Mapping Candel Therapeutics' Sprint To The BLA Finish Line

A conversation with Paul Peter Tak and Seshu Tyagarajan of Candel Therapeutics and Life Science Connect's Jon O'Connell

With the remaining runup to a BLA submission for its lead candidate, aglatimagene besadenovec (CAN-2409), measured in months, Candel Therapeutics has entered a period of sophisticated coordination.

The viral immunotherapy company has targeted submission for the end of the year. Between now and then, it must wrap its clinical data into a compelling narrative for regulators while setting the stage to begin shipping product as close to the starting gun as they can. The steps involved in that dance include scaling up manufacturing with its CDMO and priming the supply chain without overextension.

 In the first of this two-part interview, company leaders answered my questions about their strategy for balancing preparation for commercial launch with prudent risk management.

Can you provide a quick overview of the mechanism of action and where we're at on aglatimagene besadenovec’s path to BLA for prostate cancer and other indications?

Paul Peter Tak: Aglatimagene besadenovec, which we also refer to as CAN-2409, works in a unique way. It’s a completely new mechanism of action that leads to education of the patient’s own immune system on how to recognize and eliminate cancer cells not only at the site of injection but also at the site of uninjected distant metastases in conditions like metastatic non-small cell lung cancer (NSCLC). Additionally, you don’t need to inject all the lesions, and you don’t need to repeat treatment continuously.

It requires just two or three administrations of aglatimagene in total. How does it work? We select a tumor, and depending on the tumor type, we decide where we inject. In localized prostate cancer, we infiltrate the whole prostate within 15 to 20 minutes in an outpatient clinic setting. It’s actually a procedure that’s less traumatic than a standard-of-care diagnostic prostate biopsy.

This is followed by a two-week course of valacyclovir tablets. Together, the aglatimagene injection and the valacyclovir course constitute a single treatment cycle. In prostate cancer, patients complete three such cycles in total, and it is this regimen that generates the long-term, durable anti-tumor immunity that has been demonstrated across multiple solid tumors.

In lung cancer, we focus on metastatic disease, and we select one or two lesions in the thorax, which can either be the primary tumor or metastases in the lymph nodes. We use these lesions to teach the immune system how to recognize and eliminate the tumor cells throughout the body.

We plan to submit a biologics license application (BLA) for aglatimagene in localized intermediate- to high-risk prostate cancer in Q4 2026. The FDA has granted both Fast Track designation and Regenerative Medicine Advanced Therapy (RMAT) designation to aglatimagene for the treatment of localized prostate cancer. Additionally, we’re preparing to initiate a pivotal Phase 3 clinical trial in NSCLC in Q2 2026, following a positive end-of-Phase 2 meeting with the FDA.

Can you describe your manufacturing strategy? Candel uses a mix of contract manufacturing and is building in-house capabilities. What are you pulling in-house and why?

Paul Peter Tak: Our high-level strategy is to work with a CDMO. We brought in a very experienced team to oversee this under the leadership of Seshu Tyagarajan, Ph.D., chief technical and development officer at Candel. We created a very strong manufacturing team, quality team, and regulatory team in-house. Together these groups do some of the work internally and outsource some work. We believe such a model has significant benefits, as it allowed us the flexibility of not building a huge infrastructure prematurely.

Basically, we wanted to see the data from the Phase 3 clinical trial first. To build a huge infrastructure prematurely would mean that if the data are negative, it could be the end of your company. We were prepared to survive in any scenario, even if the data would be negative, because we also have other programs that are very promising, like aglatimagene in NSCLC, or our second asset, linoserpaturev (CAN-3110), in recurrent high-grade glioma.

The good news is that we achieved the primary endpoint supported by secondary endpoints in our pivotal Phase 3 prostate cancer trial. Previously, we had already done all the preparatory planning work and therefore we were able to press the button one day after the data readout in December 2024. Once the data were positive, we triggered all the major CMC investments. As you can see, it’s a very tight timeline of only two years from starting major CMC workstreams to BLA submission.

This flexible, externalized approach reflects how we think about the business more broadly — it’s what I’d call dynamic portfolio management. We wait for the next clinical inflection point before making major investments. In terms of manufacturing, we have no desire to bring it in-house, but we brought in the right team at the right time and grew it after data readout, when the program was de-risked. The same principle applies to commercialization. We work with external organizations that bring all the capabilities we need and that we can scale up or down as needed, with the advantage of having access to those people from day one, rather than going through lengthy search and recruitment.

