FIELD OF INVENTION

The present invention relates to polymer-conjugated monomethyl fumarate derivatives, and related compositions that treat relapsing-remitting multiple sclerosis and psoriasis.

BACKGROUND OF THE INVENTION

Dimethyl fumarate (DMF) is the active pharmaceutical ingredient of Tecfidera®, a prescription medicine developed for the treatment of relapsing forms of multiple sclerosis (MS), (Tecfidera label) also termed “relapsing-remitting multiple sclerosis” (RRMS). (Gold et al., 2015). Delayed-release Tecfidera capsules were approved by the US Food and Drug Administration (FDA) in 2013 as a first-line oral treatment for RRMS. DMF is also effective against psoriasis and has been approved in Europe for that indication.

DMF has immunomodulatory, anti-inflammatory, and antioxidant properties that are effective in treating MS. It acts by activation of the Nrf2 pathway that induces expression of antioxidant proteins that protect motor neurons and astrocytes against oxidative stress (Scannevin et al., 2012). However, DMF has a very short half-life of 12 minutes after gastrointestinal absorption (Al-Jaderi et al., 2016). DMF is rapidly hydrolyzed by esterase in the gastrointestinal tract to monomethyl fumarate (MMF) prior to entering systemic circulation (eq. 1). The half-life of MMF in circulation is 36 hours (Al-Jaderi et al., 2016), with a Tmaxof about 2.5 hours (Bromprezzi et al., 2015). Thus, DMF is a prodrug of MMF, which is the active metabolite responsible for the pharmacological activity of DMF.


Mechanisms of Action

MMF has been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway both in vitro and in vivo in animals and humans (Scannevin et al., 2012). The Nrf2 transcriptional pathway is the main cellular defense system for responding to diverse potentially toxic stimuli, including inflammatory and oxidative stress. By activating this pathway, DMF/MMF reduces inflammatory responses and promotes neuroprotection in both peripheral and central nervous system.

Furmarates including DMF have been shown to be effective in the treatment of psoriasis, by diminishing IL-6 and TGF-α secretion (Ockenfels et al., 1998). DMF inhibits Janus kinas (JAK) signaling and interferes with intracellular protein trafficking. This inhibits the release of pro-inflammatory cytokines, such as IL-12, IL-23, and TNF, whereas the release of anti-inflammatory cytokines, such as IL-10, was increased (Al-Jaderi et al., 2016).

MMF crosses the blood brain barrier and dampens the neuro-inflammation in the central nervous system (Parodi et al., 2015). While studies have established that both DMF and MMF can elicit an antioxidant response in human astrocytes, the assessment of cellular viability under oxidative stress determined that MMF treatment resulted in less toxicity compared to DMF (Scannevin et al., 2012). The cytoprotective effects against oxidative stress of MMF was mediated via the Nrf2 pathway (Scannevin et al., 2012 and Linker et al., 2011). Various studies have identified similar anti-inflammatory, immunomodulatory, neuroprotective, antioxidant, anti-tumor and apoptotic effects for both DMF and MMF in various cell types (Al-Jaderi et al., 2016, Parodi et al., 2015, Linker et al., 2011). Although the mechanism of action of DMF and MMF may not be identical, MMF is the most bioactive metabolite of DMF and all the therapeutic effects of DMF in MS are mediated by MMF. MMF does not deplete glutathione or inhibit mitochondrial and glycolytic function making MMF a better drug. It has also been established that gavage administration of DMF in an experimental autoimmune encephalitis (EAE) mouse model showed a neuroprotective effect through modulation of microglial activation, a critical component of the immunomodulatory cascade in neurodegenerative diseases such as MS (Parodi et al., 2015). The active metabolite in this study was MMF.

Linker et al., 2011 and Scannevin et al., 2012 showed that fumarates exert neuroprotective effects dependent on Nrf2 mediated anti-oxidative pathways. In vitro, MMF-protected cultured neurons and astrocytes from H2O2induced cell death. This study found that MMF leads to direct modification of Kelch-like ECH-associated protein 1 (Keap1) at cysteine residue 151. It has been shown that activation of Nrf2 results from covalent modification of free cysteine residues in the Nrf2-binding adaptor protein Keap1 that targets Nrf2 for ubiquitin-mediated degradation leading to suppression of Nrf2 function. Modification of cysteine 151 by electrophiles renders Keap1 incapable of interacting with Nrf2 and thus leads to stabilization of Nrf2, its accumulation in the nucleus and activation of induction of Nrf2-dependent expression of antioxidant and cytoprotective genes.

