Cutaneous T-Cell Lymphoma (CTCL) is an orphan disease with a high unmet medical need. Long-term efficacy of current treatment options is limited with intolerable side effects. The development of effective therapies for inflammatory and hyperproliferative dermatological diseases is challenging, and progress has been slow, leaving patients with few therapeutic options.
PIQUR Therapeutics lead compound, bimiralisib, has shown encouraging clinical activity and a manageable safety profile in preclinical in vitro and in vivo studies. The results of which support the current phase II, proof-of-concept study which is evaluating the safety, efficacy, and pharmacodynamics of topical bimiralisib in healthy volunteers and patients with CTCL. Similarly, PIQUR is currently investigating the anti-proliferative and anti-inflammatory activity of topical bimiralisib in mild to moderate plaque psoriasis as a proxy for other diseases with hyperproliferative and inflammatory components.
The phosphoinositide 3-kinase/mechanistic target of rapamycin (PI3K/mTOR) signaling pathway plays an important role in cell survival and cell growth. Aberrant activation of the pathway is commonly observed in many human cancers and dermatological inflammatory and hyperproliferative diseases. Therefore, molecules that specifically block these signaling pathways represent an important development in targeted therapies for dermatological disease with a high unmet medical need.
PIQUR set out to develop a compound with PI3K/mTOR dual activity. The rationale being that simultaneous inhibition of PI3K and mTOR, rather than one or the other, could potentially block or reduce the progression of lesions and benefit related inflammatory and hyperproliferative dermatological diseases.
The following list identifies hyperproliferative / inflammatory diseases in ongoing clinical studies with topical application of bimiralisib.
- Cutaneous T-Cell Lymphoma (ongoing Phase IIa study)
- Plaque Psoriasis (ongoing Phase IIa study)
Cutaneous T-Cell Lymphoma (CTCL)
The treatment of cutaneous T-cell lymphoma (CTCL), which includes its most common forms, mycosis fungoides (MF) and the aggressive variant known as Sezary syndrome (SS), has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. MF lesions often respond to skin-directed therapies like topical corticosteroids, mechlorethamine, carmustine and/or topical retinoids. However, long term efficacy of these therapies is limited, with potentially intolerable side effects, highlighting the need for new safe and effective skin-targeted therapy options. Psoralen and Ultraviolet A (PUVA) therapy is fairly efficacious but also has a high risk of side effects.
Several deregulated genes/proteins and signaling pathways have been associated with CTCL. Aberrant activation of the PI3K/mTOR signaling pathway has been confirmed in CTCL, including MF and SS variants. Therefore, dual PI3K/mTOR inhibition by topical bimiralisib holds the potential for a new treatment of CTCL.
Plaque Psoriasis (PPSO)
Topical products remain the mainstay of psoriasis treatment, including corticosteroids, vitamin D and retinoids, and can effectively treat mild to moderate PPSO. However, long-term treatment with corticosteroids is associated with substantial side effects, driving the search for efficacious steroid-free topical treatment alternatives. In more severe and/or extensive cases, topical preparations are often combined with oral medications, light or biological therapies.
The characteristic lesions of psoriasis are due to the hyperproliferation of skin cells (keratinocytes). The PI3K/mTOR pathway is a prominent driver of cellular proliferation. Supporting a direct implication of the PI3K/mTOR pathway in psoriasis, several studies showed that the PI3K/mTOR pathway is indeed prominently overactivated in human psoriasis (Huang et al, 2014; Chamcheu et al, 2016). Another study showed that proliferating skin cells are substantially more dependent on glucose for their growth, development and function than normal skin cells (Zhang et al, 2018). Bimiralisib prevents glucose uptake, which subsequently results in the blockage of proliferation.
Based on these factors, PIQUR believes that topical bimiralisib has clinically relevant activity not only in psoriasis but also in other dermatological skin diseases with hyperproliferative components.
PIQUR successfully completed preclinical profiling and the Good Laboratory Practice (GLP) toxicology studies with their most advanced compound, topical bimiralisib.
Phase IIa Clinical Studies
Compelling data from preclinical studies supported the initiation of two phase IIa studies to evaluate topical bimiralisib’s (1) safety, efficacy and pharmacodynamics in patients with CTCL and (2) antiproliferative and anti-inflammatory activity in mild to moderate plaque psoriasis. Both studies have completed recruitment.
From Lab to Clinic
PIQUR is advancing bimiralisib’s development for the clinical benefit of patients with indications of high unmet clinical need. Results from the preclinical studies combined with bimiralisib’s mechanism of action suggest that the topical formulation will have the following advantages over current treatments for inflammatory and hyperproliferative dermatological diseases:
- good tolerability allowing long-term use
- no inflammatory trigger
- little or no pain.
It follows that topical bimiralisib also has the potential to be applied on larger areas of skin.
The future of topical dermatological treatments hinges on developing products with improved patient outcomes, good tolerability, no inflammatory triggers, minimal risk of infection and with little or no pain. Research and development of topical bimiralisib at PIQUR offers new treatments for medical dermatology.