New os­teo­poro­sis drug de­ploys ge­netic tool to build bone with­out break­ing it down

The Buffalo News - - NATIONAL NEWS - By Gina Kolata

WASH­ING­TON – The Food and Drug Ad­min­is­tra­tion on Tues­day ap­proved an os­teo­poro­sis drug that rep­re­sents the first new treat­ment ap­proach in nearly two decades – a strat­egy based on a rare gene mu­ta­tion in peo­ple with bones so dense that they never break.

About 10 mil­lion peo­ple in the United States have os­teo­poro­sis. World­wide, about 200 mil­lion peo­ple have brit­tle bones; 1 in 3 women, and 1 in 5 men, will suf­fer a frac­ture be­cause of os­teo­poro­sis, of­ten of the hip or spine. For many, the break leads to a down­ward spi­ral of dis­abil­ity.

Stan­dard treat­ments, drugs called bis­pho­s­pho­nates, stop the loss of bone but do not build it. The al­ter­na­tives, parathy­roid hor­mone and a de­riv­a­tive, build bone but also break it down, lim­it­ing the ther­a­peu­tic ef­fect.

The new drug, ro­mosozumab (brand name Even­ity), de­vel­oped by Am­gen in col­lab­o­ra­tion with Bel­gian drug com­pany UCB, re­stores bone with­out break­ing it down, ac­cord­ing to the find­ings of two large clin­i­cal tri­als.

It was ap­proved only for post­menopausal women with a high risk of frac­ture, and will carry a warn­ing on its la­bel that it may in­crease the risk of heart at­tack or stroke, the FDA said.

“This is an ex­traor­di­nar­ily im­por­tant drug,” said Dr. Richard Bock­man, chief of the en­docrine ser­vice at the Hospi­tal for Spe­cial Surgery in New York. “It’s a true bone-build­ing drug that takes ad­van­tage of the un­der­ly­ing bi­ol­ogy of bone.”

In large clin­i­cal tri­als, pa­tients tak­ing the drug saw in­creases in bone den­sity in their spines on the or­der of 15 per­cent – a huge fig­ure, sim­i­lar to the amount of bone made in early ado­les­cence, said Dr. Clif­ford J. Rosen, an os­teo­poro­sis ex­pert at Maine Med­i­cal Cen­ter Re­search In­sti­tute and mem­ber of an FDA panel that eval­u­ated the data.

Merely a 6 per­cent in­crease in bone den­sity can trans­late into a dou­bling of bone strength, Bock­man said. In the tri­als, pa­tients tak­ing the drugs saw a re­duc­tion in breaks, both in the spine and “clin­i­cal” frac­tures – bro­ken bones that a pa­tient no­tices, rather than, say, a col­lapsed ver­te­bra dis­cov­ered only in X-rays.

In one study, spinal frac­tures oc­curred in 127 of 2,046 pa­tients tak­ing the new drug, com­pared with 243 of 2,047 tak­ing alden­dronate, an older drug. “It’s a tremen­dous ad­vance,” said Dr. Dolores Shoback, a pro­fes­sor of medicine and an os­teo­poro­sis ex­pert at the Uni­ver­sity of Cal­i­for­nia, San Fran­cisco.

But there also was a small, un­ex­pected in­crease in heart at­tacks, strokes and sud­den deaths in that study – 50 of 2,040 pa­tients, or 2.5 per­cent, tak­ing Even­ity, com­pared with 38 of 2,014, or 1.9 per­cent, tak­ing alden­dronate.

The ef­fect was seen in one of the two large clin­i­cal tri­als, but not the other.

Even­ity will be given as a monthly in­jec­tion. Parathy­roid hor­mone is given as a daily in­jec­tion, while the drugs in the other ma­jor treat­ment class, the bis­pho­s­pho­nates, are taken as pills.

The new drug has a strik­ing back­story.

In 1964, re­searchers be­gan study­ing an un­usual group of Afrikaner pa­tients in South Africa. They were tall and heavy, but not fat. In­stead, their bones were large and dense.

Their bones grew so pro­fusely that their heads be­came dis­torted: Their jaws were large, and an over­growth of bone in their skulls im­pinged upon nerves, of­ten caus­ing deaf­ness or fa­cial palsy. Many had ter­ri­ble headaches. In some, the in­dex and mid­dle fin­gers fused to­gether.

In 2001, sci­en­tists re­ported that all th­ese ef­fects re­sulted from a sin­gle gene mu­ta­tion. The find­ing led re­searchers to un­der­stand how the body con­trols the build­ing of bone.

Bones are in a state of con­stant flux, built up and bro­ken down by the body. In os­teo­poro­sis, the bal­ance is dis­rupted – more bone is bro­ken down than is made. Bone cells make a pro­tein called scle­rostin that halts the pro­duc­tion of bone and in­creases its break­down. The gene mu­ta­tion in the Afrikaner pa­tients stops the pro­duc­tion of scle­rostin, so their bod­ies keep build­ing bone with­out brakes.

Sci­en­tists rea­soned that if they could mimic the mu­ta­tion by block­ing scle­rostin with an an­ti­body, peo­ple with os­teo­poro­sis should build more bone. Once bone den­sity in­creased, pa­tients could stop tak­ing the scle­rostin­block­ing drug and switch to an older drug to main­tain the new bone. An­i­mal stud­ies were suc­cess­ful, as were clin­i­cal tri­als, cul­mi­nat­ing in two large stud­ies in­volv­ing more than 10,000 post­menopausal women.

In one trial, Even­ity was com­pared to a placebo; in the other, it was com­pared to a bis­pho­s­pho­nate. In both stud­ies, women tak­ing Even­ity ended up with more bone and fewer frac­tures.

In Jan­uary, Even­ity was re­viewed by an ad­vi­sory com­mit­tee to the FDA, which voted 18-1 for ap­proval – but called for Am­gen to do more re­search to un­der­stand the pos­si­ble car­dio­vas­cu­lar side ef­fects.

“There is a tremen­dous need for this med­i­ca­tion, and there is an amaz­ing amount of mor­bid­ity and mor­tal­ity with this disease,” said Dr. Fred­er­ick G. Kush­ner, a car­di­ol­o­gist at the Heart Clinic of Louisiana and a panel mem­ber who voted to ap­prove the drug.

The next step, Bock­man said, is for com­pa­nies to de­velop pills so pa­tients do not have to have monthly in­jec­tions.

New York Times

A new drug that re­stores bone with­out break­ing it down was ap­proved only for post­menopausal women with a high risk of frac­ture, and will carry a warn­ing on its la­bel that it may in­crease the risk of heart at­tack or stroke.

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