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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
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.
Study 105 (for neutropenia induced by docetaxel, which has intermediate risk for FN)
Study 106 (for neutropenia induced by TAC, a chemotherapy with high FN risk)
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.
“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.
“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.
“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.
About Study 105 (Intermediate Risk CIN)
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)
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.
Cautionary Note Regarding Forward-Looking Statements
Neulasta is a registered trademark of Amgen, Inc.