DRUG DELIVERY - Using the IPEG™ Delivery System to Topically Treat Rare Diseases in Dermatology While Limiting Systemic Absorption

INTRODUCTION

There are many unmet needs in medical dermatology, espe­cially in rare diseases that may not have any approved therapies. In many of these cases, oral therapies are often used off-label, which have demonstrated efficacy but may be associated with systemic toxicity, which then limits their safe chronic use. Recent research has demonstrated that novel topical formulations of these oral therapies may represent safer treatment options that can lead to clinically meaningful outcomes in many rare derma­tologic diseases, including congenital ichthyosis. At Timber Pharmaceuticals, we are advancing innovative clinical research that is evaluating high-potential, low-risk treatments for rare derma­tologic diseases using unique topical vehicles combined with es­tablished medications that enable the targeted delivery of therapies to the epidermis and dermis while minimizing systemic absorption.

THE IPEG™ SYSTEM & HOW IT WORKS

Timber’s patented IPEG™ delivery system is a novel thera­peutic approach that uses a proprietary combination of differently sized polyethylene glycol (PEG) molecules combined in a very pre­cise ratio to provide targeted delivery of our active pharmaceuti­cal ingredient (API) – isotretinoin – to pathologic skin layers. This design enables more of our API to be delivered to the epidermis and upper layers of the dermis while minimizing systemic absorp­tion, which could potentially avoid all of the systemic side effects (including teratogenicity) known to occur with some oral drug for­mulations in dermatology. In addition to providing targeted de­livery of our drug to specific skin layers, the IPEG system was developed to stabilize chemically challenging compounds without the need for irritating excipients and solvents, such as ethanol.

While our API in the IPEG system is fully dissolved, the high molecular weight PEG is not soluble in the low molecular weight PEG. This allows our drug formulation to provide a managed re­lease of the isotretinoin from the vehicle system in a way that bal­ances the thermodynamic activity of our drug with its resulting environment. We also believe the sustained humectant properties of the IPEG system may enhance drug delivery across the stratum corneum, the outermost layer of the epidermis.

The IPEG system was applied to the development of TMB-001, an investigational topical formulation of isotretinoin for the treatment of moderate-to-severe subtypes of CI, which is a group of rare genetic keratinization disorders that leads to dry, thick­ened, and scaling skin. Most dermatologists are familiar with oral isotretinoin, a type of retinoid derived from vitamin A used pre­dominantly for treatment of severe recalcitrant nodular acne, and the rationale for retinoids in CI has been well established in prior clinical research. However, the higher doses of retinoids that must be administered to CI patients (compared to subjects with acne), coupled with the potential need for life-long, chronic treatment in CI, has limited the use of these compounds in real-world prac­tice. Oral isotretinoin has been associated with toxicities, includ­ing teratogenicity (ie, may cause birth defects in a developing embryo or fetus), mood changes, mucocutaneous effects (eg, cheilitis, xerosis, eye irritations), and interactions with other antibiotics (such as doxy- or minocycline). Our innovation was to successfully dissolve isotretinoin, which is a very challenging compound from a formulation standpoint, into a stable topical formulation that re­duces systemic absorption, maximizes penetration into the epidermis and upper dermis, is well tolerated in terms of local­ized skin reactions, and allows for chronic use over larger areas of the body.

With traditional delivery methods of medications for dermatologic diseases, there are often side effects, including burn­ing and localized skin reactions, particu­larly with alcohol-based formulations. As a result, patient compliance with proper medication application is a major limita­tion to chronic use. For example, the only other topical isotretinoin formulation ever commercially developed (available in se­lect European countries) used a vehicle system that was more than 95% ethanol, as it is generally known that isotretinoin is soluble in ethanol.¹ However, this vehicle system has proven to be unfavorable in treating large areas of skin, particularly skin that is inherently compromised, as is the case of patients living with CI. It was for this reason we needed to significantly change the vehicle formulation combined with isotretinoin that we would pursue as part of our CI development program, ultimately leading to the TMB-001 formula­tion. Though ethanol is well known for enhancing skin penetration, in direct com­parative studies, the TMB-001 formulation using IPEG technology was found to de­liver 2.5 times as much drug to pathologic skin layers compared to the ethanol-based formula.² TMB-001 has demonstrated the potential to maximally deliver isotretinoin topically to specific affected areas of skin while minimizing systemic delivery and potentially reducing side effects. This year, the FDA granted Fast Track and Breakthrough designations to TMB-001.

