While the efficacy benefit of peroxisome proliferator-activated receptor gamma (PPARγ) activating agents has been well established in clinical practice, the side effects including weight gain, fluid retention, and increased risk of heart failure are a serious concern and have limited the clinical utility of existing PPARγ agonists.

In terms of its structural development and molecular biology, INT131 was carefully designed de-novo to antagonize PPARγ full agonist side effect activities using an approved TZD as the target. The overall program objective was to develop a moiety which would have the desirable biological/clinical profile of strong efficacy with minimal or no side effects of the PPARγ full agonists.  A scientifically rigorous, multi-year effort brought forth INT131. There is strong, consistent data at each stage of INT131’s development that this effort was successful and that the scientific intent for the molecule is being realized.

In chronic nonclinical studies, achievement of the targeted product profile has been validated for safety both in rodents and non-human primates. In animal disease models, INT131 achieves a high level of efficacy for desirable anti-diabetic actions but has low or no activity for other receptor mediated side-effects such as edema and adipogenesis.  In humans, proof-of-concept Phase 2a data indicate the targeted profile can be achieved. The strategy is to develop INT131 through Phase 3 ready.

PPARγ full agonists activate changes in expression across a large set of genes, with some responsible for desirable anti-diabetic efficacy and others for undesirable side-effects.  Therefore, side-effects are linked with efficacy, resulting in an undesirable, compromised clinical profile. Furthermore, it has been well established that side effects are correlated with the breadth of PPAR activity, with greater activity corresponding to greater propensity for side effects.

With an understanding of the inherent limitations of full PPARγ agonism in mind, INT131 was developed using a strategy to design a selective PPARγ modulator that could bind to the receptor with high affinity but not activate the full spectrum of PPARγ activities (selective modulator).  Such a designer molecule would thereby retain the antidiabetic actions of PPARγ full agonists but eliminate crippling side effects.

There is strong precedence for the success of this modulator approach for another nuclear receptor: both tamoxifen and its successor raloxifene are selective estrogen receptor modulators (SERMs) that are designed to optimize the therapeutic actions of estrogen receptor activation while minimizing the side effects. As a genuine SPPARM, INT131 acts in a context dependent manner (depending on the tissue and the environment) to alter expression of a subset of the PPARγ genes, and is thereby able to separate therapeutic benefits from unwanted side effects. INT131 is not a TZD and thus represents a new chemical class of PPARγ ligands. 

INT131 is a high potency selective PPARγ modulator.    INT131 binds to PPARγ with a potency of ~10 nM, which makes it >20-fold more potent than either rosiglitazone or pioglitazone.  Characterization of binding beyond potency reveals the efficacy for INT131 for inducing PPARγ receptor activities.  In cell-based reporter assays designed to detect full agonist activity, INT131 activates PPARγ with a maximal activity of only 5-10% of that of rosiglitazone (Figure 1, left).  Similarly, in fluorescence resonance energy transfer assays, INT131 causes recruitment of selected coactivators with a maximal activity of about 10% of that of rosiglitazone (Figure 1, right).

Figure 1.  INT131 is a potent selective PPARγ modulator.  Left panel.  Cell-based reporter assays were performed with increasing concentrations of INT131 (green line) and rosiglitazone (black line).  Right panel.  Fluorescence resonance energy transfer (FRET) assays were performed with PPARγ and a fragment of the coactivator DRIP205 in the presence of increasing concentrations of INT131 (blue line) and rosiglitazone (black line).

INT131 does not promote adipocyte differentiation in-vitro: Consistent with its high potency/low activity profile in the full agonist cell-based reporter and FRET assays, INT131 causes virtually no adipocyte differentiation or triglyceride accumulation in human and mouse pre-adipocytes in vitro (Figure 2).  Moreover, INT131 blocks most of the potent effects of rosiglitazone to promote fat cell differentiation (data not shown). Thus, INT131 has the desired, non-adipogenic profile.

Figure 2.  INT131 does not promote adipocyte differentiation.  Human (left panel) or mouse (right panel) preadipocyte cells were treated with INT131 or rosiglitazone and lipid accumulation was measured.  In the right panel, INT131 is the red line and rosiglitazone is the black line.

Animal models show a progression in development of PPARγ full agonist induced side effects predictive of clinical experience and thus are of great utility in understanding the underlying mechanisms and in characterizing new compounds.  It is well established that the fluid retention seen in animal models is predictive of this side effect in the clinic and the subsequent cardiac effects seen in animal models are also thought to translate to humans. Plasma volume expansion is manifested by a decrease in hematocrit, typically with onset within the first months of TZD treatment of patients or in animal models. Consistent with this side effect are secondary increases in heart size and heart weight, observed in animals. Longer exposures are marked by cardiac hypertrophy and sometimes death in a dose and time dependant fashion

INT131’s ability to separate PPARγ mediated therapeutic efficacy from full agonists’ undesirable side effects is offered by comparison safety data from studies conducted in rats. Treatment of rats with pioglitazone results in edema and cardiac hypertrophy in 3 months at exposures 6 fold higher than human efficacious exposure levels while INT131 was not associated with these effects at exposures two orders of magnitude higher than human efficacious exposures over 6-months. Chronic nonhuman primate studies have also showed high multiples. The safety margin in healthy animals is consistent with the separation of therapeutic effects from side effects observed for INT131 treatment of rodent models of diabetes.

TZD-induced peripheral edema which frequently occurs in patients receiving TZD therapy is especially problematic in patients receiving concomitant insulin therapy. It is of special concern for patients who have heart disease and cannot tolerate the extra fluid volume. In addition, there is strong evidence that activation of PPARγ in fat causes adipocyte differentiation and contributes to the undesirable weight gain.  As a consequence, these drugs are not recommended for patients with New York Heart Association Class III and IV heart failure.

INT131 has demonstrated the ability to achieve the target product profile in a Phase 2a proof-of-concept study performed in patients with T2DM. Results are planned to be presented at upcoming scientific forums and subsequently published.

The INT131 clinical development plan is directed at translating these findings to establishing a novel treatment for T2DM patients offering greater safety than is currently available to control their disease.