On the heels of an FDA orphan drug designation for lead compound PU-H71 in myelofibrosis, privately held Samus Therapeutics Inc. moved the small molecule into a phase Ib dose-escalation study in patients with the bone marrow disorder. PU-H71 is designed to target the epichaperome, a protein complex present in more than half of the cancers tested by the company, a spinout of Memorial Sloan Kettering Cancer Center (MSKCC).

The multicenter trial follows initiation of a single-center study of PU-H71 in metastatic breast cancer (MBC).

The bigger win, however, could come in neurodegenerative disease – specifically, Alzheimer's disease (AD) – where Boston-based Samus is preparing to advance the brain-permeable epichaperome inhibitor PU-AD into the clinic by year-end. Preclinically, the molecule was shown to reduce tau, restore long-term memory, improve spatial learning, restore synaptic plasticity and increase survival.

Epichaperome complexes enhance the efficiency of aberrant cellular processes, contributing to the pathophysiology of a variety of diseases, including inflammation in addition to cancer and neurological disorders. The high-molecular-weight complexes form under conditions of abnormal stress, as cells become biochemically "rewired," explained Jonathan Lewis, CEO and executive chair.

In cancer, epichaperome complexes can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. PU-H71 is engineered to target those complexes with a level of specificity that allows it to interfere with the function of diseased cells without affecting normal cells.

In 2016, company co-founder Gabriela Chiosis and colleagues reported in Nature that the chaperones heat-shock protein 90, or Hsp90, and heat-shock cognate protein 70, or Hsc70, serve as nucleating sites for the physically and functionally integrated epichaperome complexes, suggesting that the tightly integrated chaperome units can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background.

In myelofibrosis, the epichaperome is complicit in optimizing the JAK-STAT pathway, allowing JAK2 to form dimers that evade inhibition with an inhibitor such as Jakafi (ruxolitinib, Incyte Corp.), according to Srdan Verstovsek, chief of the section for myeloproliferative neoplasms (MPNs) in the leukemia department and director of the clinical research center for MPNs at the MD Anderson Cancer Center and lead clinical research advisor for the phase Ib myelofibrosis study. By inhibiting epichaperome function and breaking this mechanism, investigators hope to show that PU-H71 increases the anticancer activity of JAK2 inhibitors.

The two-part, open-label myelofibrosis study is expected to enroll 30 patients who have active disease following a minimum of six months of treatment with ruxolitinib, according to Cortellis Clinical Trials Intelligence. PU-H71 is being added to ruxolitinib to assess the candidate's safety, tolerability, pharmacokinetics and preliminary efficacy.

In MBC, PU-H71 is being evaluated in combination with Abraxane (nab-paclitaxel, Celgene Corp.) in a small open-label trial in patients with HER2-negative MBC to identify an optimal dosing regimen.

In contrast to cancer, selectively inhibiting the epichaperome complex in neurodegenerative diseases results in neuronal survival – essentially, "reverting to a non-Alzheimer's state," Lewis said – with no effect on normal cells. PU-AD, which crosses the blood-brain barrier efficiently, is being evaluated in a PET/SPECT biomarker brain imaging study and completing IND-enabling studies before advancing into the expected phase I start later this year.

The Alzheimer's field 'is evolving significantly'

Samus was launched by MSKCC about seven years ago based on the discoveries of founders Chiosis and Larry Norton in the Chiosis labs in molecular pharmacology and chemistry at MSKCC. Chiosis, now a scientific advisor to Samus, is a professor at MSKCC, Weill Cornell Medicine and Rockefeller University and chairs the molecular pharmacology program in chemical biology at the Sloan Kettering Institute. Her research is centered on elucidating the pathogenic roles played by molecular chaperone proteins and on developing methods to target them selectively.

Norton, an oncology advisor to the company, is deputy physician-in-chief for breast cancer programs, medical director of the Evelyn H. Lauder Breast Center and chair of clinical oncology at MSKCC.

Samus began to gain traction in 2016 when Lewis was brought on board after serving more than a decade as chair and CEO of Ziopharm Oncology Inc. He oversaw the incorporation of Samus and its relocation from New York to Boston. At the same time, its license agreement with MSKCC was broadened from an exclusive focus on cancer to include "the entire breadth" of therapeutic applications from the technology platform, Lewis said.

With the first molecule now in the clinic, Samus is intent on moving quickly into AD, which is "increasingly the real focus" of the company, he added, though he declined to cite a timetable to top-line findings for either program.

Lewis also was tight-lipped on the nuts and bolts of the small company. The "vertically integrated team" is supplemented with a group of "extremely knowledgeable and deeply experienced" academics who serve as advisors in oncology or neurodegenerative disease. Dick Bagley, president and chief financial officer, also joined Samus in 2016 from Ziopharm, where he held the same roles following a long career in biotech and big pharma that saw him named a founding director of the Biotechnology Industry Organization, or BIO. Barbara Wallner, chief scientific officer, was chief technology officer and senior vice president of technology operations at Ziopharm after beginning her career at Biogen Inc., where she invented the psoriasis biologic Amevive, and subsequently serving in a variety of capacities at other biopharmas.

Samus – the company's name harkens to the Someș, a river in eastern Europe, and also alludes to the female protagonist of a Japanese science fiction game – expects to grow over the next year "in a limited and focused way" as its candidates advance through the clinic, Lewis said. The closely held company is entirely financed by an undisclosed group of private investors that has committed to fund the ongoing and planned studies in cancer and AD.

For now, Samus is content to take a deliberate, step-by-step approach to advance its assets rather than looking at the end game, according to Lewis. He acknowledged, however, that the company has enjoyed inbound interest and entertained "very early" meetings with several pharma companies, where discussions continue.

"We're focused on doing this ourselves to get to the next level," he told BioWorld. The company has faith in its approach to PU-H71 in cancer and even greater confidence to accelerate PU-AD.

"The Alzheimer's field, in general, is evolving significantly now," Lewis said. He cited "the big shift" by regulators in developing guidance for biomarker-driven studies to address an indication littered with drug development failures – the latest reported just this week. (See BioWorld, June 13, 2018.)

"There's a big shift in terms of trying to gain accelerated approval with a biomarker definition," he said. At the same time, the medical community is in the process of redefining the disease based on a more rigorous molecular definition.

"We have a novel target that we think is highly biologically relevant, based on an enormous body of scientific data," Lewis said. "We're trying hard to take that relevant science into a well-defined population where we have a potential biomarker that we think is relevant and take a very step-by-step approach to clinical trials. We do recognize this is an enormously difficult field, but we're using approaches that were successful in the world of cancer and in the world of HIV and AIDS and letting the data help us to answer these questions in a step-by-step way."