TMB-001: A NOVEL ISOTRETINOIN FORMULATION SHOWS PROMISE

With proof of concept established for TMB-001 and positive results from the Phase 2a and Phase 2b clinical trials, Tim­ber’s lead product candidate is currently being assessed for efficacy, pharmacoki­netics and safety in the pivotal Phase 3 AS­CEND clinical trial. ASCEND will also investigate an optimal dosage strategy for maintenance therapy with TMB-001. In June 2022, Timber announced the first four patients were enrolled in the trial, which is a global (US, Canada, Italy, Ger­many, and France) randomized, parallel, double-blind, vehicle-controlled study ex­pected to enroll more than 140 partici­pants 6 years of age or older with moderate-to-severe CI, including recessive X-linked ichthyosis (RXLI) and autosomal recessive lamellar ichthyosis (ARCI-LI). These subtypes affect about 80,000 peo­ple in the US and nearly 1 million patients globally, and lead to cutaneous manifes­tations that include large, dark scaling throughout the body. More serious symp­toms can include limited range of motion, chronic itching and wounds, an inability to sweat normally (which can lead to heat stroke and death), risk of infections, im­paired eyesight or hearing, and countless other comorbidities, which have a signifi­cant impact on patients’ physical and emotional health and quality of life.

Participants in the ASCEND study are randomized 2:1 to TMB-001 (0.05% isotretinoin) or vehicle control ointment (two participants on TMB-001 for every one participant on vehicle) for 12 weeks, at which point eligible participants in both arms of the study are randomized again to either once-a-day or twice-a-day TMB-001 treatment for an additional 12 weeks to provide valuable information on longer term treatment with the compound. Given their potency, to minimize the initial sensi­tization period, often seen with treatment with formulations of retinoids, there is a 3-week, once-a-day induction period in the ASCEND study. Patients randomized to re­ceive TMB-001 0.05% are required to also use a standardized bland emollient (Cetaphil™) to add moisture to the skin. After the first 3 weeks, the dosing fre­quency in the following 9-week treatment period will increase so participants receive either TMB-001 0.05% or vehicle twice daily, with use of the bland emollient dis­continued unless needed for control of lo­calized skin reactions. By reducing the initial sensitization period dosing, we are hopeful that TMB-001 will be better toler­ated in most patients, reducing the need for any potential drug discontinuations.

Prior clinical data of TMB-001 demonstrate its promise to fulfill an unmet medical need for CI patients, who are currently limited to off-label use of oral ther­apies or emollients, creams, lotions, and keratolytics that generally offer little or no benefit in alleviating the biological root cause of their ichthyosis. Data from the Phase 2b CONTROL study support this promise, which the FDA reviewed in a pos­itive end-of-Phase 2 meeting that resulted in a clear path to progress to the pivotal Phase 3 ASCEND study.

The Phase 2b CONTROL study was a randomized, double-blind, vehicle-con­trolled study designed to assess the efficacy and safety of two concentrations of TMB-001 (0.05% and 0.1% isotretinoin) for the treatment of RXLI and lamellar ichthyosis in 33 patients 9 years of age or older. Participants applied TMB-001 twice daily for 12 weeks.

