Oncology
NXP200
Paradox Breaker BRAF Inhibitor
NXP200 is an oral small-molecule, paradox breaker BRAF inhibitor. It is designed to block the BRAF pathway without triggering the paradoxical activation seen with first-generation BRAF inhibitors.
- Oral, brain-penetrant
- Class I, II and III BRAF mutations
- Breakthrough Therapy Designation in China
How it works
NXP200 is a paradox breaker BRAF inhibitor.
First-generation BRAF inhibitors such as Tafinlar® (dabrafenib) and Braftovi® (encorafenib) inhibit V600-mutated BRAF, but also cause paradoxical activation of the MAPK signaling pathway. This drives treatment resistance and secondary skin cancers. Adding a MEK inhibitor reduces, but does not eliminate, these effects.
NXP200 potently inhibits Class I (V600), Class II and Class III BRAF mutations while disrupting BRAF dimerization and avoiding the paradoxical activation of the pathway induced by first generation inhibitors. NXP200 has also demonstrated robust brain-penetration.
| BRAF mutation | First-generation BRAF inhibitors, with paradoxical activation | NXP200 inhibition, without paradoxical activation |
|---|---|---|
| Class IBRAF V600 | Inhibited | Inhibited |
| Class IIDimerizing, RAS-independent | Not inhibited | Inhibited |
| Class IIIRAS-dependent | Not inhibited | Inhibited |
Class II and III BRAF mutations are not inhibited by first-generation BRAF inhibitors.
Clinical data
In a completed dose escalation study in patients with BRAF V600-mutated solid tumors, NXP200 showed an acceptable safety profile and durable single-agent activity. The response rate was above 40% in adults with low- and high-grade gliomas, including one complete response, and durable responses were also seen in patients with NSCLC, colorectal and papillary thyroid cancers.
Early data with a second-generation salt form of NXP200 showed markedly improved pharmacokinetics and greater single-agent clinical activity. NXP200 has received Breakthrough Therapy Designation in China for the treatment of BRAF V600-mutant recurrent or progressive high-grade glioma. These studies were conducted by Haisco Pharmaceutical Group in China.