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July 19, 2017

The Prodrug Opportunity: Making Good Drugs Better

Elegance in Chemistry, Product Development, and Marketability

The Prodrug Opportunity: Making Good Drugs Better

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  • Prodrug technology has been successfully utilized to develop therapeutics and treat patients for more than 100 years. Many of the world’s best known and most widely used pharmaceuticals are, in fact, prodrugs—with aspirin being the industry’s poster child. Approximately 7% of all drugs approved globally are prodrugs. Elegant in concept, prodrugs are inactive, bioreversible derivatives of active-drug molecules that must undergo an enzymatic or chemical transformation to release the parent drug, which can then elicit its desired pharmacological effect in the body. 

    The therapeutic rationale of a prodrug is to improve the physicochemical, biopharmaceutical, or pharmacokinetic properties of an active pharmaceutical ingredient (API). Key properties that prodrugs seek to modify generally fall within one or more of the ADME categories (Absorption, Distribution, Metabolism, and Excretion) with the end goal being the creation of a new chemical entity (NCE) that optimizes the performance, utility, and potential life-cycle management of the parent drug. 

    The prodrug approach seeks to create enhanced versions of already-known pharmacological agents and leverage those enhancements to increase the marketability of the drug. Some of these ways in which a parent drug can be improved are: increasing solubility, enhancing lipophilicity, improving the bioavailability, extending the half-life, imparting an extended-release profile, reduced interpatient variability, and targeted tissue/organ delivery. Simply put: prodrugs work by making good drugs better. 

    Prodrugs also offer a “have your cake and eat it, too” risk-reward profile. Not only can prodrugs make good drugs better, but the development-time horizon can be significantly shorter than a traditional NCE because the active ingredient has previously been demonstrated to be safe and effective. Often, prodrugs can utilize the 505(b)(2) NDA pathway. In addition, because prodrugs are considered NCEs, they may be eligible for patent protection as novel compositions of matter, provided that all other applicable regulatory requirements are met.

    Despite these advantages, in the world of drug discovery, prodrugs are sometimes mistakenly viewed as “science-light” because, in most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the parent drug. This point of view understates the reality that prodrug design is a vastly complex scientific process.

    Prodrug development requires a comprehensive understanding of the physiochemical and biological properties of the active agent to produce the desired improvements, while maintaining the overall safety and efficacy of the parent drug. Additionally, prodrug science demands in-depth knowledge of the chemical relationship between parent drug and ligand (or promoiety), and the enzymatic and/or chemical reactions that occur in the body when administered. 

    Several crucial factors must be carefully considered when designing a prodrug. These include:

    • Parent drug selection. Not all drugs or drug categories are well suited for prodrug development. The parent drug must be “chemically receptive” and present an advantageous need-solution opportunity. 
    • Ligand or promoiety identification. Ideally, the ligand that is combined with the parent drug to form the prodrug conjugate should be safe and rapidly excretable from the body. The choice of ligand should also be considered with respect to the disease state, dose, and duration of therapy.
    • Parent vs. prodrug dynamics. The ADME properties of both the parent drug and prodrug need to be thoroughly understood and researched to determine where and to what degree the prodrug will enable the desired improvements.
    • Degradation. As noted above, the ideal prodrug is one where the parent and ligand cleave cleanly, and the active agent is absorbed (providing its therapeutic benefit) while the ligand is rapidly excreted. This process does not always happen perfectly—chemical or enzymatic reactions can sometimes produce unexpected results—so an understanding of degradation by-products that may impact stability is of paramount concern in prodrug discovery and development.

