The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
