Glaxo Smith Kline de­vel­ops grain-size nerve im­plants to tar­get ill­ness

Glax­oSmithK­line is ex­per­i­ment­ing with grain-size im­plants that treat dis­ease

Bloomberg Businessweek (Asia) - - NEWS - With Ellen Huet

When Kris Famm was 15, he be­came ob­sessed with pho­to­syn­the­sis. He lived with his par­ents and older brother, Fredrik, on a farm not far from the Baltic coast in south­east­ern Sweden, in an ex­panse of gen­tle hills threaded with forests of birch and spruce. It was a par­adise for two en­er­getic boys, and they spent most of their free time out­side, of­ten with their grand­fa­ther. Lead­ing Kris and Fredrik on long hikes through the woods, he taught them about trees and wildlife and the rich­ness of the land, which he was the last in the fam­ily to till.

The late 1980s and early ’90s were a time of ris­ing en­vi­ron­men­tal con­cern in Sweden. Cli­mate change was en­ter­ing the public con­scious­ness, and the first traces of ab­nor­mal ra­di­a­tion from Ch­er­nobyl had been de­tected at a Swedish nu­clear plant. To the teenage Kris, it seemed like the world would de­stroy it­self with­out find­ing a rad­i­cal new source of clean power. Pho­to­syn­the­sis, he thought, must hold the key: If plants could pro­duce in­fi­nite energy from noth­ing but air, water, and sun­light, why couldn’t hu­mans?

“I re­mem­ber think­ing, ‘There is this se­cret all around us, and we should be able to put it to use,’” Famm says. “There is clearly, in na­ture, a sci­en­tif­i­cally an­chored way of do­ing this.” He re­solved to learn ev­ery­thing he could about bio­chem­istry. For his high school the­sis, Famm de­vised a se­ries of experiments to mea­sure the ef­fi­ciency of pho­to­syn­the­sis when leaves were coated with dif­fer­ent dyes and waxes.

Famm is now 38, with a floppy thatch of blond hair and a singsong ac­cent that gives away his Scan­di­na­vian roots. He’s traded the bu­colic plea­sures of ru­ral Sweden for a maze-like re­search cen­ter squeezed be­tween a high­way and a rail line in Steve­nage, north of Lon­don. On a blus­tery Tues­day in March, Famm is cramped into a sort of modernist gar­den hut, about the size of a large cube van, set up in a court­yard.

The com­plex be­longs to Glax­oSmithK­line, the $100 bil­lion Bri­tish phar­ma­ceu­ti­cal com­pany, where Famm is in charge of de­vel­op­ing a class of treat­ments called bio­elec­tron­ics. The idea is to cre­ate im­plants the

size of a grain of rice, or even smaller, that can be bolted di­rectly onto nerves to treat dis­eases, aug­ment­ing or re­plac­ing drugs. With internal bat­ter­ies to send tiny elec­tric pulses, the im­plants could al­ter nerve sig­nals to loosen up air­ways in asthma suf­fer­ers, for ex­am­ple, or re­duce in­flam­ma­tion in the gut from Crohn’s dis­ease. Even can­cer is a long-term tar­get. Side ef­fects could be min­i­mal, in the­ory, com­pared with those of drugs, which flood the body with foreign mol­e­cules. Doc­tors could stop wor­ry­ing about pa­tients for­get­ting to take pills.

Like pho­to­syn­thetic energy, bio­elec­tron­ics lever­age some­thing that al­ready ex­ists: the ner­vous-sys­tem con­nec­tions link­ing ev­ery part of the body to the brain. “You pig­gy­back on the cir­cuits that are there,” Famm says. “These ca­bles go to and from all our or­gans. They’re there to con­trol our phys­i­ol­ogy.”

