ProNAi Reports Significant Activity and Ongoing Durable Responses in Relapsed or Refractory Non-Hodgkin’s Lymphoma with PNT2258

VANCOUVER, Canada and PLYMOUTH, MI, USA I December 5, 2014 I ProNAi Therapeutics Inc., a private hematology/oncology company dedicated to developing and commercializing a new class of therapeutics based on its proprietary DNAi^® platform, today reported that a number of patients with relapsed or refractory Non-Hodgkin’s Lymphoma treated with its first DNAi-based therapeutic, PNT2258, achieved meaningful therapeutic outcomes and continue to exhibit durable clinical responses.

The interim results from the ongoing pilot Phase II trial of PNT2258, a DNAi-based therapeutic targeting BCL2, are being reported in a poster presentation at the 56^th Annual Meeting of the American Society of Hematology (ASH), being held in San Francisco. The investigators for the study concluded that:

• PNT2258 treatment results in significant, durable responses in patients with relapsed or refractory non-Hodgkin’s Lymphoma (r/r NHL).
• Eleven of the thirteen (11/13) patients treated achieved clinical benefit, with ongoing Progression Free Survival (PFS) extending to 18 months and beyond.  
• PNT2258 is demonstrably active in patients with diffuse large B-cell lymphoma (DLBCL). All four of the patients (4/4) with DLBCL responded to PNT2258, with three patients achieving complete responses (CR) and one patient achieving a partial response (PR), with durations extending to greater than 500 days.
• Durable and clinically meaningful CR’s and PR’s were achieved in subjects with aggressive disease, such as Richter’s transformation and Burkitt’s-like DLBCL.
• Noteworthy durable CR’s and PR’s were also observed in subjects with advanced stage follicular lymphoma (FL).
• PNT2258 therapy is safe and very well-tolerated with dosing periods up to and exceeding 18 months. 

“These results demonstrate that PNT2258 is an obviously active, well-tolerated therapeutic that warrants advanced clinical development,” said Dr. Nick Glover, President and CEO of ProNAi Therapeutics. “As such, in the coming months we will be initiating robustly designed studies of PNT2258 as a single agent in patients with refractory or relapsed DLBCL and in Richter’s transformed DLBCL, areas of high unmet medical need in which PNT2258 appears to be particularly effective. Given PNT2258’s favorable safety profile and the prospect for a BCL2-targeted agent to augment complementary mechanistic approaches, combination clinical studies with other targeted agents are also being planned.”

Study Details
The primary objective of the pilot Phase II open label efficacy study (PNT2258-02; NCT01733238) was to determine anti-tumor activity and collect safety data on recurrent or treatment-refractory NHL patients receiving single-agent PNT2258.

Of the 13 patients treated, four were diagnosed with DLBCL; five patients were diagnosed with FL, two with mantle cell lymphoma (MCL) and two with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The median age of the patients was 63, and they had received an average of two prior systemic treatments. Nearly half (46%) of the subjects were refractory to prior treatment.

Patients received 120 mg/m² of PNT2258 intravenously on days 1-5 of a 21-day cycle for 6-8 cycles, and then continued with 100 mg/m² on days 1-2 of a 28-day cycle, until disease progression.

Efficacy Results

• Eleven of the thirteen (11/13) subjects treated with single-agent PNT2258 derived clinical benefit.
• All four of the subjects (4/4) with DLBCL responded to PNT2258, with three CR’s and one PR, with durations extending to greater than 500 days.
• Four subjects, including two with DLBCL and two with FL, continue to be treated with PNT2258.
• Subjects with aggressive Richter’s transformed and Burkitt’s-like DLBCL attained durable clinical responses with PNT2258.
• Ten of the thirteen (10/13) subjects remained on study for more than 100 days.
• Subjects with DLBCL and FL remained on study longest.

Table 1. Responses to treatment assessed by blinded, independent read using revised IWG (Cheson* 2007) criteria

*JCO February 10, 2007 vol. 25 no. 5 579-586
**Denotes PR by Cheson 2007 criteria and CR by 2014 Lugano criteria (Cheson BD, Fisher RI, et al. doi: 10.1200/JCO.2013.53.5229). ***Denotes patient with PR while undergoing treatment with PNT2258 and subsequent radiotherapy to single remaining lesion resulting in CR. Patient remains disease-free.
+ Denotes patient still receiving PNT2258.

Safety Results

• PNT2258 is safe and well tolerated when administered to patients with advanced NHL for dosing periods up to and exceeding 18 months.
• The majority of adverse events were grade 1 and 2 requiring, at most, supportive care measures. There were no drug-related discontinuations from treatment.
• Hematologic and metabolic adverse events were minimal and most often occurred in subjects with pre-disposing conditions such as transfusion dependent anemia and thrombocytopenia.
• PNT2258 did not precipitate tumor lysis and there was no evidence of significant metabolic adverse events even in subjects with high-volume disease that achieved durable clinical responses to treatment.

Poster Presentation:
A poster of these data will be presented at the 56^th Annual Meeting of the American Society of Hematology, being held in San Francisco. The poster (Abstract #1716) is entitled: “The BCL2 Targeted Deoxyribonucleic Acid Inhibitor (DNAi) PNT2258 Is Active in Patients with Relapsed or Refractory Non-Hodgkin’s Lymphoma”. The poster will be presented from 5:30 – 7:30 pm PT on Saturday, December 6^th, 2015 at the Moscone Center, West Building, Level 1.

About PNT2258 and DNAi
PNT2258 is the first clinical stage DNAi-based therapeutic, and is designed to exquisitely target the regulatory region of the BCL2 gene, modulating transcription and effecting BCL2 function. PNT2258 is a proprietary liposomal formulation of PNT100, a 24-base phosphodiester DNA sequence. The liposomes are specialized anionic and pH “tunable” nanoparticles composed of four lipids.  After intravenous injection, PNT2258 achieves systemic distribution, where PNT100 enters into nuclei to target the non-coding, non-transcribed regulatory region of the BCL2 gene upstream of the promoter start site resulting in an anti-proliferative and apoptotic effect.

ProNAi’s proprietary DNAi^® (DNA interference) therapeutic platform delivers rationally-designed DNA oligonucleotides into cells in order to target sequences residing within 5′-non-coding regions of the genome. These regulatory regions are susceptible to DNAi hybridization during transcription, cell cycling and gene up-regulation. The specific hybridization of the DNAi oligonucleotides with the targeted complementary strand of genomic DNA modulates transcription, affecting the function of the target gene.

About ProNAi Therapeutics
ProNAi Therapeutics is a private company dedicated to developing and commercializing a new class of therapies based on its proprietary DNAi^® platform for patients with cancer and hematological diseases. ProNAi’s lead DNAi drug PNT2258 is specifically designed to treat cancers that overexpress BCL2. To date, 35 patients have been treated with PNT2258 in a Phase I and a pilot Phase II trial, with compelling efficacy and safety results reported. In May 2014, ProNAi raised approximately $60M from leading healthcare investors. For more information, please visit www.pronai.com.

SOURCE: ProNAi Therapeutics