 2024. Accessed July 23, 2026. https://www.kedglobal.com/regulations/newsView/ked202402020010
5. Kolon TissueGene Shares to Resume Trading on KOSDAQ. Kolon Life Science. Accessed July 23, 2026. https://www.kolon.com/en/media/newsDtl?detailsKey=8032
6. Kolon TissueGene moves arthritis gene therapy into spine trial after FDA green light. Korea Biomedical Review. July 9, 2025. Accessed July 23, 2026. https://www.koreabiomed.com/news/articleView.html?idxno=28182
7. Lee B, Parvizi J, Bramlet D, Romness DW, Guermazi A, Noh M, Sodhi N, Khlopas A, Mont MA. Results of a Phase II Study to Determine the Efficacy and Safety of Genetically Engineered Allogeneic Human Chondrocytes Expressing TGF-β1. J Knee Surg. 2020;33(2):167-172. doi:10.1055/s-0038-1676803
8. Cherian JJ, Parvizi J, Bramlet D, Lee KH, Romness DW, Mont MA. Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage. 2015;23(12):2109-2118. doi:10.1016/j.joca.2015.06.019