The un­der­ly­ing con­cepts are well-es­tab­lished, and early ver­sions of what he’s de­scrib­ing are al­ready on the mar­ket. Still, the project is a long-odds bet that Glaxo is vir­tu­ally alone in mak­ing among its Big Pharma peers. It has started a $50 mil­lion ven­ture fund for bio­elec­tron­ics and funded about 100 out­side sci­en­tists, along with an in-house re­search team of 30, be­cause the mi­cro­gad­gets may of­fer a so­lu­tion to the ruth­less arith­metic of drug development. The past decade has seen huge ad­vances in con­ven­tional molec­u­lar ther­a­pies for a wide range of dis­eases, but the treat­ments are com­ing at ever-higher prices. The av­er­age new drug takes 10 years and $2.6 bil­lion to get from lab to phar­macy, ac­cord­ing to in­dus­try group PhRMA. At the same time, hos­pi­tals and in­sur­ers in the U.S., the world’s most prof­itable mar­ket, are re­sist­ing high prices, squeez­ing re­turns. The im­plants, and the ad­vances lead­ing to them, would all be patentable, giv­ing their in­ven­tors a lock on the pro­ceeds.

Although Glaxo is nowhere near aban­don­ing tra­di­tional drug development, the com­pany needs a hit more than most. Core earn­ings per share, its pre­ferred mea­sure of prof­itabil­ity, have fallen in 8 of the last 10 quar­ters. Glaxo’s block­buster asthma treat­ment, Ad­vair, is about to face generic com­pe­ti­tion in the U.S., and ma­jor tri­als of a new heart drug and a can­cer vac­cine have failed in the fi­nal stages. The com­pany’s shares have lagged those of its peers for the last sev­eral years.

To make mat­ters worse, Glaxo has largely missed out on the break­throughs in im­mune ther­apy and hep­ati­tis drugs that have su­per­charged ri­vals such as Merck and Bris­tolMy­ers Squibb. Also, a bribery scan­dal in China led to a $489 mil­lion fine in 2014. In March, Glaxo’s chief executive, An­drew Witty, said he’d step down in 2017 amid in­vestor crit­i­cism of a weak re­search and development pipe­line.

The ner­vous sys­tem is a bit like a com­puter. Neu­rons are ei­ther on or off, one or zero, fir­ing elec­tric im­pulses called ac­tion po­ten­tials in pat­terns that carry in­struc­tions from the brain. In­tro­duc­ing new elec­tri­cal pulses can tweak those pat­terns, block­ing some com­mands and en­cour­ag­ing oth­ers. Sci­en­tists now be­lieve the pulses’ pre­cise wave­length and frequency mat­ter im­mensely and may need to change mo­ment by mo­ment to have the de­sired ef­fect.

Early pro­to­types of bio­elec­tron­ics are be­ing tested in rats. Those im­plants—about the size of a pill and pack­aged in resin, metal, or ce­ramic—are wire­lessly pow­ered. Glaxo is plan­ning ini­tial hu­man tri­als for three ma­jor chronic dis­eases next year us­ing third-party de­vices, with the first im­plant de­vel­oped by the com­pany it­self to fol­low in 2019. It won’t spec­ify the dis­eases it’s look­ing into, but arthri­tis and di­a­betes are where the big money is. Three of the world’s top five best-sell­ing drugs are pri­mar­ily used for arthri­tis, led by Ab­bVie’s Hu­mira, which pulls in more than $14 bil­lion a year.

Us­ing elec­tric­ity as medicine isn’t a stretch. Pace­mak­ers have been around since the 1930s. The ear­li­est mod­els had to be hand-cranked to gen­er­ate volt­age. More re­cently, deep-brain stim­u­la­tion has be­come a com­mon treat­ment for Parkin­son’s dis­ease. Elec­trodes are threaded far into the brain from a bat­tery typ­i­cally im­planted in the torso.

