Seattle deal and ImmunoGen data mark growing interest in conjugate field
News over the last few days from two of the most closely watched antibody drug conjugates (ADC) in development points to growing progress in a field which has promised much, but has largely failed to deliver so far.
Encouraging results from a trial of Roche and ImmunoGen partnered-product, T-DM1, and a lucrative licensing deal for Seattle Genetics’ SGN-35 with Takeda, certainly suggests progress is being made. With a number of ADCs now generating late stage data and getting closer to regulatory scrutiny, it might not be long before a new conjugate manages to reach the market.
Despite the compelling logic behind combining a toxic payload with a specific and targeted antibody, that can carry the agent directly to the tumour site, side effects and drug resistance have been hard to overcome (Therapeutic focus – Antibody drug conjugates set to improve on poor track record, May 29, 2009). After many years of research and set backs, several ADCs are now approaching pivotal data points and T-DM1 and SGN-35 are looking the most promising seen for a number of years.
T-DM1, a molecule that combines the Swiss company’s blockbuster breast cancer therapy Herceptin and a cytotoxic agent developed by ImmunoGen, probably has the most chance of reaching the market first. The partners announced results from a potentially pivotal phase II trial at the San Antonio Breast Cancer Symposium earlier this week.
Patients with advanced HER2 positive breast cancer who had failed on at least five other therapies, including Herceptin and Tykerb, were treated with T-DM1, prompting a 32.7% overall response rate. It is too early for the response duration to be measured, but with a median follow-up of 8.3 months, only one third of the 36 responders had relapsed. Seven patients have had responses lasting at least six months, and median progression free survival was 7.3 months.
In such a refractory population these results could well be sufficient for regulatory approval, and Roche is currently deciding whether to make an application with the regulators. Either way, further data which will probably be announced at Asco next year will be closely watched.
Snapping up the opportunity
The molecule just acquired by Takeda is a little further behind, and addresses a different area. Seattle will receive $60m upfront in exchange for ex-US and Canadian rights to SGN-35, a conjugate called brentuximab vedotin, an anti-CD30 monoclonal antibody linked to the cytotoxic agent monomethyl auristatin E. The target, CD30, is expressed on Hodgkin lymphoma, various T-cell cancers and other haematologic malignancies.
As well as tiered double-digit royalties, Seattle might receive milestones worth up to $230m, and both companies are sharing development costs outside of Japan. Data from a pivotal phase II trial of SGN-35 in relapsed or refractory HL are expected in the second half of 2010.
Seattle is certainly uniquely exposed to success with ADCs. The company has signed more than seven licensing deals around its ADC platform over the last few years and, according to RBC Capital Markets, seven of the seventeen clinical-stage ADCs across the industry use Seattle’s ADC technology, a number that could well grow considering the deals it has in place.
Overcoming the effects
However, ImmunoGen is also very deep in the area. Last week, results from another of its ADCs were reported at Ash, this time partnered with Sanofi-Aventis, SAR3419. In a study in patients with non-Hodgkin’s lymphoma who had relapsed after Rituxan therapy, the drug produced an objective response in five out of 27 evaluable patients, and tumour shrinkage was observed in the majority of patients.
However, blurred vision emerged as a recurring side effect, which appeared to be linked to dose. Although the company believes this is manageable, it is a side effect seen with other ImmunoGen ADCs, and is something that will be looked out for in the future.
There are a handful of other late-stage conjugates in development. A phase III trial in follicular lymphoma with CMC544, being developed by Pfizer, was scrapped in February this year due to slow enrolment, but data from a phase III study in B-cell lymphoma is due next year. Active Biotech’s Anyara is in a pivotal trial for renal cell carcinoma which completed enrolment in June, with results due towards the end of 2010 or early 2011.
Overcoming the side effects clearly remains a key challenge for this field, but with further encouraging results from these late stage candidates, and the others not far behind, interest in this space should continue to grow.