By Jonathan D. Rockoff And Joseph Walker 

A few years ago, the drug companies dominating mergers-and-acquisitions headlines were largely household names, from Pfizer Inc. and Merck & Co. to Novartis AG.

These days, a new generation of deal makers is making news, with names distinctly less familiar: Actavis PLC, Endo International PLC and Valeant Pharmaceuticals International Inc. Within the past few weeks, two other relatively under-the-radar companies, Mylan NV and Teva Pharmaceutical Industries Ltd., also entered the fray.

Combined, these lesser-known players have signed or proposed takeovers worth a combined $180 billion in recent months, causing investors and bankers to sit up and take notice.

They've also become major revenue generators, racking up some $52 billion in combined sales last year, up 86% from 2010. The growth of Actavis and Valeant, the most aggressive corporate acquirers, is even more remarkable. Through last Friday, Actavis had a market value of more than $119 billion, a 22-fold increase since 2010; Valeant's value soared 32 times over the same period to $84.73 billion. But Actavis's and Valeant's debt has also risen substantially, nearly doubling as a percentage of total assets since 2010, according to FactSet.

Behind their rise are several factors. Low borrowing costs have opened the door for new players to bulk up through deal-making. Countries including Ireland have offered lower-tax havens for companies that bought native firms and relocated. Once reincorporated, these companies have an M&A advantage in that companies they acquire can often benefit from their lower tax rates. And investors have rewarded deal-making by driving up shares of acquisitive companies, which, in turn, has made takeovers involving stock more affordable.

Several of the new chief executives come from outside the pharmaceutical industry, making them unsympathetic toward some of the sector's traditions, such as heavy research spending.

"It's very difficult for people who've grown up in the industry to be agents of change," Endo Chief Executive Rajiv De Silva, a former McKinsey & Co. consultant, says. "The biggest question mark is around the traditional large pharmaceutical companies and whether those business structures will continue as they have."

Cost-cutting has been a major focus of the new pharmaceutical barons' deals. Thousands of employees have lost their jobs, including the researchers once considered the industry's lifeblood. Some analysts and industry officials question the strategy, arguing it undermines drug-development programs that could provide sizeable sales down the road.

"You may have two or three years of improved earnings growth just from cost cuts. But after that, there's nothing else to cut," said David Maris, a pharmaceuticals analyst at BMO Capital Markets.

The pharmaceutical industry's more traditional names aren't sitting out the M&A frenzy. Earlier this year, Merck bought antibiotic maker Cubist for $8.4 billion, and Pfizer agreed to buy Hospira Inc. and its injectable drugs for $16 billion.

Yet now they share the spotlight with companies like Mylan, originally spelled Milan, after a founder who won a 1961 coin toss with a partner over whose name the West Virginia drug distributor would adopt. Milan Puskar and Don Panoz started out selling medicines to doctors and pharmacists from a Pontiac Bonneville, according to the company website.

In large part due to acquisitions, Mylan is now the second-biggest seller of generic drugs in the U.S. after Teva, according to IMS Health, with revenue of $7.8 billion last year.

Executive Chairman Robert Coury has been an architect of the company's ascent since he began advising Mylan in 1995. He joined the board in 2002 and became CEO soon after. Since Heather Bresch took over as CEO in 2012, Mylan's market capitalization has quadrupled from around $9.2 billion to more than $36 billion.

In February, Mylan completed the $5.7 billion purchase of Abbott's European generics business, which allowed it to lower its tax rate by reincorporating in the Netherlands, from Pennsylvania. Earlier this month, Mylan launched a bigger takeover bid, offering $28.9 billion for Ireland-based Perrigo Co. PLC, a little-known maker of cough-and-cold remedies and infant formula that retailers such as Wal-Mart and Walgreens sell under their own names.

Within days, Teva swooped in and made an unsolicited $40 billion bid for Mylan itself, fearing that if Mylan completed its Perrigo takeover, the combined company would be too big for Teva to swallow, according to a person familiar with the matter.

It was the biggest proposed health-care deal this year and an aggressive move by Teva CEO Erez Vigodman as he looks for new sources of sales growth to offset sales the company expects to lose as its multiple sclerosis drug, Copaxone, faces generic competition.

Mr. Vigodman had served on Teva's board since 2009, but was otherwise a pharmaceutical industry outsider, having previously led the world's largest maker of generic chemicals used in agriculture. Israel-based Teva, founded in 1901 as a drug wholesaler that made deliveries by donkey and camel, began making drug copies for Israelis when the new country restricted imports. Sales in the U.S. took off after Teva recognized the potential in a 1984 U.S. law authorizing sales of generic drugs.

No drug company has gotten bigger faster in recent years than Actavis, a once relatively small seller of generic drugs. The company took off when Watson Pharmaceuticals bought Switzerland-based Actavis in 2012 and adopted its name. It then snapped up Ireland-based Warner-Chilcott in a tax-lowering inversion deal.

Brent Saunders, a 45-year-old former PricewaterhouseCoopers compliance expert, became Actavis CEO after the company's roughly $25 billion takeover of Forest Laboratories last July. Less than a year later Actavis completed a roughly $66 billion purchase of Botox maker Allergan Inc.

In doing so it beat out Valeant and its ferociously acquisitive CEO, Michael Pearson. Mr. Pearson was a McKinsey pharmaceuticals consultant who hadn't heard of Valeant when the company's chairman approached him to become CEO in 2007. Valeant, originally called International Chemical & Nuclear Corp., was best known for its founder Milan Panic, who took a leave from running the company at one point to serve as prime minister of Yugoslavia.

Since becoming Valeant CEO in early 2008, Mr. Pearson has overseen 56 publicly announced deals worth $34.6 billion, according to Dealogic. Last month, Valeant agreed to buy stomach-drug maker Salix Pharmaceuticals Ltd. for $11.1 billion, beating out a surprise rival bid from Endo.

The jockeying pitted Mr. Pearson against Endo's Mr. De Silva, who worked under Mr. Pearson at Valeant and McKinsey. Before joining Endo as CEO in 2013, Mr. De Silva was president at Valeant, where he helped execute Mr. Pearson's M&A strategy.

Mr. De Silva, 48, a native of Sri Lanka who came to the U.S. to attend Princeton University on a scholarship, has pursued a bevy of deals to remake Endo. The company reincorporated in Ireland last year after acquiring Paladin Labs Inc., for $2.7 billion. Last January, Endo completed a $2.6 billion purchase of Auxilium Pharmaceuticals Inc., best known for its testosterone and erectile dysfunction treatments.

"The fact that companies like ours have the ability and capital to make bold moves, that is not a surprise," says Mr. De Silva. "We have a lot of shareholders who are supportive of what we're doing and debt markets that are very favorable at the moment."

Write to Jonathan D. Rockoff at Jonathan.Rockoff@wsj.com and Joseph Walker at joseph.walker@wsj.com

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