ADCs: A booming field for new cancer-fighting therapies

Six years after the first antibody-drug conjugate (ADC) was pulled from the market, the pipeline is once again filled with an array of potent new treatment candidates. The reach of commercially available ADCs is also expanding rapidly, making the technology particularly attractive to companies large and small. 

At last count, there were more than 50 of the drugs in development, up from the 30-some being worked on in 2014. 

"Of those 50-odd [ADC] clinical candidates in development, 12 integrate ImmunoGen technology," ImmunoGen CEO Mark Enyedy said in an interview. "Eight are being developed by our partners, and four are being developed by ImmunoGen … so we have a large presence in the market."

ADCs seek to deliver highly potent doses of cytotoxins directly to tumors in a way that avoids many of the side effects of chemotherapy on healthy cells. The technology has three components: monoclonal antibodies attached to cancer-killing drugs by chemical linkers. Most ADC efforts center around various cancers, but research is starting to extend further into other disease areas as well.

The concept of ADCs "has been around a long time ... but it turned out to be difficult to implement," Cowen & Co. analyst Boris Peaker said in an interview. There are currently only two FDA-approved ADCs on the market, Roche's Kadcyla (ado-trastuzumab emtansine) and Seattle Genetics' flagship Adcetris (brentuximab vedotin).

Pfizer's Mylotarg (gemtuzumab ozogamicin)—the first ever approved ADC—was pulled from the market in 2010 after safety concerns cropped up. 

Revenue for Kadcyla, approved in 2013, is growing at about a 10% annual clip, with sales being driven primarily by demand in Europe. Even as Kadcyla is being investigated for other applications, its sales are expected to total between $700 million and $800 million globally for 2016.

Meanwhile, Adcetris, first approved in 2011 in the U.S. and 2012 in Europe, is commercially available in 65 countries, has treated 35,000-plus patients, and is being pushed into emerging markets. Sales of the drug are increasing by about 20% year-on-year, with Adcetris bringing in $195 million in North American sales during the first nine months of 2016. The company expects it to top $500 million in worldwide sales this year.  

Building the best ADCs

Adcetris and Kadcyla may have been ahead of their time, but companies like ImmunoGen, Seattle Genetics and Mersana Therapeutics are working to develop the next generation of ADCs.

There is debate over how to build the components of ADC technology most effectively. The industry trend is to go toward fewer payloads but make them more toxic, though some companies are moving in the direction of less toxic, bigger payloads, and it's "hard to make a call on which is better," Peaker said. "You can argue in either direction. At the end of the day, you have to prove it in the clinic."

Mersana, which is developing various ADCs based on its Fleximer platform technology, is embracing bigger payloads.

"The traditional approach is limited to three, maximum four payload molecules on a given antibody ... but we have demonstrated we can put 15 and sometimes 20 molecules on an antibody – and the more payload on the antibody, the more efficiencies the payload can have," Anna Protopapas, Mersana's president and CEO, said in an interview. "So that's a big differentiating factor for our technology."

Mersana also has designed "a payload that in many ways detoxifies itself when metabolized by the body," thus making treatments more tolerable, she said.

In October, the FDA cleared Mersana's IND application to begin Phase 1 clinical trials for its lead oncology drug candidate: XMT-1522, which defines a new class of targeted therapies for HER2 breast cancer and is being co-developed with Takeda Pharmaceutical Co.

"We'll be dosing our first patients before the end of the year, which is an exciting development for our company," Protopapas said.

Protopapas said Kadcyla targets about 20% of breast cancer patients "expressing HER-2 at a very significant level,” whereas another 55% of patients don't express HER-2 at high enough levels to be eligible for Kadcyla, and that's where Mersana's product can help. Some lung cancer and gastric cancer patients also express HER-2 and will be targets of its product, she added.

Over at Seattle Genetics, CEO Clay Siegall is bullish on ADCs and continued innovation.

"Seattle Genetics is the leader in ADC technology and products in the world. As such, it is important for us to be the innovation leader, so we put a lot of time and resources ... into advancing how antibodies are engineered, how linkers are engineered, how powerful the drugs are and where they work," Siegall said in an interview. "We're studying all the parts and pieces."

In the end, Siegall joins ImmunoGen's Enyedy and others in the expanding therapeutic field who see benefits from using ADCs as part of an arsenal.

ADCs are "an excellent opportunity to treat cancer patients," but they won't supplant chemotherapy or immunotherapy, Siegall said. Oncologists will need an array of tools – "a basket of perhaps 70 or 80 drugs" – to address cancers which likely in the future will be designated by their features, such as whether they are CD-30 positive, and not by the site where the tumor is found, he said.

"We're now looking at targeted, pinpoint drugs," Siegall said, "and looking at how we can do this in the future and do it better."

Filed Under: Drug Discovery Clinical Trials
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