The primary endpoint of the trial was determined by a reduction in the Visual Index for Ichthyosis Severity (VIIS) scaling score, a novel scale that was validated by researchers at Yale University and which garnered positive attention in the CI com­munity. The primary endpoint was met if there was a 50% or greater reduction from baseline in the VIIS scaling score (or VIIS-50) at Week 12, which was considered a clinically meaningful change. The major secondary endpoint included reduction in overall ichthyosis severity, as measured by a 2-point improvement using the Investi­gator Global Assessment (IGA) scale (IGA ≥2-grade), a well-known scale in the der­matology community.

Topline results from the CONTROL study announced in October 2021 demonstrated a reduction in targeted and overall severity of CI in patients treated with topical IPEG-based TMB-001. Specif­ically, in the intent-to-treat (ITT) and per protocol (PP) populations, results reported:

• In the PP population, 100% (nominal p= .04) and 40% (nominal p= ns) of patients treated with TMB-001 0.05% and 0.1%, respectively, achieved VIIS-50 compared to 40% in the vehicle group.
• In the ITT population, 64% (nominal p= 0.17) and 40% (nominal p= ns) of pa­tients treated with TMB-001 0.05% and 0.1%, respectively, achieved VIIS-50 compared to 33% in the vehicle group.
• In the PP population, 100% (nominal p=.002) and 60% (nominal p=ns) of patients treated with TMB-001 0.05% and 0.1%, respectively, achieved a ≥2 point improvement in the IGA at week 12 compared to 10% in the vehicle group.
• In the ITT population, 55% (nominal p=.02) and 40% (nominal p=ns) of pa­tients treated with TMB-001 0.05% and 0.1%, respectively, achieved a ≥2 point improvement in the IGA at week 12 compared to 8% in the vehicle group.
• In terms of safety, TMB-001 was gener­ally well tolerated with a similar inci­dence of adverse events (AEs) across treatment groups. The most frequent AEs were local adverse effects common for such topical treatments (e.g., burn­ing/stinging), which lessened in severity and frequency beyond the first 2-4 weeks. There were no treatment-related serious adverse events (SAE).³

A sub-analysis of the CONTROL study presented at the American Academy of Dermatology (AAD) 2022 Annual Meeting found that TMB-001 0.05% demonstrated a substantially greater proportion of pa­tients achieving VIIS-50 and ≥2-grade IGA improvement compared with vehicle re­gardless of RXLI or ARCI-LI subtype. Results reported:

All patients in the PP analysis with RXLI who received TMB-001 0.05% achieved VIIS-50 compared to 75% receiving ve­hicle and all patients with ARCI-LI who received TMB-001 0.05% achieved VIIS-50 compared to 17% receiving vehicle.

• Improvement of ≥2-grade IGA score was observed in all patients in the PP analysis with RXLI who received TMB-001 0.05% compared to 25% receiving vehicle, and in all patients with ARCI-LI who received TMB-001 0.05% com­pared to no patients receiving vehicle.
• For patients with RXLI who received TMB-001 0.05%, the median time to achieving VIIS-50 was 28 days compared to 50 days for patients who re­ceived vehicle. For patients with ARCI-LI who received TMB-001 0.05%, the me­dian time to achieving VIIS-50 was 32 days compared to 86 days for patients who received vehicle.
• The safety and tolerability profile of TMB-001 remained consistent with the known safety profile of topical retinoids. No significant systemic AEs were identified. Most AEs reported were application site reactions and were similarly distributed among patients with both RXLI and ARCI-LI who received TMB-001 0.05%.

Based on the clinical success that TMB-001 has shown to date, including results from the completed Phase 2a and CON­TROL studies, there is an important opportunity to significantly improve the lives of people living with CI who currently have no FDA-approved treatments and limited standard of care options.

SUMMARY

Every rare disease has its own set of nuances that should be considered on a case-by-case basis, and proper choice of drug, dose, and vehicle for the particular disease is key. Still, the IPEG delivery system upon which TMB-001 is based may be useful in treating many other rare skin conditions in addition to CI. For ex­ample, there are other rare disorders of keratinization, such as Darier’s disease, for which IPEG-based products could be helpful treatments. Certain blistering conditions, such as epidermolysis bullosa or conditions affecting mucosal surfaces, might benefit from the IPEG delivery system as well. However, it is also likely that many other technologies will be needed to address the tremendous diversity present in rare dermatologic diseases.

