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Silenseed Files for $36.4M IPO as it Nears Phase II Trial for Pancreatic Cancer Therapy

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NEW YORK (GenomeWeb) – Israeli RNAi drug developer Silenseed has filed to go public in the US, looking to raise around $36.4 million to support the continued clinical development of its oncology pipeline and the implantable delivery system that enables it.

According to Silenseed CEO and Co-founder Amotz Shemi, the company had been exploring opportunities to raise the money needed to conduct the clinical testing of its flagship pancreatic cancer treatment, which recently completed a Phase I study, eventually deciding to pursue an initial public offering on the Nasdaq.

Should it complete the IPO, Silenseed also intends to move a portion of its operations to the US, which is expected to help the firm establish big pharma partnerships and improve communications with the clinical sites testing its drug candidates, he noted. The company's headquarters, he added, will remain in Israel.

Silenseed's core technology is called LODER — short for local delivery of RNAi — and essentially comprises a miniature biodegradable polymeric matrix containing siRNAs that is implanted into a tumor. It is designed to protect the RNAi molecules from degradation while slowly and steadily releasing them over a period of several months. Preclinical data on the system were published late last year.

In 2010, the company initiated a Phase I study to test the LODER system in pancreatic cancer using siRNAs designed to silence the tissue-signaling gene KRAS, which is frequently mutated in the disease. In the trial, 15 patients with locally advanced pancreatic tumors who received 0.025 mg, 0.75 mg, or 3 mg doses of KRAS-targeting siRNA contained in one, two, or eight LODERs, respectively. They also received weekly treatments of the chemotherapeutic gemcitabine.

That trial has recently been completed, with data showing that the system is safe and well-tolerated, Shemi said. Notably, no tumor progression was detected in any of the patients eight to 12 weeks after treatment, and some showed tumor response. A subset of four patients were later treated with the chemotherapy cocktail Folfirinox, and two of these remain alive almost two years later.

On these encouraging data, Silenseed had been planning to seek orphan drug status for the pancreatic cancer therapy — known as siG12D-LODER — and move into a pivotal clinical trial. According to the firm's IPO filing with the US Securities and Exchange Commission, developing the treatment up through a new drug application filing would cost roughly $16 million, prompting the decision to tap the US public market.

In anticipation of consummating the public offering, Silenseed has already laid the groundwork for that follow-on study to begin before year end. It is designed to enroll up to 124 patients with unresectable locally advanced pancreatic cancer who will receive either 3 mg doses of KRAS-targeting siRNAs contained within eight LODERs plus either gemcitabine or Folfirinox, or chemotherapy alone.

The primary endpoint of the study, which will primarily be run at Memorial Sloan Kettering Cancer Center and Johns Hopkins School of Medicine, will be progression-free survival. In the SEC filing, Silenseed noted that although the trial is starting as Phase II, it could be expanded into Phase III. Proof-of-concept data are expected by mid- to late-2015.

Elsewhere in its pipeline, Silenseed has a prostate cancer program that will take advantage of a next-generation delivery technology dubbed LODER-slow that is designed to release siRNAs over six to 24 months, compared with the three to four months for the existing LODER approach.

In its SEC filing, Silenseed said that it has identified two targets for its prostate cancer program: the polycomb group transcriptional repressor BMI-1, which is frequently upregulated in the disease and has been shown to be involved in malignant transformation; and neurophilin and tolloid-like 2, or NETO-2, which the company said is highly expressed in prostate cancer stem cells.

In in vivo studies, LODERs containing siRNAs against either of the two targets, as well as empty LODERs, were implanted into subcutaneous tumors in mouse models. Analysis of tumor tissue showed that treatment led to a suppression of cell division and necrosis, with no effects seen in control animals.

The company's third program focuses on glioblastoma multiforme (GBM), and will use another variation on the LODER approach called LODER-nano. Silenseed has not yet identified therapeutic targets for this program, but has made strides with the delivery technology.

"Distribution of drug within the entire tumor is a long-standing issue" for existing GBM treatments, Shemi explained. "It is well known that the transport of drug from the peripheral arteries to the core of the tumor doesn't really happen."

LODER-nano combines the polymetric matrix of the first-generation system with siRNA-bearing nanoparticles designed to diffuse into the entirety of the tumor where they release their payload.

Specific details about this next-generation technology are not being made public, Shemi said, although the company is preparing data on it for peer-reviewed publication. Additionally, a patent application covering LODER-nano — No. 20130122096 — has been published by the US Patent and Trademark Office.

Currently, Silenseed expects that it will retain the rights to siG12D-LODER in the US and other key markets. But it hopes to find partners for the prostate and GBM programs, as well as in areas outside of oncology — an effort Shemi said would be aided by the company having a presence in the US.

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