Tarveda’s Phase II Miniature Drug Conjugates Deliver Better Targeting, Less Toxicity than ADCs

Tarveda Therapeutics is advancing its miniature drug conjugates into Phase IIa trials, using a platform that combines the best aspects of small molecules and antibody drug conjugates while addressing their deficiencies. Specifically, the platform, dubbed Pentarin®, delivers more precise oncology medicine for patients with solid tumor malignancies and, therefore, minimizes toxicity to healthy tissue.

“Pentarin rapidly and deeply penetrates solid tumors to selectively accumulate and release anti-cancer payloads,” Drew Fromkin, CEO, said during August’s LifeScience Partners’ Summer Symposium.

The drugs delivered via Pentarin accumulate selectively and remain in the tumor to sustain the release of their payloads, but clear normal tissues quickly. Their half-life in plasma is measured in hours, rather than the days and weeks of other antibody drug conjugates (ADCs).

The miniature drug conjugates offer a manufacturing advantage, too, Fromkin pointed out. Unlike ADCs, which are made using biological processes, Pentarin therapeutics are produced by chemistry, which lowers manufacturing complexity and costs.

“We have two programs in clinical trials, a range of program in discovery, and others in sight of the clinic,” Fromkin told the audience. He said he expects to meet several key milestones for the two lead programs during the next 6 to 18 months.

The lead Pentarin program, PEN-866, is in Phase Ib/IIa trials. It has a Topo-1 inhibitor payload (SN-38), a small molecule binding ligand, and an optimized linker. The company chose HSP90 as the binding ligand because, as Fromkin said, “Up to 75% of solid tumors have activated HSP90.” PEN-866 exhibits a high binding affinity to HSP90, but not to normal tissue. The platform uses tuned linkers to achieve the desired cleavage kinetics. Within the tumor, intracellular trapping moderates payload accumulation.

The Pentarin platform can be designed for multiple types of targets – including signaling pathways, cell cycles, and DNA – and multiple types of payloads, such as small molecules and radioisotopes.

Preclinical trials showed concentrations of PEN-866 were significantly higher than for irinotecan, even after 15 days. Likewise efficacy, measured by tumor volume, was notably improved.

Of the 26 patients in the Phase I proof of concept trial, “One patient saw a 50% reduction in tumor volume,” Fromkin said. Eleven achieved disease stability. The remainder continued to progress, as they had under irinotecan therapy.

Human trials support the preclinical data and show activity in multiple tumor types, thus suggesting possible applications targeting tumors in squamous cell, endometrial, sarcoma, pancreatic, gastric, and small cell lung cancers.

“Two of the patients in the Phase I trial underwent biopsies,” Fromkin said.

Each of those biopsies (one at day one and one at day seven) showed higher concentrations of the conjugate and its payload in tumors. At day one, the biopsy showed a 318nM accumulation in the tumor compared to 94.7nM in plasma.

In contrast, SN38 showed 86.8nM in the tumor and 2.43nM in plasma. The tumor biopsy that was performed at day seven showed 31nM of PEN-866 in the tumor and 0.27nM in plasma. This is notably higher than for SN38, which showed an accumulation of 2nM in the tumor. Any quantities remaining in the plasma were below the level of detection.

Plans for additional single agent and combination studies are moving forward. Fromkin noted that the therapy may be suitable for such combinations as PEN-866+PARP (based on demonstrated synergies with PARP), and PEN-866+5FU/Leucovorin.

HSP90 targeting is an important component of the PEN-866 program that extends its applicability to multiple tumor lines, including H460 for non-small cell lung cancer and H69 for small cell lung cancer.

“Conjugates (such as HSP90-Lutetium) have been optimized for low liver and kidney retention, while maintaining uptake and retention in the tumor,” he said.

Tarveda just published a preclinical study in Molecular Cancer Therapeutics, for instance, detailing HSP90-binding miniature drug conjugate to overcome PI3K inhibition in solid tumors.

Another Pentarin program, PEN-221, also is entering Phase IIa trials. Designed to treat neuroendocrine tumors (NETS), this trial focuses on the gastrointestinal (GI) system. It uses a somatostatin receptor 2 (SSTR2)-targeting peptide linked to the DM1 payload. As yet, the program has completed enrollment of a post-PRRT treatment cohort in GI NETS and enrollment of an initial cohort with small cell lung cancer.

“This is a different type of program,” Fromkin said. “The disease is not all that aggressive, but it goes on for years. There are only two drugs available now, and neither is curative. Of those, patients receiving one of them can only be dosed four times. We think these patients need a number of new drugs.”

PEN-221 looks to slow the advancement of the tumor. Patients can be identified using standard imaging agents to identify SSTR2 expression.

“Later this year we expect to announce the trial outcome,” Fromkin said. In terms of development, “we expect to collaborate and to advance the drug to registration in early in 2021.”

So far this year, Tarveda has advanced trials for PEN-221 and PEN-866, presenting data from the later at ASCO last June, and has identified conjugate with new targeted payloads to advance.

Before year’s end it also expects to also announce data from the PEN-221 trials for the GI NETs cohort, and to begin combination studies for PEN-866. It also plans to develop new HSP90-binding miniature drug conjugates and, based on that, identify its next clinical program.

Tarveda Therapeutics expects to close a $20+million funding round in the next few months, which will take it well through 2021. “We have exciting opportunities to take these compounds forward,” Fromkin noted.