The U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application allowing Yantai (Shandong Province; China) -based biopharmaceutical company RemeGen to initiate a Phase II clinical trial of disitamab vedotin, previously known as RC48, in the United States. 
Distamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate or ADC with a higher affinity to HER2 compared to standard of care, links a humanized HER2 targeting monoclonal antibody via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker to a monomethyl auristatin E (MMAE) payload.
In pre-clinical animal models, the investigational drug demonstrated a superior anti-tumor activity compared to other treatments. The novel drug was the first ADC drug approved for human clinical trials in China and today is studied in multiple late-stage clinical trials across solid tumor types.
Distamab vedotin is generally well-tolerated and has shown significant anti-tumor activities in a number of HER2+ cancer, including in some HER2 low expressors (IHC +2, FISH negative patients).
In China, distamab vedotin is being developed across 5 indications, including gastric cancer, urothelial cancer, late-stage breast cancer, non-small cell lung cancer (NSCLC), and bile duct cancer. The investigational drug which has received FDA Orphan Drug Designation is currently in pivotal clinical trials in China for the treatment of patients with gastric and urothelial cancers.
Unresectable Urothelial cancer
The focus of the new US-based clinical study of distamab vedotin is testing the drug as a potential new treatment for human epidermal growth factor receptor 2 (HER2) positive metastatic or unresectable urothelial cancer. This cancer, also known as transitional cell carcinoma or TCC, is by far the most common type of bladder cancer and the third-largest type with HER2 positive cancer. Based on the number of patients being diagnosed, the disease represents the ninth most common cancer worldwide and the fourth most common cancer in men in the United States.
“[According to the National Cancer Institute] an estimated 81,400 new cases of urothelial cancer will be diagnosed in the United States in 2020” noted Jianmin Fang, Ph.D., founder and Chief Executive Officer of RemeGen.
“[We’re] committed to decreasing this number and helping fulfill the unmet medical need for patients. Thanks to the clearance from the FDA, we are one step closer to providing a novel treatment option for this devastating disease.”
Cell proliferation and differentiation
HER2, a member of the epidermal growth factor receptor family, plays a major role in cell proliferation and differentiation. Amplification or overexpression of HER2 is seen in several tumors, including approximately 15–30% of invasive breast cancers and 10–30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. Overexpression has also been seen in other tumors such as ovary, endometrium, lung, colon, and head, and neck.
In breast cancer, HER2 gene amplification is associated with shorter disease-free and overall survival. And amplification of HER2 has been recognized as a significant predictor of both overall survival and time to relapse. 
HER2 directed therapies have, over the last few decades, dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers. The results in other HER2 overexpressing cancers have, however, been disappointing. But in addition to distamab vedotin a crop of novel HER2 targeting antibody-drug conjugates, including trastuzumab deruxtecan (Enhertu®, Daiichi Sankyo/AstraZeneca) and (Vic-)Trastuzumab Duocarmazine (SYD985; Byondis) are expected to change this.
Topline data presented from its China-based Phase II clinical trial distamab vedotin during the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2019, showed significant anti-tumor activities in a number of HER2-positive urothelial cancer patients, making it the first potential targeted, biologic therapy for HER2+mUC in a disease state with no new treatments in nearly 20 years. 
This trial, which enrolled 43 patients with a median age of 64 years old, 37 patients had visceral metastasis. Fourteen patients (32.6%) had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second-line treatment.
The objective response rate (ORR) was 60.5% (95% CI: 44.4%, 75.0%) and the Disease Control Rate (DCR) was 90.7% (39/43). At the time of the poster presentation during the ASCO annual meeting in June 2019, the median PFS for the overall study population had not yet been reached, however, for 9 patients who started their trial participation with distamab vedotin before to Jun 30, 2018, the median PFS was 7.8 months (95% CI: 4.9, 10.7). The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy.
The IND clearance for distamab vedotin’s first US-based clinical trial arrives on the heels of RemeGen’s recently completed U.S. $ 100 million-plus financing, co-led by Lilly Asia Ventures and Lake Bleu Capital. This round of investment was supported by global institutional investors including Vivo Capital, Janchor Partners, OrbiMed, Hudson Bay Capital, and the company’s existing investors. Loyal Valley Capital and China Reform Conson Soochow Overseas Fund also invested through the purchase from existing shareholders.
“Reaching this funding milestone […] allows us to further pursue our vision of developing [the] biologics of the future. Through research, development, manufacturing, and commercialization of novel biologics – most notably monoclonal antibodies and antibody-drug conjugates – [we] aims to fulfill the unmet medical needs of patients everywhere facing conditions such as […] cancer, bringing us one step closer to the future of medicine,” Fang concluded.
This funding is designed to support the company’s early-stage drug discovery platform, continued development of the company’s R&D pipeline, and the expansion of its manufacturing facilities. The proceeds of the financing will also advance the commercialization efforts of distamab vedotin.
A Phase II Study of RC48-ADC in Subjects With HER2 Positive Metastatic or Unresectable Urothelial Cancer – NCT03507166
A Study of RC48 in Subjects With HER2 Overexpressed Metastatic Biliary Tract Cancer – NCT04329429
A Study of RC48-ADC in Subjects With Advanced Non-small Cell Lung Cancer – NCT04311034
An Open-label, Single-arm, Multicenter, Phase II Study of RC48-ADC to Evaluate the Efficacy and Safety of Subjects With HER2 Overexpressing Locally Advanced or Metastatic Urothelial Cancer – NCT03809013
Study of RC48-ADC Administered Intravenously to Subjects With HER2-Positive in Advanced Malignant Solid Tumors – NCT02881190
A Study of RC48-ADC in Local Advanced or Metastatic Gastric Cancer Subjects With the Overexpression of HER2 – NCT03556345
A Study of RC48-ADC Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer – NCT03500380
Study of RC48-ADC in Patients With HER2-Positive Advanced Malignant Solid Tumors – NCT02881138
JS001 in Combination With RC48-ADC in Treatment of HER2-Positive Advanced Malignant Solid Tumors – NCT04280341
RC48-ADC Administered Intravenously to Subjects With HER2-Positive in Advanced Breast Cancer – NCT03052634
A Study of RC48-ADC (Antibody Drug Conjugate) and JS001 to Evaluate the Safety and Pharmacokinetics of Subjects With Locally Advanced or Metastatic Urothelial Cancer – NCT04264936
A Study of RC48-ADC in Subjects With HER2-negative Locally Advanced or Metastatic Urothelial Cancer – NCT04073602
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