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Data for BeyondSpring’s Lead Asset, Plinabulin, for Chemotherapy-Induced Neutropenia (CIN) Prevention Shows Differentiated Profile Compared with G-CSF and Adds Additional Protection to G-CSF
BeyondSpring Presented Latest Clinical Results at 2018 American Society of Hematology (ASH) Annual Meeting
  • Plinabulin monotherapy is an equally effective single-dose-per cycle agent as pegfilgrastim, but with minimal bone pain vs. pegfilgrastim in intermediate neutropenic risk CIN

  • Plinabulin and pegfilgrastim combination demonstrates superior CIN efficacy in high neutropenic risk chemotherapy, and almost eradicates pegfilgrastim-induced bone pain

  • Plinabulin mobilizes CD34+ progenitor cells into the peripheral blood through a mechanism of action different than G-CSF or Plerixafor, potentially presenting a new option for hematopoietic cell transplantation (HCT)

NEW YORK , Dec. 04, 2018 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (NASDAQ: BYSI), a global biopharmaceutical company focused on the development of innovative cancer therapies, reported new data from its lead asset, Plinabulin, for the prevention of chemotherapy-induced neutropenia (CIN). The results, presented at this year’s American Society of Hematology (ASH) Annual Meeting, continue to build the evidence that Plinabulin has a unique mechanism of action (MOA) compared with G-CSF, and is a potential new option for CIN in intermediate risk chemotherapy patients as a single agent. Additionally, data was presented at ASH that supports the combined use of Plinabulin and pegfilgrastim in chemotherapy patients at high risk for CIN and febrile neutropenia and may improve results over G-CSF alone, the current standard of care in the prevention of CIN.

CIN is a side effect from chemotherapy for cancer patients, and despite the broad use of G-CSFs for more than 25 years, febrile neutropenia and resultant hospitalization remains an unresolved clinical problem. The ultimate goal for chemotherapy is to treat cancer and prolong patients’ lives. But patients treated with high risk chemotherapy (febrile neutropenia or FN rate > 20 percent), even using G-CSF still have very high severe neutropenia risk (>80 percent, some at 100 percent), which requires chemotherapy dose reduction or delays in subsequent cycles. Many publications showed that cancer patients with <85 percent of relative dose intensity (RDI) of chemotherapy translates to 50 percent of overall survival compared with patients with >=85 percent RDI. In addition, bone pain is a common side effect of G-CSF, which limits patient compliance with G-CSF and results in suboptimum chemotherapy dosing. An ideal agent in high febrile neutropenia risk chemotherapy is desired to prevent severe neutropenia and reduce side effects such as bone pain.

  • In intermediate risk chemo patients (FN rate at 10 – 20 percent), the risk/benefit ratio analysis of G-CSF use often presents an unfavorable profile, a growth factor for cancer cells and introducing unwanted side effects such as bone pain or thrombocytopenia, among others. As a result, NCCN guidelines caution against the use of G-CSF in these patients. An ideal agent in intermediate risk chemo is desired to be an effective CIN agent similar to G-CSF, but with a superior safety profile, represented by Plinabulin monotherapy.
     
  • In high risk chemo patients, G-CSF is recommended to be used to contain FN rate and lower mortality rate, as high as 18 percent in first cycle. Clinical studies have demonstrated that Plinabulin plus G-CSF in this population delivers superior efficacy in severe neutropenia reduction as well as significant improvements in side effects compared with monotherapy G-CSF.

Study 105 (for neutropenia induced by docetaxel, which has intermediate risk for FN)
The study evaluated patients with advanced or metastatic non-small cell lung cancer (NSCLC) and was a multicenter, open label, randomized study. In a head-to-head comparison in docetaxel (75 mg/m2 day 1) treated patients, Plinabulin (at doses of 5 mg/m2, 10 mg/m2 and 20 mg/m2) is compared with pegfilgrastim (at 6 mg), in a total of 55 patients in a four-cycle study. One dose of Plinabulin was given on Day 1, while one dose of pegfilgrastim was given on Day 2 in a 21-day treatment cycle. Results for the most effective Plinabulin dose is presented below, where DSN is the duration of severe neutropenia:

Cycle 1 Pegfilgrastim 6 mg
(n=14)
Plinabulin 20 mg/m2
(n=14)
DSN (grade 4) (day) 0.5 0.5
% neutropenia (grade 4) 14% 14%
% bone pain 35% 0% from Day 3
Thrombocytopenia (all cycles) Yes No
Immune suppression Yes No
Anticancer No Yes

In addition, BeyondSpring evaluated CD34+ cell counts in the blood by measuring CD34+ levels pre-dose and at multiple time points through Day 8 of treatment with docetaxel, both with and without Plinabulin. CD34+ measurements were obtained in at least nine patients on both Day 0 and Day 8 for each Plinabulin dose. Patients treated with Plinabulin had statistically significant increases in CD34+ levels at Day 8 in a dose-dependent manner (p<0.0004). These data indicate that Plinabulin could potentially be a new option for hematopoietic cell transplantation (HCT) and these findings deserve further study.

