Lyrica Braces Against Incoming Generic Competition: New Indication Added by FDA

You may wonder how Lyrica is doing while strolling by Silverman Hall in this gorgeous Spring weather. The treatment for Fibromyalgia, approved in 2004 and protected as Northwestern University's intellectual property, is a best-seller at Pfizer ($4.6B in 2018). The only product sold by the company that can beat Lyrica's yearly sales is Prevnar 13, a vaccine for the prevention of pneumococcal disease ($5.8B). Together, this pair constitutes 1/5 of the company's sales.

Originally expected to terminate in December of 2018, the exclusivity protection for the drug is clear until one week after graduation: June 30, 2019. Where did this 6-month extension come from, and how did Pfizer make it work?

Pregabalin is a ligand for the α2δ subunit of proteins acting as voltage-gated calcium channels. These two tertiary structures are joined by a cysteine bridge and respond to Gabapentinoids. Gabapentinoids are molecular compounds related to the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that block the calcium channels (see Structure-function of proteins interacting with the α1 pore-forming subunit of high-voltage-activated calcium channels, Frontiers in Physiology).

There are four isoforms of this subunit found in humans, one shown above. The WFA domain shown in purple and the δ peptide shown in cyan have a gold section in between denoting the disulfide bond stabilizing the cysteine bridge. The proposal of this bond was delivered in 2011 when a group mutated the Cysteine 404 residue (shown to the right)) and observed a great decrease in calcium channel functionality in response to a +90 mV depolarizing pulse (see Identification of a disulfide bridge essential for structure and function of the voltage-gated Ca2+ channel α2δ-1 auxiliary subunit, Cell Calcium).

Drugs approved by the FDA lose their exclusivity after 5 years, generally speaking. The key points from the FDA's Development Process page are below.

  • New Chemical Entity Exclusivity (NCE) – 5 years
  • Pediatric Exclusivity (PED) – 6 months added to existing Patents/Exclusivity
The first step was winning exclusivity approval for Lyrica as a new chemical entity (NCE). This came in December of 2004 when Northwestern University patented the drug. Licensed to Pfizer for manufacturing, Lyrica went on to sell successfully. The onset of generic competition came in 2015 and the FDA used that event to establish the beginning of Pfizer's 5-year sales exclusivity. This was scheduled to terminate on December 30, 2018.

By granting pediatric exclusivity for a 6-month period, the FDA extended Pfizer's position until June. The indication that the FDA recognized was pediatric epilepsy.

A setback in Alzheimer's Medicine: Biogen and Eisai Discontinue Phase 3 Trials of Aducanumab in Alzheimer's Disease


Who doesn't love monoclonal antibodies (mAbs)? The vanguard of cellular specificity, these protein machines speed around with monovalent affinity and bind selectively. The latest developments in Alzheimer's research have led to a mAb that can selectively attack structures related to the disease, but the companies researching the clinical uses of the biologic compound are no longer certain that trials will yield meaningful results.

To quote the company:
Biogen and Eisai, Co., Ltd. today announced the decision to discontinue the global Phase 3 trials, ENGAGE and EMERGE, designed to evaluate the efficacy and safety of aducanumab in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease dementia. The decision to stop the trials is based on results of a futility analysis conducted by an independent data monitoring committee, which indicated the trials were unlikely to meet their primary endpoint upon completion. The recommendation to stop the studies was not based on safety concerns.

To clarify, "endpoints" are quantifiable results that are measured during trials to implement a statistical qualification for success.

Where did Biogen get its hands on this monoclonal antibody treatment? Who owns the patent?
Biogen licensed aducanumab from Neurimmune under a joint development and license agreement.
How was this biologic compound discovered?
Aducanumab is a human monoclonal antibody (mAb) derived from ... cells collected from healthy elderly subjects with no signs of cognitive impairment or cognitively impaired elderly subjects with unusually slow cognitive decline using Neurimmune’s technology platform called Reverse Translational Medicine (RTM).
How does the RTM platform work?
Researchers find healthy subjects and gauge their response to disease-related proteins, looking for common antibody presence. Then they take them. Think vampires.
Is Neurimmune's RTM platform for isolating immunotherapeutics a reliable way of finding effective, specific, and appropriate immunotherapeutics?
Certainly not.
Is a mechanism of action presented along with candidate antibodies through RTM?
Also no.
Is there any real advantage in discovering antibodies through RTM?
At the very least, what we know cannot hurt us. They're guaranteed 100% human.

Nature published an article related to this antibody back in 2016 (see The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease, Nature). The research demonstrated that "In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner," but the recent futility analysis conducted by an independent data monitoring committee discouraged the manufacturer from pursuing extensive clinical trials. The use of immunostaining of "autopsy tissue from patients with AD ... confirmed binding of aducanumab to bona fide human Aβ fibrils" and brought one of many promising findings delivered in the paper.

Clearly, there is much left to understand about neuroscience and the Amyloid β amino acid chains of roughly 40 residues that constitute the amyloid plaques found in the brains of Alzheimer patients. Even global Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies are not too big to fail. Even when they made it onto a Nature Cover.

ISP Sci. Rev. 14 (2019)
Editor: John Hruska
Editor-in-Chief (aka did nothing): Shiwei Wang
Integrated Science Program
Northwestern University

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