What Glaxo and a clutch of other com­pa­nies and re­search or­ga­ni­za­tions en­vi­sion is far more am­bi­tious: tiny de­vices that might sur­round a bun­dle of nerve fibers like a cuff, bristling with even smaller elec­trodes re­sem­bling spokes on a tiny wheel. They’d be ca­pa­ble of au­tonomously mon­i­tor­ing symp­toms at the source and ad­just­ing their elec­tri­cal out­put ac­cord­ingly, per­haps for a pa­tient’s whole life­time.

There’s a daunt­ing list of chal­lenges to over­come first, but one stands out: un­der­stand­ing the body’s supremely com­plex wiring. Sci­en­tists still don’t know which neu­rons con­trol which or­gan func­tions, or how to finely ad­just their be­hav­ior. As Ed­ward Boy­den, who leads a brain-map­ping ef­fort at MIT, says, “The hard part of neu­ro­engi­neer­ing is the ‘neuro’ part.”

Famm came to Bri­tain in 2002 to work on a doc­tor­ate in molec­u­lar bi­ol­ogy at Cam­bridge. He’d dreamed of fol­low­ing in the foot­steps of James Wat­son and Fran­cis Crick, the dis­cov­er­ers of the DNA mol­e­cule, and he started work­ing in the same in­sti­tute where the two made their break­through in 1953. Famm’s su­per­vi­sor was Greg Win­ter, a sci­en­tist whose re­search on an­ti­bod­ies led to the development of Hu­mira and the cre­ation of a string of biotech com­pa­nies. Win­ter was a de­mand­ing men­tor, cov­er­ing Famm’s the­sis drafts in red­penned margina­lia in­struct­ing him to junk whole sec­tions of “waf­fle” and zero in on a few spe­cific con­cepts. Famm was fo­cused on an­ti­body en­gi­neer­ing, the de­sign of finely tar­geted pro­teins to fight dis­ease.

Even though Cam­bridge was re­spon­si­ble for “some of the best years in my life,” Famm says, he strained against the de­lib­er­ate pace of academia and what seemed like a vast dis­tance be­tween foun­da­tional re­search and real-world prod­ucts. He left the lab for a job at con­sult­ing firm McKin­sey in 2006. Famm says his aca­demic col­leagues thought he was mak­ing a “pact with the devil”—ex­cept Win­ter, who told him it was the right move for mak­ing a big sci­en­tific im­pact later on. Af­ter three years as a con­sul­tant, Famm went to work as a strate­gist for Glaxo’s R&D department, a job

that re­quired him to scan the hori­zons of med­i­cal re­search for the most promis­ing and prof­itable con­cepts.

Glaxo’s drug­mak­ing roots date to the 1840s, when one of its pre­de­ces­sor com­pa­nies had a hit with Beecham’s Pills, a Vic­to­rian lax­a­tive made of aloe and gin­ger that was also mar­keted for “fe­male ail­ments.” The mod­ern com­pany is an as­sem­blage of smaller ones cob­bled to­gether through decades of merg­ers and ac­qui­si­tions. Some lab coats still bear the pale blue logo of Glaxo Well­come, which ceased to ex­ist in 2000 af­ter it merged with Smith Kline Beecham.

By the time Famm ar­rived, the com­pany’s need for new revenue was get­ting acute. Patent pro­tec­tion had ex­pired on four of Glaxo’s 15 best-sell­ers in 2008, and in 2010 a ma­jor drug for di­a­betes, Avan­dia, had to be largely pulled from the mar­ket af­ter stud­ies sug­gested it might con­trib­ute to heart at­tacks. The same year, Mon­cef Slaoui, a Moroc­can-born molec­u­lar bi­ol­o­gist who headed R&D, con­vened a small group to ex­plore break­throughs in areas be­yond tra­di­tional drug­mak­ing. Famm was on the team. The in­struc­tions were “to look at the con­ver­gence be­tween technology, IT, and bi­ol­ogy to see if there was some­thing there,” he says. “A some­what vague brief.”

