XYone is a clinical-stage biopharmaceutical company focused on discovering and developing first-in-class therapeutic agents targeting MUC1-C oncoprotein.

MUC1 is encoded by a single transcript which undergoes auto-cleavage into two subunits that form a stable non-covalent complex.  The extracellular MUC1 N-terminal subunit (MUC1-N) is the mucin component which sheds from the cell surface and circulates in the blood stream. Early attempts at targeting MUC1 (particularly with antibodies) by other companies focused on this shed MUC1-N subunit and were ineffective. Therefore, there are currently no FDA-approved agents that target MUC1.

XYone has identified the “Achilles Heel” of MUC1, the MUC1-C subunit that signals proliferation and survival to the interior of the cell.  MUC1-C is an oncogenic protein that is aberrantly overexpressed in most human carcinomas and certain hematologic malignancies. XYone is developing agents that target this oncogenic transmembrane protein.

Why Target MUC1-C?

Endocrine Science

XYone is solving the problems present in the clinical treatment of hormonal disorders such as hypogonadism (Low testosterone condition), Hypothyroidism (Low Thyroxine condition) & other hormonal deficiencies. These typically. have therapeutic solutions that have poor delivery (pharmacokinetics) and almost no personalized or rational dosing. Through our research we are creating the first in class, programmable release, aqueous, nano/micro particle formulation for testosterone and other hormones where we can program the delivery to create solutions which go from the current one size fit all, empirical treatments to personalized, rational dosing regimens.

Our first focus is Testosterone & we are proud to announce that our work is being supported by NIH/SBIR grants and we are partnering with the leading institutions in the world to bring our research to the clinic including Brigham & Women’s Hospital, Mayo Clinic, Center for Disease Control, and Karolinka Institute and others.

Accurate measurement of Androgens

Definitive diagnosis and rational management of androgen disorders currently face a number of challenges.

Current methods for measuring free testosterone (fT) are technically challenging and inaccurate. The widely used direct immunoassay and tracer analog techniques for measuring fT have been shown to be significantly erroneous. Equilibrium dialysis, the reference method against which other methods are compared, is labor-intensive and cumbersome, and therefore has had limited clinical adoption. As an alternative, free testosterone can be computed from the total testosterone, SHBG, and albumin concentrations. Recently, Endocrine Society’s Expert Panel acknowledged the experimental problems in fT measurements and concluded that

“…the calculation of free testosterone is the most useful estimate of free testosterone in plasma…”

However, we have demonstrated that even the calculated fT values derived from the prevailing equations, based on linear law-of-mass action models or empiric equations, differ systematically from free testosterone measured by equilibrium dialysis by as much as 40%.

Our team has developed an accurate free testosterone determination method based on the fundamental discovery of testosterone partitioning. While examining the mechanistic origin of this systematic inaccuracy in free testosterone values using the linear model of SHBG:testosterone association, we discovered that the SHBG dimer exhibits conformational allostery in binding testosterone. Our TruT™ companion diagnostic, incorporating the correct parameters and non-linear dynamics in T:SHBG association has resulted in a framework for accurate determination of free testosterone values.

The TruT algorithm improves the accuracy of fT calculations, reducing the potential for misdiagnosis, and better informing providers when designing treatments.

Testosterone, like other hormones (estrogen, vitamin D), is a hydrophobic molecule with limited solubility in water/blood. Accordingly, nature has devised transport proteins that carry testosterone from the primary synthesis site (testes) to the target organs. In blood, testosterone is therefore partitioned into bound form (albumin and SHBG bound) and free fraction; free testosterone molecules enter the target cells and trigger signaling cascades. Therefore, accurate determination of free testosterone is central to definitive diagnosis of hypogonadism.

Circulating testosterone is bound tightly to the SHBG protein with high affinity and to albumin with substantially lower affinity; therefore, alterations in SHBG greatly affect free testosterone concentrations. SHBG levels are quite sensitive to overall health status and age. This has significant clinical implications; for example, two patients may produce equal amounts of total testosterone but one may express higher level of binding protein, lowering the free testosterone concentrations. Accordingly, if sole clinical marker for diagnosis is based on total testosterone, individuals with high binding protein levels will be misdiagnosed and not receive the necessary care. Therefore, accurate determination of free testosterone levels is central to definitive diagnosis of androgen related disorders.

Conditions that lower SHBG – obesity, type 2 diabetes, nephrotic syndrome, liver disease, hypothyroidism, use of androgens or glucocorticoids – can lower total testosterone levels to below the normal range, while free testosterone levels might remain within the normal range. In these instances, sole reliance on total testosterone to establish a diagnosis of hypogonadism could result in misclassification.

