Shaurya Gilani, Carl Schoellhammer, Kalyn Specht
Nov 21, 2022
In a recent interview with DeciBio, June Park, CEO of siRNAgen, covered a wide range of topics such as the rapid growth in the siRNA market, expanding RNAi indication areas, and rise of globalization
Thanks for joining us today, June! To begin, could you please give us a brief background on yourself?
I’m a Korean American chemical and biological engineer passionate about developing patient-centric, sustainable therapies. I was born and raised in Korea in a family of biotech entrepreneurs, and science and music became my way of bridging cultures when I moved to Bay Area at the age of 10. It was while at MIT that I found my two passions: for therapeutic development, while taking a class with Professor Cooney and working in the Langer lab; and for the business of healthcare, while taking classes at the Sloan business school. After realizing just how complex the US healthcare system is, I joined a healthcare consulting firm called Putnam Associates to learn more. There, I got to work with many of the top global biopharma on commercial and strategic drug development. Learning about the different patient journeys and treatment paradigms across the world helped me understand some of the key considerations in developing and launching a drug. I also got to see how often great science failed to translate to great drugs, or how great drugs could save, yet still further burden patient lives. I wanted to bring the focus back to both the science and the patients, so I went back to the lab, this time at the other Cambridge across the pond working on supramolecular biomaterials and stem cells for my PhD. Joining the Gates Cambridge scholar community opened my US-centric views and augmented my interests in patient-centric drug development with sustainability and health equity. It was also during grad school that I became fascinated by my dad’s invention, the self-assembling double conjugate siRNA platform called SAMiRNA. We started working on the platform together and shared the vision to develop curative therapies with sustainability – both environmental and economic – in mind. That brought me to siRNAgen Therapeutics where we develop curative sustainable siRNA therapies for chronic conditions.
Thanks for that intro! What drove you to pursue siRNA-based therapies instead of other modalities?
Double helices were introduced early in my life. My parents started our family and their oligo business around the same time in the late 80’s. Growing up with the human genome maps instead of band posters around the house seemed normal enough in my childhood, and I think this early exposure ultimately drew me to work on siRNA at Bob’s group as an undergrad at MIT. I mean, it was just remarkable how siRNA could dial down any gene of choice.
This elegant gene-level control contrasted with the small molecules, antibodies, and cell therapies I saw at Putnam. The TKIs and I/O, despite transforming the treatment paradigm and extending patient lives, were by no means cures. Small molecules often seem to target too generally and lead to the inevitable development of resistance with a host of safety issues from systemic dosing. Antibodies, I admired for their specificity but felt limited when it came to intracellular targets. Cell therapies – especially the early data of CART were incredible to follow with their potentially life-long durability and curative potential but realized there are still numerous hurdles like manufacturing and CMC as well as potential safety issues.
RNAi works at the genetic (technically translational but trying keep things simple!) level. A gene equaling a target means the lead discovery can be far more efficient: today we have the whole genomic library, so for any gene of interest, we can theoretically knock it down and get a therapeutic lead, cutting down months, if not years, of discovery phase research. When delivered properly, it can beautifully knock down any genes for almost a year as seen with the inclisiran data from Alnylam and Novartis – it’s essentially a repeat-dose cure. Imagine, if you can replace your usual once-a-day drug with a single RNAi dose every 6-12 months during your doctor’s visit. We are looking at a future where we no longer worry about forgetting to take medicines for the rest of our life. I love the future that RNAi therapeutics hold for us. This theoretically unlimited drugability and robust therapeutic durability are just some of the clear advantages over other modalities like small molecules, antibodies, and even cell therapies which are limited to druggable proteins often at the cell surface.
Of course, there are many challenges to siRNA. Afterall, this Nobel prize-winning science took decades to reach the market, and today there still aren’t many siRNA drugs out there.
What do you consider the major challenges of RNAi therapeutics?
Beyond the now-expired IP-related challenges, siRNA had several main challenges including safety, stability, manufacturing, and most importantly, delivery.
1) RNAi is essentially a defense mechanism against viruses, and evolution has programmed innate immune stimulation to protect us against the viral hallmark of double-stranded RNAs. This means RNAi alone can cause a host of safety issues.
2) RNases are everywhere, chomping down naked RNA rapidly. This led siRNAs to require heavy modifications or encapsulation with various nanoparticles or exosomes to “hide” from RNases.
3) Heavy modification hasn’t made manufacturing any easier, and encapsulation required various additional formulation steps.
