Blockbuster antibodies face a unique set of challenges

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When Bristol-Myers Squibb's Yervoy recently won approval from the FDA, the analysts at Deloitte Recap chalked that up as the 25th such regulatory milestone for a monoclonal antibody credited to a group of biotech companies they've been tracking closely.

Some years ago Recap selected a roster of classic biotechs--developers much like Medarex, which pushed ahead on Yervoy until Bristol bought them out--and 12 of them were responsible for launching the clinical trials on 24 of the 29 FDA-approved mAbs that reached the market. Now that mAbs are generating big revenue, $24 billion in sales in 2009, the field is growing even hotter. Today, 27 of their select group are currently testing 130 mAbs in 211 indications.

Lisa Natanson (pictured), an analyst at Deloitte Recap, has completed an exhaustive analysis of their work and has reached some conclusions that will be of interest to any developer in the field. According to her report, the mean time it takes to go from IND to approval for a mAb is 7.6 years. But given the complexity of their targets and the kind of high unmet medical need they're in pursuit of, development times are growing significantly longer over time. Surprisingly, Deloitte Recap also concludes that most of the special regulatory programs designed to cut development times don't work for mAbs, a point that developers need to pay particularly close attention to as they lay out new timelines for programs.

Compared to the overall drug development field of large and small molecules, mAb developers have achieved a relatively high rate of success. Deloitte's group racked up an overall compound approval success rate of 23 percent, Phase I to market, with notable success in immunological and/or inflammatory indication pursuits (24 percent) and cancer indications (14 percent).

Not so surprisingly, given the blockbuster potential of these drugs, the field is likely to continue to demonstrate rapid growth.

Just looking at the last two mAb approvals, Yervoy and Human Genome Science's Benlysta, you can see that "this class of molecules continues to meet unmet med needs and be innovative," says Natanson.

"People are aware that mAbs have higher success rates than traditional small molecules," says Natanson. "That's driving it. Regulatory success is driving it." And despite the fact that a majority of these new mAbs arrive with black box warnings, "they have had great success because they are truly innovative."

Looking over oncology drugs in the pipeline, Deloitte Recap had earlier concluded that all the different tools available for reducing development times--fast track, accelerated approval, priority review and orphan drug status--had a "synergistic" effect in cutting development times. But that doesn't hold true for mAbs.

"Here development time is not amenable," says Natanson. "It's stubbornly consistent." Priority review was the only program that might offer a positive benefit.

Of all the mAbs that won priority review designations, roughly one in two saw their development times cut significantly--while the other half did not benefit. And fast track status was actually associated with higher-than-average development times, perhaps because it is "accorded for very serious life threatening unmet medical needs and therefore the complexity is higher and you see longer development times."

Natanson found that as developers ramp up new programs, the amount of time it takes to gain an approval is going up significantly--from a mean average of 6.7 years in the 1994-2003 period to 8.3 years in the 2004-2011 period. And that's because developers need more time in the clinic, rather than more time discussing applications with regulators.

"Those development times are going up by a large amount," says the analyst.

That trial trend may be driven by developers tackling more complex diseases. The end points may be more stringent, suggests Natanson, who's also frank to say she's not entirely sure what's behind that trend. But she's not in the least doubtful about where mAbs are headed in the scheme of biotech things.

Says Natanson: "I think you're going to see continued huge investments as long as successes are achieved. That type of drug is a drug that will be successful. At some point it's likely that this will tap out, like any technology. I would think that for the short term you will continue to see heavy investment."

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