After a $50M IPO, Sirnaomics aims to market the first RNAi drug for oncology
Elise Mak ·02/23/2022
Feature


To date, siRNA drugs have been approved for liver-released diseases only and Sirnaomics is among the few players that try their hand at oncology. “First things first, siRNA therapeutics is required to go beyond liver related diseases,” CEO Patrick Lu told PharmaDJ.


Sirnaomics CEO Patrick Lu


Following a $50 million IPO in Hong Kong last month, Sirnaomics became the first RNA therapeutics specialist to go public. Now, it also aims to be the first to market an RNAi drug for oncology.


It is moving towards the goal, with both lead programs STP705 for skin and liver cancer and STP707 for multiple solid tumors in phase II and phase I clinical stage, respectively. This month, the company has moved STP707 to a phase I trial in solid tumors and received a nod from the FDA to proceed with an IND for primary sclerosing cholangitis (PSC).


STP-705 and STP-707 are dual-targeting TGF-ß1/COX-2 inhibitors based on Sirnaomics’ polypeptide nanoparticle (PNP) delivery platform. While STP-705 is being evaluated for local delivery, STP-707 uses a different carrier for systemic delivery administered intravenously.


“Sirnaomics aims to have the first oncology RNAi drug product on the market,” CEO Patrick Lu told PharmaDJ, adding that the company has “strong data readouts in oncology.”


For now, Sirnaomics is focusing on siRNA and mRNA.


“First things first, siRNA therapeutics is required to go beyond liver-related diseases. mRNA is also needed for other types of vaccines and therapeutics. Delivery is still the key for future success,” Lu said. 


“Sirnaomics is putting in tremendous effort for better and targeted deliveries for both siRNA and mRNA drugs and vaccines,” he added.


Leveraging polypeptide nanoparticles


The key that sets Sirnaomics apart from other players is the PNP delivery platform, which enables local or systemic administration of RNAi therapeutics and targets beyond liver hepatocyte cells.


“Sirnaomics histidine-lysine PNP is a polypeptide-based siRNA and mRNA delivery system,” Lu explained. “Based on the cell-penetrating peptide property and the peptide motif targeting property, this PNP formulation is able to enter various cell types efficiently with preference to activated endothelial cells.”


The PNP delivery platform is based on a branched histidine lysine polypeptide (HKP) that is readily synthesized in the laboratory. This polypeptide can self-assemble into a nanoparticle that encapsulates the siRNA to protect it in the bloodstream and promote cellular uptake and delivery to the target within the cell, Sirnaomics said in its prospectus.


The company believes that PNP-formulated siRNA has improved delivery efficiency based on its effective cellular uptake and efficient endosomal release into the cytoplasm, which are crucial characteristics for RNAi delivery platforms.


“The histidine-mediated protonation can further enhance siRNA payload with efficient endosome escape,” Lu said. “Our PNP delivery system has been validated for tumor, liver and lung target knockdown, which demonstrated a broad therapeutic application potential, in comparison to lipid nanoparticle (LNP) and GalNAc-based delivery.”


Consistent manufacturing and beyond liver hepatocytes


The PNP delivery platform is designed to improve manufacturing and target selection in oncology, two pain points found with the LNP technology and GalNAc-based delivery platforms.


While the LNP technology requires multiple base ingredients and makes manufacturing more complex, Sirnaomics said its PNP delivery platform requires fewer ingredients and process steps.


Using a microfluidic technology, the platform can achieve consistency in loading nanoparticles with siRNA and homogeneity of nanoparticles, which can produce consistent drug concentrations between batches that Lu described as “pharmaceutical-grade drug production.”


And while LNP technology demonstrated relatively high toxicity, the PNP delivery platform generated products with low immunotoxicity and high efficiency of delivery into the cell. The PNPs have very high RNA payload packing efficiency (>97%) and can carry multiple RNA molecules directed at different targets.


Sirnaomics also aims to battle more than liver-related diseases.


Sirnaomics’ PNP delivery platform can target various cell and tissue types other than liver hepatocytes, such as tumor cells, lung cells and non-hepatocyte liver cells. This is an improvement over GalNAc RNAi delivery platforms used by competitors that only deliver RNAi trigger cargo to hepatocyte cells in the liver.


STP707 for solid tumors


STP707 is poised to prove that the PNP delivery platform can be applied to develop drugs with wide therapeutic windows.


Lu said that Sirnaomics has two sets of antitumor efficacy data that support using STP707 to treat multiple solid tumors, such as hepatocellular carcinoma (HCC) and other metastasized tumors.


“First, using STP705 local siRNA therapeutic treatments for isSCC, BCC and HCC, we have observed promising clinical results which validate the target selection of STP707, simultaneously knocking down TGF-β1 and COX-2 expression. The anti-tumor activity was further revealed, showing increased CD4+ and CD8+ positive T cells in the tumor microenvironment (TME),” he said.


