Targeted drug demonstrates safety, potential to stop cancer growth in early trials
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A targeted cancer drug developed by researchers at Norwegian University of Science and Technology and spin-off company APIM Therapeutics has demonstrated positive findings in phase 1 trials, according to a paper published in Oncogene.
“What we learned from phase 1 is that there was not a dose-dependency in terms of toxicity or efficacy, and that is consistent with its mode of action,” researcher Marit Otterlei, PhD, professor of molecular medicine at Norwegian University of Science and Technology, told Healio. “It selectively affects modified, stressed cells, and increasing the dose doesn’t cause it to target the nonmodified or natural cells. So, increasing the dose does not increase potential efficacy.”
Otterlei and her colleague, Jens-Peter Marschner, MD, chief medical officer at APIM Therapeutics, spoke with Healio about the process of developing the novel drug, known as ATX-101, the challenges they faced at the funding level, and the potential implications of this new treatment.
Healio: What inspired you to develop this drug?
Otterlei: I was doing research on DNA repair and was especially interested in replication associated with DNA repair. During this research, we looked at the multiple proteins and identified a new proliferating cell nuclear antigen (PCNA)-interacting motif. PCNA is a protein that is essential for DNA replication and repair. We looked more closely into this motif and saw that the proteins containing the motif were involved in multiple different stress responses. We thought if we could shut down the cellular stress response, 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 so that we could block this stress regulation. It took about 4 or 5 years to develop a drug that could work this way.
Healio: How did you conduct the phase 1 study on this drug?
Marschner: In our phase 1 study, which was conducted in Australia, we investigated four different doses of ATX-101 with a primary endpoint of safety. We wanted to see if there is a dose-limiting toxicity or a maximum tolerated dose. It is quite a safe compound; we haven’t identified the maximum tolerated dose. There was no dose-limiting toxicity, or even any grade 3 or grade 4 adverse events.
Healio: Apparently treatment with this medication does not cause hair loss in patients?
Marschner: Correct. The typical side effects that we see with toxic treatments like chemotherapy have not been observed with this medication. This was independent of the dose, whether it was 20 mg/m2 up to 40 or 60 mg/m2. This is because this drug works via a highly specific targeting of PCNA in stressed cells. If it is specific to those cells and does not target healthy cells, then you don’t have a safety issue. That is exactly what we have demonstrated here.
Healio: 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, is has been challenging and time-consuming to raise funds; this has also caused delays in our development program. On the contrary, everything has gone as planned scientifically and clinically and this makes us optimistic about future investments.
Marschner: In addition, we should mention the current economic situation we are facing with the inflation that’s there. In Europe, unfortunately, we have this war now, so we’re more in a depression rather than upgrading our economic situation. So, the willingness to invest is low currently.
Healio: What is next in your work on this topic?
Otterlei: Now that we have the safety data for the monotherapy, we are focusing on combinations. Preclinically, it was confirmed that we potentiate the effect of each single compound when we combine them. Our proof-of-concept study is a combination of ATX-101 with a platinum-based therapy in patients with platinum-sensitive ovarian cancer. This is running in Australia, and we have the safety part finished — it’s the same safety profile as in the phase 1 study. The other ongoing study is at Columbia University. That investigator-initiated study started with ATX-101 as monotherapy, and the investigators have treated some patients and done some preclinical experiments, as well. They say with this patient population we should move into the combination. So, we will start a phase 2 study of combination therapy soon.
Healio: Is there anything else you would like to mention on this topic?
Marschner: PCNA plays a role in all cells and, therefore, in all tumors. So, we have no limitation in terms of the tumor type. The same is true for the combination with anticancer therapies. There is a potentiating effect. So, we could build up a clinical development program that is much broader. For instance, we would like to start a study in glioblastoma or platinum-resistant ovarian cancer because it was shown that platinum-resistant cells move back into platinum sensitive if they are treated with ATX-101. So, we have so many ways to broaden our development spectrum. It is still limited by financing,
References:
- Lemech CR, et al. Oncogene. 2023;doi:10.1038/s41388-022-02582-6.
- Røst LM, et al. Oncogene. 2023;doi:10.1038/s41388-022-02579-1.
For more information:
Jens-Peter Marschner, MD, can be reached at APIM Therapeutics, c/o Sparebank 1 Regnskapshuset SMN, Rådhusveien 12, 7100 Rissa, Norway; email: jpmarschner@apimtherapeutics.com.
Marit Otterlei, PhD, can be reached at Norwegian University of Science and Technology, Postboks 8900, NO-7491 Trondheim, Torgarden, Norway; email: marit.otterlei@ntnu.no.
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