Targeted drug demonstrates safety and potential to stop cancer growth in early trials

According to an article published in Oncogene.

“What we learned from phase 1 is that there was no dose dependency in terms of toxicity or efficacy, and this is consistent with its mode of action,” said the searcher. Marit Otterlei, PhD, professor of molecular medicine at the Norwegian University of Science and Technology, Healio told Healio. “It selectively affects modified and stressed cells, and increasing the dose does not cause it to target unmodified or natural cells. So increasing the dose does not increase potential efficacy.

Otterlei and his colleague, Jens-Peter Marschner, MD, Chief Medical Officer at APIM Therapeutics, spoke with Healio about the development process for the new drug, known as ATX-101, the challenges they faced with funding and the potential implications of this new treatment .

Good morning: What inspired you to develop this drug?

Marit Otterlei

Otterley: I was researching DNA repair and was particularly interested in replication associated with DNA repair. During this research, we examined multiple proteins and identified a novel pattern of interaction with proliferating cell nuclear antigen (PCNA). PCNA is an essential protein for DNA replication and repair. We took a closer look at this motif and found that proteins containing the motif were involved in multiple different stress responses. We thought that if we could shut down the cellular response to stress, it would affect cancer cells more than normal cells because they are more stressed and dysregulated. Then we started to develop this drug containing this new motif in order to be able to block this regulation of stress. It took about 4 or 5 years to develop a drug that could work that way.

Good morning: How did you drive the phase 1 study on this drug?

walkers: In our phase 1 study, which was conducted in Australia, we investigated four different doses of ATX-101 with one primary safety endpoint. We wanted to see if there was a dose-limiting toxicity or a maximum tolerated dose. It is a fairly safe compound; we have not identified the maximum tolerated dose. There was no dose-limiting toxicity, not even grade 3 or 4 adverse events.

Healio: Apparently, a treatment with this drug does not cause hair loss in patients?

walkers: Correct. The typical side effects we see with toxic treatments like chemotherapy have not been seen with this drug. This was independent of the dose, whether it was 20 mg/m² up to 40 or 60 mg/m². Indeed, this drug acts via a very specific targeting of PCNA in stressed cells. If it’s specific to those cells and doesn’t target healthy cells, then you don’t have a safety concern. This is exactly what we have demonstrated here.

Good morning: What challenges did you encounter in the development of this drug?

Otterlei: The pharmaceutical industry in Norway is less developed than in the rest of Europe. Moreover, the willingness to invest in high-risk drug development projects is limited. Therefore, it was difficult and time-consuming to raise funds; it also caused delays in our development program. On the contrary, everything went as planned scientifically and clinically, which makes us optimistic about future investments.

walkers: In addition, we must mention the current economic situation that we are facing with the inflation that is there. In Europe, unfortunately, we have this war now, so we are more in a depression rather than improving our economic situation. Thus, the will to invest is currently low.

Good morning: What is the next step in your work on this subject?

Otterlei: Now that we have the safety data for monotherapy, we are focusing on combinations. In preclinical it has been confirmed that we potentiate the effect of each compound when we combine them. Our proof of concept study is a combination of ATX-101 with a platinum therapy in patients with platinum-sensitive ovarian cancer. It’s taking place in Australia, and we’ve completed the safety part – it’s the same safety profile as in the phase 1 study. The other ongoing study is at Columbia University. This investigator-initiated study began with ATX-101 as monotherapy, and the researchers also treated some patients and performed preclinical experiments. They say that with this patient population, we should move to combination. We will therefore soon start a phase 2 study on the combination therapy.

Healio: Is there anything else you would like to mention on this?

Marschner: PCNA plays a role in all cells and therefore in all tumors. So we have no limitation in terms of tumor type. The same applies to the combination with cancer therapies. There is a potentiating effect. Thus, we could build a much broader clinical development program. For example, we would like to start a study on platinum-resistant glioblastoma or ovarian cancer, because platinum-resistant cells have been shown to become platinum-sensitive again if treated with ATX-101. So we have many ways to expand our development spectrum. It is still limited by funding,

The references:

For more information:

Jens-Peter walkers, MARYLAND, can be contacted at APIM Therapeutics, c/o Sparebank 1 Regnskapshuset SMN, Rådhusveien 12, 7100 Rissa, Norway; email: [email protected].

Married Otterleidoctorate, can be contacted at Norwegian University of Science and Technology, Postboks 8900, NO-7491 Trondheim, Torgarden, Norway; E-mail: [email protected].

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