Issue:March 2023

EXECUTIVE INTERVIEW - Purple Biotech Ltd.: Developing First-In-Class Oncology Therapies

Purple Biotech Ltd., headquartered in Rehovot, Israel, is a clinical-stage company developing first-in-class oncology therapies that seek to overcome tumor immune evasion and drug resistance. The company’s pipeline includes CM24 and NT219. The company is advancing CM24, an mAb that targets CEACAM1, an immune checkpoint protein that allows tumors to evade the immune system; it is evaluating CM24 in a Phase 2 trial as a combination therapy with the PD-1 inhibitor nivolumab and chemotherapy for metastatic pancreatic cancer. This study is conducted in clinical collaboration with Bristol Myers Squibb. NT219 is a novel small molecule dual inhibitor targeting two critical tumor-resistance pathways; the company is currently advancing it in a Phase 1-2a trial as monotherapy treatment and in combination with cetuximab for various solid tumors. Purple Biotech recently acquired Immunorizon Ltd., a private company developing multi-specific T and NK cell engagers that selectively activate the immune response inside the tumor microenvironment. The acquisition provides Purple Biotech with an expanded portfolio of investigational tri-specific antibody compounds that target multiple tumor antigens, the first being 5T4, and offer the potential to further expand to additional targets.

 Drug Development & Delivery recently interviewed Gil Efron, Chief Executive Officer of Purple Biotech, to discuss the company’s focus on identifying and developing promising molecules that may offer first-in-class approaches to treating devastating cancers with large unmet medical needs.

Q: What is your approach to finding existing molecules, whether small molecules or biologics, that may offer new therapies for intractable cancers that are difficult to treat under current standards of care? How do you uncover the hidden potential of these promising compounds?

 A: The world of biotech and pharmaceutical research is replete with investigational assets that have not yet been funded for the clinical trials needed for regulatory submission or even to establish clinical proof-of-efficacy. Purple Biotech sees enormous opportunity with some of these “hidden gems,” and focuses on identifying, in-licensing, and developing promising and innovative oncology assets. We thoroughly vet the potential of these assets through our own research, engagement with other companies and laboratories, and the insights of our external advisors. We seek assets that are potentially first-in-class approaches to solving major unmet medical needs in cancer treatment and that offer synergies with other molecules in our portfolio and synergy with our capabilities. Our commitment to truly innovative approaches is nicely illustrated by CM24 and NT219, two clinical-stage, first-in-class drugs being developed to treat some of the world’s most devastating cancers. Additionally, our recent acquisition of the innovative, first-in-class tri-specific oncology assets will create synergies with our existing assets and broaden our pipeline.

Q: Can you explain the transition from Kitov Pharma to Purple Biotech? Why did the company shift its focus to first-in-class oncology therapeutics?

A: During December 2020, Kitov Pharma Ltd. announced it was changing its name to Purple Biotech Ltd. and its stock began trading on the NASDAQ and TASE exchanges as PPBT. This name change signaled the completion of a transition that reflected a corporate decision to focus resources on developing innovative oncology assets targeted at difficult-to-treat cancers with high unmet medical needs. The excitement of clinically developing potential first-in-class therapies for such cancers was reinforced by the acquisitions of CM24, a novel mAb targeting CEACAM1, an immune checkpoint molecule that supports tumor immune evasion and survival through multiple pathways, and NT219, a novel small molecule dual inhibitor of IRS and STAT3, two molecular targets known to be associated with resistance to inhibitors of the MAPK pathway. At Purple Biotech, our clinical development efforts initially seek the most efficient path to clinical proof-of-concept before expanding to additional indications or product combinations, based on clinical evidence. This strategy allows us to stratify our disease targets efficiently and streamline clinical development of investigational compounds that would benefit as broad a set of patients as possible.

Q: How does CM24 restore the ability of patients’ immune systems to invade and kill solid tumors, preventing metastases? What is unique about CM24’s mode of action?

A: CM24 targets CEACAM1, a well-recognized immune checkpoint protein that lowers the ability of the immune system to kill cancer cells. CM24 facilitates immune system access to tumors by unlocking CEACAM1’s checkpoint mechanisms that prevent T cells and “natural killer” (NK) cells from attacking and destroying cancer cells. Because CEACAM1 is over-expressed on multiple types of solid tumors, CM24 may provide a way to turn off this tumor defense mechanism in several oncology disease states. We are currently partnered with Bristol Myers Squibb in a Phase 2 trial to investigate the use of CM24 in combination with nivolumab to treat metastatic pancreatic patients who express high levels of CEACAM1. In addition, we believe CM24 can also contribute to reducing metastases by blocking adhesion of cancer cells to CEACAM1 expressed on neutrophil extracellular traps, and we are hopeful that strong proof-of-concept data against CEACAM1 in metastatic pancreatic cancer will support investigations of other cancer therapies.

