Tocagen expects the results of its Phase 3 trial by the end of 2019, in which it is testing a unique form of gene therapy to produce a chemotherapeutic agent within the microenvironment of brain tumors. Crucially, this avoids the usual systemic adverse effects of chemotherapy, while also stimulating an immune response for longer term cancer killing.

Marty Duvall, Tocagen CEO said this dual mechanism of action, coupled with a favorable safety profile and durable objective responses in early trials, earned Tocagen’s investigational drug, Toca 511 & Toca FC, Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for treatment of recurrent high grade glioma. Patients with this form of a brain cancer typically live about eight months.

In addition to the breakthrough designation, Tocagen received the equivalent designation, PRIority MEdicines (PRIME), from the European Medicines Agency.

Toca 511 is a retroviral replicating vector that selectively infects cancer cells with a yeast gene that produces an enzyme, which transforms Toca FC (a pro-drug) into the chemotherapeutic agent fluorouracil (5-FU) within the infected cancer cells. Toca 511 is injected into residual brain tumor during surgery, whereas Toca FC is taken orally. When the pro-drug Toca FC reaches the infected cancer cells in the tumor microenvironment, 5-FU is produced, killing the cancer.

Then, as the cancer cells die, they release a unique set of cancer antigens and other biomolecules that alert the patient’s own immune system to the cancer, resulting in a sustained immune attack.

“With each cycle of Toca FC,” Duvall said, “the cascade of effects are akin to repeat vaccinations against the tumor, resulting in an immune surveillance system to prevent tumor regrowth.”

As part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Duvall about the breakthrough designation for Toca 511 & Toca FC and what it has meant for the company.

Duvall has been Tocagen’s CEO since November 2016. Before joining Tocagen he was executive vice president and chief commercial officer of ARIAD Pharmaceuticals and was senior vice president and general manager for the oncology franchise at Merck & Co. Duvall received a bachelor’s degree in chemistry from Muhlenberg College, master’s degree in chemistry from Johns Hopkins University and master’s degree in business administration from the University of Kansas.

WuXi: What qualifies Toca 511 & Toca FC for FDA’s Breakthrough Therapy designation (BTD)?

Marty Duvall: The standard FDA has set for BTD includes early clinical evidence that suggests an investigational therapy may provide a substantial advance over the current standard of care. The program also supports more frequent access to the FDA, including senior managers, with the overall goal of increasing the development efficiency of promising new treatments in areas of high unmet need where existing regimens aren’t effective enough.

In the case of Toca 511 & Toca FC, our initial program is in recurrent brain cancer, clearly an area of high unmet need. We had encouraging data from our Phase 1 trials that were different from the current standard of care, which is typically single agent chemotherapy.

In a group of 23 patients in one of our Phase 1 trials, five patients achieved a very durable complete response to our therapy and lived beyond three years, which is really remarkable. In contrast, responses in this setting are normally very rare and patient survival is typically measured in months.

In addition to a favorable safety profile, what the FDA found particularly compelling was the MRI scans of the brain where they could see tumor growth pre-treatment and tumor shrinkage post-treatment. We were conducting MRI scans on patients in the study about every two months and, in the responding patients, we observed that the tumors disappeared and, importantly, weren’t coming back.

An additional factor that resonated with the FDA was our preclinical evidence supporting our proposed mechanism of action for Toca 511 & Toca FC. This body of preclinical data, which was unpublished at the time, provided strong evidence of a robust immunological mechanism of action that helped explain our observations of sustained tumor shrinkage in the MRI scans. That really helped tie the story together.

With a similar data package in hand, we also received the equivalent designation from the European Medicine Agency, called PRIME designation, which should also expedite development time in Europe.

WuXi: How does your drug candidate differ from existing therapy?

Marty Duvall: Existing therapy for patients with newly diagnosed brain cancer typically involves multi-modality treatment involving surgery, radiation and chemotherapy. This approach does not aim to activate the immune system against the tumor and unfortunately, in most cases, the tumor grows back.

Upon tumor recurrence, patients have very few treatment options and the NCCN (National Comprehensive Cancer Network) guidelines recommend patients participate in a clinical trial.

In contrast to current treatments, we are developing a multi-modality therapy involving surgery and immunotherapy designed to activate a patient’s own immune system against the cancer and lead to long-term tumor control or elimination. Initially, we have been evaluating our cancer-selective immunotherapy regimen in the recurrent setting, but we plan to combine our regimen with the standard of care in the newly diagnosed setting in a clinical trial sponsored by the NCI (US National Cancer Institute) starting this year.

Our regimen involves two components: Toca 511 & Toca FC. Toca 511 is an engineered retroviral replicating vector and Toca FC is an extended-release formulation of 5-FC.  These two components work together to kill cancer cells.

First, Toca 511 is administered to a patient during surgery. It selectively infects the remaining cancer cells and delivers a gene called cytosine deaminase, or CD. Toca 511-infected cancer cells then stably express the CD enzyme. These cancer cells are now primed for the second part of the treatment.

