Korea Suspends First Approved Gene Therapy Pending Component Discrepancy Probe
Executive Summary
South Korea’s first approved gene therapy has been suspended from sale in the country, while recruitment in an ongoing US Phase III program has been temporarily halted, after findings that an active cell component may differ from the data submitted at the time of approval. While both manufacturer and regulator see no safety risk, results from an official Korean probe are due in mid-April.
South Korea’s ministry of food and drug safety (MFDS) has asked Kolon Life Science Inc. to suspend the manufacturing and sale of Invossa (TG-C), the country’s first approved gene therapy, after determining that one of its two main active components may be different to that in the data submitted at the time of approval, apparently due to evolving production and testing technology.
A temporary halt has also been placed on a US Phase III development program by the company as a precautionary measure.
Kolon Life said it had voluntarily suspended on April 1 all sales and distribution of the product in South Korea, where it was approved in July 2017 as the world's first allogeneic cell-mediated gene therapy for degenerative osteoarthritis (OA). (Also see "First Approval For Kolon's Invossa But No Disease-Modifying Status" - Scrip, 14 Jul, 2017.) The near-term intention is to get re-verification from the MFDS about the consistency of the cell line used in South Korea.
TG-C is a combination of an allogeneic (donor) cell and gene therapy that involves the administration of primary human chondrocytes (cartilage cells) and chondrocytes transduced to express the therapeutic growth factor TGF-ß1 (transforming growth factor- ß1). The therapy is delivered via single, direct intra-articular injection.
The Invossa product approved in South Korea consists of a vial each of Solution No. 1 (human chondrocyte, or HC) and No. 2 (transduced human chondrocyte, or TC), and was approved specifically for the treatment of moderate knee osteoarthritis (Kellgren & Lawrence Grade 3) with symptoms such as pain that persist despite three or more months of conservative treatment.
At present, the product is supplied to 443 hospitals and clinics in the country, and the ministry has asked these to prescribe alternative treatments until the results of an official probe. Based on the results of this analysis, expected in mid-April, the ministry said it will impose administrative measures including a potential Invossa sales halt on the company if any violations are found, in line with the provisions of the national Pharmaceutical Affairs Act.
In the worst case scenario, the ministry could completely cancel the marketing license for the therapy and the company might have to re-file for approval, according to Kiwoom Securities.
Product In US Trials Different?
The issues stem from a finding by Kolon Life during an ongoing Phase III program in the US. (Also see "Disease Modifying Status Targeted As Kolon's Novel OA Therapy Enters US Phase III " - Scrip, 10 Jul, 2018.) Through its US subsidiary Kolon TissueGene Inc., formerly known as TissueGene Inc., Kolon found that the cell used in solution No. 2 in the US trials was different to that stated in the data submitted in support of the Korean approval, the ministry said.
Given the possibility that the actual cell being used in commercial sales in South Korea could be the same as that in the US, the ministry decided to halt sales while it investigates the exact cause of the possible variation.
The product being used for the US clinical trials is manufactured at BioReliance Corp., while that sold in South Korea is manufactured at the Chinese contract services group WuXi AppTec Inc., according to the ministry, which claims it uses GP2-293 (human embryonic kidney 293 cell) to manufacture TGF-B1, which is inserted into cartilage cells during the manufacturing process for Solution No. 2.
The TGF-B1 gene is separated and refined to be inserted into cartilage cells, but during this process the company estimates that part of the human embryonic kidney cells may have been inserted due to incomplete separation and refining.
Based on the data obtained so far, the MFDS' view is that there are no major concerns over product safety as there haven’t been any reports of side effects that since clinical trials began 11 years ago. During manufacturing, Solution No. 2 (TC) is irradiated and after injection to help growth of cartilage cells in Solution No. 1, and ceases to exist in the body after two weeks.
In addition, at the time of product approval in Korea, there weren’t any particular issues with the toxicity test results submitted to the ministry. Since the product was launched in that market, there had been a total of 102 reported cases of adverse effects by this March 30, but these relate mainly to issues such as injection site pain and swelling, the ministry noted.
