[Edaily Reporter NA EUN-KYUNG ] As TG-C (formerly Invossa) from Kolon TissueGene, Inc.(950160)failed to demonstrate pain relief in its U.S. Phase 3 clinical trial, “pain”—considered the biggest challenge in the development of osteoarthritis treatments—is once again drawing attention. In contrast, “Cartistem” from MEDIPOST CO., LTD.(078160), which is intended for the same indication, met its primary endpoint—including pain relief—in its Japanese Phase 3 clinical trial. By comparing the clinical trial designs of the two therapies, we examined why demonstrating pain relief is difficult and identified key points to watch in Cartistem’s U.S. Phase 3 clinical trial.

“Pain Relief

Is Harder Than Cartilage Regeneration”… Placebo Is the Key

According to a filing by Kolon TissueGene, Inc. on the 13th, in the first trial of the U.S. Phase 3 study for TG-C, neither the Visual Analog Scale (VAS) nor the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)—both of which were co-primary endpoints at the 12-month mark—demonstrated statistical significance compared to the placebo group. In contrast, MEDIPOST CO., LTD.’s Cartistem, in a Phase 3 clinical trial in Japan, set the WOMAC—which evaluates pain and function—and the ICRS—which assesses the degree of cartilage damage—as co-primary endpoints and achieved statistical significance in both compared to the active control group.

To understand the reasons behind the divergent results of these two trials, it is first necessary to examine the characteristics of pain as an indicator in osteoarthritis clinical trials.

In osteoarthritis trials, pain is a representative patient-reported outcome (PRO) measure. While cartilage regeneration can be confirmed via magnetic resonance imaging (MRI) or arthroscopy, pain assessment inevitably relies on PROs. It is common for pain in the control group to decrease simply due to the anticipation of treatment. Since the placebo effect can last from 6 months to 1–2 years depending on the patient, the timing of the evaluation also influences clinical outcomes.

Even the U.S. Food and Drug Administration (FDA) uses subjective measures—such as the Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)—where patients directly rate their pain levels, as primary outcome measures due to the lack of objective biomarkers.

Furthermore, cartilage regeneration does not necessarily lead to reduced pain. This is because even if cartilage damage improves, pain may persist due to other causes, such as synovitis, meniscal tears, or ligament issues.

Another issue is that patients cannot be kept hospitalized throughout the duration of a clinical trial. Patients may return to their daily routines, exercise, or lose weight, and if pain is severe, they may take permitted pain relievers. This means that various variables—such as the placebo effect, physical activity levels, weight changes, analgesic use, and whether rehabilitation is performed—cannot help but influence the results, in addition to the actual therapeutic effect. A MEDIPOST CO., LTD. official expressed the difficulty, stating, “In clinical trials for osteoarthritis treatments, it is not easy to accurately record or adjust for lifestyle factors that affect pain, such as physical activity levels, weight changes, and occupational activity levels.”

The industry views the recent failure of TG-C’s U.S. Phase 3 clinical trial as another example illustrating these characteristics of pain metrics. Kolon TissueGene, Inc. explained that the placebo response in the control group was stronger than expected, but the exact cause is still under analysis.
All-Out

Effort to Reduce Pain Variables… Why Did TG-C Fall Short

? Both Cartistem and TG-C were developed as therapies aimed at improving cartilage structure, but their approaches differ. Cartistem uses allogeneic mesenchymal stem cells derived from umbilical cord blood to induce cartilage regeneration and regulate inflammation, whereas TG-C is a cell-gene therapy that utilizes transgenic cells expressing transforming growth factor beta-1 (TGF-β1)—a signaling molecule (cytokine) that regulates cell growth, differentiation, immune responses, and tissue regeneration—to induce anti-inflammatory M2 macrophages.

Both companies implemented measures during the clinical trials to reduce variability in pain indicators. A MEDIPOST CO., LTD. representative stated, “We put special effort into selecting patients with baseline pain levels above a certain threshold for the Phase 3 clinical trial in Japan, and we restricted patients’ use of analgesics, systemic steroids, immunosuppressants, and additional intra-articular injections during the trial.” This was done to minimize confounding variables that could affect pain levels as much as possible.