Study 106 (for neutropenia induced by TAC, a chemotherapy with high FN risk)
The study evaluated patients with breast cancer and was a multicenter, open label, randomized study. In a head-to-head comparison of TAC (docetaxel, doxorubicin and cyclophosphamide, Day 1 dose) treated patients, Plinabulin monotherapy at various doses (10 mg/m2, 20 mg/m2 and 30 mg/m2), and Plinabulin at 20 mg/m2 combined with pegfilgrastim at various doses (6 mg, 3 mg and 1.5 mg), were compared with pegfilgrastim at 6 mg, in a total of 115 patients in a four-cycle study. One dose of Plinabulin was given on Day 1, while one dose of pegfilgrastim was given on Day 2 in a 21-day treatment cycle.

The study results showed that, after TAC, single agent Plinabulin’s median absolute neutrophil count (ANC) on Days 7 and 8 in the first cycle were above 1.0x109 cells/L (avoids grade 3 and 4 neutropenia), while the pegfilgrastim median ANC on Days 7 and 8 were below 1.0x109 cells/L (grade 3 and 4 neutropenia). The observed complementary MOA led to testing the combination of Plinabulin and pegfilgrastim, which had a median ANC on all days in the first cycle above 1.0x109 cells/L.

 
Pegfilgrastim 6 mg

(n=21)
Plinabulin 20 mg/m2 +
Pegfilgrastim 6 mg

(n=16)
Plinabulin 20 mg/m2 +
Pegfilgrastim 3 mg

(n=21)
DSN (grade 3/4) mean (day) 1.4 ± 1.0 0.9 ± 1.1 1.6 ± 1.6
DSN (grade 3/4) median (day) 1.0 0.5 2.0
% neutropenia (grade 3/4) 81% 50% (p=0.0456) 57%
% neutropenia (grade 4) 57% 38% 52%
ANC nadir mean (109 cells/L) 0.77 ± 0.90 1.15 ± 0.94 0.88 ± 1.02
ANC nadir median (109 cells/L) 0.47 1.00 0.49
% bone pain 95% 6% (p<0.0001) 33% (p<0.0001)
% bone pain (over 4 days) 33% 0% (p=0.0124) 10%

“The rationale for developing this combination is the observation that pegfilgrastim and Plinabulin have different neutrophil recovery time courses, which may represent complimentary MOAs: Plinabulin acts through a G-CSF-independent pathway that involves IL-6 signaling at tissue level, whereas pegfilgrastim works through G-CSF signaling. Importantly, we observed no systemic IL-6 related adverse events such as fever, chills, hypotension or myalgias, in any of our clinical trials in over 450 cancer patients. Plinabulin’s MOA appears to be highly effective in the first week of the chemotherapy cycle, when pegfilgrastim does not prevent grade 4 neutropenia. The benefit for grade 4 neutropenia with pegfilgrastim appears to occur primarily in the second week of the cycle. The data we presented at ASH confirmed that adding Plinabulin to pegfilgrastim offers protection against grade 4 neutropenia in Week 1 and 2 of the chemotherapy cycles. An unexpected benefit with the addition of Plinabulin to pegfilgrastim was that it almost eradicated bone pain induced by pegfilgrastim. Collectively, the data presented may suggest—based on benefits such as grade 3 and 4 neutropenia frequency, grade 4 neutropenia frequency and ANC nadir—that Plinabulin, when added to full dose of pegfilgrastim (6 mg), can lead to superiority for CIN while mitigating pegfilgrastim-induced bone pain versus the full dose (6 mg) of pegfilgrastim alone. We also evaluated the combination with a half-dose of pegfilgrastim (3 mg) with Plinabulin, and the data suggest that this combination has the potential to also be effective compared with the pegfilgrastim full dose (6 mg), while significantly reducing pegfilgrastim-induced bone pain. Plinabulin itself has a very favorable safety profile,” said Dr. Douglas Blayney, Global Principal Investigator for the Plinabulin CIN studies and Professor of Medicine at Stanford University School of Medicine.