US Phase III Halted, In Talks With FDA
According to a corporate disclosure to the Seoul stock market, Kolon TissueGene in the US has confirmed that the TC active ingredient (transduced human chondrocyte) has actually derived from the 293 cell, and not from human chondrocytes. It has notified this finding to the US FDA in relation to the US trials, and the two sides have begun to discuss the matter. The company has temporarily halted recruitment for the Phase III trial in the interim.
Kolon also said that it believes the variation will not affect the product’s safety and efficacy, as it had been using the 293 cell as the transduced human chondrocyte in its preclinical, Phase I and Phase II trials.
It claimed its perception that TC was derived from human chondrocytes was based on an analysis of TC characteristics in 2004, although Kolon TissueGene had recently informed Kolon Life that TC had been confirmed to have actually derived from the 293 cell.
The two entities are using the same cell line and the 293 cell is used to produce various retroviral vectors for gene therapies. Kolon Life said it had been consistently using the 293 cell from clinical samples through to commercialized products, and so remained confident on safety and efficacy, but now plans to reconfirm the consistency of the cell used in South Korea through analysis by an external institution.
“We apologize for raising concerns from patients. As soon as we get reconfirmation of the safety of Invossa, we will try to meet expectations of patients through prompt resumption of supply,” the company stressed.
During a briefing with local reporters in Seoul, Kolon Life reportedly further explained that the reason for the apparent variation in the active ingredient is due to a difference in technology between 2004 and now, which affected the analytical results. During the 2004 analysis, the ingredient was determined as human chondrocytes, but using the latest technology (STR test) it was confirmed as the 293-derived cell. In effect, only the name has changed, according to some local media.
The STR test wasn’t required by the US FDA, but was a necessary step given that a contract producer was manufacturing the therapy for US clinical trials, noted Kolon Life, reportedly adding that in Korea, Invossa was manufactured at its Chung Ju plant at the time of the MFDS approval.
US Trial Design
In November last year, Kolon TissueGene dosed its first patient in the pivotal US Phase III clinical trial for knee osteoarthritis. The study will enroll close to 1,020 patients in about 60 sites across the US, and will assess pain and function endpoints as well as MRI, X-ray and liquid biomarkers.
In addition to demonstrating significant improvements in pain relief and function, the trials are designed to show structural benefits, including a delay in disease progression. If successful, Invossa could achieve a disease-modifying osteoarthritis drug, or DMOAD, label claim from the FDA, which would be a first for any osteoarthritis drug approved in the US.
The pivotal Phase III program consists of two planned trials: TGC12301, a double-blind, placebo-controlled study to determine the efficacy of TG-C in subjects with Kellgren and Lawrence Grade 2 or 3 OA of the knee; and TGC15302, a double-blind, placebo-controlled study to determine the efficacy and effectiveness of TG-C in subjects with Kellgren and Lawrence Grade 2 or 3 OA of the knee.
Blow To Kolon’s Reputation, Korean Biotech?
Although any action against Invossa is yet to be determined by the MFDS, the news still came as a blow to the company’s reputation as a leading Korean gene therapy developer, as well as to the country’s broader biotech/pharma sector, which is increasingly pursuing the development of innovative medicines.
Kolon has high hopes for the commercial success of Invossa given that its prescriptions have been rising sharply, and gene and cell therapies in general are one of the main focus areas the biotech sector in the country is aiming to nurture.
Shares in Kolon Life and Kolon TissueGene, which are both traded on Korea’s Kosdaq market, fell by their daily limit on April 1 following the news, which hurt investor sentiment in the broader biotech and pharma sector.
The issue also highlights the manufacturing challenges being faced by developers of gene therapies, which are expected to increase as companies progress more and more complex such products through clinical trials and commercialization. (Also see "Gene Therapy Manufacturing Make-Or-Buy Options Weighed" - Pink Sheet, 22 Mar, 2019.)
From the editors of PharmAsia News.