FDA acceptance of the investigational new drug (IND) application for SM-88, a metabolic inhibitor that targets cancer cells, gave the green light to developer Tyme Inc., through wholly owned subsidiary Tyme Technologies Inc., to begin enrolling patients in a multicenter phase II study targeting breast cancer.

Tyme considers SM-88 a type of immuno-oncology drug, although with a different mechanism than the programmed cell death protein 1, or PD-1, programmed death-ligand 1, or PD-L1, and cytotoxic T-lymphocyte-associated protein 4, or CTLA-4, assets that have taken the industry by storm.

"We didn't start as pharma people," said Steve Hoffman, Tyme's co-founder, president and CEO. Indeed, the SM-88 inventor has a background in physics and electro-optics and has worked in the chemistry, aerospace and laser optics fields.

"I look at the world as being a collective of different ideas that people do effectively," Hoffman told BioWorld Today. "We realized we had something very important and we wanted to go forward and do it in the best way possible."

SM-88 is designed to penetrate only living cancer cells, where it introduces multiple mechanisms to kill them without toxic effects and without involving healthy body tissue. Although the exact mechanism of action remains unknown, SM-88 may induce the transfer of electrons in cancer cells that allow catalyzed external free radicals to react and stress them, creating an engineered metabolic response that results in decreased mucin defense to reactive oxygen.

Tyme has one issued and four pending patents on the technology, which essentially targets what Hoffman called "the path to manipulate what cancer eats in its first-line diet." SM-88 "denatures" that path in such a way that the mucin protective layer becomes compromised.

Hoffman called other immuno-oncology efforts "very, very valid," but added, "If mucin can be denatured, that makes it easier for the body to attack it – which our agent does – and, potentially, for other agents that are effective against cancer to become more potentiated."

A predecessor company, Luminant Biosciences LLC, previously demonstrated the promise of Tyme's approach. Luminant completed a single-center, open-label, proof-of-concept study for SM-88 in 30 late-stage cancer patients with relapsed or highly refractory disease, including individuals with breast, pancreatic and primary lung cancers as well as glioblastoma. The trial was conducted under an institutional review board (IRB)-sanctioned compassionate use protocol, Hoffman said.

In the study, patients received one to 10 cycles of treatment, each consisting of daily administration, five days per week, for six weeks, according to Cortellis Clinical Trials Intelligence. Results from 25 patients, published last year, indicated complete response was observed in two patients, partial response in three, stable disease in 18 and progressive disease in two. During cycle one, improvements were noted by nearly all subjects in Eastern Cooperative Oncology Group Performance Status, European Organization for Research and Treatment of Cancer Quality of Life and self-reported pain scores.

SM-88 was well tolerated, and drug-related adverse events (AEs) in cycle one were mild to moderate and self-limiting, with no therapy required, according to Cortellis. Most AEs occurred within the first cycle of treatment, with the exception of hyperpigmentation, which eventually occurred in all subjects.

For Tyme, the real excitement was that, nine to 10 months following treatment with SM-88, when most patients would have been expected to succumb to their disease, almost all were still alive.

"We realized we were on to something," Hoffman said.

The company continued to follow patients as long as the IRB could be renewed. Three years out, most patients from the trial were still alive, and only a single death was directly attributable to cancer that progressed.

'A STANDARD METABOLIC NATURE TO THE DISEASE'

Since Luminant was a self-funded venture, Hoffman and co-founder Michael Demurjian, chief operating officer, rolled the assets into New York-based Tyme, adding an experienced scientific and medical advisory board and otherwise conforming to guidelines established by the FDA for drug development companies to "hold the next round of clinical trials that we were going to do," Hoffman explained.

Tyme plans to complete a small pharmacokinetics study before moving into the phase II study around year-end.

Breast cancer was selected as the initial indication due to the "all too frequent" turn to surgery as the first and most promising treatment option, Hoffman said. "That's not to say that surgery isn't a good remedy from the standpoint of survival," he added. "But we wanted to offer other options."

In the proof-of-concept study, even BRCA-positive and triple-negative breast cancer patients showed responses, according to Hoffman. Based on those results, he expects a fairly rapid response in the phase II.

"We think in six to eight weeks after dosing begins, we're going to see some interesting changes that would be reportable and a decent data group" that might justify moving development "more expeditiously," he said.

The company also hopes to advance the agent either into multiple arms or additional phase II studies in other primary cancers – perhaps pancreatic or non-small-cell lung cancer – based on the premise that SM-88 weakens the defenses of the disease. "We believe there's a standard metabolic nature to the disease," Hoffman explained, "and if you can control and manipulate it – and in this case, we've created a molecule that does that effectively – you make it vulnerable to reactive oxygen or other free radical methods, in addition to making it reactive to other chemotherapies and modalities of care."

Based on its view of treating cancer as a chronic condition, Tyme sees plenty of opportunity for SM-88. To ramp up, the company recently completed a deal with the alternative investment group Global Emerging Markets, which raised $9 million for the company in return for an 18 percent ownership stake. As part of that deal, Tyme agreed to a reverse merger into one of Global's existing shell companies for a listing on Nasdaq. Following completion of due diligence, that deal cleared earlier this month, Demurjian said, giving Tyme ample cash to run the phase II breast cancer study, though he didn't rule out the possibility of an additional raise to fund studies in additional indications.

Tyme has about 10 employees and expects to grow modestly over the next year. As for the long term, the company plans to take its time evaluating options, from a joint venture or licensing deal with big pharma to a venture round or a run at the public markets.

"We have a number of entities reaching out to us, including companies in this vertical," Demurjian said. "We're exploring other options out there and leaving all of them open."

The immediate focus is on getting the phase II study under way and accruing data to guide future development.

"At the end of the day, it's really about putting out a new tool that oncologists can use," Hoffman said. "Whatever is the best way to get that tool into the market – into the hands that use it and the bodies that need it – is what will dictate our path."