By Melane Sampson
Closely held Pacylex Pharmaceuticals is developing a first-in-class oral cancer therapy with a novel, broad mechanism of action designed for refractory cancers as both a monotherapy and a future combination therapy.
“Despite major advances in cancer care, fewer than one-third of patients with acute myeloid leukemia (AML) survive five years after diagnosis,” Michael J. Weickert, PhD, CEO of Pacylex, says in an interview with BioTuesdays.
“Our lead drug candidate, zelenirstat, has demonstrated the ability to eliminate leukemia and lymphoma tumors and inhibit lung and breast cancer tumors in multiple animal models, including drug-resistant patient-derived tumor models. We have conducted two Phase 1 studies in heme and solid tumor cancers and are now working to bring this new medicine into the next stage of clinical development in multiple indications.”
He explains that Pacylex is focused on inhibiting N-myristoyltransferase, or NMT, a biological pathway not previously targeted in cancer therapy of any other disease. Myristoylation is a post-translational modification that enables proteins to attach to cell membranes and participate in signaling pathways essential to cancer-cell survival, proliferation, angiogenesis, and energy production.
By interrupting this process, NMT inhibitors may simultaneously disrupt several core cancer mechanisms. According to Dr. Weickert, this multi-pathway effect could help overcome one of oncology’s greatest challenges—drug resistance.
“It turns out that cancer cells repurpose many myristoylated proteins to support uncontrolled growth and proliferation,” he says. “When you inhibit myristoylation, cancer cells are far more vulnerable than normal cells because multiple cancer-driving pathways are disrupted simultaneously.”
Pacylex’s lead candidate, zelenirstat, is an orally available small molecule optimized for NMT inhibition and designed as a once-daily therapy. The company believes the convenience of oral dosing, combined with a potentially favorable safety profile, could provide a significant competitive advantage.
“We believe zelenirstat has substantial potential because it is a once-a-day oral pill with a mechanism that appears both potent and well tolerated,” Dr. Weickert contends.
The company originated as a diagnostics venture investigating adenosyltransferase enzymes as cancer biomarkers. After generating evidence suggesting these enzymes could also represent therapeutic targets, Pacylex licensed a portfolio of more than 500 small-molecule inhibitors from the University of Dundee. The compounds had originally been developed for African sleeping sickness before being abandoned.
From that portfolio, Pacylex selected zelenirstat as its lead program and transitioned into a clinical-stage oncology company.
Dr. Weickert points out that zelenirstat has completed a Phase 1 dose-escalation study involving 29 heavily pretreated patients with advanced solid tumors and lymphoma. Most participants had failed four prior lines of therapy before entering the study.
Although the trial’s primary objective was safety, the company observed signs of efficacy at higher dose levels.
“This was the first time an NMT inhibitor had ever been administered to humans, so establishing safety was the priority,” Dr. Weickert says. “What surprised us was the degree of durable stable disease we observed at the higher doses.”
He adds that patients receiving doses between 20 mg and 210 mg experienced relatively limited toxicity. The most significant adverse events were gastrointestinal and included mild nausea and vomiting. Importantly, Pacylex did not observe many of the toxicities commonly associated with chemotherapy, such as neutropenia, alopecia, arrhythmias, renal toxicity, or severe skin reactions.
At the 210 mg dose level, four of seven patients remained on therapy for at least six months, several remained on treatment for eight months, and one patient continued treatment for approximately 18 months.
“It was remarkable to see progression-free survival improve by roughly 140% in a study not designed to demonstrate efficacy,” Dr. Weickert says. “We also observed statistically significant improvements in overall survival.”
Pacylex is now prioritizing AML, particularly in combination with venetoclax, the backbone therapy used in many AML regimens.
Dr. Weickert emphasizes that venetoclax has become a major commercial product in leukemia treatment, generating billions in annual sales. However, resistance typically emerges within 15 to 18 months, leaving relapsed patients with poor survival prospects.
“One-third of AML patients never respond to venetoclax-based therapy, and most responders eventually relapse,” he says. “Median survival after resistance develops is often only one to three months.”
Pacylex believes zelenirstat may address several resistance mechanisms simultaneously. The drug’s effects on mitochondrial function and oxidative phosphorylation may counteract metabolic adaptations associated with venetoclax resistance.
