[Edaily Reporter KIM SAE-MI ] “I absolutely do not consider this a clinical failure; I view it as a partial success.”

Jeon Seung-ho, co-CEO of Kolon TissueGene, Inc.(950160), made this remark on the 21st during a press conference held in Gangseo-gu, Seoul, to announce the results of the U.S. Phase 3 clinical trial for the osteoarthritis cell-gene therapy “TG-C” (formerly Invossa).

The lineage of K-Bio’s “half-success” starting with Helixmith Co., Ltd

“Half-success” is no longer an unfamiliar term in the domestic biotech industry. The person often cited as the originator of this expression is Kim Sun-young, former CEO of Helixmith Co., Ltd(084990).

In September 2019, following the announcement of the results from the U.S. Phase 3 clinical trial (DPN Phase 3-1) for “Engensis” (VM202), a candidate drug for diabetic neuropathy, former CEO Kim described the trial as an “incomplete success.” However, Engensis failed to demonstrate statistical significance compared to the placebo not only for the primary endpoint but also for key secondary endpoints. While safety was relatively good, the drug’s efficacy was not proven.

Helixmith Co., Ltd raised the possibility that the drug’s efficacy might have been masked by drug interactions and launched an investigation, but several months later concluded that no such interactions had occurred. Subsequently, the drug failed to meet the primary endpoint in both the Phase 3-2 and the Phase 3-2b extension trials, and the planned Phase 3-3 trial was repeatedly postponed and never even initiated.

In November of the same year, * Mezzion Pharma Co., Ltd.(140410)* assessed the global Phase 3 clinical trial (FUEL) of “Udenafil,” a treatment for patients who have undergone the Fontan procedure, as a “half-success.” The rationale was that while the primary endpoint—peak oxygen consumption (peak VO₂) during maximal exercise—did not reach statistical significance, improvements were observed in some secondary endpoints. Based on these results, Mezzion Pharma Co., Ltd. submitted a marketing authorization application to the U.S. Food and Drug Administration (FDA) in 2021, but withdrew the application the following year after being required to conduct additional clinical trials.

Subsequently, the company initiated an additional confirmatory trial, FUEL-2, while retaining the primary endpoint but excluding “Super Fontan” patients with excellent baseline exercise capacity. This trial is still ongoing, and Udenafil has not yet been approved as a treatment for Fontan surgery patients.

Park Seung-guk, CEO of HANALL BIOPHARMA CO.,LTD(009420), also described the 2020 U.S. Phase 3 clinical trial (VELOS-2) for the dry eye disease treatment “HL036” as a “half success.” This was because, although both co-primary endpoints—ICSS and ODS—failed, nominal significance was observed in some secondary endpoints.

HANALL BIOPHARMA CO.,LTD elevated the positive secondary endpoints to primary endpoints for the follow-up Phase 3 clinical trial (VELOS-3), but failed to achieve statistical significance for both endpoints. HANALL BIOPHARMA CO.,LTD is making another attempt by setting the non-anesthetic Schirmer test—a secondary endpoint that showed significance in VELOS-3—as the primary endpoint for a new Phase 3 clinical trial (VELOS-4).

Similar cases have continued recently. ShinpoongPharmaceutical(019170)failed to demonstrate superiority over the comparator at Week 6 for one of the co-primary endpoints in the Phase 3 clinical trial of its intra-articular injection “SP5M002” in 2025, but viewed it as a “half-success” by emphasizing that non-inferiority was achieved at Week 12. CHA Vaccine Research Institute(261780)(now ARIBIOLAB) also internally assessed its Phase 2b clinical trial of the chronic hepatitis B vaccine “CVI-HBV-002” as a “half success,” noting that while it failed to meet the primary endpoint, it demonstrated an improvement in HBV-specific T-cell immune responses. The company subsequently shifted its strategy from monotherapy to combination therapy with an siRNA treatment.

A “Half Success” Declaration Followed by a New Attempt… What Were the Results?

