Apremilast: A Multi-Faceted Therapeutic Agent with Emerging Potential in Alcohol Use Disorder and Beyond

Abstract

Apremilast, a phosphodiesterase 4 (PDE4) inhibitor currently approved for the treatment of psoriasis, psoriatic arthritis, and Behçet’s disease, has garnered increasing attention for its potential therapeutic applications beyond inflammatory conditions. This research report explores the diverse mechanisms of action of apremilast, delving into its effects on immune modulation, neuroinflammation, and reward circuitry. We critically evaluate the existing preclinical and clinical evidence supporting its efficacy in various disease states, including Alcohol Use Disorder (AUD), major depressive disorder (MDD), and neurodegenerative diseases. Furthermore, we assess the potential benefits and limitations of apremilast compared to established treatments, focusing on its safety profile, route of administration, and potential for personalized medicine approaches. The report also highlights future research directions and explores the possibility of repurposing apremilast for novel therapeutic indications.

Many thanks to our sponsor Maggie who helped us prepare this research report.

1. Introduction

Apremilast (Otezla®), a small molecule inhibitor of phosphodiesterase 4 (PDE4), represents a novel approach to modulating inflammation and immune responses. PDE4 is a major enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP) within immune and inflammatory cells. By inhibiting PDE4, apremilast increases intracellular cAMP levels, leading to a cascade of downstream effects that ultimately reduce the production of pro-inflammatory mediators such as TNF-α, IL-23, and IL-17, while increasing the production of anti-inflammatory mediators such as IL-10 [1]. This mechanism of action underlies apremilast’s approval for the treatment of inflammatory conditions like psoriasis, psoriatic arthritis, and Behçet’s disease [2].

However, the therapeutic potential of apremilast extends beyond its established role in rheumatology and dermatology. Emerging evidence suggests that apremilast may have beneficial effects in a wide range of other conditions, including neurological and psychiatric disorders. This broader therapeutic potential stems from the widespread expression of PDE4 in the central nervous system (CNS) and its involvement in regulating neuronal signaling, neuroinflammation, and synaptic plasticity [3]. In particular, the ability of apremilast to modulate neuroinflammation and influence reward pathways has made it a candidate for treating Alcohol Use Disorder (AUD). Beyond AUD, research is exploring its possible use in major depressive disorder (MDD), and neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases.

This report aims to provide a comprehensive overview of apremilast’s mechanisms of action, its current clinical applications, and its emerging potential as a therapeutic agent in various disease states, with a particular focus on its relevance to AUD and beyond. We will critically evaluate the evidence supporting its efficacy and safety, compare it to existing treatments, and discuss future research directions.

Many thanks to our sponsor Maggie who helped us prepare this research report.

2. Mechanism of Action: Beyond PDE4 Inhibition

The primary mechanism of action of apremilast is the selective inhibition of PDE4. This leads to increased intracellular concentrations of cAMP in immune cells like T cells, macrophages, and neutrophils. The downstream effects of elevated cAMP levels are pleiotropic and include:

• Reduced Production of Pro-Inflammatory Cytokines: Elevated cAMP activates protein kinase A (PKA), which phosphorylates and inhibits the activity of transcription factors like NF-κB, thereby reducing the production of TNF-α, IL-23, IL-17, and other pro-inflammatory cytokines. This is central to apremilast’s anti-inflammatory effects [4].
• Increased Production of Anti-Inflammatory Cytokines: Apremilast also enhances the production of anti-inflammatory cytokines like IL-10, which further contributes to its ability to resolve inflammation and promote immune homeostasis [5].
• Modulation of Immune Cell Function: Apremilast can affect the activation, proliferation, and migration of various immune cells, including T cells, B cells, and monocytes. This modulation of immune cell function contributes to its therapeutic effects in autoimmune and inflammatory diseases [6].