After approval, we’ll bring the sales force in-house, which typically takes three to four months. We also don’t need a huge sales force as we’ve found that 80% of patients are treated in 20% of centers, so we can have a very focused effort.

This is a new model for the industry. We’ve seen companies invest heavily in manufacturing infrastructure before having clinical data, only to fold when they couldn’t raise the capital needed to get to data readout — and we may never know whether those medicines work. The same risk applies on the commercial side, when investments in fixed infrastructure are made prematurely. Our externalized model gives us the flexibility to scale up rapidly after approval without carrying that overhead in the meantime.

Seshu Tyagarajan: From a manufacturing strategy perspective, we are using Millipore Sigma (formerly SAFC) as our CDMO. They are our clinical and commercial partner for manufacturing this product. SAFC has manufactured viral vectors for over 30 years. They have a good track record of commercializing viral vectors, and we would be among their next commercial programs. So, there’s a lot of clinical and commercial expertise residing within the CDMO, and they also have the ability to leverage the expertise from the overall Millipore Sigma extended organization as well. Both the drug substance and drug product are being manufactured at Millipore Sigma, and to date they have successfully manufactured multiple small-scale and large-scale runs there. As Paul Peter mentioned, the majority of CMC activities were triggered only after we obtained positive Phase 3 results. As a result, there is a tremendous amount of work being done externally at Millipore Sigma and other contract testing laboratories and internally by the manufacturing and the quality groups, within a short period of time to ensure that we file a comprehensive Module 3 for the BLA by the end of 2026.

From a big picture perspective, it’s worth emphasizing a key fact that shapes the entire manufacturing story and that is, aglatimagene besadenovec is an adenovirus, not an adeno-associated virus (AAV). This distinction matters enormously, because it appears to be a common area of confusion even among people familiar with these two platforms.

Adenovirus manufacturing is a well-established, straightforward platform with standard upstream and downstream processes, no exotic raw materials, no need for plasmids, and a relatively low MOI needed for infection. The empty/full capsid ratio, a significant concern for AAV, is not a major issue here given our favorable viral particle to infectious unit (VP/IU) ratio. Generally speaking, these are two very different manufacturing platforms, with the adenovirus platform providing us the important advantages of scalability, consistency, and cold chain simplicity.

In terms of what we are building in-house, we have our own analytical development group and our own quality control (QC) lab that will run certain selected assays, while we are working with several contract testing labs, such as BioReliance, Eurofins, and others, for running the remaining tests. We are applying a holistic approach wherein drug substance and drug product are manufactured at Millipore Sigma, and release testing and characterization testing is being done at several laboratories, one of which is the Candel QC laboratory. We are bringing in-house a combination of product-specific assays and certain labor-intensive assays, as well as simple and easy assays.

This capability was implemented to provide us with options to choose which assays to outsource and which ones to keep in-house. This allows us to be efficient and to minimize costs while building a strategic platform for Candel in the long run.

Can you share some of the hurdles you’ve encountered with, for example, purification and mitigating aggregation when tech transferring a virus/prodrug therapy to a CDMO? How did you address them?

Seshu Tyagarajan: We started tech transferring this program about three years ago to our CDMO with multiple goals in mind. Obviously, the primary goal was a successful tech transfer that led to a robust process that was scalable and transferrable. Additionally, we had the challenge of taking a 15-year-old process and bringing it to current standards, but having to draw a fine line between the need to modernize the process and the requirement to show comparability between the clinical process and the commercial process. This is tough, and we approached it by leveraging some of the necessary improvements in technology, while trying to keep the process as similar to the original process as possible. We were successful in doing both, and what we can say is that, fundamentally, both the clinical and commercial processes are quite similar in terms of the core principles applied to cell expansion, infection, clarification and downstream purification.

Another challenge when outsourcing a part of your work, especially as big a project as manufacturing is, is to ensure proper, timely, and open communication between both teams. Having open communication channels and good working relationships among both teams and establishing an escalation mechanism are key to the success of the program.

During the tech transfer, there were some smaller hurdles throughout the development phase, where certain steps needed to be repeated a couple of times before finalization, but the one place where we spent a good amount of time was in the tangential flow filtration (TFF1) stage of downstream purification.

