TRANSDERMAL DELIVERY - SkinJect’s Doxorubicin-Loaded Dissolvable Microneedle Array (D-MNA): A Revolutionary Approach to Transdermal Drug Delivery

INTRODUCTION

Skin diseases are amongst the most prevalent non-fatal con­ditions impacting 25% of the world population. These skin dis­eases are negatively impacting the quality of life, causing loss of productivity and increase in healthcare costs. Amongst skin dis­eases, non-melanoma skin cancers, particularly Basal Cell Car­cinoma of the skin (BCC), result in substantial healthcare expense and loss in productivity. BCC is the most common cancer in the world. In US alone, 5 million new cases of BCC are diagnosed every year.

The holy grail in improving treatment outcomes in skin dis­eases and substantial reduction in healthcare cost revolves around developing transdermal drug delivery systems (TDDS). TDDS are advantageous due to their high bioavailability, low sys­temic toxicity, and improved patient compliance. There are dif­ferent types of transdermal delivery systems currently under development; to deliver large molecules dissolvable microneedle arrays are emerging as a front runner.

Medicus Pharma’s wholly owned subsidiary, SkinJect, is fo­cused on advancing the clinical development program of a TDDS to non-invasively treat Basal cell carcinoma of the skin using patented dissolvable doxorubicin containing microneedle arrays (D-MNA). The investigational product represents a significant ad­vancement in precision drug delivery technology. The following explores the D-MNA treatment, highlighting its drug delivery mechanisms, advantages over traditional treatments, and clinical potential.

THE EVOLUTION OF MICRONEEDLE ARRAYS

Transdermal drug delivery systems have long been an area of interest due to their potential to bypass the gastrointestinal tract and liver, thereby improving bioavailability and reducing systemic side effects. Microneedle arrays are a subset of transdermal drug delivery systems that utilize tiny needles to penetrate the stratum corneum, the outermost layer of the skin, enabling the direct de­livery of drugs into the dermal layer.

Microneedle arrays come in various forms, including solid, coated, hollow, and dissolvable. Dissolvable microneedle arrays, like the one developed by SkinJect, are particularly innovative as they encapsulate the drug within a biodegradable matrix that dissolves upon application, ensuring com­plete drug release and minimal waste.

DOXORUBICIN: A KNOWN ANTI-TUMORAL AGENT

The active drug used in SkinJect’s D-MNA, Doxorubicin, is an anthracycline an­tibiotic widely used in oncology for its potent anti-tumoral properties. Its mecha­nism of action involves intercalation into DNA, disrupting the replication process and ultimately leading to cell death. How­ever, systemic administration of doxoru­bicin is associated with significant side effects, including cardiotoxicity, which lim­its its use.

DESIGN & COMPOSITION OF D-MNA

The SkinJect D-MNA is a tip-loaded dissolvable microneedle array, each array measuring 15 x 15 mm and containing 400 microneedles, each 750 microns deep. The microneedles are designed to dissolve upon insertion into the skin, re­leasing the embedded drug directly into the peri-epidermal space. Key components include:

• Doxorubicin HCl: A potent cytotoxic agent used in oncology.
• Citric Acid and Sodium Phosphate: Buffering agents ensuring drug stability.
• Trehalose Dihydrate and Car­boxymethyl Cellulose (CMC): Structural components that facilitate the dissolu­tion of the microneedles.
• USP Water: The solvent.

MECHANISM OF ACTION

Upon application, the microneedles penetrate the skin’s upper layers, dissolv­ing to release doxorubicin directly at the tumor site. This localized delivery en­hances drug concentration at the target site while minimizing systemic exposure and associated side effects. The matrix dis­solves completely, leaving no residual ma­terial, thus enhancing patient safety.

