Many current efforts in oncology drug development are focused on overcoming the challenges posed by the tumor microenvironment, which serves as both a barrier to some treatments and a potential source of new immuno-oncology approaches. Purple Biotech is looking to unlock the power of the tumor microenvironment to overcome drug resistance and improve outcomes for cancer patients. Purple’s Chief Executive Officer Gil Efron spoke with Pharma’s Almanac Editor-in-Chief David Alvaro, Ph.D., about the tumor microenvironment, Purple’s scientific approach, its two first-in-class clinical assets, NT219 and CM24, and the promise of its newly acquired tri-specific antibody.

David Alvaro (DA): Can you give us a brief introduction to the history of Purple Biotech, from the company’s founding and through the recent pivot toward oncology?

Gil Efron (GE): The company that is now Purple Biotech was established more than 10 years ago. At the beginning, we were developing Consensi, a drug intended to treat osteoarthritis and high blood pressure. In 2018, the company received U.S. FDA approval for this drug, and it was launched in the United States in 2020.

A year before this FDA approval, in 2017, the company decided to transition into oncology. Our first acquisition in this field was a molecule called NT219, which is a dual inhibitor of the IRS1/2 and STAT3 pathways. In 2019, we acquired a second asset, CM24, which is an mAb that targets CEACAM1, an immune checkpoint protein that is highly expressed in many cancer types. By the end of 2020, we decided to complete the shift into oncology — the launch of our approved drug had not been successful, so we decided to close that program and focus fully on oncology. As part of that process, we renamed the company Purple Biotech.

DA: I’m always curious about how names are chosen. Why Purple?

GE: For me, purple is a vibrant color. It’s a joy, a reflection of the positive part of people’s lives. But that’s just my interpretation. One of the things I like about the name is that each person can interpret it in a different way, but we think it’s distinctive in the industry.

DA: How would you characterize Purple’s scientific focus within oncology and where you identified opportunities?

GE: Oncology is always evolving rapidly, but the industry has converged on the understanding that the primary current challenges in cancer treatment reside within the tumor microenvironment. That is where we are focusing our efforts: to try and harness the tumor microenvironment to prevent resistance to treatment and to improve cancer treatment overall. Our molecules are intended for that purpose.

 There are a few key elements that differentiate Purple from other companies in the field. First, we are investigating first-in-class assets. We began by looking at the tumor microenvironment, but when we chose our assets and their indications, we were also considering the markets, because I believe that there is always a close connection between drug development and the underlying business opportunities. We want to be sure that we are looking to target the right indications where we can really provide efficacy and results, as well as an opportunity that would be attractive to a future buyer, which would probably be one of the larger pharma companies.

From there, the key question is how to design the studies, which I think is another differentiator for Purple Biotech. We decided that, starting in Phase II, we would design randomized studies to ensure that we can achieve meaningful and robust results and outcomes.

Finally, we are very much looking forward to expanding our pipeline. We believe that an oncology company should have multiple drugs in development, and that we can create synergy between newly acquired molecules and our current assets, as well as with our in-house capabilities. In this way, we believe we can create value, both from a clinical perspective and from a business perspective.

A perfect example of this strategy in action is our recent acquisition of Immunorizon Ltd., a private company developing multispecific T and NK cell engagers that selectively activate the immune response inside the tumor microenvironment. The acquisition brought us a portfolio of investigational tri-specific antibody compounds that target multiple tumor antigens, the first of which is 5T4. We expect to bring the first of these investigational compounds to an IND submission within two years.

DA: Can you expand on the two current clinical candidates in your pipeline?

GE: The mechanism of action of CM24, our first program, is targeting CEACAM1, a checkpoint protein in the immune system. After signing a collaboration agreement with Bristol Myers Squibb (BMS), we started our CM24 development journey with a Phase I study in combination with nivolumab. About six months ago, we completed a dose escalation study — having reached the maximum dose that we were looking for — and then entered a Phase II study, which is being conducted in the United States, Europe, and Israel as a second-line treatment for metastatic pancreatic cancer patients. We designed this study to have interim data analysis ready at the end of 2023 and top-line analysis at the end of 2024.

The second clinical program is NT219, which targets the IRS1/2 and STAT3 drug resistance pathways that are involved in tumor survival. We started that program with a Phase I dose escalation study in two arms: a monotherapy arm and a combination arm with an EGFR inhibitor called cetuximab. We are currently at the fifth dose level in the monotherapy arm and the fourth dose level in the combination arm, and we aim to initiate a Phase II study in recurrent and metastatic head and neck cancer.

DA: How would you characterize the unmet medical need for both metastatic pancreatic and head and neck cancers and the opportunity to advance the standard of care for those indications?

GE: Beginning with metastatic pancreatic cancer: the prognosis for these patients is not very good. There are about 60,000 new metastatic cases per year in the United States alone, and the five-year relative survival rate is about 11%. A significant number of patients do not respond following first-line treatment to get to the second line, and overall survival rate in the second line with chemotherapy, which is the standard of care, is even worse — five-year survival is about 3%. There is clearly a significant unmet medical need in this indication.