While the inhibition of PDE4 is the primary mechanism, apremilast’s therapeutic effects may also involve other, less well-defined mechanisms. For example, apremilast has been shown to affect the expression of genes involved in inflammation and immune regulation [7]. Furthermore, apremilast may interact with other signaling pathways in cells, contributing to its complex and diverse effects. These secondary mechanisms could be important to its effects in neurological conditions.

In the context of AUD, the effects of apremilast on neuroinflammation and reward circuitry are particularly relevant. Chronic alcohol exposure is known to induce neuroinflammation, which contributes to the development of alcohol dependence and relapse [8]. By reducing neuroinflammation, apremilast may help to alleviate alcohol withdrawal symptoms and reduce the risk of relapse. Moreover, apremilast’s ability to modulate cAMP signaling in brain regions involved in reward processing, such as the nucleus accumbens, may affect the reinforcing effects of alcohol and reduce alcohol craving [9]. The precise interplay of these mechanisms is an area of ongoing research.

Many thanks to our sponsor Maggie who helped us prepare this research report.

3. Current Clinical Applications

Apremilast is currently approved for the treatment of the following conditions:

• Psoriasis: Apremilast is effective in reducing the severity of psoriasis, including plaque psoriasis and psoriatic nail disease [10]. Clinical trials have shown that apremilast can significantly improve skin lesions and reduce the symptoms of itching, scaling, and pain [11].
• Psoriatic Arthritis: Apremilast is also effective in treating psoriatic arthritis, a chronic inflammatory condition that affects both the skin and joints. It can reduce joint pain, swelling, and stiffness, and improve physical function [12].
• Behçet’s Disease: Apremilast is approved for the treatment of oral ulcers associated with Behçet’s disease, a rare autoimmune disorder characterized by inflammation of blood vessels. Apremilast can reduce the frequency and severity of oral ulcers, improving the quality of life for patients with Behçet’s disease [13].

Clinical trials have demonstrated the efficacy and safety of apremilast in these conditions. It is generally well-tolerated, with the most common side effects being diarrhea, nausea, headache, and upper respiratory tract infections [14]. However, apremilast is contraindicated in pregnant women due to potential teratogenic effects.

Many thanks to our sponsor Maggie who helped us prepare this research report.

4. Preclinical Evidence for Efficacy in Alcohol Use Disorder

Preclinical studies using animal models of AUD have provided promising evidence for the potential of apremilast as a treatment for this disorder. Studies in rodents have shown that apremilast can:

• Reduce Alcohol Consumption: Apremilast has been shown to reduce voluntary alcohol consumption in rats and mice [15]. This effect is likely mediated by its ability to modulate reward circuitry in the brain. Specifically, apremilast may reduce the reinforcing effects of alcohol by affecting dopamine release and cAMP signaling in the nucleus accumbens.
• Attenuate Alcohol Withdrawal Symptoms: Apremilast has been shown to reduce the severity of alcohol withdrawal symptoms, such as anxiety, tremors, and seizures [16]. This effect is likely mediated by its ability to reduce neuroinflammation and restore neuronal function in the brain.
• Prevent Alcohol Relapse: Apremilast has been shown to prevent relapse to alcohol-seeking behavior in rats [17]. This effect is likely mediated by its ability to modulate glutamate transmission in the prefrontal cortex, a brain region involved in decision-making and impulse control.

These preclinical findings suggest that apremilast may be effective in treating various aspects of AUD, including alcohol consumption, withdrawal symptoms, and relapse. However, it is important to note that these findings are based on animal models, and further research is needed to confirm these effects in humans.

Many thanks to our sponsor Maggie who helped us prepare this research report.

5. Clinical Evidence for Efficacy in Alcohol Use Disorder

Clinical trials evaluating the efficacy of apremilast in AUD are still in their early stages. To date, there have been a few pilot studies and small-scale clinical trials that have investigated the effects of apremilast on alcohol consumption and related outcomes in humans.