ADVANTAGES OVER TRADITIONAL TREATMENTS

Precision Delivery
D-MNA allows for precise delivery of doxorubicin to Basal Cell Carcinoma sites, improving efficacy compared to topical creams that may not penetrate deeply enough to effectively kill cancer cells. The precision of the microneedles ensures that the drug is delivered directly to the affected area, maximizing therapeutic effects while minimizing systemic effects.

Minimized Side Effects
By localizing drug delivery, the D-MNA eliminates systemic exposure to dox­orubicin, thereby minimizing the risk of side effects such as cardiotoxicity. This is particularly important in oncology, where the therapeutic index is often narrow, and systemic side effects can limit the efficacy of treatment.

Non-Invasive
Unlike the current standard of care, painful surgical excision or Mohs micro­graphic surgery, D-MNA offers a non-in­vasive alternative with reduced risk of bleeding, scarring, and infection. This of­fers patients a treatment option with a bet­ter quality of life, particularly those who may be averse to painful and aesthetically unpleasant surgical procedures.

Enhanced Stability & Handling
The inclusion of buffering agents like citric acid and sodium phosphate ensures the stability of doxorubicin, while the solid-state storage of the arrays simplifies han­dling and transportation. This enhances the practicality of the D-MNA, making it easier to store, transport, and use in vari­ous clinical settings.

CLINICAL DEVELOPMENT & TRIALS NONCLINICAL STUDIES

Initial nonclinical studies utilized murine and human models of squamous cell carcinoma and melanoma, as there are no Basal Cell Carcinoma animal mod­els. In murine models, D-MNA treatment significantly increased cell death, elevated pro-inflammatory cytokine levels, and im­proved survival rates compared to con­trols. In ex-vivo human squamous cell carcinoma samples, D-MNA induced sig­nificant tumor cell death and modulated the tumor microenvironment toward an anti-tumor phenotype.

Pharmacokinetic studies in mice and minipigs showed that doxorubicin deliv­ered via D-MNA remained localized at the application site, with minimal systemic ex­posure. Blood level measurements con­firmed undetectable doxorubicin in plasma of D-MNA-treated animals, under­scoring the efficacy of localized delivery.

PHASE 1 CLINICAL TRIALS

A Phase 1 open-label dose escalation trial completed in 2021 evaluated the safety and tolerability of D-MNA in Basal Cell Carcinoma patients. The study en­rolled a total of 13 subjects, used a 3+3 dose escalation design with four dose groups (25 μg, 50 μg, 100 μg, and 200 μg) and a placebo control group.

 RESULTS

• Safety: No serious adverse events (SAEs) or dose-limiting toxicities (DLTs).
• Tolerability: The D-MNA was well-tol­erated across all dose levels, with min­imal local reactions.
• Efficacy: Preliminary assessments indi­cated positive responses in Basal Cell Carcinoma lesions, with 6 patients showing complete lesion response at each dose level.

The Phase 1 trial also monitored vari­ous biomarkers to better understand the biological response to D-MNA treatment. Biomarkers such as inflammatory cy­tokines and immune cell infiltration were assessed, providing insights into the mech­anism of action and potential immune-modulating effects of the treatment.

FUTURE DIRECTIONS

Building on the success of the Phase 1 trial, notably the pristine safety outcome and complete clinical response on histo­logical examination of 6 Basal Cell Carci­noma patients, SkinJect plans to initiate a Phase 2 trial to further evaluate D-MNA’s safety and efficacy among a larger Basal Cell Carcinoma patient cohort in Q3 of 2024. In addition to evaluating safety, tol­erability, and efficacy, the trial will aim to optimize the dosage and administration schedule to maximize therapeutic out­comes. Particularly, the study is designed as a double blinded, randomized trial set to enroll up to 60 subjects among 5-6 clin­ical study sites. The study will further eval­uate the 100 and 200 μg dose levels against a placebo control group.

One of the clinical sites participating in the Phase 2 trial will also be incorporat­ing both artificial intelligence (AI) and con­focal microscopy as supplemental endpoints. The company aim is to mini­mize invasive intervention at all levels.