In the spring of 2011, Famm and other ex­ec­u­tives gath­ered at Glaxo’s town­house office in May­fair, Lon­don’s Bent­leysand-bling district, and watched a pre­sen­ta­tion on vestibu­lar im­plants. The de­vices can help pa­tients whose sense of balance has been dam­aged by dis­ease. Placed in the in­ner ear, they mea­sure the move­ment of the head and con­vert that in­for­ma­tion into pre­cise elec­tri­cal pulses they feed by elec­trodes into nerve branches and the brain, de­liv­er­ing in­for­ma­tion di­rectly into the ner­vous sys­tem. They’re anal­o­gous to a cochlear im­plant for hear­ing, which is to a tra­di­tional soundampli­fy­ing hear­ing aid as an F-22 is to a hot-air bal­loon. “It sounds ob­vi­ous in ret­ro­spect,” Famm says. “Couldn’t you do it else­where in the body? And why isn’t it done else­where in the body?” He and Slaoui had found their big idea.

The two spent much of the next 18 months vis­it­ing sci­en­tists around the world, even if their re­search seemed only loosely rel­e­vant. One trip was to the Ge­or­gia In­sti­tute of Technology in At­lanta to meet with ma­te­ri­als sci­en­tist Zhong Lin Wang. His work has demon­strated the fea­si­bil­ity of “self-pow­ered nan­ode­vices,” which can gen­er­ate their own elec­tric­ity from tiny vi­bra­tions in their en­vi­ron­ment. Zhenan Bao, a pro­fes­sor of chem­i­cal en­gi­neer­ing at Stan­ford, was con­sulted for her take on in­ter­ac­tions be­tween nerves and elec­tri­cal fields.

As they learned more, Famm and Slaoui needed to an­swer a big ques­tion: Would Glaxo try to de­sign im­plants to in­sert di­rectly into the brain to treat dis­ease else­where in the body? Or would it tar­get the pe­riph­eral ner­vous sys­tem, the net­work that con­nects to tis­sues, mus­cles, and or­gans? Try­ing to do both, they wor­ried, might be too sprawl­ing and costly. Yet an­other trip, to Switzer­land, helped settle the is­sue. The pair had gone to a cam­pus of boxy labs in Lau­sanne to visit Henry Markram, an Israeli neu­ro­sci­en­tist who leads part of the Euro­pean Union’s flag­ship brain-science project. His re­search fo­cuses on map­ping and imag­ing the bil­lions of con­nec­tions in neu­ral tis­sue.

Markram gave his vis­i­tors 3D glasses to view a model of a mouse’s cor­ti­cal col­umn, a rel­a­tively straight­for­ward piece of pe­riph­eral neu­ral anatomy that none­the­less con­sists of mil­lions of cells. The com­plex­ity was mind-bog­gling—ex­actly Markram’s point. As Famm and Slaoui drove back to the air­port, they agreed that to de­liver mon­ey­mak­ing medicines in the next decade, they’d have to fo­cus on the pe­riph­eral ner­vous sys­tem.

Famm set out to build a small team and re­cruit part­ners at univer­sity labs. MIT’s Boy­den was an early sup­porter, as was Brian Litt, the name­sake of the Univer­sity of Penn­syl­va­nia’s Litt Lab, which de­vel­ops brain im­plants us­ing ex­otic ma­te­ri­als such as graphene. In 2013, Glaxo made its bio­elec­tron­ics ef­forts public. In a com­men­tary that year in Na­ture, Famm and aca­demic col­lab­o­ra­tors in­vited read­ers to “imag­ine a day when elec­tri­cal im­pulses are a main­stay of med­i­cal treat­ment” and an­nounced an ini­tial pro­gram to fund as many as 40 ex­ter­nal re­searchers. That num­ber has since more than dou­bled, and the com­pany has col­lected some pow­er­ful al­lies. Darpa, the Pen­tagon’s skunk works, is fund­ing experiments at MIT, Johns Hop­kins, and else­where, while the National In­sti­tutes of Health has in­tro­duced a $230 mil­lion pro­gram to en­cour­age re­search.

