"NK cell therapy for biliary tract cancer, Targeting approval after completing clinical trial next year "

Selecting healthy donors and a feeder-free culture method...differentiated the quality of allogeneic natural killer (NK) cells

The current Phase 2b is comparing the combination group to the Keytruda monotherapy group...70 out of 128 patients had completed trials

Interim results showed an ORR of 28.6%...the company is also pursuing the cell supply business

SMT Bio is accelerating the commercialization of its allogeneic natural killer (NK) cell therapy, SMT-NK Inj, which has been under development for over 10 years.

The company previously confirmed combination potential with 'Keytruda' in previous phase 1/2a clinical trials. The current phase 2b trial directly compares the 'Keytruda' monotherapy group with the combination group. The goal is to complete the clinical trial next year and apply for conditional product approval.

Daily Pharm met with Lee Joo-yong, CEO of SMT Bio, to hear about the technical differentiation of SMT-NK injection, the clinical strategy for biliary tract cancer, and the commercialization plan through cell supply.

Selecting healthy donors… differentiating the quality of allogeneic NK cells

SMT-NK injection is an allogeneic cell therapy administered to patients after isolating NK cells from the peripheral blood of healthy donors and culturing and activating them for about two weeks.

In the autologous method, cell activity can vary depending on the patient's health status and immunity. SMT Bio focuses on reducing quality variation between donors by using cells from healthy donors.

The company calculates an immunity index by scoring five indicators—interferon-gamma secretion capacity, NK cell ratio, survival rate, initial cell count, and proliferation rate—and selects donors with high activity. The company has registered this technology as a patent in South Korea.

CEO Lee emphasized, "Using the blood of a healthy person does not mean all cells yield the same performance," and added, "The efficacy and consistency of the treatment can be secured only by quantitatively selecting donors with high immune activity."

In the cultivation process, the company does not use feeder cells to support cell proliferation. Through a feeder-free culture method aimed at reducing the risk of external cell contamination, the company reports an SMT-NK injection purity of 98.2%.

In preparation for commercialization, SMT Bio is also pursuing the standardization and automation of the culture process, as well as the development of cryopreserved formulations. Lee pointed out, "The entire process, from donor selection to feeder-free culture and high-purity production, is the company's competitiveness."

Confirming the effect when combined with Keytruda… proving value through control group comparison

SMT Bio selected advanced biliary tract cancer as its first indication. This is based on the judgment that biliary tract cancer is often discovered in an advanced state, and the treatment alternatives available after first-line treatment are limited.

Biliary tract cancer is classified as a so-called 'cold tumor,' where immune cells cannot sufficiently penetrate the tumor. While 'Keytruda' blocks the PD-1/PD-L1 pathway to restore T cells' anticancer activity, SMT-NK injection directly attacks cancer cells through the innate immune pathway.

Lee explained, "While 'Keytruda' releases the suppression of T cells, NK cells attack the tumor through another pathway," and added, "The core of the combination strategy is for NK cells to boost 'Keytruda's' response by altering the immune environment around the tumor."

The phase 1/2a clinical trial conducted from 2019 to 2021 enrolled 40 patients with advanced biliary tract cancer refractory to chemotherapy. The objective response rate (ORR) was 17.4% in the 23 patients in the full analysis set and 50.0% in the 8 patients in the per-protocol set who completed the clinical trial plan. No severe adverse events directly related to the combination therapy or dose-limiting toxicities were observed.

However, because it was a single-arm trial without a control group, it was difficult to isolate whether the therapeutic effect was due to the addition of SMT-NK injection. The current phase 2b is designed to compare progression-free survival (PFS) by dividing 128 patients with advanced biliary tract cancer into a 'Keytruda' monotherapy group and an SMT-NK injection combination group.

At the time of the interview, 70 patients had completed the clinical trial. In the interim results compiled by the company, the combination group's objective response rate (ORR) was 28.6%, and the disease control rate (DCR) was 50.0%. As the clinical trial is ongoing, the figures may change in the final analysis.

Lee evaluated, "What investors asked the most was whether the effect was due to 'Keytruda' rather than the effect of SMT-NK injection," and stated, "Since we are directly comparing the 'Keytruda' monotherapy group and the combination group this time, we will be able to prove the difference between the two groups with data."

Aiming to apply for approval next year… commercialization through cell supply

SMT Bio plans to complete the Phase 2b trial around April or May next year, after completing the remaining patient enrollment and follow-up observations. After that, the plan is to prepare a clinical study report and apply for conditional product approval from the Ministry of Food and Drug Safety (MFDS) in the second half of next year.

A variable is the orphan drug status of biliary tract cancer. When the company started the clinical trial, it designed the number of patients and the development plan based on the orphan drug criteria. However, as the number of biliary tract cancer patients in South Korea is increasing, further confirmation is needed on whether the same regulatory pathway will be maintained at the time of the application for approval.

Lee anticipated, "If the regulatory status changes at the time of the application for product approval, we may have to review our approval strategy again," and added, "We will specify the application strategy based on the final clinical results and consultations with regulatory agencies."

After targeting biliary tract cancer, the indications will be expanded to pancreatic cancer and neuroendocrine tumors. In pancreatic cancer, combination with 'FOLFIRINOX' is being considered, and in neuroendocrine tumors, combination with 'Lutathera ' is being considered. Once the production process stabilizes, there are also plans to develop chimeric antigen receptor natural killer (CAR-NK) cell therapies targeting CA19-9 and carcinoembryonic antigen (CEA).

Until the new drug is approved, cash flow will be supplemented through cell supply and quality inspection businesses targeting hospitals and research institutions. This method uses the cell culture, donor selection, and quality control technologies and facilities established during the development of the SMT-NK injection.

From 2022 to 2024, the company received 7 approvals for therapeutic use for biliary tract cancer patients without alternative treatment options. In line with its advanced regenerative medicine system, it is also preparing to launch autologous NK cell supply and stem cell isolation and purification businesses.

Lee stated, "The cell supply and inspection business is not a diversification unrelated to new drug development, but a business utilizing already secured technologies and facilities," and added, "By integrating biliary tract cancer clinical trials, investigator-initiated trials, treatment plan approvals, and cell supply, we will build a company where NK cells are delivered to patients."