4) But the ultimate challenge comes down to the delivery. Tropism – getting into the right cells – is just the first step. Once the cells engulf the siRNA package into an endosome – severe simplification could call it a cellular trash can – siRNA needs to escape into the cytoplasm before getting discarded to be “activated”. Many tackle this “great endosomal escape” problem by bursting out of the endosome (https://www.liebertpub.com/doi/10.1089/nat.2022.0004). This effectively translates to exploding a trash can in your home – a toxic mess.
Various siRNA technologies have been developed to address some of these challenges through conjugation and encapsulation strategies with varying degrees of success.
Today’s prevailing technology is to conjugate RNAi with GalNAc, a tiny sugar that’s taken up by the ASPGR into the liver. It’s a powerful delivery mechanism for the liver. What most folks don’t mention is that ASPGR is pretty unique – this particular receptor has about ten times faster turnover rate than most typical receptors, and our bodies are excellent at getting rid of tiny, unusual chemicals in the body, usually within a matter of seconds to minutes. This is why GalNAc has been so incredibly successful in targeting the liver – but other conjugate strategies trying to deliver beyond the liver have been less successful. The conjugates using different receptors with a slower turnover rate just get washed straight out of our system via metabolic clearance.
Nanoparticles have better luck with the problem around metabolic clearance, being far bigger than the conjugates, but the lipids necessary for nanoparticle formulation have been historically plagued with toxicity issues. This has made many folks draw away from the nanoparticle approaches because safety, along with efficacy, is of course the two axioms of therapeutic development, and conjugates have been so effective.
SAMiRNA overcomes these major issues around siRNA to deliver safely and efficaciously beyond the liver.
So, what are the major advantages of SAMiRNA over other therapeutic modalities?
SAMiRNA’s modularized platform enables delivery of siRNA to difficult organs like the brain. It’s a double conjugate with the oligonucleotide in the middle flanked by a hydrophobic and hydrophilic end. Hydrophobic interactions drive the supramolecular assembly into micellar structure and targeting moieties can be added to the hydrophilic end. This structure has several benefits:
1) It hides the unmodified double-stranded RNA from triggering innate immune stimulation. No more toxicity, hello excellent safety profile. We have validated the safety of our platform in various animal models including mice and non-human primates, or NHP, for intravenous RoA, as well as in over 150 people for topical RoA.
2) Flanking the RNAi protects it from the environment, making our molecule room temperature stable in solution for up to a year. This is unheard of amongst the nanoparticle communities. Remember the nanoparticle-based Pfizer and Moderna vaccines that required ultra-freezers of -20°C and -80°C? This means we can reduce the cold-chain burdens, saving energy and improving access to developing countries. SAMiRNA could make drug development and distribution more equitable and sustainable.
3) Our single molecule, self-assembling design significantly simplifies manufacturing, in fact by about 2/3 of a typical LNP formulation. Again, this means our platform could be more sustainable than a typical siRNA therapy.
4) But the most exciting aspect of SAMiRNA is that we overcame the two major hurdles in delivery: metabolic clearance of small conjugates and endosomal escape. With a far longer serum half-life and combined with various targeting moieties, systemic siRNA delivery could be significantly improved, as seen by our brain platform. We’ve found that our linker chemistries enable effective endosomal escape without bursting, preventing toxicity.
Our first proof of concept was with the CNS platform where we systemically delivered siRNA to the brain across the blood-brain barrier to achieve high KD efficiency. We’re excited to share some of these data at the upcoming RNAi-Based Therapeutics Summit.
Do you think we’ve overcome some of those initial, large hurdles for delivery?
Tropism will continue to be a major hurdle until we can deliver effectively to all the desired areas, and of course, new challenges will continue to arise with new technology. For example, I think one of the hottest RNAi platforms is the antibody-RNAi conjugates. An antibody is an effective way to target, and RNAi can be modified to improve stability, so some are now conjugating the antibody to RNAi to enhance tropism. But then the new challenges arise around endosomal escape and manufacturing burden – imagine cleanly attaching a giant protein (the antibody) to a tiny oligo, not to mention optimizing linkers for the endosomal escape, ensuring stability, self-life for deployability if we care about health equity, and any cause for toxicity. The key message here is that great technologies will continue to come out, and we as a community will have to continue to strive towards making safe, efficacious drugs that are ideally also easy to manufacture and distribute for scalability and deployability. We’re all working towards overcoming these hurdles, and I think these are all the way our SAMiRNA platform shines.
