[Press Release, Jan 18, 2020 / unofficial translation ]



Meeting Results of the Advisory Committee for the Safety and Efficacy Assessment of COVID-19 Therapeutics



1. Current Review Status of COVID-19 Therapeutics for Market Authorization

□ On January 17 (Monday), the Ministry of Food and Drug Safety (MFDS, Minister Kim Ganglip) held the “Advisory Committee for the Safety and Efficacy Assessment of COVID-19 Vaccine/Therapeutics” (hereinafter “advisory committee”) meeting on the clinical test results of Celltrion’s monoclonal antibody therapeutics candidate (Regkirona Inj).

○ The advisory committee meeting is a mandatory procedure of MFDS held to get advices on clinical, non-clinical, and quality data from various experts.
- Eight external experts in the clinical trial field, including infectious disease, virology, and clinical statistics, and four experts from MFDS attended the meeting.


2. Advice and Results of the advisory committee meeting\

□ During the advisory committee meeting, various advice was given on whether clinical trial results demonstrate efficacy and safety of Regkirona Inj.

<< Efficacy >>
○ (Endpoint of Clinical Efficacy) To identify whether the time to recovery was faster among the treatment group and the therapeutics is clinically effective:
- The treatment group was administered Regkirona Inj. or a placebo when having any of seven COVID-19 symptoms (e.g., fever) severely or moderately during the clinical trial, and the severity of all symptoms was measured twice a day for 14 days. In addition, the time it took for every symptom to be disappeared or improved was also measured.
- As a result, it took 5.34 days for the drug treatment group* to recover from COVID-19 symptoms compared to 8.77 days for the placebo group. It shows that the treatment group recovered from the COVID-19 symptoms about 3.43 days earlier than the placebo group.
*40mg of Regkirona Inj. per 1kg body weight
- The advisory committee considered that it proves a clinically meaningful result because the reduction of time to recovery was statistically significant when Regkirona Inj. was administered.

○ (Endpoint of Mechanism of Action) To identify whether SARS-CoV-2 binds to the therapeutics instead of human cells to prevent infection in the human body:
- Testing of SARS-COV-2 was conducted using nasopharyngeal specimen collected* from subjects in the treatment group to measure the transition time from SARS-CoV-2 positive to negative. And then the transition time between the treatment group and the placebo group was compared.
* Specimens were collected every day for 7 days and then 14, 21, and 28 days from the date of administration.
- The result of testing confirmed that there was no significant difference in the transition time from SARS-CoV-2 positive to negative between the treatment and placebo group.
- The advisory committee considered that a reduction of transition time from SARS-CoV-2 positive to negative was not statistically significant according to the SARS-CoV-2 test results. However, it was considered that viral loads tend to decrease in the body after administering the drug.
- The committee also noted that the reduction of the transition time was not clinically significant as the diagnostic assay for SARS-CoV-2 used were not standardized, and considering the limits of the diagnostic assay for SARS-CoV-2, the transition time gained from the trial is not statistically significant.

○ (Proportion of patients requiring hospitalization and oxygen therapy) As an auxiliary method to assess the drug’s efficacy, it was also observed whether the proportion of patients requiring hospitalization and oxygen therapy reduced in the treatment group for 28 days from the date of drug administration.
- The advisory committee confirmed that the proportion of patients requiring hospitalization or oxygen therapy because of COVID-19 tended to decrease when administered the drug.
- However, as it was not the primary point to consider in this clinical trial, a statistical testing method was not specified during the clinical trial planning stage. Therefore it was considered that reaching to a conclusion based on this is difficult.
- The committee considered that it is difficult to know the drug’s efficacy on the mortality rate because there were no cases of death reported for both the treatment and control groups.
- As such, they agreed that conclusion and implication of the reduced proportion of patients requiring hospitalization and oxygen therapy, among others, should be determined through the Phase III clinical trial to be conducted with many patients in the future.

<< Safety >>
○ Adverse events for 28 days after administration, and the frequency, type and severity of adverse reactions caused by the specific route of administration, were continuously observed to verify safety of the drug.
- Hypertriglyceridemia and hypercalcemia were solicited adverse events, which already identified during the Phase I.
- In addition, most of the reported adverse events were mild or moderate, and the ratio was similar between the treatment and control groups. Furthermore, there were no serious, life-threatening cases.
- Regkirona Inj. is administered by intravenous (IV) infusion, and common adverse reactions of IV infusion such as itching and injection site pain rarely occurred both in the treatment and control groups.

□ Based on the above opinions, the advisory committee recommended marketing authorization of Regkirona Inj. on condition of conducting Phase III clinical trial. They also gave some recommendations for the product’s effects and efficacy.

< Recommended indication>
Improving the clinical symptoms in outpatients with mild to moderate severe acute SARS-CoV-2 infection (ages 18 and over) who meet the following criteria:
1) Those whose oxygen saturation exceeds 94% in indoor air
2) Those who do not requiring supplemental oxygen therapy
3) Those who had symptoms within seven days before drug administration

< Recommendations of the advisory committee >
_ In the Phase III clinical trial, it should be confirmed that Regkirona Inj significantly reduce morbidity(from mild-moderate to severe) in a sufficient number of patients.
_ For the use of this drug in the clinical field, a detailed guideline should be established after having discussion with relevant organizations.
_ A separate clinical trial subject to patients requiring auxiliary oxygen therapy is recommended with Regkirona Inj, and existing therapeutics for severe disease or other immunomodulators.

○ MFDS will review the submitted data, including expert advices, indication(draft), and recommendations from this advisory committee meeting, and some of the remaining quality data. Based on the final results of the review, the Central Pharmaceutical Advisory Committee, a legal advisor of MFDS, will provide its advice on safety, efficacy, and other points to consider for approval of Regkirona Inj.


3. This Week’s Plan for Approval and Review

○ (Therapeutics) This week (the fourth week of January), MFDS plans to request Celltrion to submit additional data for Regkirona Inj., including some quality data* that have not yet been submitted.
* Some data for safety and drug substance management

○ (Vaccine) For the AstraZeneca vaccine, MFDS has requested (January 15) additional data for its review. As soon as the data are submitted, the Ministry will thoroughly assess the vaccine’s effects for prevention and validity of indicated dosage and administration, and review the quality data assessment for national lot release.
- Moreover, this week (the fourth week of January), MFDS plans to conduct an on-site inspection of the manufacturing facility (SK Bioscience) for the assessment of manufa