The activity in the immuno-oncology company Alligator Bioscience has been high over the past year. In parallel with an intense news flow, where the start of the study with the main project ATOR-1015 stands out, a multi-million-kroner revenue has been recorded from South Korea. In addition, two of this year's Nobel Prizes have a direct connection to the company's main project, which has apparently made the company even more visible on the international industry radar. Below, Alligator's CEO Per Norlén tells more about the past year and what awaits in 2019.
Alligator Bioscience operates in a field that is certainly competitive, but which is also forecast to be very lucrative in the foreseeable future. After having licensed out ADC-1013 to the world's largest pharmaceutical company Johnson & Johnson - a deal potentially worth SEK 6 billion - the Lunda company is now well on its way to being able to boast mainly clinical projects in the pipeline.
On December 11 of this year, the company's clinical phase I study began with ATOR-1015, the company's main project after the out-licensing of ADC-1013, a milestone that could eventually lead to a deal of at least the same magnitude as the one with J&J.
Per Norlén, CEO of Alligator Bioscience, what event would you highlight as the most important for the company when you look back on 2018?
– The start of the clinical phase I study with ATOR-1015 is the most important milestone of the year for Alligator. We are the first in the world with a new concept, a tumor-localizing CTLA-4 antibody, which we believe can be the solution to the single biggest challenge in immuno-oncology today, making CTLA-4 drugs tolerable. The target molecule has previously been confirmed to be effective, but the use of CTLA-4 blockers has been significantly limited by very severe, often life-threatening, side effects. ATOR-1015, through its ability to selectively activate the immune system in the tumor, but not in the rest of the body, provides an opportunity to get around this problem. The solution lies in our bispecific concept where we have created a drug that actively seeks out tumors.
What significance do you think this will have for your business?
- ATOR-1015 has the potential to change the landscape of future cancer treatment. The side effect profile evaluated in the recently initiated Phase I clinical trial will be very important, both for ATOR-1015's continued path to market and for a successful out-licensing. We will have established safety data in 18-24 months, i.e. towards mid-2020. If the results we have seen in preclinical studies can be confirmed in our clinical development program, it puts us in an excellent position for future discussions with potential partners.
»For next-generation products, we have built in functions with our technology that mean the molecule is not active until it reaches the tumor, which takes the concept of tumor-directed immunotherapy to a new level and could be crucial for the patient«
The first approved immunotherapy, Yervoy, was approved by the FDA in 2011 and revolutionized cancer research. The underlying findings behind Yervoy were also awarded this year's Nobel Prize in Medicine. However, the treatment has many side effects. Instead, you are developing next-generation immuno-oncology drugs that selectively activate the immune system in the tumor, but not in the rest of the body. Can you elaborate on how your products differ from the first-generation immunotherapies?
– Alligator is truly differentiated compared to most other immuno-oncology companies through our way of developing tumor-targeted cancer drugs. The majority of our products are dual-acting, i.e. they activate the immune system via two different target molecules, partly to target and increase the effect but also to minimize side effects. For the next generation of products, we have built in functions with our technology that mean that the molecule is not active until it reaches the tumor, which takes the concept of tumor-targeted immunotherapy to a new level and could be crucial for the patient.
»ATOR-1015 could change the landscape of future cancer treatment«
ATOR-1015 is bispecific and, like Yervoy, binds to the target protein CTLA-4, but also to the receptor OX40. How does ATOR-1015 differ from Yervoy in terms of immune activation and side effects?
– The mechanism of action is basically the same, i.e. ATOR-1015 and Yervoy activate the immune system by blocking CTLA-4, and by knocking out regulatory T cells. The difference is partly that Yervoy activates the immune system systemically, throughout the body, while ATOR-1015 primarily activates the immune system locally at the tumor, and partly that ATOR-1015 has a dual-action function and the potential to have an even stronger clinical effect, since it also activates the immune system via OX40.
