景凱 發言日期 108/01/15 發言時間 17:41:59 發言人 袁鴻昌 發言人職稱 總經理 發言人電話 03-6587721 主旨 本公司JKB-122小分子新藥治療自體免疫性肝炎(AIH) 之第二期臨床試驗統計結果 符合條款 第43款 事實發生日 108/01/15 說明 1.事實發生日:108/01/15 2.公司名稱:景凱生物科技股份有限公司 3.與公司關係(請輸入本公司或聯屬公司):本公司 4.相互持股比例(若前項為本公司，請填不適用):不適用 5.發生緣由:本公司JKB-122小分子新藥治療自體免疫性肝炎(AIH)之第二期臨床試驗評估指標之統計結果。6.因應措施:無。7.其他應敘明事項:一、研發新藥名稱或代號：JKB-122二、用途: 藉由拮抗Toll-Like Receptor 4 (TLR4)之作用，治療自體免疫性肝炎(AIH)。三、預計進行之所有研發階段:二期臨床試驗、三期臨床試驗及新藥查驗登記審核。四、目前進行中之研發階段:(一)提出申請／通過核准／不通過核准／各期人體臨床試驗(含期中分析)結果：說明第二期臨床試驗結果如下1.臨床試驗介紹(1)試驗計畫名稱: 利用JKB-122小分子新藥治療自體免疫性肝炎之第二期臨床試驗。(2)試驗計畫目的: 主要為評估JKB-122使用於自體免疫性肝炎患者的療效。(3)試驗階段分級: 第二期臨床試驗。(4)試驗藥物: JKB-122膠囊5毫克(第一週)至40毫克(第24週)。(5)宣稱適應症: 自體免疫性肝炎(6)試驗計畫受試者收納人數: 美國地區20人2.評估指標說明及其統計結果及統計上之意義(1)評估指標說明：由於本試驗屬於美國FDA孤兒藥試驗，採用藥量遞增(第一週5毫克至第24週40毫克)開放式(open label)試驗，故不採用雙盲及安慰劑組方式。試驗期間進行藥物之有效性以及安全性評估。主要指標為達到麩丙酮酸轉胺脢(ALT)下降>50%或回到正常值；次要指標為麩草醋酸轉胺脢(AST)，丙麥胺酸轉移脢(GGT)等生物標記在24周治療後之變化。(2)試驗結果：A.本試驗於主要指標(麩丙酮酸轉胺脢(ALT)下降>50%)達到統計上顯著效果(P=0.004)，其中產生效應組(responder group)於第24週與第0週相比，麩丙酮酸轉胺脢(ALT)下降達 -70.0 IU，下降百分比達 -80.6%，產生效應組(responder group)達完成用藥受試者比率31.3%。B.產生效應組(responder group)於下述次要指標皆達到統計上顯著效果：a.麩草醋酸轉胺脢(AST)下降達 -32.8 IU，下降百分比達-67.2% (P=0.022)b.丙麥胺酸轉移脢(GGT)下降達 -77.0 IU，下降百分比達-66.8% (P=0.033)C.產生效應組(responder group)於鹼性磷酸脢(ALP)下降達 -17.8 IU，下降百分比達 -29.4%，顯示正向趨勢效果：D.此外，JKB-122用藥安全性皆無疑慮。以上指標下降代表正向效果。(3)單一臨床試驗結果(包含主、次要評估指標之統計學P值及統計學上是否達顯著意義)，並不足以充分反映未來新藥開發上市之成敗，投資人應審慎判斷謹慎投資。(二)未通過目的事業主管機關許可或各期人體臨床試驗(含期中分析)結果未達統計上顯著意義者，公司所面臨之風險及因應措施: 不適用。(三)已通過目的事業主管機關許可或各期人體臨床試驗(含期中分析)結果達統計上顯著意義者，未來經營方向：持續進行JKB-122開發計畫。(四)已投入之累積研發費用: 因涉及未來國際授權談判資訊，為避免影響授權金額，以及保障投資人權益，暫不揭露。五、將再進行之下一研發階段:(一)預計完成時間: 預計2019年第二季向FDA遞出臨床三期試驗申請，其臨床之規劃尚待與FDA討論定案。(二)預計應負擔之義務:無，本公司自有專利與技術。六、疾病普及率及市場狀況：(一)依據TechNavio及工研院預估，AIH的市場2015年約在251.7百萬美元，預估2022年將可達700百萬美元。年複合成長率為22.7%。(二)目前AIH並無核准的治療藥物，現行療法主要使用類固醇及免疫抑制劑來控制病情，惟無法根治；患者必須長期服用藥物，並衍生出較多嚴重副作用。(三)本公司開發模式係以研發為本並對外授權，由未來國際授權對象主導銷售。七、新藥開發時程長、投入經費高且並未保證一定能成功，此等可能使投資面臨風險，投資人應審慎判斷謹慎投資。
A Phase 2, Pilot Study of JKB-122 to Assess Liver Tests (ALT) in Autoimmune Hepatitis (AIH) Patients Who Are Refractory or Intolerant to Current Therapies This is a Phase 2, pilot study in which JKB-122 is given once daily for 24 weeks to subjects with AIH who have liver enzymes that are 1.25 to 10 times the upper limit of normal (ULN) and who have had a failed response to, incomplete response to, intolerant to, ineligible to or unwilling to take current immunosuppressant therapies. Current immunosuppressant therapy is defined as prednisone or other steroids with or without azathioprine. Failed response is defined as being non-responsive to or worsening in symptoms (elevated Alanine Aminotransferase (ALT)/aspartate aminotransferase (AST) and/or total bilirubin) despite compliance with the standard of care (SOC) over a 6 months period. Incomplete response is defined as lack of a sustained normalization of elevated ALT/AST to current standard of care (SOC) for at least 6 months. "Refractory" to the current therapy includes patients who had a failed response to, or incomplete response to the current therapy. Subjects will be at least 18 years of age, either male or female and will have been on therapy for AIH and have not had a normalization of ALT with the current therapy.
