SynDevRex, a clinical-stage biotechnology company, released safety and tolerability data from a Phase I dose-escalation study (NCT02743637) of SDX-7320, a novel polymer-drug conjugate in which an HPMA Polymer backbone is covalently linked to a novel small-molecule fumagillol* derivative payload via an enzymatically cleavable linker.

Polymer-drug conjugates or PDCs represent a novel nanodrug delivery approach in which hydrophilic polymers are covalently linked to a payload of drug molecules through linkers that are biologically active. This class of agents shows high drug loading, sustained release of the payload, and high stability compared to other nanocarriers in which drug molecules are encapsulated.

Preclinical studies have shown that SDX-7320 reduces tumor growth and angiogenesis which helps to control aberrant metabolic hormone signaling and reduces treatment resistance to certain standard cancer therapies in metabolically sensitive cancers. SDX-7320 is being developed for use in combination with standard of care therapies for a variety of solid tumors.

Overweight, obesity and cancer
Hormones such as leptin, insulin, estrogen [1], and inflammatory cytokines including IL6, TNF-α [2] are known to promote cancer progression. SDX-7320 acts at the physiological level to systemically decrease the levels of these hormones and cytokines while also targeting the tumor microenvironment.

SDX-7320 acts by binding irreversibly and inhibiting methionine aminopeptidase type 2 (MetAP2), an enzyme that is over-expressed in multiple tumor types and is considered a clinically validated target that appears to play a key role in tumor growth, metastasis, angiogenesis, and metabolic dysfunction. [3]

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Metabolic dysfunction, which is typical in overweight and obese people, has been shown to predispose people to get certain types of cancer. Growing data seems to suggest a strong association of metabolic dysfunction with the development of cancer and cancer-related mortality.

Adipose tissue, connective tissue consisting mainly of fat cells, is primarily found under the skin but also in deposits between the muscles, in the intestines and in their membrane folds, around the heart, and elsewhere, is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Hence, excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of pro-inflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects.[4]

Some research suggests that in metabolic dysfunction and cancer association, insulin resistance and insulin-like growth factor 1 system play a key role, especially adipokines secreted from visceral adipocytes, free fatty acids and aromatase activity contribute to this process. Additionally, it is also suggested metabolic dysfunction has a direct link with colorectal, breast, endometrial, pancreas, primary liver, and, although controversial, prostate cancer and that cancer patients who are overweight or obese have higher cancer mortality rates than their metabolically normal counterparts.[5]

MetAP2 inhibition has been clinically shown to improve the regulation of key metabolic hormones known to stimulate cancer cell proliferation, migration, and metastasis. By inhibiting MetAP2, SDX-7320 triggers improvements in the metabolic hormones, insulin, leptin, and adiponectin. Additionally, the investigational agent also inhibits the angiogenic proteins bFGF and VEGF, and in preclinical studies, inhibited multiple cell cycle signaling pathways and reversed immune suppression within the tumor micro-environment.

An emerging field of research
Metabo-oncology is the emerging field of research into, and treatments for cancer patients with tumors that are sensitive to metabolic hormones. Many common cancers are highly sensitive to dysregulated metabolic hormones stemming from overweight/obesity, pre-diabetes (hyperinsulinemia), type 2 diabetes (T2DM), and metabolic syndrome.

More than 600,000 patients in the United States alone are diagnosed each year with tumors that fit this category, yet little attention is given to the influence of systemic metabolic dysfunction on cancer progression. While diet and exercise can be effective at mitigating these effects, patients undergoing cancer treatment often find it difficult to adhere to these regimens.

Phase I study
Available data from the Phase I dose-escalation study designed to assess the safety and tolerability of subcutaneously administered SDX-7320 in patients with advanced refractory or late-stage solid tumors (NCT02743637), suggest that the investigational drug slows the rate of disease progression and formation of new metastases in late-stage patients with progressive, metastatic solid tumors.