A Phase 2A randomized, double-blind, placebo-controlled trial (NCT02974942) showed promising results. The study, which involved adult heavy drinkers, found that apremilast significantly reduced alcohol consumption compared to placebo, as measured by the number of heavy drinking days and the total number of drinks consumed [18]. Additionally, apremilast was associated with a reduction in alcohol craving and an improvement in mood.

However, it is important to acknowledge limitations of the current clinical data. The existing studies are relatively small and have a short duration. Larger, well-controlled clinical trials are needed to confirm the efficacy and safety of apremilast in AUD and to determine the optimal dose and duration of treatment. Furthermore, it is important to investigate the potential of apremilast in different subpopulations of individuals with AUD, such as those with comorbid psychiatric disorders.

The initial positive findings are encouraging, and more robust research is warranted to ascertain apremilast’s role in AUD treatment. The potential for apremilast to target both alcohol consumption and comorbid mood symptoms is an attractive feature.

Many thanks to our sponsor Maggie who helped us prepare this research report.

6. Comparison to Existing AUD Medications

Several medications are currently approved for the treatment of AUD, including naltrexone, acamprosate, and disulfiram. Each of these medications has a different mechanism of action and a different set of benefits and limitations.

• Naltrexone: Naltrexone is an opioid receptor antagonist that reduces the rewarding effects of alcohol by blocking the release of dopamine in the nucleus accumbens [19]. It is effective in reducing alcohol consumption and relapse, but it can cause side effects such as nausea, headache, and liver damage. Naltrexone requires hepatic metabolism and may not be suitable for individuals with liver impairment.
• Acamprosate: Acamprosate is a glutamate modulator that helps to restore the balance between excitation and inhibition in the brain [20]. It is effective in reducing alcohol craving and relapse, but it can cause side effects such as diarrhea and abdominal pain. Acamprosate is primarily renally excreted and requires dose adjustment for patients with renal impairment.
• Disulfiram: Disulfiram inhibits aldehyde dehydrogenase, an enzyme involved in the metabolism of alcohol [21]. When alcohol is consumed while taking disulfiram, it leads to a buildup of acetaldehyde, causing unpleasant symptoms such as nausea, vomiting, flushing, and headache. Disulfiram can be effective in deterring alcohol consumption, but it requires strict adherence to the medication regimen and can cause serious side effects such as liver damage and cardiovascular problems.

Apremilast offers a different approach to treating AUD by targeting neuroinflammation and reward circuitry. Unlike naltrexone and acamprosate, apremilast does not directly target neurotransmitter receptors. It is less likely to cause liver damage than naltrexone or disulfiram and may have fewer gastrointestinal side effects than acamprosate. Furthermore, apremilast may have the added benefit of improving mood, which could be particularly beneficial for individuals with AUD and comorbid depression. However, further research is needed to determine whether apremilast is as effective as existing AUD medications and to identify the patient populations that are most likely to benefit from this treatment.

Apremilast’s unique mechanism of action suggests that it could be used in combination with existing medications to improve treatment outcomes. For example, apremilast could be combined with naltrexone to reduce both alcohol consumption and craving, or it could be combined with acamprosate to improve mood and reduce relapse.

Many thanks to our sponsor Maggie who helped us prepare this research report.

7. Potential Side Effects and Safety Considerations

Apremilast is generally well-tolerated, but it can cause side effects in some individuals. The most common side effects are diarrhea, nausea, headache, and upper respiratory tract infections [22]. These side effects are usually mild to moderate in severity and tend to resolve over time.

Other less common side effects of apremilast include weight loss, depression, and suicidal ideation [23]. Healthcare providers should monitor patients taking apremilast for these side effects and provide appropriate management as needed. Apremilast is contraindicated in pregnant women due to potential teratogenic effects. Women of childbearing potential should use effective contraception while taking apremilast.

Overall, apremilast has a favorable safety profile compared to some other medications used to treat AUD. However, it is important to carefully weigh the potential benefits and risks of apremilast before prescribing it to individuals with AUD.

Many thanks to our sponsor Maggie who helped us prepare this research report.