Autoimmune hepatitis: Treatment
Author: Michael A Heneghan, MD, M Med Sc, FRCPI Section Editors: Sanjiv Chopra, MD, MACP Elizabeth B Rand, MD Deputy Editor :Kristen M Robson, MD, MBA, FACG
INDICATIONS FOR TREATMENT — The decision to treat a patient with autoimmune hepatitis is based on the severity of symptoms, the magnitude of the serum aminotransferase and gamma globulin elevations, histologic findings, and the potential for side effects. We treat patients who fulfill any of the following criteria:
●Serum aminotransferase levels greater than 10-fold the upper limit of normal
●Serum gamma globulin level greater than twice the upper limit of normal
●Serum aminotransferase levels greater than twice the upper limit of normal along with:•Symptoms•An elevated gamma globulin level, even if less than twice the upper limit of normal•An elevated conjugated bilirubin level•Interface hepatitis on biopsy
●Histologic features of bridging necrosis or multiacinar necrosis
●Cirrhosis with any degree of inflammation on biopsy (see 'Cirrhosis' below)
●Children (see 'Children' below)Our approach is generally consistent with guidelines from American Association for the Study of Liver Diseases (AASLD) and the British Society of Gastroenterology (BSG). However, it does differ in a few ways. The AASLD guideline only recommends treatment for patients with gamma globulin levels greater than twice the upper limit of normal if the aminotransferases are at least fivefold the upper limit of normal, and does not recommend treatment for patients with gamma globulin levels less than twice the upper limit of normal unless the aminotransferases are greater than 10-fold the upper limit of normal. Our concern with the AASLD approach is that the level of serum aminotransferase or gamma globulin elevation does not correlate perfectly with the degree of histologic injury. In many cases, we have found that therapy may be required when serum aminotransferases or gamma globulin levels are elevated to a lesser degree than suggested by the AASLD guideline. Our approach also differs from the BSG guideline, which recommends treating if the serum aminotransferase levels are greater than fivefold the upper limit of normal, regardless of other criteria for treatment.Treatment may not be required in asymptomatic patients with normal or near-normal serum aminotransferase and gamma globulin levels who have minimal necroinflammatory activity on liver biopsy. Such patients are at a relatively low risk of disease progression. However, it is reasonable to offer treatment to a patient with histologic evidence of interface hepatitis without bridging necrosis or multiacinar necrosis, particularly if the patient is young (age less than 50 years) and is unlikely to have severe side effects related to therapy. Patients who are not treated should be monitored for signs of disease progression. If symptoms develop, if the aminotransferase or gamma globulin levels increase, or if histologic evidence of active disease is seen on follow-up biopsies, treatment should be reconsidered using the above criteria. (See 'Glucocorticoid monotherapy' below and 'Monitoring and follow-up' below.)Treatment is not recommended for patients with cirrhosis and inactive disease (characterized by the absence of inflammatory cells on liver biopsy and normal or near-normal serum aminotransferases) [3,4]. Such patients may be at increased risk for the development of glucocorticoid-related side effects, and the benefit of treatment is uncertain. On the other hand, treatment generally is recommended for patients with cirrhosis and active inflammation. (See 'Cirrhosis' below.)
GENERAL APPROACH TO TREATMENT — Our approach is to begin treatment with glucocorticoid monotherapy (prednisone or prednisolone 60 mg per day followed by a taper to a maintenance dose) in most patients (table 2 and algorithm 1 and algorithm 2). For patients with mild disease (eg, asymptomatic patients with aminotransferase levels <10 times the upper limit of normal), lower-dose prednisone monotherapy (20 mg per day) is an alternative.In patients with moderate to severe disease who are at increased risk for side effects from glucocorticoids (eg, those with brittle diabetes, osteoporosis, emotional lability, a history of psychosis, or poorly controlled hypertension), we will use a combination of lower-dose prednisone (30 mg per day) and azathioprine (50 mg per day) for initial treatment. (See 'Induction therapy' below.)The American Association for the Study of Liver Diseases recommends initial therapy with either glucocorticoid monotherapy or a combination of a glucocorticoid and azathioprine [3], whereas the British Society of Gastroenterology and European Association for the Study of the Liver recommend initial treatment with a glucocorticoid and azathioprine rather than glucocorticoid monotherapy [4,5]. For patients at high risk for glucocorticoid side effects, combination therapy permits administration of lower doses of prednisone. Budesonide may be an alternative to prednisone in these patients, though long-term data on safety and efficacy are lacking. (See 'Glucocorticoid plus azathioprine' below.)Azathioprine is a prodrug of 6-mercaptopurine, and both have been associated with aplastic anemia in patients with no thiopurine methyltransferase (TPMT) enzyme activity (which leads to the preferential production of 6-thioguanine, which results in aplastic anemia) (figure 1). If azathioprine is used, TPMT phenotyping should be obtained prior to initiating treatment. (See "6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in patients with inflammatory bowel disease", section on 'TPMT phenotyping'.)Subsequent management will depend on how the patient responds to the initial treatment (remission, incomplete response, failed treatment, drug intolerance) and whether the patient relapses if treatment is withdrawn. In some cases, treatment can be withdrawn completely whereas other patients require maintenance therapy. (See 'Subsequent management' below and 'Probability of responding to treatment' below.)
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