When it comes to outmaneuvering big pharma for market share, most small biotechs don't stand a chance. Every once in a while you'll see a David take down a Goliath, but most of the time, the giants are a safer bet. But some smart smaller companies have found ways to "play nicely" with their larger competitors by improving the efficacy of existing treatments marketed by those competitors -- a strategy that could pay off big for investors in these stocks.

The advantages of this symbiotic strategy are twofold. First, it turns would-be competitors into allies. This can provide opportunities for funding via collaboration and could potentially even lead to a buyout.

Second, this cooperative strategy takes advantage of huge, well-established marketing departments. Big pharma (and big biotech, for that matter) spends exorbitant sums convincing doctors to adopt their therapies as the standard. Well, if Standard A works twice as well with Sidekick B prescribed alongside it, you better bet Sidekick B will benefit from the marketing of Standard A + Sidekick B without having to lift a marketing finger.

This all boils down to a matter of finance. Between collaboration revenue during development and lower marketing expenses post-approval, companies working cooperatively seem less likely to run into the cash burn problems so common in the world of tiny biotechs. Here are three biotechs that do this very well.

Eyes on the prize 
Ophthotech
(NASDAQ:OPHT) is a favorite of mine because it plays on the "graying of America" -- that is, the reality that the population of senior citizens is on the rise, bringing incidence of age-related maladies with it. More than 10,000 baby boomers turn 65 every day, and so it is inevitable that treatment reliance on medication for many age-linked indications will increase in coming years. Currently, there are three big drugs in the space: Regeneron's Eylea, Roche's Avastin, and Novartis' Lucentis. 

Enter Ophthotech and its drug Fovista, which aims to improve the efficacy of existing treatments for wet age-related macular degeneration, or wet AMD. Ophthotech is testing the combination of Fovista and Eylea, and enrollment was also recently completed for a phase 3 trial testing Fovista alongside Lucentis. Novartis got its skin in the game after impressive phase 2 results, nabbing up ex-U.S. rights to Fovista in a deal worth up to $1 billion plus royalites, giving Ophthotech a comfortable cash position while still retaining U.S. rights to the drug.

If Fovista continues to post strong results in clinical trials, it could become part of standard wet-AMD treatment (regardless of doctors' preference for Lucentis, Eylea, or even Avastin) and quickly reach billion-dollar blockbuster status.

An angel for pancreatic cancer patients? 
Oncology is the area of healthcare research that holds arguably the most intrigue. Pancreatic cancer has proven particularly difficult to treat, making the diagnosis one of the most dreaded -- and an area of research that could offer tremendous upside for any company that can develop an effective treatment.

Halozyme (NASDAQ:HALO) is tackling this difficult indication on the head with PEGPH20, which is set to begin its phase 3 trial next year. This drug has posted impressive results thus far, doubling progression-free survival for a specific subgroup of pancreatic cancer patients in a phase 2 trial when taken alongside the current standard of care (gemcitabine/Abraxane), as compared to a control group receiving only gemcitabine and Abraxane.

Halozyme boasts a strong balance sheet and should be able to finance operations for quite some time due to drug development partnerships with the likes of AbbVie, Pfizer, Johnson & Johnson, and more. These companies clearly see promise in Halozyme's proprietary enzyme technology that could eventually improve existing therapies for a host of indications outside of just pancreatic cancer.

Meanwhile, if PEGPH20 gains FDA approval, analysts are expecting peak sales of $1.5 billion for the drug.  All told, there are plenty of opportunities for Halozyme to grow far beyond its current $2 billion market cap.

Money for nothing 
You can't understand Portola's (NASDAQ:PTLA) story without first detouring through the current market for blood thinners, or anticoagulants. Warfarin was the long-standing standard of care in this market, with a new generation of drug called Factor Xa inhibitors only recently beginning to seize market share. These drugs, such as Xarelto from Johnson & Johnson and Eliquis from Pfizer, have better efficacy and a superior safety profile to warfarin.

The only thing standing in the way of widespread adoption of Factor Xa inhibitors is that anticoagulants sometimes need to have their effects quickly reversed in the case of emergency surgery or other bleeding events. Warfarin can be reversed with a simple dose of vitamin K, but no antidote exists for Factor Xa inhibitors. Thus, many doctors are sticking with the older drug, particularly for patients deemed at higher risk of suddenly needing an antidote.

This is what makes Portola's story a bit different from the others' -- rather than improve the effectiveness of Eliquis or Xarelto, Portola is developing andexanet alfa as a reversal agent to these Factor Xa inhibitors. The company recently announced positive data from its phase 3 trial, which also confirmed that the drug is well-tolerated.

Because the approval of this antidote would do wonders for boosting sales of Factor Xa inhibitors, Portola has inked lucrative agreements with pharmaceutical giants like Johnson & Johnson, Pfizer, and Bristol-Myers Squibb for the development of andexanet alfa, while still maintaining commercial rights to the drug worldwide. Seems to me like Portola is getting a free lunch!

Still not without risk
While I personally think these three companies offer an extremely favorable balance between risk and reward, investors have to remember that the biotech industry is quite volatile. Share prices can skyrocket or plummet depending on the outcome of binary events such as clinical outcome trials, and many clinical-stage biotech companies have been hit hard in the midst of the recent broader market correction.

As such, although I have personally built small positions in each of these three companies, I would only recommend them to investors with high risk tolerances. However, I think the importance of playing nicely with others, in the context of drug development, is largely under-appreciated, and I believe the strategy will go a long way to making these great stock picks for the long term.

Kristine Harjes owns shares of Halozyme Therapeutics, Ophthotech, and Portola. Beyoncé surprisingly has no position in HALO, at least not to the author's knowledge. [Editor's note: Bad puns abound whenever Kristine is in the room. We think it's a good thing. Mostly.] The Motley Fool has no position in any of the stocks mentioned. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.