Glaxo has also started an XPrize-style chal­lenge for ex­ter­nal re­searchers, with $6 mil­lion avail­able for teams try­ing to cre­ate a work­ing im­plant. Famm, who leaves most of the lab work to oth­ers while he over­sees strat­egy, won’t dis­close the com­pany’s to­tal out­lay. He says only that the ul­ti­mate startup costs will be “very much on par with those you of­ten see quoted for molec­u­lar medicines”—or po­ten­tially in the bil­lions. He thinks the eco­nomics af­ter that could be much more at­trac­tive than those of tra­di­tional drugs, be­cause de­vices could, in the­ory, be re­pur­posed for many dif­fer­ent dis­eases with only slight tweaks to their fir­ing pat­terns.

Glaxo’s am­bi­tion is to de­liver a mar­ketable prod­uct in the next decade. But to tar­get spe­cific bun­dles of nerve fibers, doc­tors will need to fig­ure out which neu­ral “cir­cuits” con­trol a given or­gan func­tion, and such a “func­tional map” of the ner­vous sys­tem doesn’t yet ex­ist. “The technology we have to­day is re­ally quite lim­ited in terms of tar­get­ing,” says Doug We­ber, the man­ager of Elec­tRx, Darpa’s bio­elec­tron­ics pro­gram. To be use­ful, those maps will also need to show how pat­terns and fre­quen­cies of stim­uli af­fect an or­gan. Or, as Slaoui says, “What does it mean to ac­cel­er­ate your heart­beat in terms of elec­tri­cal sig­nals? Is it beep-beep-beep? Or beeeeeeeep, beep, beeeeeeeep?”

MIT’s Boy­den is at­tempt­ing to map nerves through “ex­pan­sion mi­croscopy”: He sur­rounds a sam­ple with poly­mers sim­i­lar

to those found in di­a­pers, then adds water, en­larg­ing them to a scale at which their in­tri­cate con­nec­tions can be stud­ied more eas­ily. An­other av­enue of study in­volves an ex­otic-sound­ing dis­ci­pline called op­to­ge­net­ics. First, an ar­ti­fi­cial virus changes neu­rons’ ge­netic makeup to make them sen­si­tive to light. Re­searchers then use light to switch them on and off and mea­sure the re­sponses fur­ther down­stream. That makes it pos­si­ble to un­der­stand which neu­rons con­trol a par­tic­u­lar or­gan func­tion and ul­ti­mately tar­get them with im­plants.

Glaxo will also need to de­velop the fol­low­ing: small power sources that can last decades; com­put­ers within the im­plants ca­pa­ble of read­ing and an­a­lyz­ing bi­o­log­i­cal sig­nals and ad­just­ing out­put; and ma­te­ri­als that won’t de­grade over time or harm frag­ile nerves. At tiny scales, Slaoui says, metal and plas­tic don’t al­ways play well with hu­man tis­sue. “Most of the ma­te­ri­als are edgy, and bi­ol­ogy is smooth,” he says.

One sub­stance for which Glaxo and Darpa are fund­ing re­search is shape-mem­ory poly­mer, which is stiff at room tem­per­a­ture but flex­i­ble when heated. Elec­tron­ics can be lay­ered onto the stiff sur­face; then the poly­mer is heated into a form that hugs tightly around a nerve, al­most like shrink-wrap. Pro­to­type de­vices are three times thin­ner than a hu­man hair, placed by sur­geons “with steady hands and mi­cro­scopes,” re­searcher Wal­ter Voit says. Other ap­proaches could in­volve ad­he­sives or mag­nets.