    Based on these factors, prodrug development has proven effective with several functional groups including carboxylic, hydroxyl, amine, phosphate/phosphonate, and carbonyl. Prodrugs produced via the chemical modification of these groups include esters, carbonates, carbamates, amides, phosphates, and oximes. Of these, esters are the most common prodrugs, with approximately 49% of all marketed prodrugs being activated by enzymatic hydrolysis. Representative of this is perhaps one of the most well-known prodrugs on the market today, Vyvanse® (lisdexamfetamine dimesylate). Other notable prodrug products include Tenofovir (antiviral for treatment of HIV-1 and hepatitis B), Valaciclovir (antiviral for treatment of herpes zoster, genital herpes, and herpes labialis), Valganciclovir (antiviral for treatment of cytomegalovirus [CMV] retinitis and prevention of CMV disease in D+/R- transplant recipients), Latanoprost (prostanoid selective FP receptor agonist for reduction of intraocular pressure), and Levodopa (precursor of dopamine for treatment of Parkinson’s disease).

    Approved by the FDA for patients 6 to 12 years in 2007 and for adults in 2008, Vyvanse was designed as a prodrug of d-amphetamine for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).  Though marketed products at the time, such as Adderall® and Ritalin®, were determined to be safe and effective in treating the symptoms of ADHD, there was a recognition within the medical community that those drugs presented challenges for certain patients as well as society (e.g., stimulant abuse). Vyvanse was introduced as a prodrug with a design that differed from other formulation approaches by leveraging enzymatic hydrolysis to convert the therapeutically inactive prodrug molecule to the active drug, d-amphetamine.

    In clinical studies, the prodrug construct of Vyvanse was shown to enable long-term efficacy throughout the day in both children and adults with once-daily dosing, addressing a key ADHD unmet need. Additionally, Vyvanse demonstrated an ability to lower the rates of inter-patient and intra-patient pharmacokinetic variability, reduce the risk of pH-mediated food or drug interactions, and lower the potential for abuse or diversion, which at the time of Vyvanse’s development was a new and growing significant societal concern that continues through today. Further, because these properties of Vyvanse were not formulation-based, patients could sprinkle the prodrug on food or dissolve in a liquid for ingestion, thereby providing a benefit to pediatric patients.

    Adding to Vyvanse’s value, and showcasing the overall value potential of prodrugs, the leading amphetamine-based ADHD drug at the time of Vyvanse’s FDA approval, Adderall XR®, was nearing its patent expiration. As a prodrug, Vyvanse had the potential to secure extended patent exclusivity beyond a typical drug formulation because Vyvanse and all prodrugs are generally considered NCEs. Collectively, these advantages made Vyvanse an extremely attractive ADHD option, resulting in Shire’s $2.6 billion acquisition of New River Pharmaceuticals, the developer of Vyvanse. 

    Today, Vyvanse is the branded market-share leader in ADHD. However, in the future, Vyvanse may not be the only ADHD prodrug available as drug developers, such as KemPharm, and its prodrug product candidates of methylphenidate (KP415 and KP484), seek to replicate and improve upon the success of Vyvanse. In proof-of-concept studies of KP415, the data suggested that its design could allow for the development of a product with once-daily dosing with a potentially improved onset and a long duration of action attributes that may benefit pediatric and adolescent patients with ADHD. Proof-of-concept studies of KP484 demonstrated an extended-release d-methylphenidate profile, with a potentially longer duration of action as compared to a current-marketed ADHD methylphenidate product, that may benefit and be best suited to the daily demands of adult ADHD patients that do not typically require a rapid onset. Should KP415 and KP484 demonstrate positive data in their pivotal clinical studies, KemPharm expects to file NDAs for FDA review in 2018 and 2019, respectively, with possible marketing approval shortly thereafter. Much like the success with Vyvanse, this timing could work to KemPharm’s advantage as several branded ADHD drugs, including Vyvanse itself, are facing patent-cliff pressure. 

    There is much to be appreciated about the often-underappreciated prodrug. Its elegance in chemistry, development, and marketability make prodrugs a very compelling pharmaceutical option, particularly for those companies seeking to rapidly capitalize on a specific patient-treatment need or a life-cycle management opportunity. Though significant expertise is required to successfully identify and develop prodrug candidates, the overall risk-reward profile can be highly attractive. For this reason, prodrugs continue to garner attention by companies across the pharmaceutical spectrum.

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