“There are multiple biological pathways through which venetoclax resistance emerges,” Dr. Weickert says. “What is exciting is that zelenirstat appears to inhibit many of those pathways at the same time.”
The company has also observed strong synergy between zelenirstat and venetoclax in AML cell-line studies. “Both drugs target mitochondrial biology through complementary mechanisms,” he explains. “Together they generate a much stronger apoptotic signal than either drug alone.”
Pacylex recently completed enrollment and dosing in an AML study conducted at MD Anderson Cancer Center in Texas. According to Dr. Weickert, all patients treated at the 140 mg dose level achieved stable disease, while one patient at the 210 mg level achieved a complete response.
“That was our first complete response, which was very encouraging,” he says.
The company now plans to advance a lower-dose combination regimen of zelenirstat and venetoclax into a multicenter Canadian Phase 2 study targeting relapsed or refractory AML patients who have progressed on venetoclax-containing regimens.
The planned trial will enroll 20 patients and is designed to demonstrate that zelenirstat can restore sensitivity to venetoclax. Pacylex believes even modest response rates could be clinically meaningful in this highly refractory patient population.
“No approved mutation-agnostic therapy currently delivers meaningful responses in venetoclax-refractory AML,” Dr. Weickert says. “We believe zelenirstat attacks biology that existing therapies do not address.”
The company estimates the planned multicenter Canadian Phase 2 study will require approximately $7 million in financing and could generate primary analysis data within 12 months, including regulatory approvals, patient enrollment, dosing, and initial response assessments. Dr. Weickert notes that conducting the study in Canada also provides access to non-dilutive government research tax credits, helping extend the impact of invested capital.
“The feedback from investors and strategic partners has been consistent—they want to see Phase 2 data,” Dr. Weickert says. “This combination study represents our fastest path to generating that data.”
Pacylex believes the program could potentially support an accelerated regulatory pathway if results are sufficiently compelling.
The company is currently pursuing funding through a combination of strategic pharmaceutical partnerships, institutional investors, venture philanthropy, and mission-driven capital sources.
According to Dr. Weickert, successful results from the study could position Pacylex for larger partnering discussions, Series B financing, or potential acquisition interest from pharmaceutical companies developing next-generation AML therapies.
“We believe this study could become a major value inflection point for the company,” Dr. Weickert says. “If we demonstrate the ability to overcome venetoclax resistance in relapsed or refractory AML, that would represent a highly differentiated clinical outcome in a patient population with very limited treatment options.”
Pacylex also believes the program may offer a relatively rapid regulatory pathway. Under current FDA guidance, a successful open-label Phase 2 study in venetoclax-refractory AML could potentially support accelerated approval discussions while confirmatory Phase 3 studies are conducted.
Beyond AML, the company is exploring additional applications for zelenirstat, including checkpoint inhibitor sensitization, radiosensitization, and antibody-drug conjugates.
In preclinical studies, combining zelenirstat with checkpoint inhibitors such as Keytruda restored sensitivity to immunotherapy in head and neck cancer models. “If we can restore sensitivity to immune checkpoint inhibitors, that represents a multi-billion-dollar opportunity,” Dr. Weickert asserts.
Pacylex is also investigating zelenirstat as a radiosensitizer in glioblastoma, where preclinical studies suggest it may outperform currently available radiosensitizing agents.
In addition, the company is pursuing partnerships involving antibody-drug conjugates, or ADCs, an increasingly important oncology treatment category. “ADCs currently rely on only a few highly toxic payload classes,” Dr. Weickert says. “There is enormous interest in identifying new payload technologies.”
Pacylex recently reported preclinical data generated with Heidelberg Pharma (FSE: HPHA) showing that ADC-linked zelenirstat increased potency against solid tumors by between 20-fold and 1,000-fold.
Looking ahead, Dr. Weickert says the company sees potential applications beyond oncology, including antiviral, inflammatory, and autoimmune diseases.
“No one has ever targeted this biology clinically before,” he concludes. “We believe we are only beginning to understand the full potential of this platform. Overcoming venetoclax resistance addresses a growing unmet need in AML as use of venetoclax-based regimens continues to expand globally.”
Editor’s Note: This article does not constitute an offer to sell or the solicitation of an offer to buy any securities of Pacylex Pharmaceuticals, and shall not constitute an offer, solicitation or sale of any security in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
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