“Second, [through] administrating STP707 intravenously using a mouse tumor model, we demonstrated a potent anti-tumor activity with clear indication of the positive T cell penetration. This anti-tumor activity was further enhanced when [used in] a combined regimen with a PD-L1 antibody,” he added.


Lu noted that data from nonhuman primate models showed a “very confident safety profile” of STP707. No dose-limiting toxicity was observed in non-human primates at a dose representing roughly 30 times the human equivalent dose proposed for a clinical trial for treatment of solid tumors by IV administration.


With the right drug target selection, a dual inhibitor design, efficient and TME-targeting delivery, a repeated dosing safety profile, and early favorable clinical readouts with local administration, he said STP707 could bring “a strong therapeutic approach superior to other methods.”


Sirnaomics is developing STP707 for the treatment of liver and other cancers as well as fibrosis of the liver and lung via systemic administrations. It plans to submit an IND in China for phase I clinical trials for HCC as part of the global multicenter clinical trials.


Depending on what comes out of the phase I solid tumor basket study, the company may initiate phase II trials in tumor types such as metastatic cutaneous squamous cell carcinoma, non-small cell lung cancer (NSCLC), HCC, and cholangiocarcinoma (CCA).


Phase IIa success with STP705


While Sirnaomics is trying to expand to more solid tumors with STP707, it first tasted success with STP705 that proved its PNP delivery platform did work in treating cancer, starting with non-melanoma squamous cell carcinoma in situ (isSCC).


“We are the first company globally to achieve positive phase IIa clinical outcomes in oncology for an RNAi therapeutic,” Sirnaomics wrote in the prospectus. In the study, 19 out of 25 patients with non-melanoma isSCC showed complete tumor cell clearance.


The company moved on to a phase IIb clinical trial for isSCC in May 2021 in the U.S. and expects interim results in the second half of this year.


“The data generated so far has demonstrated a strong safety profile as well as high efficacy with 90%. Complete response rates in subjects with isSCC are in the recommended phase IIb dosing levels,” Michael Molyneaux, Sirnaomics’ Chief Medical Officer, told PharmaDJ. “In the isSCC study, we have also seen improvement in the skin response scores which suggests improved cosmetic results after treatment with STP705.”


“We have also demonstrated dose response with strong safety profile as well as durable skin response score improvement in our interim skin basal cell carcinoma (BCC) study,” he said, adding that final results from the study could come in the second half of this year.


Sirnaomics is also developing STP705 for dermal fibrosis and solid liver tumors. The candidate is in a phase I/II trial for the treatment of keloid scarless healing and a phase I study for HCC and CCA in the U.S.


Upping its game in GalNAc and mRNA


To stay differentiated, Sirnaomics added favor to the conventional GalNAc RNAi delivery platforms that most competitors are using. It has developed the GalAhead and PDoV-GalNAc delivery platforms, which enable specific delivery to liver hepatocytes with high potency and allow for dual- and multi-gene targeting.


“The GaLAhead structure currently represents the smallest RNAi trigger. It not only exhibits benefits of CMC process and safety profile but shows long-lasting therapeutic efficacy for more than 27 weeks with one-time dosing,” Lu explained.


“On the other hand, PDoV-GalNAc design is trying to improve the endosome escape efficiency. Using a mouse model, we do observe an earlier target knockdown with our PDoV-GalNAc structure than another well-validated GalNAc structure, using the same siRNA sequence with the same chemical modification pattern,” he added.


Lu shared that both platforms have been advanced to late-stage preclinical development.  The GaLAhead Factor XI program has already been moved into an IND enabling study and the company will file an IND later this year.


With the PNP and GalNAc RNAi delivery platforms, Sirnaomics is set to expand its pipeline.


“For PNP-based delivery, we have different target pairs for oncology and anti-fibrosis applications. We also use the PNP delivery system for mRNA vaccine product development,” Lu said.


“As for the two GalNAc delivery platforms, we have single-target GalNAc-siRNA drug candidates and a dual-targeted GalNAc-siRNA drug candidate,” he added.


Sirnaomics’ pipeline


To separate the work for mRNA-based products, Sirnaomics has a subsidiary called RNAimmune. It takes the PNP delivery platform further to develop the PLNP platform that combines polypeptides and lipids.


The company believes the combination of the HK polypeptide and liposome components in the PLNP can make cellular delivery of the mRNA cargo more efficient through better endosomal escape once the PLNP enters the cell. PLNP also makes manufacturing simpler, and products formulated using this platform are expected to be stable at ambient temperatures eliminating the need for cold chain storage and transportation.


RNAimmune is working in preclinical research of prophylactic vaccines for influenza and COVID-19, as well as therapeutics and vaccines for certain cancer types and rare diseases. It is developing RIM730, a prophylactic vaccine candidate for preventing COVID-19.

Keywords: $50M IPO Sirnaomics first RNAi drug
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