Monoclonal Antibodies have revolutionized medicine. Since 1986, more than 20 Antibody drugs have been approved, with sales of $26 Billion in 2007 alone and expected to nearly double to $49 Billion in 2013. Sales are highly concentrated, with the top five drugs - Avastin, Rituxin Herceptin, Humira, and Remicade accounting for 78% of 2007 sales. It is rather amazing that Avastin and Herceptin has maintained such strong sales in the face of a deluge of cheaper small molecule competitors for their respective targets: VEGF and HER2.
Rituxin and Herceptin look to have patents expire in 2015 and will be vulnerable to generic biosimilars - Teva (NASDAQ:TEVA) is currently running clinical trials on a Rituxin biosimilar and is already selling one in India. To that end, Roche has looked to new technologies to extend the life of its multi-billion dollar Anti-CD20 and Anti-HER2 franchises.
Roche (OTCQX:RHHBY) is developing a follow-on fully humanized Anti-CD20 it claims is more potent than Rituxan. Roche is applying a technology called glyco-engineering, where a post-translationally added sugar called fucose is removed from the antibody. This helps to increase the antibody’s binding to the receptor as well as increase antibody-dependent cellular cytotoxicity, aiding in the destruction of target cells.
As for Herceptin, its Anti-HER2 drug, Roche is in late stages of developing an Antibody-Drug-Conjugate (ADC) in partnership with Immunogen (NASDAQ:IMGN), consisting of Herceptin linked to a toxic payload. After Herceptin binds to its receptor, the toxin is released into the cell. (In this case, a potent anti-microtubule.) Results from a phase IIb trial for this drug, T-DM1, were deemed good enough that Roche will use the data to file for an NDA.
New Technology Controlled by a Few Players
As with the development of fully humanized monoclonal antibodies, Antibody-Drug-Conjugate technology is concentrated in a few hands. Seattle Genetics (NASDAQ:SGEN), along with Immunogen are clear leaders in applying this technology. The key to this technology is the linker between the antibody and the toxin. The linker must remain stable long enough in the bloodstream to reach its target and allow the toxin to enter the cell where it is either enzyme cleaved or pH cleaved. These toxins are much more potent then those used in typical chemotherapy. Too much release in the bloodstream would lead to unwanted side effects. If the linker is too stable, the toxin will not be released.
Seattle Genetics has two proprietary ADCs in the clinic, one in late stage trials for Hodgkin’s Lymphoma and a second in early stage trials for non-Hodgkin’s Lymphoma and Renal Cell Carcinoma. An ADC being co-developed with Agensys is also in Phase I. Results for brentuximab vedotin, or SGN-35, their promising late stage compound, are expected later this year. Analysts expect very good data second half this year. The company expects to file for approval first half 2011.
ADC technology from Seattle Genetics is being used by a host of companies. Late last year, it signed lucrative deals with Takeda/Millenium for $60 Million upfront and $230 Million in milestones and with GSK for $12 Million upfront and $390 in milestones. In September last year, Bayer made a milestone payment to the company as it filed an IND for an ADC using their technology. This March, it also received a milestone payment from Genentech when an IND was filed for an antibody using their ADC technology.
In the clinic, Medimmune has advanced a Seattle Genetics ADC into Phase I. The company furthest along in developing ADCs with their technology is Celldex (NASDAQ:CLDX). It recently announced initiation of randomized Phase IIb trials for an ADC.
Seattle Genetics is also on the front lines of Antibody Glyco-engineering. Much of the current work in this area requires the use of recombinant cells - this is how Roche engineered their new Anti-CD20 antibody. Seattle Genetics invented a technique, Sugar Engineered Antibody (SEA), where modified sugars added to cell culture media inhibit the addition of Fucose incorporation into the mature antibody. Their technology is cost-effective, easy to implement, and can be used across multiple cell lines for antibody production.
Seattle Genetics has said it intends to license out the SEA technology as well as using it in their own programs.
This is one company with two ways to empower antibodies. Both technologies are validated. ADCs are in all phases of clinical trials, with one drug approved (Mylotarg). Roche’s Glyco-engineered 3rd generation Anti-CD20 antibody is now in Phase III trials.
Just as PEGylation improved and advanced recombinant protein therapies, ADC and Glyco-engineering will change the course of therapeutic antibodies development.
Disclosure: Long SGEN, CLDX