The Food and Drug Administration (FDA) began requiring drug efficacy, in addition to safety, for approval in 1962 based on the Kefauver-Harris Amendment. Despite this requirement, many drugs that have been approved by FDA have limited efficacy (eg, drugs that treat cancer or Alzheimer’s disease). In many cases, some portion of the limited efficacy is due to dosing limitations, route of administration, or formulation issues.

One possible solution to address the dosing, route of administration and formulation issues that contribute to the limited efficacy has been the development of prodrugs for some of the minimally effective drugs. Prodrugs are pharmacological substances administered in an inactive or less active form and are then converted into active drugs by metabolism or physico-chemical transformation in the body after administration. Some prodrugs exist naturally, including L-dopa, psilocybin, and aspirin; others, such as codeine, were discovered serendipitously during drug development. The specific advantage of some prodrugs is often related to issues of limited bioavailability (low systemic exposure) or high first pass extraction (elimination by the liver through metabolism before the drug gets to the blood stream), instability of the active drug, dosing limitations, or tolerability.

NCE Status for Prodrugs

An important consideration from a commercial protection standpoint when developing a prodrug of a previously approved active compound is whether the prodrug will be designated as a new chemical entity (NCE) by FDA. An NCE is defined in the Code of Federal Regulations (CFR) a drug that “contains no active moiety that has been approved by FDA in any other application”. Further, an active moiety is defined as “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”. (21 CFR §314.108)

The determination that the new drug is an NCE is critical because NCE status allows for 5 years of market exclusivity (also referred to as Hatch-Waxman exclusivity) after approval regardless of the patent situation. NCE exclusivity is granted for products “containing chemical entities never previously approved by FDA either alone or in combination”. This type of exclusivity protects against submission of applications (ANDA and 505(b)(2)) by a different manufacturer using the same prodrug (NCE) for a 5-year period, except for those containing a certification of patent invalidity or noninfringement, which allows for submission after 4 years. Exclusivity for 3-years (called “other” exclusivity) may be granted for a drug product that contains an active moiety that has been previously approved if new clinical investigations (other than bioavailability studies) have been conducted by the sponsor in support of approval.

There is a controversial history with FDA’s decision to grant NCE status for prodrugs. In certain cases, FDA has reevaluated its decisions months or years after drug approval due to a variety of factors. One such example is that of Emend [fosaprepitant dimeglumine] injection (NDA 022023), wherein FDA reversed their exclusivity decision from 3-years exclusivity to 5-years as an NCE. The active ingredient in Emend injection (fosaprepitant dimeglumine) is a prodrug phosphoramide derivative of aprepitant, the active ingredient in Emend capsules (NDA 021549). In their reversal, FDA concluded that Fosaprepitant dimeglumine is neither an ester, salt, nor other noncovalent derivative of the molecule aprepitant and thus, by 21 CFR §314.108, FDA concluded that the prodrug was an NCE and awarded 5-years exclusivity. Although not a reversal, Vyvanse (lisdexamfetamine dimesylate) is another example of a prodrug that received 5-years exclusivity. FDA determined that the API was a new molecular entity (NME) as a non-ester covalently bonded molecule.

ALKS 8700 Prodrug for Treatment of Multiple Sclerosis

As FDA’s decisions on NCE status for prodrugs have been inconsistent (although they have reversed previous decisions to account for this), it will be interesting to follow the outcome for new prodrugs like ALKS 8700, Alkermes novel prodrug of monomethyl fumarate (MMF) for the treatment of multiple sclerosis (MS). Although MMF is not approved for MS, the closely related dimethyl fumarate (MMF) ester of fumaric acid was approved in 2013 (Tecfidera). Information on the actual chemical in ALKS 8700 that is the prodrug is not available in the patent or in the public domain at this time. However, it would be reasonable to assume that ALKS would receive 5-years exclusivity, if the compound is not a previously approved moiety.

Currently, approximately 400,000 individuals in the US and 2.5 million people worldwide have MS, an autoimmune disorder of the central nervous system. The most common form of this disease is relapsing-remitting MS, which is characterized by defined episodes of worsening of neurologic functioning followed by partial or complete recovery periods free of disease progression. Alkermes recently announced initiation of a randomized, double-blind, Phase 1 study investigating the safety, tolerability, and pharmacokinetics of several formulations of ALKS 8700 in 125 healthy volunteers.

If approved, ALKS 8700 would compete commercially with Tecfidera (dimethyl fumarate) delayed-release capsules, Biogen Idec’s multibillion dollar blockbuster therapy for MS approved last year. Tecfidera is administered as a twice-daily oral therapy that functions by suppressing the immune system. ALKS 8700 is targeted for once daily dosing with reportedly and potentially fewer side effects than Tecfidera. Administration of dimethyl fumarate (DMF), the active pharmaceutical ingredient in Tecfidera, leads to side effects such as gastrointestinal upset (nausea, vomiting, and diarrhea) and transient flushing of the skin (see prescribing information). The pharmacodynamics profile of the prodrug of MMF under development by Alkermes could demonstrate a reduction in flushing, which could improve patient adherence. Alkermes hopes to use the results of their Phase 1 study to determine the therapeutic utility and differentiating features of ALKS 8700 compared to current therapy.