Kolon TissueGene, Inc. also made efforts to track and manage analgesic use during the clinical trial period. In response to a question on this matter, a spokesperson for Kolon TissueGene, Inc. explained, “In the U.S. Phase 3 clinical trial, we required patients to discontinue analgesic use for 24 hours prior to pain assessment and implemented monthly telephone monitoring and regulations for recording concomitant medications.” The spokesperson added, “However, we are currently conducting an internal review to determine how the actual use of analgesics was linked to and managed in conjunction with pain assessments.”

TG-C demonstrated statistical significance in functional improvement based on VAS pain scores and International Knee Data Committee (IKDC) assessment scores in the U.S. Phase 2 trial, and the company anticipated success in the U.S. Phase 3 trial based on the fact that these results were replicated in the Korean Phase 3 trial. However, it failed to meet the primary pain endpoint in the large-scale confirmatory clinical trial. In effect, the efficacy observed in the earlier small-scale clinical trials was diluted in the Phase 3 trial, which involved a diverse range of institutions and patients. This case demonstrates that increasing the number of participants does not necessarily raise the probability of success for pain endpoints; rather, it can also lead to greater variability in evaluations across clinical sites, greater heterogeneity within the patient population, and an increased placebo response in the control group.

A Kolon TissueGene, Inc. official explained, “Our new Chief Medical Officer (CMO), Andy Wayman, is analyzing the overall situation—including the causes of the increased placebo response, patient population characteristics, and clinical trial operations,” adding, “Once the analysis is complete, we plan to finalize our future development strategy based on the results.”

Head-to-Head with Marginal Resection in the U.S.… 24-Month Pain Outcomes Will Decide the Outcome

CartiStem’s next challenge is

the

U.S

.

Phase 3 clinical trial. While the Japanese Phase 3 trial used hyaluronic acid injections as the control group, the U.S. trial has set surgical cartilage marginal resection as the active control. VAS and WOMAC at the 24-month mark will serve as co-primary endpoints, while the MRI-based Cartilage Reconstruction Tissue Assessment Score (MOCART) and the Magnetic Resonance Imaging Knee Osteoarthritis Score (MOAKS) will be used as structural improvement measures. Marginal resection is a treatment that can reduce pain in the short term.

The first key point to watch is the efficacy of the active control group. Marginal resection is a surgical procedure that removes damaged cartilage and inflammatory tissue, thereby reducing pain in the short term. For Cartistem to be successful, it must demonstrate superior results compared to a surgical group that provides a consistent level of pain relief—rather than a no-treatment or saline control group. However, since marginal resection is not a treatment that generates new cartilage, there is a possibility that Cartistem’s cartilage regeneration effects will become more prominent at the 24-month mark, when the short-term pain-relief effects of marginal resection begin to wane.

The second factor is the reproducibility of the Japanese results. While the key evaluation time point in the Japanese Phase 3 trial was 52 weeks, it is 24 months in the U.S. MEDIPOST CO., LTD. is expressing confidence based on the fact that the WOMAC physical function and VAS pain scores—evaluated as secondary endpoints in the Japanese clinical trial—showed significant improvement at the 1-year mark, and that these endpoints are identical to the co-primary endpoints in the U.S. Phase 3 trial. The company believes that if the cartilage regeneration observed in Korea and Japan leads to medium- to long-term pain and functional improvements, the 2-year evaluation may actually be more advantageous.

The third factor is the consistency of pain data. In multinational, multi-center clinical trials, factors such as the healthcare providers’ assessment methods, rehabilitation protocols, use of rescue medications, and patients’ weight and activity levels can vary from one institution to another. It is crucial to ensure that the baseline pain criteria and restrictions on concomitant medications applied in Japan are enforced consistently in the U.S. as well. Additionally, how statistically such data is handled—particularly if there is an increase in dropouts or patients using rescue medications—could also influence the results.

Finally, it remains to be seen whether improvements in pain and structural changes align. Even if VAS and WOMAC scores improve in the U.S. clinical trial, the drug’s value as a disease-modifying osteoarthritis drug (DMOAD)—one that goes beyond pain relief to improve joint structures such as cartilage and thereby inhibit disease progression—may be limited if cartilage regeneration is not supported by MRI findings. Conversely, if only structural improvement is confirmed but no difference in pain or function is demonstrated compared to the control group, it will be difficult to guarantee approval.

A MEDIPOST CO., LTD. representative stated, “Since we have confirmed medium- to long-term improvements in pain and function due to cartilage regeneration and repair in clinical trials in Korea and Japan, we believe that the U.S. Phase 3 clinical trial—designed to last two years—may actually work in our favor in proving the efficacy of Cartistem.”