FDA Grants Breakthrough Therapy Designation to Plinabulin for Chemotherapy-Induced Neutropenia

The FDA has granted a breakthrough therapy designation to plinabulin for chemotherapy-induced neutropenia (CIN), according to an announcement from BeyondSpring Pharmaceuticals, the drug developer. The agent has also received this designation from China’s Center for Drug Evaluation of the National Medical Products Administration (NMPA).¹

The application for the differentiated immune and stem cell modulator was based on clinical evidence from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), as well as other CIN studies that have been performed, according to the biopharmaceutical company.

“Receipt of breakthrough therapy designation from the FDA acknowledges both the significant unmet need among patients with CIN and the highly encouraging clinical results generated by plinabulin,” Douglas Blayney, MD, global principal investigator for the plinabulin CIN trials and professor of medicine at Stanford University School of Medicine, stated in a press release.

“This should expedite plinabulin’s move into the clinic, which is beneficial for patients. The currently approved CIN prevention agents are all G-CSF–based and not available to all patients,” added Blayney. “Even with the use of G-CSFs, over 80% of [patients with cancer] undergoing chemotherapy may still experience grade 4 neutropenia, which could lead to severe infection, hospitalization, and even death. Thus, CIN still represents an unmet medical need.”

Topline results from PROTECTIVE-2 demonstrated that plinabulin in combination with pegfilgrastim (Neulasta) significantly enhanced the rate of grade 4 neutropenia prevention versus pegfilgrastim alone in patients who were undergoing treatment with chemotherapy (P <.01), meeting the primary end point of a prespecified interim analysis.²

Notably, the trial also met a key secondary end point of duration of severe neutropenia (DSN) in cycle 1, favoring the plinabulin arm (P <.05). DSN in the first 8 days of cycle 1, was another secondary end point that was achieved, showing superiority in the combination arm over the monotherapy arm (P <.05).

In the phase 3 portion of the double-blind, active-controlled study, investigators set out to examine the safety and efficacy of docetaxel, doxorubicin, and cyclophosphamide (TAC) in a 21-day cycle with plinabulin at 40 mg and pegfilgrastim at 6 mg compared with pegfilgrastim monotherapy in patients with breast cancer.

In the phase 2 portion of the trial, the combination resulted in a reduction in CIN compared with pegfilgrastim monotherapy in patients who received TAC chemotherapy.3 Here, rates of grade 3 neutropenia were 81% versus 50% in the control and investigational arms, respectively (P <.05). Lower rates of grade 4 neutropenia were also observed in the combination arm compared with the monotherapy arm, at 38% versus 57%, respectively.

Moreover, patients who received treatment with the plinabulin combination experienced less bone pain compared with those who received single-agent pegfilgrastim. Bone pain for day 1 or longer was reported in 6% of those on the combination versus 95% of those on the monotherapy (P <.001). Rates of bone pain that persisted for 4 days or longer were 0% versus 33% in the investigational and control arms, respectively (P <.01).

The results from PROTECTIVE-2 were further supported by other CIN studies that were conducted, results of which confirmed the early onset action of agent in week 1 with regard to neutrophil protection in various cancer types and several chemotherapies; this is complementary to week 2 neutrophil protection achieved with G-CSFs, according to BeyondSpring Pharmaceuticals.

The full topline data from PROTECTIVE-2 are anticipated to read out in Q4 2020. Additionally, the pharmaceutical company announced its plan to file a new drug application (NDA) for the agent for this indication by the end of 2020. A NDA for the agent for the CIN indication was previously submitted to the NMPA on a rolling basis in Q1 2020.

In the United States, this designation is intended to accelerate the development and review of the agent that is planned to treat a serious or life-threatening condition in which clinical data suggest that the drug may result in significant improvement over existing treatments on 1 or more clinically significant end points.

Similarly, in China, breakthrough therapy designation was created to expedite research and development of novel agents for severe life-threatening diseases, or those that negatively impact quality of life, for which no therapies exist or with proven evidence to show clear benefit compared with existing treatment.

“The clinical profile plinabulin has shown truly represents a breakthrough in the CIN space since G-CSFs,” Ramon Mohanlal, MD, PhD, MBA, chief medical officer and executive vice president of Research and Development at BeyondSpring, added in the release. “We look forward to continuing to work with the FDA as we advance the development of plinabulin to address this urgent medical need.”

References

1. BeyondSpring receives breakthrough therapy designations from both US FDA and China NMPA for plinabulin in chemotherapy-induced neutropenia indication. News release. BeyondSpring Pharmaceuticals. September 8, 2020. Accessed September 10, 2020. https://bit.ly/2Rd7YXN.
2. BeyondSpring announces positive topline interim results from PROTECTIVE-2 (Study 106) phase 3 trial evaluating superiority of plinabulin in combination with Neulasta for chemotherapy-induced neutropenia prevention. News release. BeyondSpring Pharmaceuticals. June 15, 2020. Accessed September 10, 2020. https://bit.ly/3fval2d.