Neuromuscular blockade (NMB) reversal: an interview with Darryle Schoepp, senior vice president and head of Neuroscience and Ophthalmology, Merck Research Laboratories, Merck

Published on January 24, 2013 at 5:54 AM · No Comments

Interview conducted by , BA Hons (Cantab)

Darryle Schoepp ARTICLE

Please can you give a brief introduction to neuromuscular blockade (NMB)?

General anesthesia is made up of three components: hypnotic medicines, to induce sleep; analgesics, or medicines to inhibit pain; and NMB agents that induce muscle relaxation. Anesthesiology professionals use NMB to relax a patient’s muscles and prevent involuntary movement that could impact surgery.

What induces NMB?

There are a number of steroidal and non-steroidal agents that induce NMB by temporarily preventing the transmission of nerve impulses between a nerve and a muscle, leading to muscle relaxation. This muscle relaxation can facilitate insertion of a breathing tube, as well as providing the surgeon with optimal conditions for surgery.

Rocuronium and vecuronium are two muscle relaxants commonly used by anesthesia professionals in the U.S.

What is NMB used for?

Muscle relaxation, or neuromuscular block (NMB), plays a key role in general anesthesia by facilitating intubation so a patient can be ventilated during surgery. In addition, relaxation of skeletal muscles is often needed to perform surgical procedures and to prevent involuntary movements by the patient during surgery. Thus, NMB can help improve surgical conditions and reduce the risk of surgical complications.

Why is it important to be able to reverse NMB?

Just as it is important to relax patients’ muscles during surgery, it is also important that the effects be reversed once surgery is complete so that patients breathe independently and resume normal muscle function.

Incomplete reversal of NMB can cause post-operative complications, including breathing difficulties, vision abnormalities, weakness and fatigue. These residual effects may cause the patient to be admitted to or remain longer in the post-anesthesia care unit. In some cases, incomplete reversal of NMB may even lead to clinically relevant respiratory complications after surgery, such as pneumonia.

How was NMB previously reversed?

A commonly used agent for the reversal of muscle relaxation is neostigmine, which is often administered with an antimuscarinic agent, such as glycopyrrolate, to prevent neostigmine’s autonomic side effects, such as heart rate disturbances.

However, due to their indirect MOA, current reversal agents can only reverse moderate depth of NMB and may also be slow in reversing NMB. Moreover, they may be associated with incomplete reversal, as well as side effects that could include cardiac rhythm disturbances, gastrointestinal and pulmonary side effects.

Please can you tell us about Merck’s sugammadex sodium injection? How does this differ from previous NMB reversal methods?

Sugammadex is designed to work by a different mechanism than that of currently available reversal agents in the U.S. It works by inactivating rocuronium or vecuronium molecules directly by encapsulation and inactivation. If approved, sugammadex would be the first – and only – in a new class of medicines in the U.S. known as selective relaxant binding agents to be used in the surgical setting for NMB reversal of these two commonly used muscle relaxants. It also is capable of reversing deep blockade.

How was Merck’s sugammadex sodium injection developed?

Sugammadex was initially developed at the Newhouse Research Laboratory in Scotland, where scientists who were performing routine experiments on rocuronium began to consider ways to dissolve it.  Rocuronium has a fat-soluble steroid component. One such experiment used a cyclodextrin solution. Cyclodextrins, which are ring-shaped compounds consisting of sugar molecules, are known to dissolve steroids.  Researchers found rocuronium was soluble in the cyclodextrin solution and could be encapsulated inside the ring of the sugar molecules, stopping the muscle relaxation effect typical of rocuronium.  Following two additional years of research and testing of more than 40 different cyclodextrins, the team created sugammadex.

Why did the FDA not approve the original New Drug Application (NDA)?

In 2008, the FDA did not approve the original NDA for sugammadex sodium injection, requesting additional data related to hypersensitivity (allergic) reactions and coagulation (bleeding) events. Sugammadex was approved in the EU in 2008, and since then it has been approved in 75 countries, and marketed in most under the trade name Bridion.

Since 2008, Merck has remained committed to making sugammadex available in the U.S. As such, all of our follow-up studies to address the FDA issues related to the hypersensitivity reactions and coagulation events were designed and conducted with regular feedback from the FDA. As a result, the FDA has now deemed the additional data complete for review.

What stage of development is Merck’s sugammadex sodium injection currently at?

In the U.S., the resubmission of the New Drug Application (NDA) for sugammadex sodium injection has been accepted for review by the U.S. Food and Drug Administration (FDA), and we are hopeful that we will receive approval from the FDA and can bring this medicine to the U.S., as well.

Outside of the U.S. and the 75 countries where sugammadex is currently approved, Merck also continues to work with other countries around the world to register this medicine.

What do you think the future holds for NMB reversal?

While Merck does not speculate regarding future plans of its products or developments of its competitors, we remain very committed to making sugammadex available in the U.S. and the company is pleased the FDA has accepted the resubmission for review. 

What are Merck’s plans for the future?

Merck expects the FDA’s review of sugammadex to be completed in the first half of 2013, at which time, we hope to obtain approval and bring this medicine to the U.S. marketplace.

Beyond sugammadex, Merck remains committed to scientific excellence, and the discovery and development of innovative treatments for patient care in hospitals. We will continue to strive to develop new solutions to help our hospital-based customers deliver quality care to their patients.

Where can readers find more information?

American Society of Anesthesiologists:  www.asahq.org

American Association of Nurse Anesthetists:  www.aana.com

European Society of Anaesthesiology:  www.euroanaesthesia.org

International Anesthesia Research Society: http://www.iars.org/home/

About Darryle Schoepp

Darryle Schoepp BIGDarryle D. Schoepp joined Merck Research Laboratories in 2007 as Senior Vice President and Franchise Head for Neuroscience.  He has global responsibility for neuroscience and ophthalmology from discovery through late clinical development, and is a member of the Merck Global Scientific Strategy group responsible for therapeutic area strategies and prioritization of the Merck pipeline. 

Merck Neuroscience has focused its research directions in neurology, psychiatry, and ophthalmology research towards important medical needs where the science and the clinical path are the most promising, and have built industry leading drug discovery platforms and target engagement biomarkers to enable better translation into the clinic. 

Merck has established an innovative late and early stage Neuroscience pipeline with highly promising programs for insomnia, migraine/pain, schizophrenia, Parkinson's disease, and Alzheimer's disease.

Prior to joining Merck, Dr. Schoepp was a drug discovery scientist at Eli Lilly for 20 years, where from 2004 – 2007 he served as vice president of neuroscience research responsible for the company's neuroscience strategy and pipeline.

As a scientist, he is recognized for having made major contributions in the investigation of the excitatory amino acid neurotransmitter glutamate in disease pathophysiology, pharmacology and therapeutics.

Dr. Schoepp's honors include the 2002 Pharmacia / ASPET Award for Experimental Therapeutics for his research on the experimental therapeutics of metabotropic glutamate receptors in psychiatry, and 2007 Ray Fuller / ASPET Lecturer in Neurosciences in recognition of translational pharmacology work in the glutamate field. 

He has organized and/or participated in numerous international meetings and symposium, published over 200 papers and reviews, and is an inventor of 14 US patents. 

Dr. Schoepp's professional activities include Basic Pharmacology Executive Committee member of the Pharmaceutical Manufacturers Foundation, member of the American College of Neuropsychopharmacology (ACNP), and editorial board for Neuropharmacology. 

Dr. Schoepp received his bachelor's degree in Pharmacy from North Dakota State University and his doctoral degree in Pharmacology and Toxicology from West Virginia University.

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