What’s Next ? 

Following the positive results for the three ADCs, the next step is carving out a path to FDA approval for each candidate. Navigating a drug candidate towards registration may become an extremely complex task, not only due to the need to show meaningful benefit in the form of PFS or survival in larger, placebo controlled studies, but also because of the need to factor in multiple considerations. These considerations include timing issues, competing products in development, intellectual property and costs.  This is where a company’s strategic planning abilities come into play.

The path for SGN-35 is relatively simple, as the Hodgkin’s Lymphoma market is small, with very few drug candidates in the clinic. Because the unmet clinical need is limited, Seattle Genetics will probably first try to get SGN-35 approved in heavily pretreated, relapsed patients, either as mono-therapy or in combination with approved therapies. From that point, the company could try to advance SGN-35 into earlier stage patients, but the commercial rationale for such label expansion is uncertain. The widely used regimens for early stage HL are curative in more than 85% of cases and contain primarily generic compounds. Thus, market acceptance for a treatment that slightly improves likelihood for remission but costs several tens of thousands dollars might be modest.

The situation for T-DM1 is much more complex, with multiple dilemmas at hand, as the market for HER2 positive breast cancer is very active. Adding more complexity is Hercpetin’s strong presence in this market throughout the different stages of the disease. Among the decisions that need to be made are whether and when T-DM1 will eventually replace Herceptin, whether it should be combined with other drugs and which indications should be pursued in the near term future . On the one hand, the fastest route to approval is a phase III trial in Herceptin resistant patients. The advantage in going after this indication is the short trial duration and the option to get the drug approved with less stringent endpoints. However, there are multiple agents in advanced clinical stages for this patient population, including combinations with Herceptin. Two recent examples could be Genentech’s pertuzumab and Kosan’s (KOSN) tanespimycin, both of which showed encouraging activity when combined with Herceptin in Herceptin resistant patients. A registrational trial for this indication will probably involve the recently approved Tykerb+Xeloda combination as a control arm. If the PFS data of 9.6 months is indicative of the real activity of T-DM1 in larger populations, it might not be enough to show a statistically significant advantage over the 8.5 months of PFS Tykerb®+ Xeloda® demonstrated in their registrational phase III trial. In order to improve chances for approval, Genentech might want to evaluate T-DM1 combined with a chemo agent or in more frequent dosing schedule, but that will translate into a delay of more than 1 year, as every type of combination must be first evaluated for safety in a dose escalation trial.

As long as Herceptin remains the mainstay treatment in the market, Genentech should be in no hurry to replace it with its armed version, especially because it wisely cornered the field of anti HER2 antibodies using patent protection. However, Herceptin’s position may be threatened by other agents that target HER2. The most significant player in that space is Tykerb, which is currently being evaluated head-to-head against, as well as in combination with Herceptin in several different studies. Tykerb’s activity in Herceptin-resistant breast cancer, combined with the fact that it is an oral agent, make it a real threat to Herceptin. Ironically, the heat Genentech is feeling with respect to Herceptin is the best thing that could happen to Immunogen. Genentech is probably bullish on ADCs and T-DM1 regardless of market dynamics, but when a product that has $4.5 in annual sales is at jeopardy, one can count on Genentech to do whatever it takes to defend its turf.

Although the T-DM1 and SGN-35 data presented at ASCO are from small uncontrolled clinical trials, the two trials serve as a strong validation for the technology of each company due to of the patient population in both trials. In the case of T-DM1, all the patients in the trials had previously progressed during Herceptin regimens and are considered Herceptin resistant. This means that naked Herceptin can longer control the disease, let alone lead to tumor shrinkage. In the case of SGN-35, the evidence is less striking but I still find it very persuading. SGN-35 is comprised of the antibody, SGN-30, and Seattle Genetics’ linker and toxic payload. SGN-30, the naked antibody has been evaluated in similar patient population and showed only a minor effect, while SGN-35 proved to be highly effective in these patients, at substantially lower doses than those of SGN-30. Since T-DM1 and SGN-35 were evaluated as mono-therapy, the only plausible explanation for the clinical activity is the arming of the two antibodies. Just to make it clear, it does not mean that both agents will succeed in future clinical trials, but in my opinion, it means that both Immunogen and Seattle Genetics have brilliant technologies that will eventually serve as a basis for multiple approved drugs. As platform companies, the value of these companies should be derived not only from their promising pipelines but also from the huge value embodied in their platforms.     

So far, Seattle Genetics has been favored by the stock market and is currently worth four times Immunogen’s market cap. The reason for this difference is probably  Seattle Genetics’ focus on naked antibodies for blood cancers, as opposed to Immunogen who chose to focus on ADCs for solid tumors. While solid tumors represent over 90% of the oncology market, success rates in the blood cancer field are substantially higher. Bearing in mind the exploratory nature of ADCs and the disappointing results they have had to date, it is easy to understand why most investors stayed away from Immunogen. Now that ADCs are finally ready for primetime and facing wide industry adoption, Immunogen is becoming very attractive for the same reasons that made it the black sheep in the family: Its focus on ADCs and solid tumors.

For the sake of full disclosure, I am bullish on both companies and do not suggest that Seattle Genetics is a bad investment going forward, as I have expressed my thoughts on its pipeline in previous articles. Nevertheless, Immunogen currently has the lion’s share of the ADC market, as it will have eight compounds in clinical development this year, most of which are being developed and financed by its partners. These compounds include T-DM1 in collaboration with Genentech, three wholly owned compounds (IMGN242, IMGN901, and IMGN388), two compounds in collaboration with Sanofi-Aventis (AVE9633, SAR3419), one compound with Biogen-IDEC (BIIB015) and one compound in collaboration with Biotest (BT-062). There is also a lot of activity behind the scenes with Genentech and Sanofi-Aventis, which should result in a growing flow of candidates into the clinic. Needless to say, most clinical trials in oncology fail, and there is no reason to believe that ADCs will be an exception. For example, the development of IMGN242 will probably be terminated this year, after 8 years of clinical development. The AVE9633 program is another one that should be discontinued, the sooner the better. I know this sentence just cost my inbox tens of angry e-mails but the way I see it, Sanofi is wasting patients’ time and investors’ money with this one. Failures are a natural part of drug development, and this is why companies should strive to cast the widest net in order to get statistics on their side.

SGEN currently has 2 ADCs in the clinic, and is not expected to file an IND for in-house developed ADCs, until next year. Hopefully, partnerships with MedImmune and Agensys ( Now part of AstraZeneca and Astellas, respectively) will help it expand the number of ADCs in its pipeline this year.

In summary, the summer of 2008 may be remembered as the inflection point of antibody drug conjugates with the two most promising platforms being those of Immunogen and Seattle Genetics. But ADCs are not the only thing happening in the field of antibodies. Micromet, a tiny German-based company represents another promising antibody platform with the potential of transforming the cancer antibodies market as we know it. Although this platform, termed BiTE, is at a very early stage of its evolution, it already showed very impressive signs of activity. Micromet is expected to report updated data for its flagship product, MT103 at ICML in Switzerland , two days after the conclusion of ASCO.

Author is long IMGN, SGEN, MITI & SNTA