Cyclodextrin-assisted drug delivery to Central Nervous System: Mavenclad™ for multiple sclerosis treatment

In a recent study, Professors Bodor and Buchwald review the use of cyclodextrin-enabled formulations to develop oral tablets of cladribine by enhancing its bioavailability and to improve the solubility and stability of retrometabolic chemical delivery systems in general and estredox, a brain-targeting estradiol-Chemical Delivery System, in particular. (1)

Cladribine, sold under the brand name Mavenclad™, an oral tablet used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis. The active substance of the tablet is cladribine, a purine analogue. (Figure 1.) The other ingredients in tablets are hydroxypropylbetadex, sorbitol and magnesium stearate. The active ingredient, Cladribine selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia. (2)  

 Figure 1. Chemical structure of Cladribine

Modified CDs, and particularly 2-hydroxypropyl-β-cyclodextrin (HPβCD), provided dramatically increased water solubility and oxidative stability for estredox (estradiol-chemical delivery system), making its clinical development possible and highlighting the potential of brain-targeted chemical deliver systems approach for central nervous system-targeted delivery with minimal peripheral exposure. (3)

The corresponding complex dual CD-complex formed by an amorphous admixture of inclusion- and non-inclusion cladribine–HPβCD complexes led to the development of tablets that provide adequate oral bioavailability for cladribine, as demonstrated in both preclinical and clinical studies. Cladribine–HPβCD tablets (Mavenclad™) offer a convenient, effective, and well-tolerated oral therapy for multiple sclerosis, achieving worldwide approval and significant clinical success.

In this recent paper by Bodor and Buchwald, the developments are summarized and underscore the importance of tailored cyclodextrin-based approaches for overcoming barriers in drug formulation for compounds with challenging physicochemical properties, and demonstrate the versatility and clinical impact of cyclodextrin inclusion complexes in modern pharmaceutical development. Started in 2003, it ultimately resulted in a clinically approved product that received FDA approval in March 2019 (Mavenclad™ oral cladribine tablet formulated with HPβCD) after extensive clinical trials demonstrated its effectiveness in reducing annualized relapse rates and the progression of disability in patients with relapsing-remitting and active secondary progressive multiple sclerosis. (7.)

Briefly about Bodor’s retrometabolic chemical delivery system:

The first application of cyclodextrins by Bodor and coworkers was in the second half of the 1980s to improve the formulation of retrometabolic chemical delivery systems, which were introduced by the same group a few years earlier (1981) to overcome the challenge of brain-targeted drug delivery imposed by the blood–brain barrier. (4).

The BBB, formed by non-fenestrated brain capillaries with tight junctions, restricts xenobiotic entry into the central nervous system. Entrance via passive diffusion is largely limited to lipid-soluble compounds; thus, poorly lipophilic therapeutics exhibit low brain penetration and need some delivery strategy to be able to reach the Central Nervous System. Brain-Targeting Chemical Delivery Systems are an important part of general retrometabolic drug design approaches. Originating from the prodrug concept (5), Bodor’s Chemical Delivery Systems differ fundamentally in that that it incorporates some targetor moieties (Figure 2) and employs multistep activations, by which this delivery system aims to both enhance Blood Brain Barrier drug influx and reduce drug efflux. (6)   

Figure 2. Chemical structures of the molecules discussed in the recent paper (1), including βCD, HPβCD, cladribine active drug and estredox estradiol-trigonellin (targetor) moiety building up the retrometabolic chemical delivery system.

References:

1. Nicholas Bodor and Peter Buchwald Cyclodextrin Complexes for Clinical Translatability: Applications for Cladribine and Retrometabolically Designed Estredox, Int. J. Mol. Sci. 2025, 26(22), 0976; https://doi.org/10.3390/ijms262210976
2. Leist TP, Weissert R (2011). “Cladribine: mode of action and implications for treatment of multiple sclerosis”. Clinical Neuropharmacology. 34 (1): 28–35. doi:10.1097/WNF.0b013e318204cd90. 
3. Bodor, N.S.; Dandiker, Y. Oral Formulations of Cladribine. U.S. Patent 8,785,415 B2, 22 July 2014.
4. Bodor, N.; Farag, H.H.; Brewster, M.E. Site-specific, sustained release of drugs to the brain. Science 1981, 214, 1370–1372.
5. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov. 2008, 7, 255–270. [CrossRef]
6. Bodor, N.; Buchwald, P. Retrometabolic Drug Design and Targeting, 1st ed.; Wiley: Hoboken, NJ, USA, 2012; p. 418.
7. Giovannoni, G.; Comi, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Soelberg Sorensen, P.; Vermersch, P.; Chang, P.; Hamlett, A.; Musch, B.; et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 416–426.

Comment: Author of this blog is especially pleased to mention that the inventors and world-wide acknowledged experts of the retrometabolic chemical delivery systems targeting the central nervous system are Professors Nicholas Bodor and Peter Buchwald, Hungarian scientists working in the United States.