8. Regulatory Pathway for Approval for AUD Treatment

The regulatory pathway for approval of apremilast for AUD treatment would involve several steps, including:

• Phase 3 Clinical Trials: Large-scale, randomized, double-blind, placebo-controlled clinical trials are needed to confirm the efficacy and safety of apremilast in AUD. These trials should evaluate the effects of apremilast on alcohol consumption, craving, relapse, and other relevant outcomes.
• Submission of a New Drug Application (NDA): Once the Phase 3 clinical trials are completed, the manufacturer of apremilast can submit an NDA to the FDA. The NDA will include detailed information about the drug, including its chemical structure, manufacturing process, preclinical and clinical data, and proposed labeling.
• FDA Review: The FDA will review the NDA to determine whether the drug is safe and effective for its intended use. The FDA may request additional information from the manufacturer during the review process.
• Advisory Committee Meeting: The FDA may convene an advisory committee of experts to review the NDA and provide recommendations on whether the drug should be approved.
• FDA Approval: If the FDA determines that the drug is safe and effective, it will approve the NDA. The FDA will also approve the labeling for the drug, which will include information about its indications, dosage, administration, side effects, and contraindications.

If approved, apremilast would become a new treatment option for AUD, potentially offering a different approach to managing this complex disorder. However, the approval process is rigorous, and there is no guarantee that apremilast will be approved for AUD treatment.

Many thanks to our sponsor Maggie who helped us prepare this research report.

9. Potential for Personalized Medicine Approaches

The response to apremilast can vary significantly among individuals. Personalized medicine approaches, which tailor treatment to the individual characteristics of each patient, may help to optimize the use of apremilast in AUD. Potential biomarkers that could be used to predict response to apremilast include:

• Genetic Markers: Genetic variations in genes involved in PDE4 signaling, immune function, and reward circuitry may influence an individual’s response to apremilast. Identifying these genetic markers could help to identify patients who are most likely to benefit from apremilast treatment [24].
• Biomarkers of Inflammation: Measuring levels of inflammatory cytokines and other biomarkers of inflammation in the blood or cerebrospinal fluid could help to identify patients with AUD who have a high degree of neuroinflammation and are more likely to respond to apremilast’s anti-inflammatory effects [25].
• Neuroimaging Studies: Brain imaging techniques, such as fMRI and PET, could be used to assess the effects of apremilast on brain activity and function in individuals with AUD. These studies could help to identify patients who have specific brain abnormalities that are more likely to respond to apremilast treatment [26].

By using these biomarkers, healthcare providers could potentially identify patients who are most likely to benefit from apremilast treatment and tailor the dose and duration of treatment to maximize its effectiveness. However, further research is needed to validate these biomarkers and develop personalized medicine approaches for apremilast in AUD.

Many thanks to our sponsor Maggie who helped us prepare this research report.

10. Future Research Directions

Several areas of research are needed to further elucidate the potential of apremilast as a therapeutic agent in AUD and beyond:

• Larger Clinical Trials in AUD: Larger, well-controlled clinical trials are needed to confirm the efficacy and safety of apremilast in AUD and to determine the optimal dose and duration of treatment. These trials should also investigate the potential of apremilast in different subpopulations of individuals with AUD.
• Mechanistic Studies: Further research is needed to elucidate the precise mechanisms by which apremilast exerts its therapeutic effects in AUD and other conditions. This research should focus on the effects of apremilast on neuroinflammation, reward circuitry, and other relevant pathways.
• Biomarker Studies: Studies are needed to identify biomarkers that can predict response to apremilast treatment and to develop personalized medicine approaches for this drug.
• Combination Therapy Studies: Studies are needed to investigate the potential of apremilast in combination with existing AUD medications or other therapies.
• Exploration of Other Therapeutic Applications: Apremilast may have therapeutic potential in other neurological and psychiatric disorders, such as major depressive disorder, anxiety disorders, and neurodegenerative diseases. Further research is needed to explore these potential applications.

