Mirror, mirror, on the wall, who's the frailest big pharma of all? The patent cliff has certainly taken its toll over the past couple of years, weakening several successful pharmaceutical companies. Which are faring the worst during this tumultuous period? Let's look at some of the frailest companies out there.

Sickly sales
Plenty of large drug companies lost exclusivity for some drugs during recent years. However, for a few, expiration of patents wreaked havoc on the top line.

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Bristol-Myers Squibb (BMY -8.51%) really went through a world of hurt. Revenue dropped nearly 18% since the beginning of 2012 after the patent for Plavix expired. From 2011 to 2012, sales of Plavix plummeted by $4.5 billion. Ouch.

AstraZeneca (AZN 5.38%) wasn't too far behind, with revenue falling 14%. Saying goodbye to exclusivity for Seroquel IR caused much of the damage. Sales for the drug in 2012 totaled $1.3 billion, a 70% drop from the $4.3 billion earned the prior year. 

Lipitor remained the primary driver behind Pfizer's (PFE -3.85%) declining overall sales. The drug still pulled in nearly $4 billion in 2012. However, that level is still far short of the $9.6 billion from 2011.

Lilly (LLY -1.00%) felt the pain of losing exclusivity for Zyprexa in 2011, but rising sales of other drugs, particularly Cymbalta, helped cushion the blow. Likewise, generic competition for Lovenox, Aprovel, and Plavix dented revenue for Sanofi (SNY 5.90%), but the impact was offset in large part by sales growth for other products. 

Fragile futures
The biggest problem with the patent cliff is that it isn't over. More drugs will go off patent in the next few years. That, of course, means that the future for some big pharmas might look worse than the past. 

Sources: Company SEC filings and annual reports, Express Scripts. 

Lilly looks to have a rough stretch over the next three years as several blockbuster drugs go off patent. The company's current top-seller, Cymbalta, loses exclusivity at the end of this year. Humalog also loses patent protection this year, while Evista goes off-patent in 2014.

Neither Bristol-Myers Squibb nor Pfizer will fare much better. Bristol's Baraclude loses patent exclusivity this year. Abilify and Sustiva follow suit in 2015. Pfizer's Celebrex and Zyvox go off patent in 2014 and 2015, respectively. 

All isn't gloom and doom, though. Bristol should see growing sales from Onglyza, Byetta, and Bydureon -- all three part of a partnership with AstraZeneca. The company should also get a boost from Sprycel, Yervoy, and Orencia. Lilly's positives primarily stem from its animal health unit, Effient, and Forteo. 

Pfizer benefits from a wide array of drugs with double-digit annual sales growth. The company also still owns around 80% of animal-health spinoff Zoetis (NYSE: ZTS), which helps cushion some of the pain associated with the patent cliff.

Puny pipelines
The future isn't just affected by drugs currently on the market, of course. What about drugs recently gaining approval or in the late-stage pipeline? 

AstraZeneca and Bristol-Myers Squibb hope to attain success with diabetes drug Forxiga, which was recently approved in Europe but has to try again for FDA approval. AstraZeneca also expects to file for regulatory approval of another diabetes drug, SaxaDapa (gotta love that name), by 2015. Other than those, though, the company's late-stage prospects that can possibly make a difference in the next two or three years aren't overly impressive.

Bristol and Pfizer should both benefit from Eliquis, the blood thinner that recently obtained FDA approval. Some analysts say that Bristol has the best early stage pipeline in the business, but its late-stage pipeline isn't as strong.

Lilly doesn't boast the most promising late-stage lineup, either. The company had some disappointing news with a phase 3 trial of its Alzheimer's disease drug, solanezumab, in August. However, Lilly is moving forward with more trials. The company also stopped one out of three phase 3 studies under way for potential rheumatoid arthritis drug tabalumab.

Pfizer looks to be in better shape. In addition to Eliquis, the company also obtained FDA approvals for chronic myeloid leukemia drug bosutinib and rheumatoid arthritis drug Xeljanz over the last several months. Pfizer counts several other promising drugs in phase 3 trials as well.

Sanofi also seems to have decent prospects. European regulators approved cancer drug Zaltrap and diabetes drug Lyxumia over the past few months. The company also boasts several other drugs awaiting approval or in late-stage studies.

Frailest of all
With all factors considered, I'd have to say that Lilly stands (shakily) as the frailest big pharma. While the company has withstood the patent cliff better than several of the others, the impending loss of exclusivity Cymbalta, Humalog, and Evista will be very tough.

Lilly doesn't appear to have anything on the radar that will replace the revenue drop that is sure to come. I have to agree with my Foolish colleague Sean Williams that the company has "the most perilous pipeline" in the industry. The stock gained nearly 39% over the past year, but I don't expect that run to continue for long. Rear-view mirrors don't help much with seeing what lies ahead.