“Long-acting G-CSF (Neulasta® and its biosimilars) are not indicated for the mobilization of peripheral blood progenitor cells (CD34+ cells) for HCT patients. Short-acting G-CSF is indicated for CD34+ cell mobilization, however, many patients do not adequately respond to G-CSF. Plerixafor is an alternative to G-CSF, however its use is limited due to its high cost, and many patients fail to produce adequate CD34+ cells with its use. Plinabulin mobilizes CD34+ stem cells through a MOA different from G-CSF and Plerixafor. Therefore, Plinabulin could become a valid option for HCT mobilization in patients who are unresponsive to G-CSF with or without Plerixafor, which is also an area of unmet medical need,” added Dr. Ramon Mohanlal, EVP and Chief Medical Officer at BeyondSpring.

“The CD34+ finding with Plinabulin has potentially not only medical, but also commercial significance as it adds an additional indication to the Plinabulin product label, which pegfilgrastim and its biosimilars do not have. This further adds to Plinabulin’s holistic product profile, as an anticancer agent that can prevent severe CIN, without causing overt bone pain, and with protection against chemotherapy-induced thrombocytopenia,” concluded Dr. Lan Huang, BeyondSpring co-founder and Chief Executive Officer.

About Study 105 (Intermediate Risk CIN)
The study evaluated patients with advanced or metastatic NSCLC after failing platinum-based therapy, and was designed as a multicenter, open label, randomized study. In a head-to-head comparison of Plinabulin (at various doses of 5 mg/m2, 10 mg/m2 and 20 mg/m2) with pegfilgrastim (at 6 mg), a long-acting G-CSF, in a total of 55 patients, Plinabulin at 20 mg/m2 was shown to be comparable to pegfilgrastim for the prevention of CIN, as assessed by the occurrence of severe (grade 4) neutropenia and the DSN in the first cycle.

Plinabulin was given as a single dose-per-cycle 30 minutes after docetaxel chemotherapy, while pegfilgrastim was given 24 hours after docetaxel chemotherapy, consistent with its approved product label. The Phase 2 portion met its primary endpoint, which was to determine the recommended Phase 3 Plinabulin dose, and the Phase 3 trial is ongoing.

About Study 106 (High Risk CIN)
The study evaluated patients with breast cancer patients and was designed as a multicenter, open label, randomized study. In a head-to-head comparison of Plinabulin monotherapy at various doses (10 mg/m2, 20 mg/m2 and 30 mg/m2), and Plinabulin at 20 mg/m2 combo with pegfilgrastim at various doses (6 mg, 3 mg and 1.5 mg), against pegfilgrastim alone (at 6 mg) in a total 115 patients, grade 3 and 4 neutropenia frequency, grade 4 neutropenia frequency, duration of grade 3 and 4 neutropenia and bone pain were compared.

Plinabulin was given as a single dose-per-cycle 30 minutes after TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy, while pegfilgrastim was given 24 hours after TAC therapy. The primary objective of Phase 2 was to determine the recommended Phase 3 dose.

About Plinabulin 
Plinabulin, a marine-derived small-molecule, is BeyondSpring’s lead asset and is currently in late-stage clinical development for the prevention of chemo-induced neutropenia and as an anticancer therapy in non-small cell lung cancer. Studies of Plinabulin's mechanism of action indicate that Plinabulin activates GEF-H1, a guanine nucleotide exchange factor. GEF-H1 activates downstream transduction pathways leading to the maturation of dendritic cells, which in turn leads to T-cell activation and the up-regulate of IL6 in the tissue micro environment, contributing to the prevention of neutropenia.

About BeyondSpring
BeyondSpring is a global, clinical-stage biopharmaceutical company developing innovative immuno-oncology cancer therapies with a robust pipeline from internal development and from collaboration with the University of Washington in de novo drug discovery using a ubiquitination platform. BeyondSpring’s lead asset, Plinabulin, is in a Phase 3 global clinical trial as a direct anticancer agent in the treatment of non-small cell lung cancer and two Phase 2/3 clinical programs in the prevention of chemotherapy-induced neutropenia. BeyondSpring has a seasoned management team with many years of experience bringing drugs to the global market.

Cautionary Note Regarding Forward-Looking Statements
This press release includes forward-looking statements that are not historical facts. Words such as "will," "expect," "anticipate," "plan," "believe," "design," "may," "future," "estimate," "predict," "objective," "goal," or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based on BeyondSpring's current knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, difficulties raising the anticipated amount needed to finance the Company's future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet our expectations regarding the potential safety, the ultimate efficacy or clinical utility of our product candidates, increased competition in the market, and other risks described in BeyondSpring’s most recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release and BeyondSpring undertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.

Neulasta is a registered trademark of Amgen, Inc.

Contact:
Media Relations:
Caitlin Kasunich / Amrita Singh
KCSA Strategic Communications
212.896.1241 / 212.896.1207
ckasunich@kcsa.com / asingh@kcsa.com

Investor Relations:
Laura Perry / Joe Rayne
Argot Partners
212.600.1902
BeyondSpring@argotpartners.com

BeyondSpring, Inc.