[Edaily Reporter Minji Son ] Regulatory authorities in South Korea and the United States have reached differing conclusions regarding “JointStem,” a stem cell therapy for degenerative knee osteoarthritis developed by NATURECELL CO.,LTD.(007390). South Korea’s Ministry of Food and Drug Safety (MFDS) rejected the product license application after determining that the efficacy confirmed in clinical trials was not sufficiently meaningful for actual patients. In contrast, the U.S. Food and Drug Administration (FDA) designated it as a Regenerative Medicine Advanced Therapy (RMAT) and a Breakthrough Therapy (BT), based on an assessment of its potential for further development.

According to the pharmaceutical and biotech industry on the 5th, NATURECELL CO.,LTD. recently requested a pre-submission meeting with the U.S. FDA regarding the Biologics License Application (BLA) for JointStem. A pre-submission meeting for a new drug application is a procedure designed to verify in advance whether the data required for review has been sufficiently prepared. The purpose is to minimize situations where an application is rejected due to insufficient data or where extensive supplemental data is required after submission.

JointStem is a treatment for degenerative knee osteoarthritis that involves culturing adult stem cells extracted from a patient’s adipose tissue and administering a single dose into the knee joint cavity. It is primarily intended for patients with severe degenerative osteoarthritis who are at the pre-surgery stage for joint replacement.

NATURECELL CO.,LTD. maintains that it can submit a Biologics License Application (BLA) for JointStem without conducting additional clinical trials following the completion of its Phase 3 clinical trial in Korea.

NATURECELL CO.,LTD. explained, “There were no requests for additional clinical trials (following the domestic Phase 3 trial), and we shared potential review issues that could arise after submission with the FDA in advance.” The official added, “Since the Phase 3 trial was conducted on Korean patients, we discussed in advance whether there would be any issues applying the results to U.S. patients and confirmed that there are no scientific concerns.”

Primary Endpoint Met, but… Korea Questions ‘Effect Size’

Nevertheless, the reason JointStem failed to obtain marketing approval in Korea was a divergence in judgment between the Ministry of Food and Drug Safety (MFDS) and the company regarding whether the confirmed efficacy was sufficiently meaningful for patients.

The domestic Phase 3 clinical trial was conducted on 261 patients classified as Grade 3 in the severity classification for knee osteoarthritis. Patients were administered either JointStem or a placebo, and the research team compared the extent of improvement in pain and joint function after six months.

As a result, the Visual Analog Scale (VAS) for pain showed an average improvement of 25.2 points in the JointStem group. The improvement in the placebo group was 15.5 points. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which comprehensively evaluates joint pain, stiffness, and the ability to perform activities of daily living, also showed an improvement of 21.7 points in the JointStem group, surpassing the placebo group’s 14.3-point improvement. Since the JointStem group demonstrated statistically significant improvements over the placebo group on both the VAS and WOMAC, the primary endpoint was met.

Statistical significance means that it is unlikely the observed difference occurred by chance. Clinical significance, on the other hand, assesses whether the difference is large enough for patients to actually perceive it and is meaningful as a therapeutic effect.

The Ministry of Food and Drug Safety (MFDS) and the Central Pharmaceutical Affairs Advisory Committee raised questions as to whether the difference in the degree of improvement between the JointStem group and the placebo group was sufficient to grant final marketing authorization, even though JointStem met the primary endpoint. They argued that even if statistical significance was established, it was necessary to determine whether the therapeutic effect was superior to that of existing treatments—to the extent that it warranted marketing authorization—in terms of clinical significance.

NATURECELL CO.,LTD. has maintained that the JointStem group showed a higher response rate than the placebo group even in the Minimum Clinically Important Difference (MCID) analysis, which assesses the proportion of patients whose symptoms improved beyond a certain threshold. However, during the domestic review process, it was pointed out that this analysis was conducted as a post-hoc analysis added after the clinical results had been confirmed.

There was also controversy surrounding structural improvements. A comparison of magnetic resonance imaging (MRI) scans taken six months after the start of the domestic Phase 3 clinical trial showed no significant difference in changes to cartilage defects between the JointStem group and the placebo group. Consequently, the most clearly observed effects in the domestic Phase 3 trial were assessed as pain relief and improved joint function rather than cartilage regeneration. Based on this, the Ministry of Food and Drug Safety (MFDS) determined that there was insufficient evidence to show that JointStem improved the structural progression of osteoarthritis, and that further review was needed to assess whether the symptomatic improvement was clinically significant enough to support product approval.