About six weeks following administration of Toca 511, patients take multiple cycles of the oral Toca FC. Based primarily on our preclinical data, the CD enzyme expressed in treated cancer cells converts the pro-drug 5-FC to high levels of the potent anti-cancer drug 5-FU right where you want it – within the tumor microenvironment. Local production of 5-FU in the tumor results in direct cancer cell kill as well as depletion of the immune suppressive myeloid cells that serve as “shields” to help protect tumors from the immune system.

This two-pronged mechanism results in activation of the immune system against the tumor, leading to clearance of the tumor and immune memory to prevent recurrence. Much of our preclinical and clinical data have been published in leading journals including Science Translational Medicine, Molecular Therapy, and Clinical Cancer Research.

We believe this dual mechanism contributes to the long-term durable complete responses observed in the clinic and increased survival compared to historical benchmarks. In addition, Toca 511 & Toca FC has a very favorable safety profile – because the chemotherapy is produced locally in the tumor, sparing normal tissues.  In contrast, systemic chemotherapy causes marked toxicity against normal tissues and hematological side effects, such as, susceptibility to infection as a result of depleting white blood cells and risk of bleeding as a result of depleting platelets.

To summarize, we believe our lead product is highly differentiated compared to current therapies and are excited about the potential impact we can have on patients in the future.

WuXi: What kind of virus are you using?

Marty Duvall: Toca 511 is a non-lytic, retroviral replicating vector or RRV for short. It is a simple gammaretrovirus with an amphotropic envelope. Our immune system eliminates this type of virus in normal cells. In contrast, when the virus infects a cancer cell, which is protected from the immune system, the virus is able to live, thrive and spread. In this way, we are able to selectively deliver a therapeutic payload to cancer cells while leaving healthy cells unharmed.

WuXi: How did you demonstrate the potential clinical benefit beyond existing treatments to secure the breakthrough designation?

Marty Duvall: The body of data we provided to FDA as part of our BTD submission included detailed mechanism of action data, clinical safety data and durable response data. We were able to show that we had preliminary clinical evidence to suggest that our regimen may be a substantial improvement over available therapy. It was the first time FDA had granted BTD for this type of brain cancer, highlighting the urgent need for new treatment options for this deadly disease.

To potentially demonstrate safety and efficacy in a randomized trial, we are now conducting a randomized Phase 3 trial evaluating the safety and efficacy of Toca 511 & Toca FC against the standard of care – lomustine, temozolomide or bevacizumab – in patients with recurrent high-grade glioma and the results are expected this year.

WuXi: What impact does the breakthrough designation have for your company?

Marty Duvall: We received breakthrough designation in February 2017 and at that time we were planning to go public. We were in the midst of preparing for an initial public offering and the breakthrough designation for our lead program was a signal to investors that our cancer selective gene therapy platform and lead product candidate held a lot of promise.

Another important aspect of the designation is its potential to expedite the clinical development of our lead program. With the breakthrough designation discussion with the FDA, we were able to move from the originally planned Phase 2/3 trial to a single Phase 3 trial, which shortened our overall development time by two or three years.

BTD really intensifies FDA’s involvement with a sponsor and provides access to senior managers of the FDA, which we believe is enhancing the efficiency of our development program and ultimately may result in a potential new treatment option for patients with this devastating disease.

As it stands today, our Phase 3 trial, named Toca 5, is fully enrolled with 403 patients involved, so the BTD has had an important impact on our company. We and the brain tumor community are eagerly awaiting the results from the Toca 5 trial and the potential impact it could have for patients.

WuXi: What role, if any, have patients played in your drug development and clinical trials, aside from participating, of course?

Marty Duvall: Coincidentally, we have a patient, care givers and advocacy meeting happening at our facility as we speak. I mention care givers and patient advocacy groups also because they each have played important roles in our progress to date and they continue to guide and help us.

In the early days of the company, prior to getting our early clinical results, the leading brain cancer foundations and patient advocacy groups provided critical funding to support our preclinical and clinical research.

Non-profits, patients and families provided a lot of guidance as they began to learn about our product and the potential promise of it. They influenced the entry criteria and quality of life measurement tools in our clinical trials, provided extensive knowledge on the patient and caregiver experience to help us better understand the disease, and they were able to guide us on our patient recruitment efforts.

I would also say, it’s the inspiration that we get every day from patients and their families. They visit us and talk with our staff. We see the lives they are living, how they continue to expand their families, return to work and experience personal milestone moments. These interactions are very powerful and provide the inspiration that helps drive the company forward. It serves as a reminder for why we do what we do. It has increased our ambition not only to treat patients with recurrent brain cancer, but also to advance our program into newly diagnosed disease so that we can potentially impact even more patients.

Also, like everyone in the pharmaceutical industry, we would say that we have a tremendous amount of gratitude for the patients who volunteer to participate in clinical trials. You can get randomized to a standard of care and maybe not get the promising new therapy. But patients understand that by agreeing to participate, they’re advancing clinical science towards the greater good of all. For that we thank them and their families who support them very much.

WuXi: Aside from the clinical benefit, what other effects will this breakthrough therapy have? Will it reduce the overall costs associated with treating the disease?