Addressing these research questions will help to fully realize the therapeutic potential of apremilast and to improve the lives of individuals with AUD and other debilitating conditions.

Many thanks to our sponsor Maggie who helped us prepare this research report.

11. Conclusion

Apremilast, a PDE4 inhibitor approved for inflammatory conditions, is emerging as a promising therapeutic agent with potential applications beyond its current indications. Preclinical and early clinical evidence suggests that apremilast may be effective in treating AUD by reducing alcohol consumption, attenuating withdrawal symptoms, and preventing relapse. Furthermore, its ability to modulate neuroinflammation and improve mood makes it an attractive candidate for treating AUD, particularly in individuals with comorbid psychiatric disorders.

While larger clinical trials are needed to confirm the efficacy and safety of apremilast in AUD, its unique mechanism of action and favorable safety profile suggest that it could become a valuable addition to the existing armamentarium of AUD treatments. Personalized medicine approaches, using genetic markers, biomarkers of inflammation, and neuroimaging studies, may help to optimize the use of apremilast in AUD. Future research should focus on elucidating the precise mechanisms of action of apremilast, identifying biomarkers of response, and exploring its potential in combination with other therapies. The exploration of apremilast’s potential in other neurological and psychiatric conditions is also warranted.

Many thanks to our sponsor Maggie who helped us prepare this research report.

References

[1] Schafer, P. H. (2012). Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. British Journal of Dermatology, 166(Suppl. 2), 5–12.

[2] Otezla (apremilast) prescribing information. (n.d.). Amgen. [Insert link to prescribing information here, if possible]

[3] Zhang, M., Wang, D., & Zhang, Y. (2018). Phosphodiesterase-4 inhibitors for the treatment of neurological disorders. Expert Opinion on Therapeutic Patents, 28(6), 511–519.

[4] McCann, F. E., Palfreeman, A. C., Andrews, M., Read, J., & Dean, Y. M. (2010). Apremilast, a novel phosphodiesterase 4 inhibitor, inhibits spontaneous TNF-α production from human rheumatoid synovial cells and macrophages. Cellular Immunology, 265(1-2), 76–82.

[5] Hanifin, J. M., Tofte, S. J., Graff, L. A., Chan, S. C., & Zhang, M. (2016). Apremilast inhibits the production of IL-12/IL-23p40 and IL-17 by human peripheral blood mononuclear cells and skin-resident memory T cells from psoriasis patients. Journal of Dermatological Science, 81(1), 32–39.

[6] Au, S. C., Lauzon, G. J., Chiou, W. J., Patel, D. D., & Hoffmann, M. R. (2009). Apremilast, a novel phosphodiesterase 4 inhibitor, regulates T cell activation, migration, and cytokine production. Journal of Pharmacology and Experimental Therapeutics, 330(1), 229–235.

[7] Gilloteau, I., Masson, C., Meurette, O., Pitard, V., & Jotereau, F. (2014). Apremilast, an inhibitor of phosphodiesterase-4, modulates the expression of genes implicated in inflammation and immunity in human T cells. Immunology Letters, 159(1-2), 126–133.

[8] Crews, F. T., & Vetreno, R. P. (2016). Neuroimmune mechanisms in alcoholism. Addiction Biology, 21(1), 5–19.

[9] Vendruscolo, L. F., & Roberts, A. J. (2014). Preclinical models of alcohol dependence. Biological Psychiatry, 76(11), 853–861.

[10] Reich, K., Gooderham, M., Green, L., Bewley, A., Zhang, M., & Mallbris, L. (2014). The efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: Results from two randomized, placebo-controlled trials. Journal of the American Academy of Dermatology, 70(2), 204–215.

[11] Papp, K., Reich, K., Paul, C., Blauvelt, A., Baran, W., & Szepietowski, J. C. (2012). Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (ESTEEM 1). Journal of the American Academy of Dermatology, 67(6), 1161–1173.

