"We've finally pushed open a door to an entirely new pathway of potential approaches to treat cancer," Walter Klemp, chair and CEO of Moleculin Biotech Inc., said about the initiation of an investigator-led phase I study of STAT3 inhibitor WP-1066 in glioblastoma at MD Anderson Cancer Center. "People have been pounding on this door for a long time, and it was painful getting here, but now it's opened."
Indeed, signal transducer and activator of transcription 3 (STAT3) is a promising but notoriously challenging target for cancer therapeutics, with fewer than 20 efforts in the clinic and no approved therapies. The only STAT3 inhibitor so far to advance to phase III is napabucasin from Boston Biomedical Inc., a 2006 spin-out from Arqule Inc. and now a subsidiary of Sumitomo Dainippon Pharma Co. Ltd., but three of its late-stage trials were terminated early for futility. (See BioWorld Today, March 1, 2012, and June 27, 2017.)
Meanwhile, dozens of STAT3 hopefuls remain in discovery or sit idle, according to Cortellis Competitive Intelligence. With little interest from pharma or big biotech, attempts to tame STAT3 have largely remained the domain of academic researchers – more than two dozen institutions have a stake in the STAT3 game – and small biotechs like Houston-based Moleculin.
But a breakthrough by a company like Ionis Pharmaceuticals Inc., which has multiple phase II studies of danvatirsen (AZD-9150, IONIS-STAT3-2.5Rx), a STAT3 gene inhibitor, ongoing – in combination with MEDI-4736 (tremelimumab, Astrazeneca plc) – in head and neck, non-small-cell lung and colorectal cancers and lymphoma, could crack the field wide open. (See BioWorld Today, Dec. 12, 2012, and Nov. 25, 2015.)
The STAT3 gene encodes a transcription factor that plays a critical role in mediating cytokine-induced changes in gene expression but has been hard to target with traditional small-molecule approaches. By targeting STAT3 mRNA with its 2.5-generation antisense oligonucleotide (ASO), Ionis showed tumor regression in several cancer models before moving into a phase I dose-escalation study that also produced evidence of antitumor activity in several patients. They included a diffuse large B-cell lymphoma patient whose response lasted for more than a year, and a non-small-cell lung cancer patient.
WP-1066's road to the clinic wound through more than a decade of preclinical experiments following its discovery by Waldemar Priebe, professor in the department of experimental therapeutics at MD Anderson and founding scientist at Moleculin, where he chairs the scientific advisory board.
STAT3 was long considered a "Holy Grail" cancer target, Klemp said, "but no one was able to target STAT3 directly," he said, forcing researchers, instead, to target the receptors. That approach led to yet another challenge, since "STAT3 can be up-regulated by any one of more than half a dozen upstream receptors and even some non-receptor pathways. If you actually try to block all of the receptors and pathways that could result in STAT3 activity, you end up killing the patient because those receptors also are necessary for normal, healthy cell function."
The hurdles rebuffed many early efforts, according to Klemp. But Priebe found another way by designing WP-1066 to inhibit phosphorylated STAT3, or p-STAT3, rather than focusing on upstream effectors of the pathways, such as growth factors, cytokines and kinases. Built from the chemical backbone of the active ingredient in propolis, a natural product of honey bees, WP-1066 is part of a portfolio of drugs with more than 700 analogues. The compound directly attacks tumor cells and is believed to indirectly stimulate the immune system, increasing a patient's natural ability to fight tumor development.
"As far as we know, this is one of the first compounds that more directly inhibits the activated form of STAT3 and doesn't care about the upstream effect," Klemp told BioWorld. "That gives us the opportunity to target STAT3 much more aggressively and effectively without the risk of a whole bunch of toxic side effects."
'We have to find another way'
Although Moleculin considers WP-1066 "a scientific breakthrough in several categories," Klemp said, the company's findings have been shown, so far, only in preclinical models, although those encompassed a wide range of tumor cells and were replicated by multiple institutions, giving the compound "a strong pedigree." The phase I, though primarily a safety study, gives the company its first opportunity to see if the compound shows evidence of down-regulating STAT3 in humans and produces the expected tumor-fighting effect.
The trial will enroll up to 33 patients, including up to 15 in a dose-ranging component, followed by an expansion cohort at the maximum tolerated dose. Secondary endpoints include overall response rate, measured every eight weeks, and progression-free survival, according to Cortellis.
Although the timetable is dictated by MD Anderson, Moleculin hopes to see data on the initial cohort by mid- to late-2019.
Glioblastoma was selected because of the interest and experience of MD Anderson scientists and $2 million in private grant support on top of two Specialized Programs of Research Excellence, or SPORE, grants from the National Cancer Institute. Nevertheless, the deadly brain cancer, which recently claimed the life of former Sen. John McCain, is an ideal setting to study WP-1066, Klemp said.
"STAT3 is up-regulated in some of the most aggressive tumors, which includes glioblastoma," he pointed out. "If you have an ability to target STAT3, it's natural to go after those tumors. For us, it's a bit of a bonus that we're starting in a disease area that has such a tremendous unmet need."
Importantly, the second cohort will include individuals with recurrent malignant glioma pre-dosed with WP-1066 14 (+ 3) days prior to surgery. Those participants also will be imaged prior to treatment with WP-1066 and within 72 hours of resection, enabling researchers to see how much drug was delivered and to what tissue.
The fact that WP-1066 has taken more than a decade to enter the clinic doesn't work against it, Klemp maintained, since, during that time, "there's been virtually no advancement in the standard of care for brain tumors."
Moleculin has a second, preclinical STAT3 entry, WP-1732, that's envisioned as a potential candidate to treat pancreatic cancer. But Klemp expects more traction in the short term with annamycin, an anthracycline in development to treat relapsed or refractory acute myeloid leukemia, and WP-1122, the lead candidate in a category of 2-deoxy-D-glucose prodrugs also targeting cancer. All of the company's prospects are based on discoveries at MD Anderson.
Once the IND for WP-1066 was opened earlier this year, Moleculin also was approached by other academic institutions to conduct trials in rare pediatric cancers, including diffuse intrinsic pontine gliomas. Those studies are preparing to proceed to the clinic.
The company has raised $30 million since going public, including a 2016 micro-IPO that raised $12 million. Klemp didn't offer specific guidance on prospects for an additional offering but admitted "we use every tool in the toolbox to keep funding rolling in." (See BioWorld Today, May 5, 2016.)
With several trials now underway, "we see a fair amount of data beginning to roll off that activity," he said. "Our intent is to use the encouraging data that may emerge from any of these trials as inflection points to bring in additional dollars."
Immuno-oncology has "sucked all of the air out of the room" in cancer therapeutics and has made impressive strides in certain tumors, but not those in the brain, Klemp said.
"Sooner or later, common sense says we have to find another way," he said. "We can't keep trying to do the same things over and over and expect a different result. We have to take a different approach. Targeting STAT3 is a radically different approach for the treatment of brain tumors."