In metastatic head and neck cancer, there have been interesting developments in the last two years. Today, the standard of care for first-line treatment is Keytruda, a PD-1 inhibitor, plus chemotherapy. In the past, first-line therapy was cetuximab, an EGFR inhibitor, which is now used in the second line. The outcome of first-line treatment with a PD-1 inhibitor is about 20% response, so a significant number of patients are progressing into the second line. The second line is primarily cetuximab, but sometimes it involves another treatment with a PD-1 inhibitor. The outcome from cetuximab, when it was in first line, was very low — less than 15% response — and if we assume a similar outcome in the second line, then despite those recent developments, there remains a significant unmet medical need in this disease.

The path we took for NT219 was to examine it in combination with an EGFR inhibitor; but EGFR inhibitors are being used to treat different indications, so we may later explore NT219 treatment for small cell lung cancer where the EGFR inhibitor plays a major role in treatment. With NT219, we have a lot of data and preclinical models in combination with other agents, so we see potential in many other indications as well.

DA: Is there anything else you can share about the collaboration with BMS for CM24 and why it was the right move for Purple? Are you looking for other collaborations or partnerships at this time or down the road?

GE: The clinical collaboration with BMS began when we acquired the CM24 asset. We sponsor the trial, and BMS supplies the drug — nivolumab –– and assists us in the development of the protocol, the design of the study, and so on. The idea was always that CEACAM1 should be targeted in combination with a PD-1 inhibitor, so the collaboration was key to investigating the potential of CM24.

At the end of the day, for the pharmaceutical industry as a whole, but particularly within oncology, many treatments are being offered as combinations, and collaborations present a major path forward for us. There is a lot of potential for collaboration in clinical development and on the commercialization of the asset, and that is something that we are definitely considering more for the future.

I can give another example, based on outcomes we had from the first three cohorts in the monotherapy arm of the Phase I study with NT219. We observed one partial response and three cases of stable disease in KRAS-mutated patients. That field is very active, especially with the new approval of KRAS inhibitors from Mirati and Amgen, which opens up a new window into collaborations that could explore our candidate in combination with those inhibitors and others.

DA: Can you preview the coming milestones for those two primary clinical programs?  

GE: For CM24, there will be analyses at the end of 2023: an interim analysis, followed by a topline analysis at the end of 2024. As a reminder, this is a randomized study, so we have a treatment arm and a control arm. The control arm has the current second-line standard-of-care, which includes two different regimens of chemotherapy. The treatment arm includes our investigational drug CM24 and nivolumab, plus the standard-of-care chemotherapy. There are also two different regimens on the treatment arm, so the analysis and the data that we have should be robust, and we’ll also have a control group. If and when we see positive data from this study, we can expand into additional indications.

We chose metastatic pancreatic cancer for CM24 both because of the high unmet medical need and because CEACAM1 is highly expressed on pancreatic cancers. However, this overexpression also exists in other tumor types, including non-small cell lung, colorectal, and other cancers. That ubiquity suggests a potential to expand into additional indications, and we are collecting data now that may set the stage for more studies.

For NT219, we are looking this year to identify the recommended Phase II dose and then to begin that expansion arm in head and neck cancer. We will have interim data from the Phase II trial, probably in 2024.

DA: Beyond identifying new indications for these candidates, how do you plan to expand the pipeline?

GE: Certainly, our recently completed acquisition of first-in-class tri-specific antibodies opens many avenues to expand our pipeline. In addition to the possibilities that these compounds suggest at their current state of development, we feel it is highly likely there will be even more value to be unlocked as we develop them further.

Beyond this acquisition, we are looking to identify and acquire both preclinical and clinical assets. Synergies with our drugs and with our capabilities are very relevant. I believe that we have a unique ability to identify assets that are overlooked by others — the two assets that we have today are examples of that — and then to take them into the clinic. To this end, we recently announced a collaboration with the largest HMO in Israel to identify potential future drug candidates from their research network, which is an example of how we could add very early-stage programs to our pipeline. 

DA: In addition to the clinical progress, do you anticipate other significant developments for the company in terms of funding, growth, and so on?

GE: We have a very strong financial position. We ended Q4 2022 with over $31 million and a cash runway that takes us to the second half of 2024. For the near term, we are focused on clinical development. I think our future will primarily involve leveraging data that we generate to be able to raise more capital and expand the programs or add assets. Another direction that we could take is to collaborate more with other parties, whether pharma companies or academic institutions. Two or three years from now, I hope to have more assets in our pipeline with a wider development program and more data flow coming in, which will enable us to continue to grow.

DA: What do you think the next few years will bring to oncology drug development more broadly?

GE: If you look back at the last few years, we saw the big promise of CAR-T, and now we are seeing the potential of more bi-specific drugs or antibodies that aim at enhancing the activity of the immune system. Maybe the next direction will be tackling solid tumors with similar agents and then taking advantage of these bi-specifics or tri-specifics in the solid tumor field.

Another likely direction would be the use of current drugs in different combinations that could enhance the response and the survival of patients. I believe that biomarkers play a major role in achieving that — every time there is a solid biomarker strategy, we see much better patient outcomes. We feel that we already see major progress in the industry.

Cancer treatment today is not what it was 10 years ago, but there are a lot of opportunities for improvement. That is why we are here — it is our mission to make that happen.