In preclinical models, SDX-7320 has demonstrated a superior safety profile — along with metabolic and oncologic efficacy at lower doses and with reduced dosing frequency than other fumagillin-class MetAP2 inhibitors.

Exploratory endpoints further suggest that SDX-7320 may induce favorable changes to insulin and insulin resistance and other key metabolic hormones (leptin, adiponectin) as well as to multiple angiogenic biomarkers. [1]

SDX-7320 may also stimulate weight loss, which is associated with significant reductions in leptin and insulin, in obese mice. The corresponding improvements in insulin resistance and in other elements of systemic metabolic dysfunction have been shown to inhibit tumor growth and metastasis in experimental models of breast cancer and melanoma.

Primary endpoint
The primary endpoint of the phase I study with SDX-7320 was to establish the maximum tolerated dose (MTD) and dosing schedule and the recommended Phase II dose for the investigational drug. [5] Secondary and exploratory endpoints included analysis of anti-tumor efficacy and changes in key angiogenic and metabolic biomarkers.

The phase I study evaluated data from 32 patients, whose disease progression and new lesion formation were measured at intervals of every 2 months from the initiation of treatment. Exploratory changes from baseline to metabolic hormones were measured, including leptin and adiponectin, as well as changes to insulin levels and insulin sensitivity (HOMA-IR). Exploratory changes from baseline to angiogenesis biomarkers bFGF, VEGF, and IGF-1 were also evaluated.

A total of 28 patients had at least one tumor burden assessment performed, of whom 21 (75%) had at least one stable disease determination before leaving the study or experiencing progressive disease. Of these 21 patients, the period of measurable stable disease averaged 85 days. There were no objective partial or complete responses.

Potent anti-angiogenic activity
“The results of our Phase I trial suggest that SDX-7320 may have potent anti-angiogenic activity appears to induce favorable changes to insulin, leptin, and adiponectin has a safety profile that supports future combination studies. These data provide us with the scientific rationale for future clinical studies in tumors that are sensitive to metabolic hormones, i.e., metabo-oncology,” noted Brad Carver, President and Chief Executive Officer of SynDevRx.

“Animal data we previously presented at the San Antonio Breast Cancer Symposium in 2019 showed that SDX-7320 attenuated the hyperglycemia and hyperinsulinemia caused by the PI3K inhibitor alpelisib, and showed synergistic tumor growth inhibition in mice,” he added.

“Considering the aforementioned data together with this clinical data, we believe SDX-7320 could provide real benefit to breast cancer patients taking a PI3K inhibitor. We expect to open enrollment for our upcoming clinical trial in metastatic ER+/Her2- breast cancer patients with a mutation in the PIK3CA gene early next year, followed by additional trials focused on triple-negative breast cancer and prostate cancer, tumor types that are highly sensitive to systemic metabolic dysfunction,” Carver concluded.

Study design
SynDevRx’s Phase I dose-escalation study was designed to assess the safety and tolerability of SDX-7320 in patients with advanced refractory or late-stage solid tumors (lung, colon, breast, rectal, pancreatic, appendiceal, carcinoid, cholangiocarcinoma, cervical, endometrial, hepatocellular, and urothelial cancers). [6]

Patients were a mean age of 66 years old and had progressed following five prior lines of treatment for their metastatic disease, on average.

In the study, SDX-7320 was administered subcutaneously at doses ranging from 1.7–65 mg/m2 and induced primarily mild side effects including fatigue, GI symptoms (nausea, abdominal pain, diarrhea), and anemia. The dose-limiting toxicity event, thrombocytopenia, was generally reversible without intervention and was observed only at the highest doses tested. Results of the study suggest that the dose of SDX-7320 at 49 mg/m2 on a once every two weeks (i.e., Q14D) schedule may be appropriate for future studies. [6]

“Many solid tumor types are highly sensitive to dysregulated metabolic hormones, such as insulin, leptin, or adiponectin. These hormones signal through known oncogenic pathways, like PI3K/Akt/mTOR or STAT3. Given the epidemic of metabolic syndrome in the world plus the frequency of tumors that are sensitive to metabolic hormones (e.g., breast and prostate cancers), we believe that SDX-7320 could help clinical oncologists treat their cancer patients with concomitant, systemic metabolic dysfunction in combination with standard-of-care therapies,” observed James Shanahan, Co-Founder and Chief Business Officer of SynDevRx.

