he Sanford-Burnham researchers develop the first experimental drug to boost brain

fragment of the molecule nitroglycerin— a second

FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart

placebo-controlled, double-blind, multi-national, multi-centre trial. 992 patients from 12 European countries were divided into three treatment arms of

drug, called NitroMemantine, combines two FDA-

disease— could bind to another site that the Lipton

equal size. Patients in the first two groups received

approved medicines to stop the destructive cascade of

group discovered on NMDA receptors. The new drug

two different doses of the tablet, while patients in the

changes in the brain that destroys the connections

represents a novel synthesis connecting this fragment

third group received placebo but had unrestricted

between neurons, leading to memory loss and

of nitroglycerin to memantine, thus representing two

access to symptom-relieving medication. The patients

cognitive decline. The decade-long study, led by

FDA-approved drugs connected together. Because

received treatment once daily for one year. House

Stuart A. Lipton, M. D., Ph. D., professor and director

memantine rather selectively binds to eNMDA

dust mites are the most common cause of allergy in

of the Del E. Webb Center for Neuroscience, Aging,

receptors, it also functions to target nitroglycerin to

the world. The condition appears early in life, is

and Stem Cell Research, who is also a practicing

the receptor. Therefore, by combining the two,

present all year round and patients face an elevated

clinical neurologist, shows that NitroMemantine can

Lipton ' s lab created a new, dual-function drug. The

risk of developing asthma and other allergies. In

restore synapses, representing the connections

researchers developed 37 derivatives of the combined

Europe ' s five largest markets, around 1.25 million

between nerve cells( neurons) that have been lost

drug before they found one that worked, Lipton said.

people have been diagnosed with persistent

during the progression of Alzheimer ' s in the brain.

By shutting down hyperactive eNMDA receptors on

moderate-to-severe and uncontrolled house dust

The research findings are described in a paper

diseased neurons, NitroMemantine restores synapses

mite-induced allergic rhinitis, however, it is

published June 17 by the Proceedings of the National

between those neurons.“ We show in this paper that

estimated that just a quarter of these are treated with

Academy of Sciences of the United States of

memantine ' s ability to protect synapses is limited,”

the existing injection- or drop-based allergy

America( PNAS).

Lipton said,“ but NitroMemantine brings the number

immunotherapy products. The MERIT trial was

The focus on a downstream target to treat

of synapses all the way back to normal within a few

designed to form a pivotal part of ALK ' s submission

Alzheimer ' s, rather than on amyloid beta plaques and

months of treatment in mouse models of Alzheimer ' s

of a registration application in Europe. The new data

neurofibrillary tangles— approaches which have

disease. In fact, the new drug really starts to work

allows for a filing in 2014; however, ALK will await

shown little success—“ is very exciting because

within hours.”

the outcome of the on-going phase III MITRA trial

everyone is now looking for an earlier treatment of

To date, therapies that attack amyloid plaques

before submitting the registration application.

the disease,” Lipton said.“ These findings actually

and neurofibrillary tangles have failed.“ It ' s quite

MITRA evaluates the efficacy and safety of

mean that you might be able to intercede not only

disappointing because I see really sick patients with

the allergy immunotherapy tablet in the treatment of

early but also a bit later.” And that means that an

dementia. However, I ' m now optimistic that

allergic asthma caused by house dust mites. Nearly

Alzheimer ' s patient may be able to have synaptic

NitroMemantine will be effective as we advance to

50 per cent of all house dust mite allergic rhinitis

connections restored even with plaques and tangles

human trials, bringing new hope to both early and

patients suffer from asthma. The trial involves 834

already in his or her brain. In their study, conducted

later-stage Alzheimer ' s patients,” Lipton said.

patients and aims to demonstrate that the allergy

in animal models as well as brain cells derived from

Phase III MERIT trial of new allergy immunotherapy

immunotherapy tablets also reduce patients ' risk of

human stem cells, Lipton and his team mapped the

tablet against house dust mite allergy.

asthma exacerbations.

pathway that leads to synaptic damage in

ALK, the world leader in allergy

MITRA TRIAL: The MERIT and MITRA trials are

Alzheimer ' s. They found that amyloid beta peptides,

immunotherapy, has reported positive outcome of the

part of the largest clinical development programme in

which were once thought to injure synapses directly,

first of two pivotal phase III trials with its new

the history of allergy immunotherapy, which has seen

actually induce the release of excessive amounts of

allergy immunotherapy tablet for the treatment of

simultaneous development activities in both Europe

the neurotransmitter glutamate from brain cells called

house dust mite-induced respiratory diseases. The

and the world ' s two largest pharmaceutical markets,

astrocytes that are located adjacent to the nerve cells.

MERIT trial meets its primary endpoint and

Japan and the USA. Once completed, this programme

Normal levels of glutamate promote memory

demonstrates that the new treatment has a significant

will have involved more than 6,000 patients. In

and learning, but excessive levels are harmful. In

clinical effect in allergic rhinitis. The positive

Japan, ALK ' s partner Torii Pharmaceutical Co. Ltd. is

patients suffering from Alzheimer ' s disease,

outcome allows for a European filing in 2014. This

undertaking two parallel pivotal phase II / III trials to

excessive glutamate activates extrasynaptic receptors,

trial also demonstrated that the treatment was well

investigate the safety and efficacy of the allergy

designated eNMDA receptors( NMDA stands for N-

tolerated and had a favourable safety profile.“ The

immunotherapy tablet in the treatment of house dust

methyl-D-aspartate), which get hyperactivated and in

robust results of the MERIT trial represent a major

mite-induced allergic rhinitis and allergic asthma,

turn lead to synaptic loss.

step forward in the treatment of the world ' s most

respectively.

Lipton ' s lab had previously discovered how a

common cause of allergy estimated to affect more

In North America, ALK ' s partner Merck &

drug called memantine can be targeted to eNMDA

than 200 million people worldwide. Allergy

Co., Inc.( known as MSD outside the USA and

receptors to slow the hyperactivity seen in

immunotherapy tablets are an efficacious and

Canada) is currently performing a phase IIb trial and

Alzheimer ' s. This patented work contributed to the

convenient treatment for the many patients

has started preparations for a pivotal phase III

FDA approval of memantine in 2003 for the

experiencing poor disease control,” says executive

clinical trial to investigate safety and efficacy in the

treatment of moderate to severe Alzheimer ' s disease.

vice president Henrik Jacobi, head of R & D at ALK.

treatment of house dust mite-induced

However, memantine ' s effectiveness has been

The MERIT trial( MT-06) was initiated by

rhinitis / rhinoconjunctivitis in adolescents and adults.

limited. The reason, the researchers found, was that

ALK in 2011 to evaluate the efficacy and safety of

The partnership with Merck also covers two other

memantine— a positively charged molecule— is

the allergy immunotherapy tablet versus placebo in

allergy immunotherapy tablets for grass and ragweed

repelled by a similar charge inside diseased neurons;

the treatment of house dust mite-induced allergic

allergy, respectively. In Q1 2013, filings for both of

therefore, memantine gets repelled from its intended

rhinitis. The primary endpoint of the trial was a

these products were submitted by Merck in the USA

eNMDA receptor target on the neuronal surface.

reduction in the combined rhinitis symptom and

and are currently under review by the US Food and

In their study, the researchers found that a

medication score. The trial was a randomised,

Drug Administration.