NATURECELL CO.,LTD. filed an administrative lawsuit challenging the MFDS’s decision to reject the marketing authorization application, and last month, the Seoul Administrative Court ruled to overturn the MFDS’s rejection. The court reasoned that, even though statistical significance was confirmed for the primary endpoint in accordance with the pre-approved clinical protocol, the MFDS’s de facto requirement for superiority over existing treatments was excessive.

However, as the MFDS has appealed the first-instance ruling, the domestic marketing authorization process is likely to be prolonged once again.

U.S. FDA Designates as RMAT and BT

In contrast,

the U.S. Food and Drug Administration (FDA)

designated Jointstem

as

both

an RMAT

and

a BT

based on domestic Phase 3 clinical trial data and long-term follow-up data. While the Korean Ministry of Food and Drug Safety strictly assessed whether the efficacy was sufficient to grant marketing authorization based solely on the data available at this stage, the FDA concluded that the treatment was worthy of rapid support for further development based on the potential demonstrated in pain relief, functional improvement, and long-term durability.

RMAT is a program that supports the development of regenerative medicine candidates targeting serious diseases that demonstrate the potential to address unmet medical needs based on early clinical data. BT also supports therapies that show significant potential for improvement in clinically important endpoints compared to existing treatments by expanding consultation with the FDA and expediting development and review procedures.

Both designations are positive in that they allow for close consultation with the FDA regarding clinical design, the composition of regulatory submissions, and review strategies. While this does not guarantee final marketing approval, it is seen as strong recognition of the product’s potential as a candidate for accelerated development.

NATURECELL CO.,LTD. reports that the improvements in pain and function confirmed in its domestic Phase 3 clinical trial, along with the sustained efficacy demonstrated in long-term follow-up observations, contributed positively to the FDA designation.

A NATURECELL CO.,LTD. official stated, “Efficacy and safety were established through the Phase 3 clinical trial, and the 5-year follow-up demonstrated that these effects and safety are maintained,” adding, “We believe the fact that these results represent key outcomes not previously reported for similar platforms or indications also contributed to the FDA’s decision.”

In fact, NATURECELL CO.,LTD. is also presenting the results of a 5-year follow-up study of Phase 2b clinical trial patients as evidence for its U.S. approval strategy. Although the study has limitations as a small-scale, single-arm JointStem trial, it is being used as supporting evidence to demonstrate the sustainability of the therapeutic effect.

The research team monitored pain, joint function, safety, and radiographic changes over five years in 11 of the 12 patients who received a high dose of JointStem in the Phase 2b clinical trial and participated in the follow-up. The results showed that the VAS score for pain and the total WOMAC score for joint function improved significantly six months after administration, and these improvements were maintained through the five-year mark. No serious adverse reactions, deaths, or malignant tumors related to JointStem were reported over the five-year period, and none of the subjects in the follow-up cohort underwent surgery on the affected knee, such as total knee replacement.

NATURECELL CO.,LTD. explained that the clinical significance and whether structural improvements were observed on MRI—which have been controversial in South Korea—are not key issues in its U.S. approval strategy.

NATURECELL CO.,LTD. official stated, “The FDA takes the position that, since the primary clinical endpoints—WOMAC and VAS—are already designed to reflect clinical significance, the efficacy of symptom improvement can be evaluated by confirming statistical significance,” adding, “Structural improvement is a clinical endpoint required when discussing indications separate from symptom improvement, such as pain or function, and is not data strictly required for approval based on symptom improvement.”

The representative added, “In early-phase clinical trials, arthroscopic examinations of patients treated with JointStem confirmed cartilage regeneration, and these findings were published in an international academic journal.”

Of course, there may be differences between the approval pathway described by the company and the FDA’s final decision. While it is possible to submit a BLA without additional clinical trials, as the company explains, there remains a possibility that during the formal review process, the FDA will re-evaluate the applicability of domestic clinical data to U.S. patients and the magnitude of therapeutic effects, potentially requiring additional data or supplemental clinical trials.

An expert who worked for many years in review at the FDA stated, “It is technically possible to file a BLA with the U.S. FDA based solely on the results of domestic Phase 3 clinical trials,” but added, “Evidence is needed to demonstrate that the efficacy and safety confirmed in Korean patients can also apply to U.S. patients, and since the FDA may require additional clinical trials depending on factors such as the magnitude of the therapeutic effect and racial differences, prior consultation is crucial.”