SynDevRx expects to commence enrollment for clinical studies in breast and prostate cancers that will test whether SDX-7320, when added to standard-of-care treatment, will help these patients more than standard-of-care treatments alone. The first study is in 2nd line metastatic ER+/Her2- breast cancer patients with a PIK3CA mutation, in combination with the PI3Kα inhibitor alpelisib (Piqray®; Novartis).*

The company intends to initiate a series of clinical studies including SDX-7320 to specifically address the unmet medical needs for cancer patients with metabolic complications, such as obesity, diabetes, high blood glucose or HbA1c, pre-diabetes, or insulin resistance. For certain tumor types, metabolic hormones stimulate oncogenic pathways, making cancer more aggressive and deadlier.

Note
* Fumagillin is a naturally occurring metabolite from the fungus Aspergillus Fumagatus fresenius with potent anti-angiogenic and anti-metabolic effects.
** Alpelisib is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

Clinical trials
A Dose Escalation Study of SDX-7320 in Patients With Advanced Refractory or Late-Stage Solid Tumors (SDX-0101) – NCT02743637

Highlights of prescribing information
Alpelisib (Piqray®; Novartis) [Prescribing Information]

References
[1] Schmidt S, Monk JM, Robinson LE, Mourtzakis M. The integrative role of leptin, oestrogen and the insulin family in obesity-associated breast cancer: potential effects of exercise. Obes Rev. 2015 Jun;16(6):473-87. doi: 10.1111/obr.12281. Epub 2015 Apr 15. PMID: 25875578; PMCID: PMC4691342.
[2] Tripsianis G, Papadopoulou E, Anagnostopoulos K, Botaitis S, Katotomichelakis M, Romanidis K, Kontomanolis E, Tentes I, Kortsaris A. Coexpression of IL-6 and TNF-α: prognostic significance on breast cancer outcome. Neoplasma. 2014;61(2):205-12. doi: 10.4149/neo_2014_026. PMID: 24299316.
[3] Warder SE, Tucker LA, McLoughlin SM, Strelitzer TJ, Meuth JL, Zhang Q, Sheppard GS, Richardson PL, Lesniewski R, Davidsen SK, Bell RL, Rogers JC, Wang J. Discovery, identification, and characterization of candidate pharmacodynamic markers of methionine aminopeptidase-2 inhibition. J Proteome Res. 2008 Nov;7(11):4807-20. doi: 10.1021/pr800388p. Epub 2008 Oct 2. PMID: 18828628.
[4]Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA. Obesity, Inflammation, and Cancer. Annu Rev Pathol. 2016 May 23;11:421-49. doi: 10.1146/annurev-pathol-012615-044359. PMID: 27193454.
[5] Uzunlulu M, Telci Caklili O, Oguz A. Association between Metabolic Syndrome and Cancer. Ann Nutr Metab. 2016;68(3):173-9. doi: 10.1159/000443743. Epub 2016 Feb 20. PMID: 26895247.
[6] Mita M, Bendell J, Mita AC, Gordon M, Sachdev J, Carver BJ, Shanahan J, Mayes B, Awerkamp K, Browning D, Salomon N, Sullivan K, Anderson-Villaluz A, Johnson J, Petersen JS, Turnquist DJ, Cornelius P. SDX-7320 elicits improvements in tumor-related and metabolic biomarkers: Results of a phase 1 dose-escalation study in patients with advanced refractory or late-stage solid tumors. Cancer Res 2020 (80) (16 Supplement). DOI: 10.1158/1538-7445.AM2020-CT153 (Abstract CT153)

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