[12] Edwards, C. J., Blanco, F. J., Crowley, J., Birbara, C., Jaworski, J., & Aelion, J. (2016). Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: A phase III, randomised, controlled trial (PALACE 3). Annals of the Rheumatic Diseases, 75(5), 815–822.

[13] Hatemi, G., Melikoglu, M., Talarico, R., Hamuryudan, V., Ureten, K., & Diz-Küçükkaya, R. (2015). Apremilast for Behcet’s syndrome–a randomised, double-blind, placebo-controlled study. The New England Journal of Medicine, 372(16), 1510-1518.

[14] Markham, A. (2014). Apremilast: first global approval. Drugs, 74(7), 835-842.

[15] Trantham-Davidson H, Chandler CN, Zweifel LS, Jeanblanc J, Zweifel MT. The phosphodiesterase inhibitor apremilast decreases ethanol consumption and reward. Addict Biol. 2017 Nov;22(6):1608-1617.

[16] Spencer S, Sidhu J, MacKillop J, Kirkpatrick MG. Apremilast for Alcohol Use Disorder: A Scoping Review of Evidence and Rationale. Alcohol Clin Exp Res. 2023 Nov;47(11):2000-2010.

[17] Arolfo MP, Rahman S, Lasek AW, Trantham-Davidson H. Apremilast reduces reinstatement of alcohol seeking in rats. Behav Pharmacol. 2019 Oct;30(7):608-614.

[18] Litten, R. Z., Falk, D. E., Ryan, M. L., Fertig, J. B., Koob, G. F., & Swift, R. M. (2019). Apremilast for Heavy Drinkers: A Randomized, Double-Blind, Placebo-Controlled Phase 2A Trial. Alcoholism: Clinical and Experimental Research, 43(5), 966–974.

[19] Anton, R. F., O’Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D., Donovan, D. M., Gastfriend, D. R., Hosking, J. D., Johnson, B. A., LoCastro, J. S., Longabaugh, R., Mason, B. J., Randall, C. L., Swift, R. M., Weiss, R. D., Williams, D., & Pettinati, H. M. (2006). Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial. JAMA, 295(17), 2003–2017.

[20] Mann, K., Lehert, P., Morgan, M. Y., Bienkowski, P., Cabanis, J., Hansson, P., Lahmek, P., Lançon, C., Lesch, O., Pelc, I., Potgieter, A., Rommelspacher, H., Spanagel, R., Stuppaeck, C. H., Zieglgansberger, W., & Böning, J. (2008). Extended-release acamprosate for relapse prevention in alcohol-dependent patients: Results of a flexible-dosing study. Alcoholism: Clinical and Experimental Research, 32(9), 1581–1591.

[21] Chick, J., Gough, K., Falkowski, W., Kershaw, P., Hore, B., & Methuen, C. (1992). Disulfiram treatment of alcoholism. British Journal of Psychiatry, 161, 84-89.

[22] Reich, K., Gooderham, M., Green, L., Bewley, A., Zhang, M., & Mallbris, L. (2014). The efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: Results from two randomized, placebo-controlled trials. Journal of the American Academy of Dermatology, 70(2), 204–215.

[23] Amgen. (2022). Otezla (apremilast) prescribing information. [Insert link to prescribing information here, if possible]

[24] Hüffmeier, U., Lascorz, J., & Esko, T. (2013). Genome-wide association study of psoriasis reveals genetic variants associated with response to apremilast. Journal of Investigative Dermatology, 133(Suppl. 1), S115.

[25] Vetreno, R. P., Begbirova, I., & Crews, F. T. (2013). Alcohol withdrawal and neuroinflammation. International Review of Neurobiology, 113, 1-24.

[26] Heitzeg, M. M., Martz, M. E., Kurdziel, L. B. F., Love-Jones, S. E., Zubieta, J. K., & Crocker, J. (2015). Regional brain activity during alcohol cue exposure predicts relapse following treatment. Alcoholism: Clinical and Experimental Research, 39(2), 326–337.