A prodrug developed via the 505(b)(2) pathway can improve an existing therapeutic while increasing the value of the asset. The therapeutics which excite us most here at Premier Consulting are drugs which deliver effective therapies to patients in need, including therapies improved by utilizing prodrugs. While not all prodrugs are eligible for development via the 505(b)(2) pathway, Premier Consulting, the industry leader, can guide you through the process to market success. We understand the competitive environment of improving a therapeutic – and focus on the medical, scientific, regulatory, and commercial success of your prodrug asset.

What Is a Prodrug?

A prodrug is by definition an inactive form of a drug that, once administered, undergoes a conversion by metabolic processes to become the active, pharmacological agent. In drug development, a prodrug asset is often capable of being developed via the 505(b)(2) approval pathway. Assets developed with a prodrug component often add much value to an existing therapeutic, but adds complexity in development.

A prodrug is useful when an existing drug is effective, but carries many unwanted side effects. The prodrug-based therapeutic often offers an improvement over an existing approved drug, and can mean improvements for the patient.

A Prodrug Example

We took a prior look at the Alkermes asset ALKS 8700 and its potential value for patients suffering from multiple sclerosis in 2014.

In 2014, we wrote that “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.”

In November 2017, Biogen and Alkermes plc announced entrance into a global license and collaboration agreement to develop and commercialize ALKS 8700, which is a novel oral formulation of monomethyl fumarate (MMF) for the treatment of relapsing forms of multiple sclerosis (MS). The formulation includes a prodrug intended to demonstrate similar efficacy of the active ingredient with fewer side effects.

ALKS 8700 is currently in Phase 3 clinical trials for MS, an unpredictable, often disabling immune-mediated disease of the central nervous system wherein relay of information between the brain and the body, as well as within the brain, is disrupted due to destruction of myelin on nerve fibers. Alkermes plans to seek approval of the ALKS 8700 prodrug under the 505(b)(2) regulatory pathway, referencing Biogen’s closely related Tecfidera^® (dimethyl fumarate), previously approved in 2013 (as described in our blog post). Briefly, Tecfidera is broken down into monomethyl fumarate, while ALKS 8700 is a prodrug of MMF and is inactive until metabolized into monomethyl fumarate. Tecfidera is known to cause abdominal pain in 18% of patients, as well as diarrhea, nausea, and/or vomiting in 9% to 14% of patients. The goal of developing a prodrug of MMF is to provide a formulation with fewer gastrointestinal side effects. The safety benefits of this drug compared to Tecfidera will be tested in a 5-week head-to-head study (EVOLVE-MS-2) that will evaluate the gastrointestinal tolerability of ALKS 8700 vs. Tecfidera.

The Arrangement for Shared Development

Alkermes will maintain responsibility for regulatory interactions with the US FDA through the initial approval of ALKS 8700. Alkermes has completed the pharmacokinetics bridging studies that establish bioequivalence between Tecfidera and ALKS 8700. In addition, a two-year safety study is underway (EVOLVE-MS-1) to support the safety of ALKS 8700 in the eventual NDA.

The agreement between Biogen and Alkermes provides exclusive, worldwide license to Biogen to commercialize ALKS 8700. The deal includes the following:

• Biogen will reimburse Alkermes for 50% of the 2017 ALKS 8700 development costs ($28 million to date).
• As of Jan 1, 2018, Biogen will be responsible for all development expenses.
• Alkermes may also receive milestone payments for ALKS 8700 up to a maximum aggregate value of $200 million for certain clinical and regulatory achievements – an initial $50 million milestone payment and $150 million if the drug is approved in the US by the end of 2021.
• Biogen will pay Alkermes a mid-teens royalty on worldwide net sales of the prodrug, including minimum annual payments for the first 5 years post-approval.
• Biogen will be responsible for all marketing activities of ALKS 8700.

Through this deal, Biogen will profit from sales of ALKS 8700, which could cut into sales of Tecfidera. Further, ALKS 8700 extends the patent life of Biogen’s fumarate franchise out to 2033 (Tecfidera patents will expire in 2027).

The Stakes

While Alkermes is looking to receive milestone payments and royalties, the deal includes wording that puts pressure on the elective EVOLVE-MS-2 head-to-head gastrointestinal tolerability study in order for Alkermes to profit from the deal. If ALKS 8700 is deemed inferior for gastrointestinal tolerability compared to Tecfidera, the $50 million upfront payment will be returned to Biogen in the form of reductions in royalty rates; further, minimum payments to Alkermes will terminate. In the case that Biogen terminates the deal based on findings of gastrointestinal inferiority, Alkermes would not get the rights to ALKS 8700 back. Initial data from the EVOLVE-MS-2 study are expected in the first half of 2018.

Premier Consulting Expertise

If you are considering improving an existing therapeutic by introducing a prodrug, there are many angles to consider which are unique to your program. Premier Consulting has in-house experts who work to create an optimal development program, to minimize the time, money, and risk inherent in development. We would love to understand your needs and discuss how we can help you increase the value of your prodrug asset under 505(b)(2). Please contact us to learn more.