DUBLIN – Neotx Therapeutics Ltd. raised $45 million in a series C round to continue clinical development of an immuno-oncology agent that already has a long clinical history behind it. Its lead molecule, naptumomab estafenatox, is a fusion protein comprising an antibody fragment that recognizes the oncofetal antigen 5T4 and a bacterial “super-antigen” comprising a modified version of the Staphylococcal enterotoxin A.

It is designed to unleash a powerful antibacterial immune response against cancer cells and is currently undergoing a phase Ib dose-escalation trial in patients with solid tumors, in combination with the PD-L1 inhibitor Imfinzi (durvalumab).

The trial very much represents a second coming for the drug, which, in a former life, was known as Anyara. Its original developer, Lund, Sweden-based Active Biotech AB, took it into a phase II/III combination trial in 513 patients with advanced renal cell cancer. The study, which pitted Anyara plus interferon alpha against interferon alpha monotherapy, failed to demonstrate any survival benefit in the combination arm.

Rehovot, Israel-based Neotx picked it up in 2016 on the basis of promising preclinical and phase I studies, in which the drug had performed well. It is now repositioning naptumomab estafenatox as an immuno-oncology agent that can boost responses to PD-1 or PD-L1 inhibitors. “The parachute was invented 500 years before there was an airplane,” quipped Neotx co-founder and CEO Asher Nathan. “Until the checkpoint inhibitor era, this was a drug that struggled a little bit,” he told BioWorld.

Asher Nathan, co-founder and CEO, Neotx

Combining it with interferon-alpha was probably its undoing the first time round, as, Nathan said, cancer patients who receive the cytokine commonly develop antidrug antibodies. “Retrospectively, they should have done a smaller trial first with interferon, to see if there was interference with antidrug antibodies.”

Its performance in earlier studies (conducted sans interferon-alpha) looked much better. One phase I trial patient with metastatic non-small-cell lung cancer who had tried three prior lines of therapy, including taxotere, took the drug plus taxotere for six months and “without any additional therapy lived for another 11 years,” Nathan said. She eventually died from a noncancer-related cause.

Naptumomab estafenatox is, of course, one of dozens of agents being tested in clinical collaborations designed to boost the response rates of PD-1 and PD-L1 inhibitors, which still remain stubbornly low almost six years after their first approvals. The study with Cambridge, U.K.-based Astrazeneca plc’s Imfinzi is currently undergoing dose escalation, and an expansion cohort will then be tested once a maximum tolerated dose is reached. An initial readout could come before the year-end, which should give some clues about its efficacy in a checkpoint-inhibitor setting.

“If this drug hadn’t been invented by Active Biotech, I think it would have been invented after the checkpoint inhibitor era,” Nathan said. It differs from most other immuno-oncology agents in its immune activation mechanism. “We’re only asking it to do what evolution has perfected over five billion years,” he said. In contrast, many other agents have an unnatural mechanism. “You’re taking an existing, complex immune system that you only partially understand, and then you’re perturbing it in ways it’s not meant to be perturbed,” he said. That type of intervention is likely to have consequences, he added.

Moreover, most immunotherapies are focused on boosting T-cell infiltration into the tumor microenvironment, “which,” he said, “we all know is not a fun place to work.” Naptumomab estafenatox works, he said, by shifting the overall immune status of patients from suppressive to a permissive state. At the same time, the construct does not lead to activation of all T cells, as T-cell engagers do. “It’s been genetically engineered to be very, very specific,” Nathan said.

The company is by no means the only firm to target 5T4, even if it is doing so in a distinctive way. Synthon Biopharmaceuticals BV, of Nijmegen, the Netherlands, is in phase I with SYD-1875, an antibody-drug conjugate (ADC) that targets the same antigen, according to ClinicalTrials.gov. So too are Oxford, U.K.-based Vaccitech Ltd. and Oxford University, with a vaccine comprising two attenuated recombinant vectors, a chimp adenovirus and a modified vaccinia Ankara, both of which express 5T4.

Aptevo Therapeutics Inc., of Seattle, and Alligator Bioscience AB, of Lund, are in preclinical development with ALG.APV-572, a bispecific antibody that targets 5T4 and 4-1BB (CD137). So too is Asana Biosciences LLC, of Lawrenceville, N.J., with another 5T4-directed ADC, ASN-004. Pfizer Inc. terminated development of another ADC, PF-06263507, after phase I development.

Neotx Therapeutics has so far raised some $60 million but has done without access to venture capital. It has been funded by high-net-worth private investors, including U.S. hedge fund billionaire J. Tomilson Hill, who has joined the company’s board, along with Korean entrepreneur Andrew Kim, who chairs NFDOS Co. Ltd., Paul Marinelli, and Neotx’s chief scientific officer, Roger Kornberg, the 2006 Nobel laureate in chemistry with whom Nathan has had a lengthy association. The company also has a high-profile chief medical officer, oncologist Marcel Rozencweig, who led Bristol-Myers Squibb Co.’s efforts in cancer drug development from 1983 to 2001.

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