Tune Therapeutics On Clinical Readiness, Technology Adoption
By Tyler Menichiello, contributing editor
Epigenetic editing is a growing branch of gene therapy that aims to regulate gene expression to treat disease rather than replace mutated or defective genes. This ability to precisely control gene expression through epigenetics may offer a more dynamic approach to treat a broader range of diseases and conditions than traditional genome editing.
One company making significant progress in the development of epigenetic therapies is Tune Therapeutics. I had the chance to speak with Tune’s EVP and head of technical operations, Heidi Zhang, Ph.D., about the company’s TEMPO platform and its lead candidate for HBV, TUNE-401. Zhang shared the lessons she’s learned from her time in industry, as well as insights into how the company is preparing TUNE-401 for the clinic. We talked about manufacturing, delivery challenges, and the ways Tune is using automation to streamline operations. She stressed the importance of stage-appropriate analytical development, as well as scaling manufacturing processes as early as possible.
Optimizing Delivery Of Epi-Effectors
Tune’s modular TEMPO platform is comprised of a DNA-binding domain (specifically, a dead version of the CRISPR Cas-9 protein that doesn’t make cuts to DNA) and mRNA that can express epigenetic effectors, or “epi-effectors” — proteins that can methylate/demethylate DNA, modify histones, and drive other epigenetic changes while keeping the DNA sequence intact.
While in theory, epigenetic editing can treat countless diseases, like any gene therapy, its potential is limited by delivery challenges. If you can’t effectively deliver to tissues of interest, then you don’t have a therapy. Therefore, the success of the therapy depends on how well it can be delivered to target cells, Zhang tells me. For TUNE-401, LNP-based delivery felt like a natural choice.
“For Hepatitis B, epigenetic therapy combined with LNP technology is a really good match,” Zhang says. Off-the-shelf LNP formulations are deployable, and their safety has been demonstrated through the COVID vaccine, she explains. Future indications may warrant different delivery methods, but a significant amount of work needs to be done industry-wide to improve delivery options. While Tune does eventually want to explore other delivery methods and indications, it’s more important in the short term to generate clinical data.
“We’re really trying to focus on what we can do with the existing technology so that we can quickly get into the clinic to achieve more proof-of-concept on the epigenetic editing itself,” Zhang tells me.
Scaling Manufacturing And Adopting Automation
Like most early-stage gene therapy companies, Tune is partnered with CDMOs — at least for its early programs. From a tech-ops perspective, Zhang says, it makes more sense to develop Tune’s first set of programs with CDMOs who have the GMP infrastructure and manufacturing resources.
“Then, once we better understand the direction we want to go for Pivotal or second generation products, that’s when we can think about doing a combination of internal and external clinical supply,” she says.
When it comes to manufacturing, one thing Zhang has learned throughout her career is the importance of scaling early. It’s easy to fall into the trap of thinking, I’m just going to get through this stage and solve all these problems later. “The reality is, there’s never time,” she says. This is especially true for advanced therapies, which are usually granted accelerated review pathways by regulatory agencies. Don’t wait until Phase 3 to think about how to scale manufacturing.
These days, one can’t talk about manufacturing without addressing the elephant in the room — automation. We’re still a way from fully automated manufacturing solutions, but there are opportunities to deploy modular automation today, in 2024. Tune is focused on identifying available automation tools to not only benefit assay and process development, but to help reduce ergonomic risk for employees, Zhang says.
“We’ve taken the modular approach,” she says, rather than focusing on end-to-end, closed systems. This includes finding ways to reduce the repetitive aspects of the job, “whether it’s pipetting or moving plates from one place to another.”
“We’ve understood the significance of automation since the very beginning,” she says. “Over the years, we’re building that up, steadily.”
Stage-Appropriate Assay Development
“In an ideal situation, assay development follows the stage-appropriate development plan,” Zhang says. Of course, reality can be far from ideal. As mentioned before, ATMP development moves faster than traditional pharmaceuticals, and it’s easy to fall into the trap of planning to figure it out later. Just like scaling manufacturing, the earlier you can establish potency assays, the better.
“This is where I think the partnership with health authorities is super important,” Zhang says. She’s seen groups make poor assay choices without understanding regulatory expectations. Referencing a specific example, she says, you don’t want to find yourself using a binding assay for a Phase 3 trial when the agency expects a cell-based potency assay that reflects the in-vivo mechanism of action.
From the beginning, development teams need to think about not only what relevant mechanistic steps they can use to demonstrate an in-vivo proof of concept, but also ask, “What are the assay formats that are more amenable to a QC environment eventually?”
“Even if at Phase 1, you may not decide to do it as a QC release assay, you may want to use it as a characterization assay so that you can start building the data into product understanding for Phase 3 and commercial,” she explains.
Another factor to consider for assay development is the rapid evolution of technology, a point that was brought up during a recent panel discussion Zhang participated in. Newer technologies are being developed all the time, so it’s important to think about how and when to introduce them into both your manufacturing process and analytical development, she says. This is an important and sometimes overlooked aspect of lifecycle management.
When it comes to developing and designing assays, it’s also important to think about transferability. Whether it’s working with CDMOs, acquiring new assets, or moving a product from phase to phase, technology transfers are inevitable. A couple months from now, on December 3 at 11 a.m. ET, I will be hosting a Bioprocess Online Live event focused on the relationship between analytical method design and transfer. Our expert panelists will weigh in and share best practices on designing transferable assays, as well as how to manage the transfer of methods on both the sending and receiving end. Be on the lookout for more details to come on Bioprocess Online.