Imagine running a business that loses money every year for more than a decade. Now, imagine those losses combined total into the hundreds of millions -- even billions -- of dollars. 

If you're Al Mann with MannKind (NASDAQ:56400P706), John Scarlett with Geron (NASDAQ:GERN), or Steven King with Peregrine Pharmaceuticals (NASDAQ:PPHM), you don't have to imagine. Each of these CEOs stands at the helms of biotechs that have operated in the red since the last century. But each also can point to a definite reason to hope for better days. Will these three longtime losers turn the corner to profitability anytime soon?

Third time's the charm
MannKind appears poised for success after years of suffering through setbacks. Since 2000, the company has accumulated net losses amounting to well over $2 billion. Twice, MannKind thought it was on the verge of winning approval for its inhaled insulin product, Afrezza -- but both times resulted in disappointments.

In June, though, MannKind finally secured that long-sought approval for Afrezza. The company now must find a partner to bring the drug to market. MannKind's CFO Matt Pfeffer stated a little over a month ago that discussions were in progress with multiple companies. 

How quickly could MannKind see a positive bottom line figure? Don't count on it happening in 2014 or even 2015. The commercialization ramp-up for Afrezza could take a while. But it's not too far-fetched to guess that MannKind might be profitable in 2016 -- just in time for Al Mann's ninety-first birthday.

Holding on
Geron was founded way back in 1990 and went public in 1996. Since then, the biotech hasn't had a single profitable year. Along the way, Geron racked up cumulative net losses topping $800 million. 

All of Geron's chips are placed on one drug: imetelstat. Unfortunately for Geron, the pathway to success for the drug hit a roadblock in March. The U.S. Food and Drug Administration placed a full clinical hold on studies of imetelstat targeting essential thrombocythemia and multiple myeloma due to concerns about potential liver problems for patients taking the drug.  A few days later, the FDA also placed a partial clinical hold on another study of imetelstat focusing on treatment of myelofibrosis that is being led by Mayo Clinic's Dr. Ayalew Tefferi.

Last month, Geron received a bit of good news as the partial clinical hold on Dr. Tefferi's study was lifted. The clinical trials sponsored by Geron itself, however, are still on hold until the biotech can show the FDA that patients taking imetelstat won't suffer from permanent liver damage.

Assuming that Geron can make a convincing argument for imetelstat, the future could be brighter than the past couple of decades. Dr. Tefferi's research found that some myelofibrosis patients taking the drug went into complete remission. By contrast, the only drug currently approved for myelofibrosis, Incyte's (NASDAQ:INCY) Jakafi, doesn't boast that kind of efficacy.

Jakafi generated over $235 million in revenue for Incyte last year and is expected to make at least $315 million in 2014. If Geron ultimately navigates the regulatory waters successfully, imetelstat could become an even bigger winner than Jakafi. Any chances of positive earnings, though, are still years away: Geron's drug is still only in phase 2 trials. 

Party like it's 1996?
Peregrine Pharmaceuticals hasn't always been unprofitable. The company made money -- way back in 1996. Net income that year came in at $325,000. So far in this century, Peregrine has amassed losses totaling over $250 million. 

Cancer drug bavituximab stands out as Peregrine's best shot for achieving better financial results. Bavituximab, in combination with docetaxel, is in a phase 3 study as a second-line treatment of lung cancer. It's also in a phase 1/2 study combined with sorafenib targeting treatment of liver cancer, as well as a handful of early stage studies focusing on different types of cancer. 

Peregrine is helped by its Avid Bioservices contract manufacturing unit. Thanks to Avid, the company generated more than $22 million in revenue during the 12 months ending April 30, 2014. That contract manufacturing revenue is subsidizing Peregrine's development effort or bavituximab but not enough to avoid losses. 

Can Peregrine beat its earnings record from 18 years ago? My Foolish colleague Sean Williams suspects that bavituximab could eventually reach annual sales of at least $600 million. Sean might not be too far off, but my guess is that the company is still at least four years away from partying like it's 1996. The phase 3 study of bavituximab doesn't wind down until the end of 2016, and then there's potential approval and commercialization hurdles assuming the data is good.

The bottom line
Despite losing lots of money, MannKind's shares are up more than 260% over the past two years. Geron's stock is up over 60% during the same period even after a big collapse in price earlier this year. Peregrine didn't fare quite as well, but shares still managed to climb 25% over the previous couple of years.

Securing a commercial partner for Afrezza should drive MannKind's stock up even more. If the FDA removes the clinical hold for imetelstat, Geron's share price will most likely explode. Any good clinical news from Peregrine's pipeline would probably send shares into orbit. The bottom line for biotech investors is that the bottom line just doesn't matter as much as it does for other industries.