Based on siRNAgen’s portfolio, it looks like you’ve targeted non-traditional indications for RNAi like fibrosis and metabolic diseases. What made you decide to pursue chronic conditions?
We chose chronic conditions because we believe the long therapeutic durability of RNAi can have the most impact on these patients. In terms of the indication areas, the unique ability of our various SAMiRNA platforms to deliver to these organs is the rationale behind our choice of inflammation/fibrosis, lung, and the brain.
I mentioned earlier that the SAMiRNA platform’s modular design enables the development of various types of platforms. Our current three platforms take advantage of the SAMiRNA design’s flexibility in tunability and stability to deliver safely and effectively using the patient-friendly route of administration.
• Our EPR platform uses the passive delivery mechanism called enhanced permeability and retention (EPR) to arrive at the leaky vasculature typical in inflamed, fibrotic, and solid cancer tissues. This is a powerful platform because it shows organ-agnostic disease tropism – a single therapy that can be generalized for various diseases across different organs and cell types. We’ve shown effective IV and SQ delivery for various disease models, including idiopathic pulmonary fibrosis (IPF) and chronic kidney disease (CKD). Our lead candidate entering the clinic next year, SRN-001 for IPF, uses this passive delivery mechanism, combined with inflammation and fibrosis-associated gene target. We anticipate this asset could be a powerful therapeutic for many of the inflammatory and fibrotic indications.
• Our CNS platform incorporates the receptor-targeting chemistry into SAMiRNA to systemically deliver across the blood-brain barrier (BBB). We have shown effective knockdown and promising therapeutic improvements in a PoC study using a mouse model of a neurological disease without safety or toxicity concerns. This is special because currently, CNS delivery of siRNA is largely done intrathecally (through the spinal cord) – this is a huge burden for patients, especially long term. This is a hot area and we’re excited to find collaborators.
• Our Lung platform delivers using inhalers to the distal alveolar regions of the lung. The lung can be a challenging organ to deliver to because of all the mucus layers and surfactants and nucleases. Because of SAMiRNA’s unique properties, we have shown effective knockdown and safety. This is another exciting platform with which we participated in the Seoul Innovation QuickFire Challenge: Scientific Advancements of Tomorrow and where we were named as awardee, which led to us joining the Johnson & Johnson Innovation – JLABS community. (https://jnjinnovation.com/news/press-releases/johnson--johnson-innovation-llc-and-janssen-korea-ltd-announce-awardees-of-the-seoul-innovation-quickfire-challenge-scientific-advancements-of-tomorrow-in-collaboration-with-seoul-metropolitan-government-and-korea-health-industry-development-institute).
Gene therapies like siRNA have huge potential for transforming the treatment paradigms and patient lives – CNS indications, in particular, have had so few therapeutic options in the past. We want to change this and empower patients and doctors with safe therapies, that work, and that can be administered without a huge patient burden.
Why not the traditional startup route of going after rare diseases?
Folks choose rare diseases because they can usually shorten the path to approval – FDA allows for accelerated clinical trials for rare diseases with high unmet needs. Sometimes even therapies with significant side effects are approved for this reason. Some of the early siRNA therapies, for instance, had a narrow therapeutic window due to poor safety profile but could be pushed to approval because the unmet needs were high. But rare means a small patient population and ultimately limited market size. So far, we made the strategic decision to pursue chronic conditions with larger prevalence, but I guess never say never.
So, you see the market as poised to really take-off?
The market has been shifting towards RNAi, especially with the expiration of key patents. I recently heard an estimate that RNAi will be responsible for ~40% of the pipeline growth in the coming years – I think this speaks to the excitement and the potential of siRNA therapies. These days, many of the major pharma seem to be actively looking to in-license RNAi therapies, if not already developing in-house. It’s been good for us, keeping our BD activities busy because everyone is looking for novel RNAi platforms.
I think some of the bottlenecks in gene therapy development overall may come with limited access to the necessary non-human primate (NHP) studies. Because RNA sequence varies between species and we can’t just translate mouse genes to humans, NHP data are an important part of RNAi therapeutics development. Not many CROs have the NHP capabilities and those that have them are often backlogged, not to mention expensive. The development cost and backlog issues can slow down the research and limit smaller startups from more efficient drug development. Our Korea location has enabled us to build a close relationship with CROs with NHP capabilities to mitigate some of these issues.
What is the timeline for siRNAgen’s products to make it through approval and onto the market? What challenges still exist in clinical testing?
