BeyondSpring Pharmaceuticals plans to initiate Plinabulin Phase 3 pivotal trial in NSCLC patients

Mechanism-Based Trial Plan Follows Presentation of Positive Phase 2 Data at 2014 ASCO Annual Meeting

BeyondSpring Pharmaceuticals, Inc., a clinical stage biopharmaceutical company focused on the development of innovative cancer therapies, today announced that it plans to initiate a Phase 3 pivotal trial of lead product candidate, Plinabulin, in patients with non-small cell lung cancer (NSCLC) in the first quarter of 2015. The planned initiation of the Phase 3 trial follows the presentation of positive data from a Phase 2 clinical trial evaluating Plinabulin at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, held on May 30 – June 3, 2014 in Chicago, Illinois.

Plinabulin is an anti-cancer agent with a unique mechanism of action. It has multi-faceted activities that have been shown to exhibit anti-tumor activity through anti-angiogenesis, obliteration of existing tumor vasculature and induction of tumor cell apoptosis via the JNK pathway.

The completed Phase 1b/2, open-label trial (NCT00630110) in patients with advanced (Stage 3b/4) NSCLC compared the efficacy and safety of the combination of Plinabulin and docetaxel to docetaxel alone. Results of the trial were presented in a poster titled “Randomized phase 2 trial of plinabulin (NPI-2358) plus docetaxel in patients with advanced non-small cell lung cancer (NSCLC),” (Abstract #8054) during a general poster session on “Lung Cancer - Non-Small Cell Metastatic”.

Dr. Lan Huang, Ph.D., Chief Executive Officer of BeyondSpring Pharmaceuticals, commented:

The data from our Phase 2 study validated Plinabulin’s unique mechanism of action and allowed us to tailor our next trial using a unique biomarker-driven approach to patients who will be most likely to benefit from treatment with Plinabulin, such as those with large lung cancer lesions, and thus more dependent on the abundant tumor vasculature. Our Phase 2 study demonstrated a longer median overall survival for this particular subset of patients – 11.5 months for combination Plinabulin plus docetaxel compared to just 7.8 months for patients receiving docetaxel alone. This is a substantial improvement compared to approved lung cancer drugs which, in pivotal trials, demonstrated overall survival of approximately 8 months. Furthermore, over the last 15 years, few drugs have received FDA approval specifically for second-line NSCLC with EGFR and ALK wild type patients, who typically have much shorter survival time than EGFR and ALK mutant patients. Given this, there is a critical unmet medical need for NSCLC patients without EGFR or ALK mutations. Our data have shown that Plinabulin activities are independent of EGFR, ALK mutations. We believe Plinabulin would be an important addition to the armamentarium for this difficult to treat disease.

In the Phase 2 portion of this study, a total of 172 patients with NSCLC who had progressed after at least one chemotherapy regimen for advanced disease were randomized 1:1 to receive docetaxel alone (75 mg/m²) or docetaxel (75 mg/m²) in combination with either Plinabulin at 30 mg/m² (30 Cohort) or 20 mg/m² (20 Cohort). A total of 163 patients were treated. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety. The study also aimed to identify, on an exploratory basis, a subset of patients that responds better to combination therapy of Plinabulin and docetaxel.

The study demonstrated encouraging efficacy results. In the 30 Cohort, median OS at a 90% confidence interval (CI) was 8.7 months for Plinabulin and docetaxel combination, compared to 7.5 months for docetaxel alone; although ORRs were comparable between treatments, 14.0% for combination and 14.5% for docetaxel alone, the DOR at 90% CI for the combination was superior to docetaxel alone, 12.7 months compared to 1.5 months, respectively, (p=0.049). Furthermore, results from the combination of Plinabulin and docetaxel 30 Cohort appeared better than those from the 20 Cohort.

In addition, post hoc exploratory analysis identified mechanism-targeted patients as those with large lung tumors (greater than 3 cm). In this subpopulation, patients who had one prior chemotherapy for advanced disease experienced apparent survival benefit from Plinabulin and docetaxel combination relative to docetaxel alone. Median OS at 95% CI for this subset was 11.5 months for the combination compared to 7.8 months docetaxel alone. Based on this observation, BeyondSpring plans to initiate a Phase 3 trial enriched for patients who will most likely benefit from the known mechanism of action of Plinabulin, namely, a tumor vasculature targeting agent with apoptotic properties via JNK pathway.

Overall, Plinaublin is well tolerated in combination with docetaxel. The majority of adverse events were mild to moderate. The most frequent adverse events were nausea, fatigue, diarrhea, constipation, and loss of appetite, occurring in less than 50% of patients. Among patients receiving Plinabulin and docetaxel combination, the most frequent severe (Grade 3) or life-threatening (Grade 4) adverse event was transient hypertension in 20% of patients, while Grade 3 or 4 neutropenia was observed in less than 8% of patients – which is much lower than the 29% of patients in the docetaxel alone group. Neutropenia is an abnormally low count of neutrophils, a type of white blood cell important in fighting infection. Severe neutropenia may lead to life-threatening infection and often necessitates reducing the dose of docetaxel. Consistent with less frequent neutropenia, fewer dose reductions of docetaxel (10%) were necessary for patients in the combination group than among patients receiving docetaxel alone (18.2%). Similar observations were made in both the 30 Cohort and the 20 Cohort.

Dr. Gloria Lee, M.D., Ph.D., Chief Medical Officer of BeyondSpring, added:

Based on these data, we are able to utilize our unique mechanism-based approach to tailor the design of the Phase 3 trial to include patients with large tumors. Starting the trial in the first quarter of 2015, we plan to enroll approximately 500 patients at up to 35 sites between China and the U.S. Following consultation with the U.S. FDA, we expect to enroll approximately 75% of patients at the China sites, with the remaining 25% enrolled through sites in the U.S. Leveraging our unique, cross-border development model, we expect to substantially enhance the efficiency of resource utilization with respect to both the enrollment time and cost for this pivotal study.