Skip links

The Prodrug Benefit of Utilizing the 505(b)(2) Pathway

Designing a new drug from scratch is costly and time-consuming. One attractive option to differentiate from currently marketed products is to chemically modify the characteristics of an existing drug to create a prodrug. Often a prodrug can improve the safety and efficacy of an approved therapeutic. Here, we discuss the basics of prodrugs, how the 505(b)(2) pathway can be utilized, and how some pharmaceutical companies are currently taking advantage of the prodrug strategy.

What Is a Prodrug?

A prodrug is inactive in its current form and therefore requires metabolic conversion after administration to become pharmacologically active. Prodrugs are formed from reversible linkage to carriers, other drugs, or molecular modifications. Esters are an especially appealing modification as this functional group can improve lipophilicity for passive membrane transport or increase the aqueous solubility of the active drug, depending on the type of ester.

Prodrugs are also useful in penetrating the blood brain barrier, which is notoriously restrictive. Removing polar groups to increase passive diffusion, mimicking a transporter substrate, or decreasing the efflux from the brain back into the blood are the main tactics a prodrug can take to access the central nervous system. The need to design a prodrug is often related to undesirable properties of the parent drug including poor bioavailability, poor site specificity, high presystemic metabolism, instability, and toxicity. Basically, the idea is to optimize the absorption, distribution, metabolism, andexcretion (ADME) of the parent drug in order to maximize the amount of active drug that reaches its site of action.

How Do Prodrugs Fit into the 505(b)(2) Pathway?

A prodrug falls under the 505(b)(2) pathway if the parent drug has already been approved and the applicant does not have a right of reference to the studies that supported approval of that product. The determination of exclusivity for a prodrug was nicely detailed in a previous Premier Consulting blog post.

Briefly, a prodrug can receive 5 years of exclusivity under the 505(b)(2) pathway if it is a new chemical entity (NCE). An NCE, as defined by the Code of Federal Regulations (CFR), is “a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505(b) of the act.” Furthermore, an active moiety refers to the “molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”

If the only difference between the prodrug and parent drug is an ester, salt, or other noncovalent derivatives, only 3 years exclusivity will be awarded. No exclusivity is given for prodrugs that do not require new clinical investigations aside from bioavailability studies. (21 CFR §314.108)

Not only is there the possibility for up to 5 years of exclusivity (or even 7 years for an orphan drug designation), but utilization of the 505(b)(2) pathway for prodrugs can provide efficiencies in the development process. The ability to rely on previously conducted research studies can shorten the time to market at a lower cost compared to a 505(b)(1) approval.

Prodrugs as Potential Opioid Abuse Deterrents

Abuse of prescription opioid pain medications has created a serious public health problem. Developing abuse-deterrent formulations of these products is a high priority. Typically, these are designed to make manipulation of the drug (e.g., crushing for subsequent use in snorting, smoking, injecting) more difficult while maintaining its efficacy when taken as directed. The FDA Guidance for Abuse-Deterrent Opioids-Evaluation and Labeling (CDER 2015) suggests that “a prodrug that lacks opioid activity until transformed in the gastrointestinal tract can be unattractive for intravenous injection or intranasal routes of abuse.” There are currently six approved extended-release opioid products with abuse-deterrent properties, but no immediate-release products with this labeling.

KemPharm recently filed an NDA utilizing the 505(b)(2) pathway for Apadaz, an immediate-release oral tablet of benzhydrocodone and acetaminophen. KemPharm used the listed drugs Vicoprofen (for the hydrocodone component) and Ultracet (for the acetaminophen component) as well as the clinically-relevant comparator Norco for bioequivalence studies. The prodrug, benzhydrocodone, is designed to not release the active hydrocodone until after metabolism in the GI tract.

The Sponsor claims hydrocodone is not released when administered intranasally and has poor solubility in the blood as part of its abuse-deterrent properties. A joint FDA advisory panel rejected the abuse-deterrent labeling but recommended approval of Apadaz. However, the FDA itself did not agree and issued a Complete Response Letter. This means that the review of the application is complete but not ready for approval in its present form. It remains to be seen what additional information is needed for Apadaz approval.

Improving Antivirals with Prodrugs

Chronic hepatitis B (HBV) is a growing problem in the United States. HBV infects the liver and patients with chronic cases are at a higher risk for cirrhosis and cancer of the liver. There are currently seven FDA-approved drugs for the treatment of HBV but none are completely effective at eradicating the virus. Interferon therapy has a lower frequency of resistance, but compared to nucleoside analogs has increased side effects, higher costs, and limited patient response.

The nucleoside analog Tenofovir (Viread®), in combination with other antivirals, is the current standard of treatment for HBV. However, like other approved HBV drugs, it is not completely effective at permanently suppressing HBV replication. Contravir’s answer to this is CMX157, a prodrug of tenofovir.

The added “lipid tail” of CMX157 is designed to aid in absorption by harnessing natural lipid uptake mechanisms in the liver. In addition, CMX157 is not metabolized to the parent drug in the GI tract or in the blood, but by intracellular phospholipases, which both reduces systemic toxicity of tenofovir and concentrates the active drug at the target site.

CMX157 is currently in Phase 2 clinical studies and it is expected that Contravir will take advantage of the 505(b)(2) pathway for its lipidated tenofovir prodrug.


Opioid abuse-deterrents and antivirals are just two examples of how prodrugs are being used to improve the safety and efficacy of existing products. As illustrated above, many of these prodrugs meet the criteria for the 505(b)(2) pathway and can get to the market relatively quickly.

Premier Consulting can find the fastest, most efficient to market development program for your prodrug product. Learn more about how we can help navigate the 505(b)(2) pathway successfully or contact us here.