Enriched siRNA Therapeutic Pipeline
Sirnaomics, Inc. has developed an enriched pipeline of siRNA therapeutic candidates using our multi-targeted siRNA designs and peptide polymer delivery systems (Table 1). Our lead product candidate STP705, has been extensively tested in a battery of pre-clinical IND enabling studies and has demonstrated a very strong safety and efficacy profile. This will be our first therapeutic to be studied in humans as we plan to file IND in 1H 2016 and complete phase 1 in 2H 2016. We anticipate following on studies in humans to be in the areas of oncology and infectious disease as we work now to complete our IND enabling studies in these therapeutic areas. We will focus the subsequent material on our three leading therapeutics.
STP705, Hypertrophic Scar Prevention and Reduction:
Hypertrophic scarring is an abnormal condition that can occur after any injury to the skin and most commonly after surgical procedures. Hypertrophic scar formation is abnormal scarring and results in scars that are large, red, raised and pruritic. If this type of scarring occurs on the face or over joints such as the hips, knees, shoulders, or hands, it can be both disfiguring and debilitating. There is no FDA-approved therapeutic for hypertrophic scar prevention and reduction and currently used off label treatments typically have been show to have minimal impact in terms of efficacy with very high recurrence rates. The market opportunity for STP705 is substantial. Each year, 42 million surgical skin procedures are performed and 62 million scars are formed in the US. Approximately 93 million people in the US are living with scars and about 169 million scars can be characterized as hypertrophic or keloids. In total, the market opportunity for STP705 in scarring prevention and reduction is estimated at $4.5-5B. If STP705 is successful at preventing or reducing scars in clinical studies, we anticipate that it could gain share rapidly in a currently underserved market. Once approved, we believe that STP705 would start with patients undergoing cosmetic procedures (6M procedures performed annually, an additional 3.4M mole removals performed annually), specifically scar revision procedures. Once use becomes more prevalent in the cosmetic procedure patient population, we expect use in other categories like office/hospital-based elective procedures (~20M) and reconstruction and trauma procedures (~13M) to take hold.
STP705 (US 8,735,567 B2) will also have utility in treatment of wounds incurred on the battlefield, wounds from burns, or wounds from surgical intervention and may have utility in treatment of diabetic wounds – many of which require limb amputation as a cure. This product can be positioned within the armed forces to treat combat casualties, within hospitals for traumatic wounds and eventually into clinics and plastic surgery offices to improve healing in elective surgery. STP705 (Cotsiranib) targeting both TGFβ1 and Cox-2 and packaged in HKP (the 1st generation nanoparticle) has been tested in mouse and swine skin excision wound models, and human hypertrophic scar tissue implant mouse models, demonstrating remarkable therapeutic benefit of scar prevention and reduction. Two big pharma companies expressed strong interest in this product candidate. Suzhou Sirnaomics has signed a partnership with a Chinese pharmaceutical company (Xiangxue Pharmaceuticals, Ltd.) for co-development of STP705 for the Chinese market with 22 millions RMB (about US$3.7 millions) investment (Table 2). STP705 offers advantages over RXi’s RXI-109 and Excaliard’s EXC-001 in terms of dosage used and routes of administration.
STP302， Colorectal Cancer Treatment：
Colorectal cancer (CRC) is the 4th most commonly diagnosed cancer in the world, and is more common in the developed countries. Globally each year greater than 1 million people would be diagnosed with CRC which resulting in about 0.5 million deaths. In the USA, an estimated 149,000 CRC cases would be diagnosed with 50,000 deaths each year. As of 2008 CRC was the 2nd most common cause of cancer in women, the 3rd most common cancer in men, and the 4th most common cause of cancer death after lung, stomach, and liver cancer. The global market for colorectal cancer treatment is extimated over $10 billion.
During the development of colorectal cancer, the expression of this target miRNA decreased from normal colorectal tissue to adenoma-adenocarcinoma, and to the final colorectal cancer. When introduced into colon cancer cell line, this miRNA is able to manipulate the processes of cell proliferation, cell cycle, and apoptosis. The expression of this target miRNA was found to be associated with survival and response to adjuvant chemotherapy in 239 patients with CRC.
When chemically synthesized miRNA mimics complexed with HKP (histidine-lysine polymer) as nanoparticle (STP302) and injected into xenographed colon cancer tissues, the group treated with STP302 showed significant slow-down and termination of cancer growth. Further testing data showed that the treatment with STP302 induced cancer cell apoptosis.
A complete pharm/tox study for STP302 has been scheduled for Q2 of 2016. A US FDA Phase I clinical application will be filed by the end of 2016.
A patent application (201510485343.0) has been filed through Chinese Patent Office, and the PCT filing is underway.
