A South Korean developer of RNAi (RNA interference) therapeutics plans to expand its U.S. operations and advance up to ten programs into clinical trials over the next three years—nearly doubling the size of its pipeline—toward its vision of becoming a top-three company in nucleic acid therapeutics.
OliX Pharmaceuticals says its expansion will include the construction of an RNA synthesis GMP manufacturing facility at its San Diego site, where eight chemists are now based—about 10% of the company’s staff, 56 of whom hold R&D positions.
The GMP facility will initially carry out oligonucleotide chemistry and analysis for investigational therapeutics to be developed in-house for clinical testing, with the potential to manufacture commercial RNAi therapeutics there.
“We have started up on planning and I think probably late second half of next year, we’ll have it up and running,” Dong Ki (DK) Lee, PhD, OliX’s CEO and Founder, told GEN in an interview about the company and its plans.
OliX plans to fund the GMP facility and its clinical expansion with proceeds from a KRW 41.5 billion ($37 million) financing completed last December. Most of OliX’s capital raise (70%) consisted of approximately $26 million in convertible bonds, with about $11 million in common stock. (Investors included Kiwoom Investment, NH Investment & Securities, Aju IB Investment and Widwin Investment, all based in South Korea.)
How soon the new GMP facility shifts to commercial manufacturing will depend on how quickly OliX progresses toward its goal of developing and advancing the ten programs, which will nearly double the company’s pipeline.
These new programs will be based on OliX’s asymmetric small interfering RNA (asiRNA) platform. asiRNA is designed to deliver gene silencing comparable to RNAi while significantly reducing small or short interfering (siRNA)-mediated side effects such as off-target gene silencing and immune stimulation. (siRNA works by interfering with the expression of specific genes with complementary nucleotide sequences by degrading messenger RNA (mRNA) after transcription, resulting in no translation.)
While chemically synthesized siRNA can trigger efficient and specific target gene silencing in mammalian cells, new therapeutics based on siRNA have not been easily developed because using siRNA to inhibit target genes leads to side effects in cells, such as off-target effects, and because siRNA is difficult to deliver to specific cells or organs effectively due to the large size and negative charges of RNA molecules.
Reducing Side Effects
A novel, chemically modified asiRNA compound called cell-penetrating asiRNA (cp-asiRNA) enables easier delivery of siRNA by inducing gene silencing through simple local administration into organs such as the skin and eyes without requiring special formulations or instruments, the company adds. Cp-asiRNA is designed to efficiently internalize and knock down target gene silencing without any transfection reagents.
“Asymmetric siRNA is just a backbone structure. It doesn’t have any kind of co-modification. To make it into a Cp-asiRNA, we conjugate a lipid moiety,” Lee said. “We started with cholesterol, and now we are expanding to other types of lipid. Conjugation of this lipid and some other chemical modification actually makes this RNA molecules self-delivering inside the cells without the need of any delivery vehicle.”
“[Cp-asiRNA] is very effective, but it doesn’t have a targeting moiety, so we are utilizing this technology for locally administrable therapeutics, such as for skin, eyes, and lungs,” Lee added.
OliX lists eight drug candidates and three broader programs in its pipeline, including two skin treatments: OLX104C for hair loss and the company’s sole clinical-phase product at present, OLX101A for hypertrophic scars.
In October, the FDA cleared OliX’s IND application for a Phase IIa trial assessing OLX101A as an adjunct therapy to reduce the recurrence of hypertrophic scars after scar revision surgery. The randomized, double-blind, intra-subject study will assess recurrence of hypertrophic scars at 24 weeks following scar revision surgery, performed on some 20-30 patients across the U.S.
U.S. Trial Planned
“We will be very soon entering into clinical trials in the U.S.,” Lee said, adding that a 30-participant Phase II trial is underway in South Korea, delayed slightly by COVID-19-related concerns. “Our hope is that either in Korea or in U.S. by the end of this year, we will get some human POC [proof of concept] data in the scar program.”
Another two pipeline candidates target lung diseases: OLX201A for idiopathic pulmonary fibrosis, and OLX204A for COVID-19. The company’s busiest therapeutic area is eye disorders where OliX is developing OLX301A for dry and wet age-related macular degeneration (AMD), OLX301D for subretinal fibrosis and wet AMD, OLX301E for wet AMD alone, and OLX304A for retinitis pigmentosa.
OliX is developing OLX301A and OLX301D through a collaboration with Clermont-Ferrand, France-based Théa Open Innovation, a sister company of Laboratoires Théa.
“We are working very hard to bring these programs to the clinic as soon as possible,” Lee said. “The GMP oligonucleotide materials are being synthesized and IND-enabling tox studies are being initiated, and we hope to get into the clinic with both of these programs in 2022.”
The alliance with Théa began in 2019 when it paid OliX €2 million (about $2.4 million) upfront for rights to ‘301A in European Union countries, the Middle East, and Africa, and expanded in October 2020 to include ‘301D and options allowing Théa to license two additional ophthalmic programs over the next two years, with Théa paying OliX an additional €8.8 million ($10.5 million) upfront for rights extended to worldwide outside Asia-Pacific. Théa also agreed to pay OliX undisclosed development and commercialization milestone payments, plus royalties.
Also in OliX’s pipeline are candidates for neuropathic pain (OLX401A), cancer immunotherapy (OLX801A)—and three GalNAc-asiRNA–based umbrella programs from which 11 potential candidates are under discovery or preclinical reviews, with liver-related indications:
- Liver fibrosis, which encompasses three programs (OLX701C, ‘701D, and ‘702A).