Parodi et al. (2015) showed that an anti-inflammatory effect of MMF is caused by switching the molecular and functional phenotype of activated microglia from classically activated, pro-inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2). Activation of HCAR2 by MMF leads to deacetylation, and thereby inhibition of NF-κB via the AMPK/SIRT1 axis triggered by the increase in intracellular calcium. Blockade of HCAR2 with an anti-HCAR2 antibody reversed the effect of MMF on the relevant pathway, demonstrating that MMF signals through HCAR2 to modulate the expression of inflammatory molecules dependent upon NF-κB activation. This demonstrates a possible role of DMF and its metabolite MMF in neurodegenerative diseases such as MS.

Taken together, these studies, and others, demonstrate viable mechanisms by which fumarates, in particular the active metabolite MMF, can favorably alter the course of the disease process in MS. Because of the anti-inflammatory, anti-oxidant, and immune modulatory properties, fumarates have also been investigated for therapy of autoimmune conditions including psoriasis and inflammatory lung diseases like asthma, neuro-inflammatory and neurodegenerative conditions such as relapsing remitting and progressive forms of multiple sclerosis, Parkinson's disease, Alzheimer's disease as well as ischemic stroke for post-Ischemic recovery (Seidel et al., 2009, Strassburger-Krogias et al., 2014, Yao et al., 2016, Ahuja et al., 2016, Paraiso et al., 2018).

Side Effects of DMF/MMF

Tecfidera delayed release DMF capsules for oral administration has several deleterious side effects including, allergic reactions, progressive multifocal leukoencephalopathy (PML, a rare brain infection leading to death or severe disability), decrease in white blood cell count, and liver problems, in turn causing exhaustion, loss of appetite, abdominal pain, dark or brown (tea color) urine, and jaundice. The most common side effects are flushing and stomach problems such as fullness, bloating, diarrhea, upper abdominal cramps, flatulence, and nausea. The GI side effects can be severe and reached an incidence up to 38% for treatment groups in clinical trials (Bombrezzi et al., 2015).

In addition, the pharmacokinetics of oral delayed release DMF capsules has several problems. The Cmaxand AUC variations are large (Shiekh et al., 2013), and were also found to be undesirably variable particularly after food (Litjens et al., 2004).

Alternative Formulations

In view of the efficacy of oral DMF in RRMS, researchers have been working to find alternative formulations of DMF/MMF for the treatment of RRMS in an attempt to alleviate some of these harmful side effects. For example, Forward Pharma is developing a delayed release proprietary DMF formulation (FP187). Xenoport is developing an MMF prodrug, XP23829. Alkermes is developing ALKS8700, an MMF prodrug. However, these drugs may still cause significant side effects. For example, XenoPort reported that its XP23829 prodrug caused frequent gastrointestinal-related side effects during its phase 2 clinical trial.

SUMMARY OF THE INVENTION

In order to address the aforementioned shortcomings in the administration of dimethyl fumarate (DMF), including adverse events and highly variable pharmacokinetics on oral administration, the present invention provides polymer-conjugated monomethyl fumarate (MMF) derivatives and related compositions or formulations. For example, one or more embodiments of the invention relate to injectable PEGylated MMF derivatives that offer improved chemical and pharmaceutical properties compared to DMF or MMF alone for the treatment RRMS. The present invention comprises compounds of formula (I),


where R1may comprise PEG or other polymeric moieties. For example, R1may comprise repeating PEG units —(CH2—CH2—O)n—, wherein n=1-455. R1may also comprise other polymeric moieties of varying sizes and structures, for example, poly(glycolide), poly(lactic acid), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), or poly(lactic acid)-butanol.

One or more embodiments of the invention may also relate to pharmaceutical compositions, for example injectable pharmaceutical compositions, comprising polymer conjugated monomethyl fumarate according to formula (I). The invention also relates to methods of treating RRMS and psoriasis for example through controlled release injectable compositions of polymer conjugated MMF, thus avoiding local high concentrations of the drug within the gastrointestinal tract upon oral administration and reducing gastrointestinal side effects.