Oncology Portfolio (US 9,012,622 B2 and US 8,541,568 B2):
There are many different cancer types and each has a market in the billions of dollars. Treatments for Colorectal Carcinoma, Glioblastoma, Breast Carcinoma and Non-small cell lung carcinoma are in the big demands within the US and around the world and may increase in prevalence in emerging markets such as China where smoking and air pollution are problematic. Hepatocellular carcinoma (HCC or liver cancer) is also increasing in Asia as a result of high rates of hepatitis infection. Melanoma is a skin cancer that is increasing in incidence in the US and European Caucasian populations. Prostate cancer and Breast cancer affect men and women respectively (although men can also get breast cancer) and while these indications are treated with a variety of drugs, antibodies and radiotherapies produced by a number of pharmaceutical companies, currently none have demonstrated the ability to cure all forms of cancer. Sirnaomics is pursuing use of siRNAs to silence aberrant genes in cancer (STP302, STP909 and STP523) and its early work has been funded by three NIH/NCI SBIR grants. We are currently developing the third generation nanoparticles to target the site of the hepatocellular carcinoma and avoid non-productive uptake by the nearby Kupffer cells. These experiments are in their early stages but a demonstration of targeted siRNA delivery to the correct cells within an organ such as the liver will allow expansion to other targeting moieties aimed at other forms of cancer or other diseases in distinct tissues. A vehicle able to deliver siRNAs to the hepatocytes within liver will have utility in other liver-based disorders such as hypercholesterolemia.
STP702 (US 8,691,781 B2), “Resistance-Proof” Influenza Prophylaxis and Therapeutics:
Our patented siRNA therapeutics (Fluquit™) shown to have efficacy against H5N1 (avian flu), H1N1 (swine flu) and newly emerging H7N9. Our team has identified siRNA inhibitors in a therapeutic against flu and has validated a vehicle for administration of these siRNAs to the lung. We believe that an inhaled siRNA able to reduce viral load by preventing viral replication can capture a significant portion of the market for therapeutics in this space. Additionally, should new strains emerge (as they inevitably will), Sirnaomics is well positioned to design appropriate siRNA therapeutics against any new strain and to provide large numbers of doses of our drug ahead of vaccine production. We have developed siRNAs against conserved regions within the viral genome that should provide wide strain specificity and a multi-targeted siRNA cocktail will prevent escape of the virus from therapeutic pressure through mutation within a single gene segment. This antiviral approach may be applicable to other respiratory viruses (e.g. RSV) or biothreat agents (e.g. EV71) and this is somehow similar to HIV tri-therapy.
STP909 (Cervisil®) Therapeutic for HPV Infection, Cervical Cancer and Other HPV-Associated Cancers
Human Papillomaviruses (HPVs) are among the most common pathogens of sexually transmitted diseases (STDs) in humans, and also implicated in the pathogenesis of genital warts, cervical cancer and several other HPV-associated cancers. It is reported that over 80% of US women by age 50 will have contracted at least one strain of HPV, which now has over 150 different species. Every year in the world there are about 490,000 new cases of cercal cancer, and with 270,000 deaths. Among the 19 “high-risk” HPVs which will lead to cervical cancer, HPV16 and 18 count for about 70% of the cases. US FDA has approved two vaccines against HPV infection, Gardasil® (2006, by Merck) and Cervarix® (2009, by GlaxoSmithKline); however there is no specific and effective antiviral therapy for HPV infection yet.
Through SiHa and HeLa cell culture systems, we selected effective siRNAs against the expression of HPV16/E7 and HPV18/E7 gene. Based on the cell biology studies, potent siRNA duplexes targeting the E7 gene in both HPV16 and HPV18 were selected. These siRNA are packaged with the HKP polymer to form nanoparticle as our drug candidate STP909 for the treatment of infection by HPV16 and HPV18.
In the rabbit model, a chimerical human-rabbit Papillomavirus (cH-RPV) was constructed to facility the in vivo efficacy studies of siRNA against HPV. In cH-RPV, fragments of HPV16 E7 genes were inserted at the end of E7 gene of Cottontail Rabbit Papillomavirus (CRPV). High potency siRNA against HPV16 and cH-RPV were selected in SiHa cells for their efficacy in knocking down of E7 gene expression. Western blots also demonstrated the decreased expression of E7 protein.
STP909 was applied for efficacy study in the skin infection rabbit animal model (SIRAM). Skin lesions were produced with inoculation of CRPV or cH-RPV on the back skin of rabbits, and treated with paste of selected siRNAs formulated with HKP. Efficacies were assessed for each of the siRNA by inhibition of Papilloma tumor growth in testing animals. The siRNA with efficacy to inhibit the growth of papilloma was selected as our drug API.
We are continuing to evaluate opportunities where siRNA and miRNA (antagomir) therapeutics combined with our delivery agents can be used to penetrate new markets. Therapeutic programs in collaboration with other institutions include validation and development of siRNA cocktails in treatment of brain cancer (glioblastoma) and prostate cancer, treatments to assist in solid organ transplantation, as well as treatments for other infectious diseases such as RSV and HPV.