What these companies have in common is that, after failing to meet the primary endpoint, they found grounds to continue development by focusing on factors outside the primary endpoint. When positive results emerged from certain secondary endpoints, safety data, or specific subgroups, they highlighted these findings. Furthermore, they attributed the cause of clinical failure not to a lack of efficacy in the drug candidate, but rather to issues in the clinical trial design—such as patient composition, placebo response, and evaluation criteria. There were also numerous cases where companies adopted endpoints with positive results as new primary endpoints or adjusted patient populations and dosing strategies to attempt a retrial.

However, there are still no cases where such retries have led to definite success or approval. Helixmith Co., Ltd failed to meet the primary endpoints in its subsequent Phase 3-2 and Phase 3-2b trials, and has not even begun its Phase 3-3 trial. HANALL BIOPHARMA CO.,LTD’s HL036 also adopted a secondary endpoint—which had shown positive results in a previous trial—as the primary endpoint for its follow-up trial, but again failed to achieve statistical significance.

Kolon TissueGene, Inc.’s TG-C also stands at a similar crossroads. In Kolon TissueGene, Inc.’s first U.S. Phase 3 clinical trial for TG-C (Study 15302), the drug failed to achieve statistical significance not only for the co-primary endpoints—WOMAC and VAS—but also for the key secondary endpoints. In the VAS assessment, the placebo group showed a greater improvement than the TG-C group, and the intergroup difference in WOMAC was only about 1 point.

Kolon TissueGene, Inc. analyzed these results, concluding that the drug’s efficacy was masked by a larger-than-expected placebo response rather than a lack of efficacy in TG-C, and stated it would investigate the cause. Concerns have been raised that this approach—attributing the failure to trial design and execution rather than the candidate compound itself—resembles the Helixmith Co., Ltd. case.

The incidence of total knee arthroplasty (TKA) and the potential for structural improvement (DMOAD) presented by Kolon TissueGene, Inc. could serve as clues for future development. However, given the small number of cases and the fact that these were not pre-defined co-primary endpoints, it is difficult to conclusively determine the success of this trial or its effectiveness in inhibiting disease progression based on these findings alone.

What does the future hold for Kolon TissueGene, Inc.’s “TG-C”?… October is the turning point A

major

turning point for TG-C

is the second Phase 3 clinical trial (Study 12301), scheduled for announcement this October. This trial was not redesigned following the failure of the first clinical trial but is an independent confirmatory trial that has been conducted in parallel with Study 15302 from the outset.

If the WOMAC and VAS results also fail in the 12301 trial, it is highly likely to be interpreted as TG-C’s failure to reproduce its symptom-improvement effects with the current patient population and study design. In this case, a de facto third confirmatory clinical trial may be necessary—either by narrowing the scope to a subgroup that demonstrated strong efficacy or by redefining the endpoints. The approval and commercialization timelines could also be delayed by several years.

Conversely, even if the 12301 trial is successful, approval is not guaranteed. While there is a chance to persuade the FDA based on this single successful clinical trial and existing data, the company will need to explain the discrepancy in results, given that the 15302 trial—which was similar in scale and design—failed to meet both its primary and secondary endpoints. It is also difficult to rule out the possibility that the FDA will require an additional confirmatory trial.

If the 12301 trial barely achieves statistical significance or yields positive results only for one of the co-primary endpoints, or for subgroup or secondary endpoints, it is likely to amount to yet another “half-success.” While this could be used as a basis for follow-up development, confirming the efficacy of TG-C will ultimately require revalidation through a newly designed clinical trial.

Ultimately, the future of TG-C depends not so much on identifying potential opportunities from a failed trial, but rather on how clearly it meets the predefined primary endpoints in the 12301 trial. A biotech industry insider noted, “It seems difficult in Korea to immediately acknowledge clinical failure,” adding, “In the case of Kolon TissueGene, Inc., even if the second Phase 3 trial for TG-C is successful, the company will need to thoroughly explain these clinical results to the FDA, so it will take a considerable amount of time to finalize its approval strategy.”