Conditions that increase SHBG – advanced age, hyperthyroidism, anticonvulsants, HIV infection, or polymorphisms in the SHBG gene – can raise total testosterone levels to well above 400 ng/dL and sometimes into the high-normal range, despite normal or even low free testosterone. Accordingly, the Endocrine Society recommends determination of free testosterone in the diagnostic evaluation of hypogonadism in conditions that alter SHBG levels to avoid misclassification in the diagnosis of hypogonadism.

Current diagnostics, including the most widely used tracer analog method, have been shown to be inaccurate and its use is not recommended. Equilibrium dialysis is widely considered the reference method but most care providers and commercial laboratories do not offer equilibrium dialysis assays due to operational complexities in performing the assay and difficulties automating the procedure. Recognizing the practical difficulties that clinicians face in obtaining accurate measurement of free testosterone by equilibrium dialysis, an expert panel of the Endocrine Society concluded that “…calculated free testosterone, using high quality testosterone and SHBG assays, is the most useful clinical marker”.

Our patent protected, novel TruT™ companion diagnostic framework provides accurate determination of free testosterone concentrations. This algorithm is based on experimental data demonstrating that testosterone’s binding to SHBG is a multi-step process involving an allosteric interaction between the two binding sites on the SHBG dimer. Estimates of free testosterone derived incorporating the allosteric coupling of SHBG monomers within the dimer provide accurate determination of free testosterone without systematic deviation from values obtained using equilibrium dialysis.

Ongoing development is focused around continued study and validation in common conditions characterized by altered binding protein concentrations. Further, the incorporation of estradiol interactions will allow for wider adoption in women where estradiol levels vary greatly across the menstrual cycle. Because hyperandrogenism in women is the second most frequent indication for free testosterone determination, understanding the competitive binding and displacement dynamics is important for proper diagnosis in both healthy menstruating women and women with hyperandrogenic disorders, such as PCOS.

Through collaborations and partnerships, the TruT™ platform presents a unique opportunity to aggregate large volumes of data and metadata across diverse populations, ultimately enabling deeper understanding of the basis of androgen disorders and other conditions.

Formulation Development

Problems with current androgen/hormonal therapies

Hormonal deficiency supplementations therapies are characterized by absence of improved formulations with optimal PK profiles and patient friendly dosing. Our first candidate is Testosterone replacement therapy (TRT).

Testosterone replacement therapy (TRT) is indicated for the treatment of androgen deficiency in hypogonadal men. The US Food and Drug Administration (FDA) has approved several testosterone formulations for the treatment of hypogonadism in men, including injectable testosterone esters, transdermal testosterone patch, transdermal testosterone gels and solution, buccal adhesive testosterone tablets, intranasal testosterone, and testosterone pellets & recently oral pills. However, each of these modes of testosterone delivery, has significant drawbacks.

A feature common to the currently available delivery methods is the high variability in bioavailable testosterone as patients vary between super- and sub-therapeutic levels. This results in undesirable side effects and high rates of treatment discontinuation. These side effects include large fluctuations in mood and sexual function. In addition, treatment-specific side effects are noted, such as inadvertent contact transfer associated with testosterone gel formulations; women and children are particularly susceptible to the significant side effects cross-contamination.

Thus, there is an unmet clinical need for improved formulations for testosterone replacement therapy (TRT). The limitations of the currently available testosterone formulations have stimulated tremendous interest in developing long-acting delivery systems that can provide uniform circulating levels of testosterone in the target therapeutic range.

nTc Nano/microparticle Formulation

To address the shortcomings of currently available testosterone formulations, the FPT team is in development of a (nTc) nano/microparticle formulation for sustained, consistent release. This novel next-generation formulation offers the promise of superior pharmacokinetics, uniform delivery of testosterone sustained for four weeks or greater, improved adherence, and treatment outcomes for patients seeking testosterone replacement therapy.

The nTc is a novel proprietary nanoparticle formulation that utilizes FDA approved biocompatible polymeric materials such as poly (lactic-co-glycolic acid), poly (lactic acid), poly (glycolic acid), poly-l- (glutamic acid), and amphiphilic components. This aqueous formulation eliminates the oil depot related adverse effects, and as shown in preliminary results, delivers testosterone uniformly without the burst release.

Personalization of Hormonal Treatments

We will be able to combine our research in both diagnostics as well as formulations to personalize the treatment of patients uniquely and precisely. Current clinical practice need multiple office visits as well as lab visits to empirically titrate the correct dosage for a patient. This process needs to be repeated regularly as patient condition changes over time and is a major contributor towards poor adherence and compliance by patients and resulting suboptimal clinical outcomes. We plan to develop personalized, finely calibrated dosimeters which will enable physicians to accurately determine the dosage for each individual.

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