At the Mayo Clinic in Rochester, Minn., sci­en­tists are work­ing with elec­tri­cally con­duc­tive syn­thetic di­a­monds, man­u­fac­tured at 3,500F, to make brain im­plants more ef­fec­tive. Di­a­monds are a good ma­te­rial for mea­sur­ing the con­cen­tra­tion of neu­ro­trans­mit­ters, such as dopamine, in real time. Per­fect­ing that process would help “close the loop” for some de­vices, al­low­ing them to mon­i­tor the im­pact they have on the brain and ad­just their set­tings au­tonomously. Be­cause of the boron used in the fab­ri­ca­tion process, the stones glow blue, like the Hope Di­a­mond.

The scale of the un­knowns and the weird-science vibe of some pro­pos­als give plenty of am­mu­ni­tion to skep­tics. “I want well-proven prod­ucts and path­ways and busi­ness mod­els. This sounds very high-risk,” says Clau­dio Nessi, the Geneva-based man­ag­ing part­ner at NeoMed Management, a med­i­cal in­vest­ment firm. “When cer­tain government agen­cies or char­i­ties get in­volved in some­thing, I don’t get in­volved. Their man­date is to look at very fu­tur­is­tic tech­nolo­gies, and los­ing money isn’t a prob­lem.”

But com­pa­nies much smaller than Glaxo are try­ing to make money with the technology. Last year the U.S. Food and Drug Ad­min­is­tra­tion ap­proved a de­vice from En­teroMedics, in St. Paul, Minn., de­signed to re­duce ap­petite in the very obese. Pitched as an al­ter­na­tive to bariatric surgery, the im­plant con­sists of a pair of quar­ter-inch-wide elec­trodes su­tured around the va­gus nerve, a high­way that runs from the brain to the ab­domen. Sil­i­cone leads are con­nected to a power and con­trol unit, the size of a deck of cards, in­serted just be­neath the skin. The ap­pa­ra­tus took more than a decade to de­velop, dur­ing which En­teroMedics lost $285 mil­lion. An­other com­pany, Neu­roPace, re­cently be­gan mar­ket­ing an epilepsy de­vice called the RNS Sys­tem, which mon­i­tors and stops seizures with a rapid elec­tric im­pulse. It in­cludes a curved power unit an eighth of an inch thick that’s placed in­side the skull. A sur­geon then threads leads through brain tis­sue to where the pa­tient’s seizures are fo­cused. It’s been in development since the late 1990s.

Drugs re­main the mon­ey­maker at Glaxo. The vast ma­jor­ity of its 13,000 R&D em­ploy­ees are devoted to de­vel­op­ing con­ven­tional medicines, and in­vestors are look­ing to those for signs of a re­cov­ery in the com­pany’s for­tunes.

A few hun­dred feet from Famm’s desk in Steve­nage are row upon row of lab sta­tions devoted to the grunt work of drug dis­cov­ery: screen­ing thou­sands of molec­u­lar com­pounds for their ef­fect on a given dis­ease. Robotic arms whir as they se­lect tiny vials for test­ing; au­to­matic dis­pensers mea­sure out liq­uids a cou­ple of nano­liters at a time. About 250 experiments oc­cur ev­ery month, draw­ing on a li­brary of more than 2 mil­lion com­pounds and gen­er­at­ing ter­abytes of data.

Molec­u­lar work is what Famm, while at Cam­bridge, was orig­i­nally trained to do. But even be­fore that, he was primed to break away. As kids, Famm and his brother, now an executive at H&M, “had a mil­lion dif­fer­ent clubs, just him and I,” he says, devoted to track­ing an­i­mals or wag­ing mock wars with neigh­bors. As the el­dest, Fredrik was al­ways the leader, with just one ex­cep­tion. He put Kris in charge of the in­ven­tion club. “There is a bit of a fron­tier in this space,” Famm says about bio­elec­tron­ics. “But that’s per­fect.” <BW>

Famm holds a bio­elec­tronic nerve im­plant

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