There is a significant opportunity for drug developers – it has been estimated that the market for products in the rare derma­tology field will see 10-fold growth throughout the next several years.⁴ No other field in dermatology – even psoriasis, atopic der­matitis, acne, or skin cancers – is expected to grow at this rapid rate in terms of research and development efforts. There are areas of significant unmet need in the rare dermatology commu­nity, and we at Timber are committed to expanding treatment op­tions in this sector to help affected patients, caregivers, and families, starting with our IPEG approach to treatment of CI that has potential additional applications in the years ahead.

REFERENCES

1. Health Products Regulatory Authority. (Aug 2018). Summary of Product Characteristics: Isotrex 0.5 mg/g Gel. https://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA1077-122-001_16082018094036.pdf
2. Rome, Z., Greenaway Evans, C. R., Brown, M. B., Caserta, F. (2021). Isotretinoin formulations and uses and methods thereof (U.S. Patent No. 10,933,018 B2). U.S. Patent and Trademark Office. https://patents.google.com/patent/US10933018B2/en?oq=10%2c933%2c018
3. Teng, J. M. C. et al. The CONTROL study: A randomized, double-blind vehicle-controlled phase 2b study of novel topical isotretinoin formulation demonstrates improvement in recessive X-linked and autosomal recessive lamellar congenital ichthyosis. J Am Acad Dermatol. 2022 Jul 21: S0190-9622(22)02398-2. doi: 10.1016/j.jaad.2022.07.028.
4. Senior, M. & Hadjivasiliou, A. (April 2022). Orphan Drug Report 2022. Evaluate. https://info.evaluate.com/rs/607-YGS-364/images/Evaluate_Orphan_Drug_Report.pdf

Zachary Rome is the Co-founder and former Chief Operating Officer of Timber Pharmaceuticals. He is also a partner at TardiMed Sciences, a life sciences company creation firm. At TardiMed, he has helped to form several life sciences companies that span multiple therapeutic areas and stages of development. He is the Co-founder and President at Patagonia Pharmaceuticals, a privately owned specialty pharmaceutical company developing treatments for rare dermatologic diseases. He was the lead inventor on all of Patagonia’s technologies and oversaw their development from concept through Phase 2 studies. He earned his BS in Marine Science and Biology from the University of Miami and his MST in Adolescent Science Biology from Pace University.

Jessica Raiz is Vice President, Program Management and Clinical Operations at Timber Pharmaceuticals. She was previously Director of Clinical Operations at Ferring Pharmaceuticals, Director of Clinical Operations at Champions Oncology, Inc. and Associate Clinical Project Management Director at IQVIA. She also previously held increasing roles of responsibility at Novartis, most recently US Clinical Operations Team Lead. She earned her MPH in Health Law and Bioethics from Boston University School of Medicine and her BA in Biology from Drew University.

Dr. Alan M. Mendelsohn is Chief Medical Officer and Executive Vice President at Timber Pharmaceuticals and is board certified in pediatrics and pediatric cardiology. He was previously Associate Vice President of Dermatology Medical Affairs at Sun Pharma, where he focused on the post-clinical development of tildrakizumab (ILUMYA), an IL-23p19 inhibitor for patients with moderate-to-severe plaque psoriasis. He also has experience as Senior Director, Rheumatology Team Leader, US Medical Affairs at Pfizer and as Senior Director of Immunology R&D at Johnson & Johnson/Janssen. He has authored or co-authored more than 200 peer-reviewed abstracts and manuscripts in the areas of dermatology, rheumatology, and cardiology. He earned his MD from the State University of New York-Downstate Medical Center, then completed a Pediatrics residency at Albert Einstein College of Medicine and then a Pediatric Cardiology fellowship at University of Michigan.