We had to work through different models to understand the root cause of the issue, troubleshoot several steps, and determine what options would work while keeping the product contact surface the same. We conducted a thorough review of all key parameters and finally we  arrived at the current TFF purification step.

Other than that, the tech transfer was rather smooth and it was more about ensuring that the process was repeatable and scalable, and the results were consistent and robust. Overall, we’ve been able to show consistency both at the small scale and the large scale. And we owe this in big part to the fact that this is an adenovirus manufacturing process with straightforward, well-developed upstream and downstream processes, easy to obtain raw materials, and simple formulation for the drug product.

In terms of mitigating aggregation, our downstream process is designed to manufacture the adenovirus drug product with very high purity while limiting the number of aggregates and impurities to acceptable levels in the final product. We further monitor these with the help of the characterization assays and release assays that are designed to ensure that the product profile is consistent with acceptable levels of purity and impurities in the drug product. Furthermore, our release assays ensure that the drug product meets our quality standards and continues to be safe and efficacious.

A first-line treatment for prostate cancer could have immediate and enormous demand. To meet it, what must change between a robust Phase 3 supply chain and a commercial one? For example, do you need more cold chain capacity?

Paul Peter Tak: Most patients in our Phase 3 clinical trial were treated in community centers that definitely did not have minus 60-degree-C or minus 80-degree-C storage. In most cases, this was stored at 4 degrees C refrigerator temperature, where the product used in the clinical trial was stable up to six months.

Because this is an adenovirus rather than an AAV, there is no complex cold chain to speak of, certainly nothing like what AAV therapies require. Long-term storage will be at minus 60 degrees C, handled through our third-party logistics partner sites. We have excellent clinical stability data, and we intend to leverage that for the new commercial process following a successful comparability study, which means we are well positioned from a stability standpoint to supply the market at launch. In terms of the demand, we are able to really scale this up, and we expect to have a very large number of vials available at the time of launch.

Seshu Tyagarajan: From a clinical versus commercial demand perspective, obviously commercial demand is significantly higher than the clinical demand. We are building our capacity to meet the projected commercial demand over two planning horizons, the initial one in one to five years, and then the second in five to 10 years.

We’re going to start with a substantial number of vials to supply the market at launch, and then we will continue to manufacture at regular intervals. As the demand increases, we have a couple of different levers that we can use. We can run more batches per year, or we can scale up to larger batch sizes. A third option, which we will evaluate post-launch, is to bring on a second supplier in a different region to diversify supply risk. We will choose which lever to pull based upon how we are meeting the demand, the timing at which the decision is being triggered, and other relevant factors.

For storage, we will store the drug product at our 3PL partners’ sites, who will then ship the product to hospitals and pharmacies. As for temperature conditions, we currently have different options, based on the availability at different sites. So, for example, long-term storage is at ≤ minus 60 degrees C, which will be at our 3PL sites. Short-term storage at community centers, hospitals, and pharmacies can either be at 2 to 8 degrees C or minus 20 degrees C, based upon availability. Together with the excellent clinical stability available for the drug product, our plan is to provide optionality and make aglatimagene very accessible to healthcare providers.

About The Experts:

Paul Peter Tak, MD, Ph.D., FMedSci, is president and chief executive officer of Candel Therapeutics. Previously, he was senior vice president, chief immunology officer, and global development leader at GSK where he oversaw the development of several medicines now on the market, including gepotidacin, belimumab sc; mafodotin; cabotegravir/rilpivirine; and tapinarof, which was acquired by Dermavant Sciences. Among other roles, he is also chair of the board of Citryll and co-founder and board director of Sitryx. His medical degree is from Amsterdam University Medical Center. He received his Ph.D. at Leiden University Medical Center.

Seshu Tyagarajan, Ph.D., RAC, is chief technical and development officer at Candel Therapeutics. Previously, she was executive director and global head of late-stage CGT-CMC Strategy at Novartis. She has led successful BLA campaigns, including a key role in submitting the BLA for Kymriah. Previous roles include posts at Merck, Roche, Biogen, and ImClone, an Eli Lilly and Company subsidiary. She received her Ph.D. in chemical and biochemical engineering from Rutgers, an M.S. in bioengineering from Purdue University and an M.Sc. in biotechnology from University of Pune, India.