– Yervoy's systemic immune activation gives rise to a wide range of severe, sometimes life-threatening side effects. We have shown in preclinical studies that ATOR-1015 is enriched in the tumor after it is administered via the blood and has a stronger immune activating effect in the tumor than in the rest of the body. I am convinced that this property will be crucial and could make ATOR-1015 the first drug that effectively manages the side effects associated with the target molecule CTLA-4. This would be a major step forward for the entire field of immuno-oncology and for patients with cancer.
CTLA-4 has previously been clinically validated, not least through Bristol-Myers Squibb's work with Yervoy. What would you say this means for the development risk in the ATOR-1015 project?
– It is extremely positive for us that CTLA-4 is so well validated in patients. The clinical development plan for ATOR-1015 can be fully targeted at the patient populations where clinical efficacy has been seen with Yervoy, i.e. malignant melanoma, lung cancer, kidney cancer and certain forms of colorectal cancer. In the first clinical study, we will define which dose to proceed with and then have the opportunity to expand with parallel studies in several of the above indications, as a single treatment or in combination with PD-1.
How big is the market potential for a drug with a CTLA-4 effect without side effects and how does ATOR-1015 relate to PD-1, which continues to appear to be the primary standard treatment?
– PD-1 inhibitors will in all likelihood dominate immuno-oncology for the foreseeable future, and other treatments should primarily be seen as combination products given with PD-1. As far as we know today, CTLA-4 is by far the most important signaling pathway. Yervoy's sales in 2017 amounted to just over $1 billion, and this was based almost exclusively on use against malignant melanoma, which is a relatively small cancer indication. The severe side effects also mean that only 25 percent of melanoma patients can take the drug. ATOR-1015 has the potential to dramatically increase that proportion. If you add to this that Yervoy has also been approved for the treatment of lung cancer, the potential increases significantly. If we can show that our concept holds up in the clinic, we can see sales of $1 billion as a base, but with a potential that is much greater.
»It is an amazing coincidence that this year's Nobel laureates in both medicine and chemistry have a direct connection to ATOR-1015«
Looking ahead, what milestones can we expect for the company in 2019?
– In 2019, the plan is that our partner Janssen Biotech, Inc. can take the drug candidate ADC-1013 to the start of combination studies, and where we still have some opportunity to achieve the next milestone payment even though it will more likely come in 2020. The open clinical study with ATOR-1015 in cancer patients is ongoing during the year. We will see initial results based on safety and tolerability, and have clear data on this towards mid-2020. Furthermore, we will enter the clinic with at least one more project, i.e. ATOR-1017, where we will submit our application for clinical trial during the summer of 2019.
What are you personally most looking forward to in the coming year?
– First and foremost, I look forward to following the clinical studies with ADC-1013 and ATOR-1015.
Finally, you describe ATOR-1015 as “Three Nobel Prize discoveries in one molecule” in your recently published paper. on the topic of immuno-oncology. Can you elaborate on this?
– It is a fantastic coincidence that this year’s Nobel laureates in both medicine and chemistry have a direct connection to ATOR-1015. James Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Medicine for their discovery that cancer can be attacked by inhibiting the immune system’s braking mechanisms via CTLA-4 and PD-1, respectively, discoveries that paved the way for the entire field of immuno-oncology. Alligator’s bispecific drug candidate ATOR-1015, a next-generation CTLA-4 antibody, has its origins in Allison’s original discoveries about this target protein.
– But that's not all. George Smith, Frances Arnold, and Greg Winter was awarded the Nobel Prize in Chemistry. Arnold developed a protein optimization technology that is related to Alligator's FIND (Fragment INduced Diversity) technology, and Smith and Winter developed a phage display technology that is used to produce antibodies with optimal properties. ATOR-1015 is built and optimized using both phage display and the protein optimization technology FIND, and activates the immune system via CTLA-4. Three Nobel Prize discoveries in one molecule, which should be a record that is hard to beat!
CEO Per Norlén presented at the LSX Investival conference in London on November 13, i.e. before the announcement that the company had initiated a clinical phase I study with ATOR-1015:
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