From The Editor | May 18, 2017

Samus Therapeutics Expands Clinical Development Program

Source: Clinical Leader
Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

Samus Therapeutics Expands Clinical Development Program

Samus Therapeutics is a privately-held, Boston-based biopharmaceutical company focused on developing novel therapeutics and diagnostics targeting the epichaperome, a foundational protein complex emergent from multiple disease states, including oncology and neurology.

“We are the ‘anti-epichaperome company,’ says Jonathan Lewis, who was brought onboard in 2016 to serve as the company’s executive chairman and CEO. “Following various forms of cellular stress, chaperome units are rewired into the epichaperome network. Targeting and disrupting the epichaperome in cancer results in cell death  and in neurologic diseases, neuronal survival,  with no apparent effect on normal cells.”

In October 2016, seminal research on the molecular characteristics and composition of the epichaperome and PU-H71 in cancer were published by the Chiosis lab in the journal Nature. PU-H71 is one of Samus’ leading anti-epichaperome candidates. It is a synthetically designed and engineered small molecule with a unique biologic mode of action. PU-H71 selectively inhibits and disrupts epichaperome complexes, the nidus of which is HSP 90.

“We believe PU-H71, unlike any other competitive agent, does not inhibit function in normal cells,” states Lewis. “This difference enables PU-H71 to impact abnormal protein networks and complexes in cancer cells to kill them and potentially avoid the serious side effects seen with other previous and current HSP (heat shock protein) inhibitors.”

Additionally, a companion PET (positron emission tomography) biomarker  to PU-H71 (PU-H71-PET) identifies intra-tumoral levels of targeted epichaperome complexes in vivo in humans. The current clinical development program includes a Phase 1b/2 study in PV/myelofibrosis, a Phase 1b study in front-line chemo-naïve metastatic pancreatic cancer, and a Phase 1b study in advanced breast cancer, with all studies conducted in combination with standard of care.   

The company’s other lead candidate small molecule, PU-AD, and an accompanying PET biomarker  (PU-AD-PET), addresses neurodegenerative diseases such as Alzheimer’s, traumatic brain injury (TBI) and chronic traumatic encephalaphy (CTE). The competitive advantage of the PU-AD therapeutic is that it focuses on abnormal tau and other proteins in the CNS (central nervous system) rewired into an epichaperome. The initial clinical focus for  Phase 1 study is neurodegenerative disease. The competitive advantages for PU-H71 and PU-AD will be applied to other epichaperome inhibitors for clinical study by the Company. 

Chaperones have long been associated with the management of cellular stress. Because of this core function, changes in chaperone and abnormal protein rewiring are believed to be at the core of many diseases, including cancer and neurologic disease. “Under chronic stresses, cells rewire the chaperones and their helpers, collectively referred as the chaperome, into the formation of large networks, referred to as the epichaperome,” says Lewis. “Because these epichaperomes maintain and drive cellular function in a disease state, they can be targeted therapeutically with little or even no effect on normal cells. This differs from therapies targeting individual elements of the chaperome, such as HSP90 inhibitors.”

 “In cancer, our development program includes early disease-directed clinical studies in myelofibrosis, metastatic pancreatic cancer, and advanced breast cancer,” says Lewis. “Leading clinicians are supporting study design and conduct. The clinicians include Dr. James Armitage for myelofibrosis, Dr. Dan Von Hoff for pancreatic, and Dr. Larry Norton for breast. In neurodegenerative disease, PU-AD has demonstrated highly compelling results in in vitro and animal models, with initial clinical study focused on Alzheimer’s .”

Expanded Clinical Program Announced

Samus Therapeutics was established as an LLC in concert with Memorial Sloan Cancer Center (MSKCC) by Dr. Norton and Gabriela Chiosis, PhD. When Lewis joined the venture in 2016, the company entered into a new and expanded licensing agreement with MSKCC to restructure and reorient its strategy, operations, and staffing. It also expected to accelerate clinical development of its anti-epichaperome small molecule platform. In April 2017, Samus Therapeutics announced the launch of an expanded clinical development program.

“Our path forward in both of these disease areas is being driven by cutting edge research out of the Chiosis lab focused on elucidating where and how epichaperome targeting can be most effective,” states Lewis. “In cancer, this research has been highlighted in a seminal publication in the journal Nature, with our clinical strategy following early results from a Memorial Sloan Kettering-directed Phase 1 study in solid and liquid tumors that, among other promising results, included two durable responses in patients with myelofibrosis who had stopped responding to  the clinically and commercially successful therapy ruxolitinib.”

A  Phase 1 study of PU-H71 under a MSKCC IND established a maximum tolerated dose with early clinical activity in both solid and liquid tumors to guide further study. The study also found PU-H71 PET was a useful biomarker.  . In February 2017, the company filed its IND for the study of PU-H71 in pancreatic cancer and has an agreement on the initiation of a MSKCC-sponsored Phase 1b advanced breast cancer trial. The Company expects to file an IND in the near future for its myelofibrosis trial based on data from the  Phase 1 study where two myelofibrosis patients who stopped responding to  ruxolitinib subsequently stayed on PU-H71 for more than 24 months in combination with ruxolitinib.  This phase 1b  trial  presents an opportunity for accelerated development and fast track approval for use with ruxolitinib whose sales already surpass $1 billion.  All three trials are expected to provide early data in 2018 to guide further advanced clinical study.   

In neurologic diseases, a new paper from the Chiosis Lab  has been submitted outlining its preclinical work for publication. In the clinic, PU-AD-PET, the biomarker for PU-AD, is being studied in a Phase 1 trial for brain cancer and neurodegenerative disease.   Lewis notes Samus is also exploring further studies in Alzheimer’s, brain concussion injury populations and traumatic brain injury under the direction of Dr. Geoffrey Ling, a neurologist at the Department of Defense, Department of Veterans Affairs and the Defense Advanced Research Projects Agency.

“From a strategy perspective, one of the greatest challenges is tackling the tremendously broad potential of epichaperome inhibition in two of the most consequential disease areas in modern medicine, and focusing in on the opportunities with the greatest potential for value creation for all our stakeholders,” adds Lewis. “To that end, we are looking at options for taking on an extensive clinical program, including raising additional capital and establishing pharma partnerships.”