Q: What is NT219, and why are you excited about its development?

A: Cancer cells have a challenging ability to activate bypass mechanisms that allow them to escape therapeutic agents. NT219 is a first-in-class dual small molecule inhibitor of two mechanisms of drug resistance, IRS1/2 and STAT3, two common resistance pathways that are present on many solid tumors and which drive tumors’ resistance to many cancer drugs (such as inhibitors of EGFR, BRAF, MEK, and KRAS). By creating effective resistance to cancer therapies, IRS1/2 and STAT3 fuel cancer growth and hamper the long-term benefit of approved cancer drugs. In early research, NT219 has shown itself able to disable these bypass mechanisms, thereby allowing cancer drugs to continue working. NT219 is the only dual inhibitor of these two resistance pathways, and we have shown the concomitant inhibition of both targets is required to restore the treatment efficacy of standard-of-care therapies. We are pursuing clinical trials to determine whether and how NT219 can be combined with existing oncology drugs to shut down the resistance pathways that limit and eventually halt the drugs’ efficacy. NT219 is currently being investigated in a Phase 1/2 clinical trial in combination with cetuximab to evaluate its effectiveness in treating recurrent/metastatic head-and-neck squamous cell carcinoma (SCCHN) as well as for its potential use as a monotherapy in multiple tumor types. Successful proof-of-concept data from this trial may hold promise for research into potential combination treatments for other types of solid tumors.

Q: There has been discussion of a potential application of NT219 as an effective adjunct to therapies targeting KRAS mutations in non-small cell lung cancer (NSCLC). Can you explain what is going on?

A: If approved, NT219 will be a valuable adjunct to approved cancer drugs by disabling the molecular processes that allow resistance to develop during treatment. This may be relevant to one of the most widely discussed and promising treatments for several cancers – KRAS inhibitors, drugs that target mutations of the cell-signaling KRAS oncogene that drive tumor growth and allow cancers to flourish. Sotorasib (Lumakras®, Amgen) was approved in May 2021 followed by adagrasib (Krazati®, Mirati) in December 2022 to tackle a specific KRAS mutation (G12C) present in a significant fraction of NSCLC patients. Numerous other compounds are in clinical trials for the same molecular target. Unfortunately, patients on these KRAS inhibitors have seen early relapse and a limited survival benefit, suggesting that combination approaches will be required to eventually break this deadlock. No other treatment is available for all other KRAS mutations, other than the G12C mutation.

Our research as well as several recent publications indicate one of the primary ways mutated KRAS genes escape these drugs and develop resistance is via IRS1/2, one of the molecular pathways that NT219 effectively shuts down. Our hypothesis is that NT219, if given in combination with KRAS inhibitors, could greatly improve the KRAS inhibitors’ effectiveness and strengthen the clinical impact of drugs such as sotorasib or adagrasib, thereby prolonging patients’ lives. In data we reported from our clinical studies, we saw a partial response in a mutated KRAS patient as well as stable disease in multiple patients who also had KRAS mutations. We are looking into these data and evaluating the potential treatment of this patient population with NT219.

Q: In addition to the clinical development of your two current assets, CM24 and NT219, do you have other irons in the fire? Where do you see Purple Biotech heading in the next 2 to 3 years?

A: Within 2 to 3 years, we would hope to have a proof-of-efficacy for CM24 to treat late-stage pancreatic cancer in combination with nivolumab and standard-of-care therapy. If CM24 gains such proof-of-efficacy and subsequent FDA approval, it would be a first-in-class therapeutic targeting CEACAM1. Additionally, NT219 is showing very promising early clinical efficacy results and will, we hope, show proof-of-efficacy in at least one combination therapy targeting difficult-to-treat cancers.

The portfolio of tri-specific antibodies that we recently acquired is a perfect illustration of our strategy to invest in innovative biologics and to expand our pipeline with additional preclinical programs. This new technology is differentiated not only by the combination of the NK and T cell engagement but also by the conditional activation at the tumor microenvironment, which we believe provides an opportunity for better therapeutic outcomes for patients. We also believe there is a potential synergy between this new technology and our current drug candidate CM24, as well as with the knowledge and expertise we have gained over the years through both preclinical and clinical development. We expect to advance the first of the newly acquired assets to an IND submission in approximately two years.

Beyond CM24, NT219 and our newly acquired multi-specific assets, we are exploring with biotech companies and academic research centers about other promising drug candidates we could in-license and develop; in some cases, we may opt to develop commercial partnerships with other companies whose focus is synergistic with our own. And finally, we continue to engage with the investment community to deepen their understanding of the value of Purple Biotech. We are building a robust investor and analyst base, and it is our hope to accelerate this process moving forward.