Marty Duvall: With BTD, we were able to determine a more efficient development path in terms of R&D spending and time. Reducing development time is very critical to delivering safe and effective medications to patients faster, so across the pharmaceutical industry the BTD program could help reduce the overall cost of treating disease by reducing major costs such as hospitalizations and managing side effects.

Also, products that extend survival and improve quality of life can enable patients to return to work or contribute to society in other ways. Leading productive lives is certainly a benefit to the greater society and reduces the overall burden on the healthcare system.

WuXi: Do you have other drug candidates in your pipeline that qualify for breakthrough designation?

Marty Duvall: Our lead product Toca 511 & Toca FC could actually become a pipeline in a product given its broad applicability to cancer, so there are other opportunities for BTD with the same product. Furthermore, when we step back and look at the Tocagen platform as a whole, we have a highly differentiated and versatile technology. We can insert a wide range of interesting transgenes into our vectors that can target specific vulnerabilities of cancer cells and we are excited to expand on these opportunities.

WuXi: What lessons can other companies learn from your successful drug development experience?

Marty Duvall: Setting clear goals and priorities, remaining focused and having the right people in place are all critical. Companies cannot afford to compromise. In terms of talent, looking for the best and brightest people who are passionate about what they do is critical to organizational culture and performance. Also, investing in the core competencies necessary to drive new products forward through the pipeline is important; as well as building deep expertise across the board.

I have learned that by listening to the perspective of external stakeholders, and particularly patients and physicians, and engaging them in a meaningful way is very important to successful drug development.

In our particular case, viral engineering and manufacturing are two key areas of core competence that drive our competitive advantage. Building on and investing in those core capabilities is important for us to remain on the leading edge of our field.

Within manufacturing, the field of gene therapy is expanding rapidly, not only in the oncology arena, but also in a number of different therapeutic areas. As a result, there is growing competition for manufacturing capacity and know-how. Few companies actually have the capabilities and experience to take a process all the way through to commercial scale. This elevates the importance of Tocagen’s in-house manufacturing team as we work closely with external contract manufacturing organizations towards a commercial product.

WuXi: Have FDA initiatives such as breakthrough therapy and fast track designations, changed the paradigm of clinical drug development? If so, how?

Marty Duvall: It’s still in its relatively early days, but the intention is right. I think we will find, in the end, with a collective dedication to innovation and advancing new treatments for patients we will see more and better drugs getting approved faster.

I think we’re getting allocation of resources and a sharpening of focus in the right areas of high unmet needs, which will lead to system-wide improvements and ultimately better patient outcomes. These designations are also an important signal to investors, increasing the interest in the investment community to fund the advancement of new technologies and products.

The various programs at FDA have also helped focus organizations on the role of biomarkers in the development of new medicines that have greater precision and patient response. At Tocagen, we are investigating a range of biomarkers and genetic profiles to help us better understand which patients are more likely to respond to the therapy.

WuXi: Looking at the entire drug development process, from discovery all the way to drug approval, what would be the 4 or 5 key areas or processes you would change or improve in order for companies to bring more and better drugs to patients each year?

Marty Duvall: Validated biomarkers that identify the patients most likely to respond are really important. Obviously, as we sharpen the focus and select the right patients, we are moving in the direction of more precise medicine that’s really targeted to, for example, a particular disease mutation. That is really important for patients and the industry as a whole.

Creative clinical trial designs that better select patients and improve response rates rather than taking on all comers and trying to show a small degree of benefit across a very large population will also be important so that sponsors can take advantage of surrogate endpoints and accelerated approval opportunities. Patient recruitment is another critical aspect, as the faster trials can enroll patients, the faster progress can be made. Unfortunately only about 5% to 10% of cancer patients participate in clinical trials so this is hampering progress.

Finally, for gene therapy in particular, it’s going to be important for companies to continue to innovate so that manufacturing processes are increasingly efficient, robust and scalable to support global commercialization efforts in areas such as oncology.

WuXi: What will be the one or two most significant technological advances in drug development over the next year or two?

Marty Duvall: In the past 30 years and in the oncology area, in particular, we were satisfied with achieving incremental benefits. For example, with chemotherapy, a patient’s overall survival was extended by a couple months at the cost of significant toxicity, unfortunately.

But now we’re in a totally different era where we have more out-of-the-box thinking, leading to bigger leaps of faith. We’re pushing technology harder to try to extend life by years and we’re trying to do more to select the right patient.

As science has improved, we are now sequencing patient tumors and obtaining genetic profiles, which is really building our knowledge and revealing the vast diversity of cancer. We’re beginning to understand what’s driving tumor evolution, and what’s causing these tumors to escape and grow back after treatment; and the importance of our immune system in the fight against cancer.

I anticipate we will continue to see major new advances in the field of immuno-oncology including the role of viruses. If you can find a way to harness the immune system to attack cancer cells as they are evolving, you have the ability to fully unlock the immune system to destroy tumors from within and achieve a longer-term sustained impact on cancer.

Our overall goal is to move the worst cancers to chronic conditions and I think science is helping to push us in that direction. I am very optimistic for the future and the impact we will have on the lives of cancer patients across the globe.