- Obesity/type 2 diabetes, three programs (OLX702B, ‘702C, and ‘702D)
- NASH, four programs (OLX702E, ‘702F, ‘702G, and ‘702H)
- Hepatitis B virus, one program (OLX703A)
The company says liver therapeutics is potentially lucrative enough to spawn a billion-dollar deal with a major global biopharma.
Expanding into mRNA
OliX plans to expand its pipeline further through a new subsidiary announced last month, mCureX Therapeutics, which will focus on developing mRNA vaccines and drugs.
mCureX’s Chief Technology officer is Dongwon Shin, PhD, whose more than 20 years of mRNA experience includes working as director of oligonucleotide chemistry for OliX, and before that as a staff scientist and senior staff scientist with TriLink BioTechnologies.
Shin is a co-holder of U.S. Patent No. 10,519,189, assigned to TriLink and covering compositions and methods for synthesizing 5′-Capped RNAs—a technology applied by Pfizer and BioNTech in their COVID-19 mRNA vaccine COMIRNATY®, which is authorized in the U.S., for emergency use.
“We actually had an expert in-house, and we thought, hey, why not?” Lee said of the decision to create the subsidiary. “But we want to keep it rather separately, because while it’s all based on RNA, siRNA and mRNA are very different.”
mCureX will initially focus on developing an mRNA-based vaccine for COVID-19 and future pandemics: “We expect this kind of pandemic to come back again and again, and we want to be ready.”
Last year, OliX signed an exclusive worldwide licensing agreement of undisclosed value with AM Chemicals (AMC) for rights to patents and expertise encompassing technology to conjugate N-acetylgalactosamine (GalNAc) to OliX’ asiRNA molecules, with the goal of enabling targeted delivery of siRNAs to liver cells.
The GalNAc-asiRNA platform targets therapeutic siRNA molecules specifically to hepatocytes through infrequent subcutaneous administration designed for long duration. The platform applies receptor-mediated endocytosis via the asialoglycoprotein receptor (ASGPR), primarily expressed on the surface of the hepatocytes, allowing inhibition of disease-causing genes in the liver.
In 2019, the FDA approved the world’s first GalNAc-conjugate RNA therapeutic—Alnylam Pharmaceuticals’ Givlaari™ (givosiran), a GalNAc-conjugated aminolevulinate synthase 1-directed siRNA indicated for adults with acute hepatic porphyria. A year earlier, Alnylam won FDA approval for Onpattro™ (patisiran), a first-in-class siRNA treatment for polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults.
“Alnylam started all this GalNAc siRNA technology, followed by Dicerna Pharmaceuticals, Arrowhead Pharmaceuticals, and so on,” Lee recalled. Dicerna develops treatments based on its RNAi platform called GalXC™, and has established established collaborations with biopharma giants that include Alnylam as well as Novo Nordisk, Roche, Eli Lilly, Alexion Pharmaceuticals, and Boehringer Ingelheim. Arrowhead’s RNAi drugs are based on its Targeted RNAi Molecule, or TRiMTM, platform.
“We are relatively new to this field. But I think that the technology is now well validated based on the several GalNAc siRNAs recently approved by FDA,” Lee said. “So now it’s really a question about which company targets the most relevant disease target genes and moves forward. We are catching up to other players in this field, so we hope to bring in multiple GalNAc siRNAs into the clinic by the end of next year or early 2023.”
With a market capitalization of $550 million, OliX is dwarfed by the bigger RNAi players: Alnylam leads the field in market cap with $19.9 billion, followed by Arrowhead ($8.3 billion) and Dicerna ($1.77 billion).
Yet OliX is aiming high. Its website includes a vision for the company: “Rise to become one of the world’s top three nucleic acid companies through continuing expansion of pipeline based on its proprietary RNAi technology and global out-licensing.”
“The RNAi field is really moving into the direction of direct conjugation of ligands, or some delivery moiety, so that you’re not using a delivery vehicle such as a liposome or LNP [lipid nanoparticle]. We are also trying to find some ligand that can replace cholesterol or GalNAc and directly conjugate to asiRNA to deliver it into additional tissue cell types, and we are currently working on that,” Lee said.
In addition to helming OliX, Lee is a professor based at the Global Research Laboratory (GRL) for RNAi Medicine at Sungkyunkwan University in Seoul. (He is also the Asian Editor of Nucleic Acid Therapeutics, a journal published by GEN publisher Mary Ann Liebert Inc.)
Headquartered in the Seoul suburb of Suwon, OliX was founded in 2010 and went public in 2018 in South Korea. Soon after, Lee said, OliX began expanding in the U.S., establishing an American home base in Cambridge, MA, where the company carries out preclinical development and pharmacology, clinical, regulatory/QA [quality assurance] operations, and CMC [chemistry, manufacturing and control] activities designed to ensure product safety, efficacy, and consistency by defining specific manufacturing processes, product characteristics, and product testing.
“I wanted to start in the Boston/Cambridge area because of the biotech community—the great people, the pool of experts,” Lee said. This location also facilitated appointing three hepatology experts on the company’s Scientific Advisory Board, all of whom hold positions with Harvard Medical School.
In San Diego, OliX operates a lab that carries out siRNA synthesis, plus chemistry and analytical method development. OliX expanded into San Diego, Lee said, by recruiting Shin and establishing a lab for him after a family member balked at relocation when OliX initially envisioned the researchers working from South Korea.
“Although we are located in Korea, in drug development you have to look globally,” Lee added. “You cannot really do anything in just local markets.”