Click image to enlarge

CONCLUSION

SkinJect’s D-MNA represents a groundbreaking advancement in transder­mal drug delivery, offering a precise, non-invasive, and effective alternative to tradi­tional BCC treatments primarily relying on Mohs surgery. According to 360iRe­search’s Global Forecast 2024-2030, Medicus Pharma Ltd. is ranked # 7 as a leading player in BCC, ahead of leading Pharma companies in the space.

By leveraging dissolvable micronee­dle technology, SkinJect enhances drug delivery efficacy, and patient safety, and ease of use. As clinical development pro­gresses, D-MNA has the potential to rev­olutionize treatment landscapes for Basal Cell Carcinoma and other non-melanoma skin cancers.

REFERENCES

1. ScienceDirect. Transdermal Delivery. Available from: https://www.sciencedirect.com/topics/pharmacology-tox­icology-and-pharmaceutical-science/transdermal-deliv­ery
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Raza Bokhari, MD, Executive Chairman & CEO, is a recipient of Philadelphia Business Journal’s 40 under 40 award. He isa physician turned serial entrepreneur and has a demonstrated successful track record in aggregating and accelerating life sciences, healthcare services and Pharmaceutical R&D companies. He is the managing partner of RBx Capital, LP and also serves as the Chairman of the Board of Parkway clinical Laboratories (PCL) a fifty-year-old College of American Pathologist (CAP) accredited, CLIA certified in-vitro diagnostic laboratory. He previously served as Executive Chairman and CEO of FSD Pharma (Nasdaq: HUGE), where his strategies successfully pivoted the company out of medicinal cannabis and into a clinical stage pharmaceutical R&D, a transition marked by a NASDAQ listing in January 2020, and raising nearly $100M institutional capital to fuel growth and expansion. He earned a Doctor of Medicine degree from the University of Punjab, Rawalpindi Medical College, and an Executive MBA from Temple University, Fox School of Business & Management. In addition to his corporate roles, he serves as the Vice Chairman of the World Affairs Council of Philadelphia. He formerly served on the Board of Temple University’s Fox School of Business and Management as Chairman of the Executive Advisory Committee and was a Trustee of the esteemed Franklin Institute and Foreign Policy Research Institute. He, through his family foundation, believes in giving back and investing in the community. In recognition of a $1 million gift, he made to his alma mater, Temple University, its Fox Business School named the Innovation & Entrepreneurship Institute Suite in his honor. The school acknowledged Dr. Bokhari in 2018 by naming him a Centennial Honoree, a special collection of entrepreneurs, visionaries, and disruptors who helped shape the Fox School and the business world since 1918. More information on Dr. Bokhari, is available at www.Razabokhari.com.

 

Edward J. Brennan, MD, FACS, Chief Medical Officer, is a veteran pharmaceutical and clinical research executive with over 25 years of drug development experience. He has held senior medical leadership roles at major companies, including Wyeth, GlaxoSmithKline, and IndiPharm. As Medical Director at Wyeth and GSK, Dr. Brennan led clinical development programs that resulted in 10 FDA drug approvals. He oversaw teams responsible for all phases of clinical research as well as interactions with regulatory authorities. His therapeutic expertise includes Immunology, Oncology, Women’s Health, and Genetic Diseases. Before industry roles, Dr. Brennan practiced medicine as an internist. He received his MD from Temple University School of Medicine after completing a Bachelor of Science in Pharmacy.

Madison Weisz, MS, is currently serving as Vice President at Medicus Pharma, where she excels in asset valuation, clinical study design, medical and regulatory writing, programming, and statistical analysis. She has a background in clinical development and data analytics, with her most significant prior roles at Ocugen Inc and the US Chamber of Commerce Foundation. Through her educational background in Applied Economics from George Washington University and her career experience in entrepreneurship and biotechnology, she offers a unique approach to biostatistics, positively impacting clinical study outcomes.