The first SAMiRNA product will in fact be available for sale starting in the first half of 2023. We had an unconventional route to commercialization by developing a hair loss cosmeceutical product. CosmeRNA, named after cosmetic RNA, provided an early validation of our platform’s potential as a topical cosmetic product for androgenetic alopecia (hair loss). We published earlier this year the results of the clinical study in Korea (https://www.nature.com/articles/s41598-022-05544-w). The safety study has been repeated in Europe by Dermatest in 2022 and we anticipate the product launch sometime early 2023. We focused on the European market first due to the more streamlined cosmeceutical trial and approval process (called CPNP, or Cosmetics Product Notification Portal). Hair loss cosmeceutical development path is a creative avenue to early revenue generation, cutting development time from 6 years to 2 years while saving millions of dollars. But this worked for us because SAMiRNA is shelf stable in solution for a year and can be applied topically, and it must also align with the pipeline strategy. siRNAgen will solely focus on therapeutic development.
Our lead therapeutic asset, SRN-001 which I mentioned above with our EPR platform, is expected to be in the clinic in the first half of 2023 – our incredible team is currently hard at work to meet this timeline. It’s an exciting, first-in-class asset that can be applied to various inflammatory and fibrotic conditions. Pulmonary fibrosis is an indication currently with no disease modifying therapy, relatively short (12 weeks) clinical trials, and rapid growth rate due to Covid-associated cases. We’re optimistic and hopeful about the outcome, in both improving patient quality of life and potentially offering a disease-modifying treatment. The Phase 1 study to be conducted in 2023 is in healthy volunteers in Korea and we plan to conduct Phase 2 onwards in the US.
Back to your corporate structure and how you mentioned you may spin out subsidiaries, how do you think about the pros and cons of such a structure and also being a subsidiary of Bioneer in South Korea?
We have had a lot of support thanks to our public parent company, Bioneer. As the first biotech in South Korea and one of the only full-stack healthcare companies in the world, Bioneer has a lot of the infrastructure from which we hugely benefited. The downside might be that we need to work extra hard to become independent as we grow. To this end, we have just finished our US domiciling process and are beginning our US institutional fundraising round. I’m excited to build out the cross-border operations between the US and our existing research powerhouse in Korea.
That’s a great segue to discuss your funding, which I understand you’re in the process of raising. Can you talk a little bit about how it’s been progressing both from the view of a smaller start-up and as a woman raising her first institutional round?
Yes, we are now raising our first institutional Series A round, which will enable us to set up the US operations, complete our Phase 1 study, and get our key platform validation data. Of course, the economy has seen brighter days, but spinning out of one of the major oligo manufacturers of the world with 20 years of research and a strong research team operating in Korea put us in a good position. Beyond fundraising, we’ve also been creative in finding other revenue streams, such as licensing of cosmetics and grants.
It’s particularly exciting times to be a small biotech startup. Vibrant global startup and biotech ecosystems like Endless Frontiers Lab (EFL) and Johnson and Johnson Innovation enable access to incredible knowledge bases and collaborative networks even for small startup like siRNAgen. It’s great be able to work towards a common goal of developing great therapies for patients in need with the entire life sciences community.
I think it’s important to talk about the female minority leadership experience, even as I sometimes feel uneasy prefacing CEO titles with “female” and “Asian” (https://www.forbes.com/sites/forbesbusinesscouncil/2022/09/06/shes-a-ceo-not-a-female-ceo/?sh=15af95274366). It’s a fact that at executive level events, there are usually very few women of color present. I initially found this disempowering but have come to own it as an advantage. First, it connected me with a network of female CEOs – incredible, strong, inspiring women – that I could learn from and rely on for support. Second, by talking about my own experience, it increased the visibility of me and my company. In the process, I was offered for unique guidance and found some incredible mentors, both men and women, that I may not have connected with otherwise. I’m looking forward to continuing to promote and see more diversity in leadership, not just in biotech but across industries and sectors.
I see we are almost out of time, so I’d like to open it up and give you the opportunity if there’s anything else pertinent that you feel we didn’t touch on?
I do want to talk a bit about the benefits of being a cross-border company. International presence brings global viewpoints, knowledgebases, and resources, and COVID has helped us connect more effectively. The Korea-East Coast locations enable a 24-hour team that operates cost-efficiently and is more resilient to crises such as supply chain shortage. In creating cross border companies, immigrants like me play an important role in bridging these teams both linguistically and culturally. As we see more of these models grow, I hope the biotech ecosystem becomes more global.
Well, we really appreciate your time today, June, and look forward to following all of siRNAgen’s developments as well as the RNAi field as a whole. Thank you again!