For part I click here
At ASH 2009, Immunogen (NASDAQ:IMGN) and its partners will present clinical data on three compounds: Sanofi-Aventis’ (SNY) SAR3419, Immunogen’s IMGN901 and Biotest’s BT-062.
SAR3419 was originally developed by Immunogen, who out-licensed it to Sanofi Aventis as part of a broad collaboration. Sanofi had previously advanced two additional drugs based on Immunogen’s technology into clinical testing, but both programs were terminated, leaving SAR3419 as the only clinical stage agent in the collaboration. Now it seems that Sanofi’s early bet on Immunogen’s technology is starting to pay off.
SAR3419 targets CD19 which is expressed in several blood cancers. The field of anti CD19 drugs is becoming very active and crowded, with two additional anti CD19 antibodies in clinical development: Micromet’s (MITI) blinatumomab and BMS’ (BMY) MDX-1342. All three have some level of activity in humans even though each one represents a different approach to targeting CD19 and it is still unclear which targeting strategy is better. Immunogen’s technology is currently leading the pack as it enjoys the resources of a large partner that can support an aggressive and broad development program.
As I discussed in a previous article, Sanofi seems quite excited about SAR3419, based on a manufacturing agreement with a Korean subcontractor and informal remarks by Sanofi and Immunogen. Adding to these was the organizers’ decision to present the SAR3419 data in an oral presentation, which probably means the data was positive enough. Based on the abstract for the presentation, which is already available, SAR3419 had clear activity in heavily pretreated Non Hodgkin Lymphoma (NHL) patients.
Of the 25 evaluable patients, 3 achieved a complete response and 2 achieved a partial response, resulting in an objective response rate of 20%. Furthermore, 68% of patients experienced some sort of tumor shrinkage. As a dose escalation trial, this study may under-represent SAR3419’s true activity since many of the patients did not receive the optimal dose. Therefore, it will be interesting to see actual results with more patients treated at the maximum tolerated dose. Another important factor is response duration, which is still unclear. In order to be considered clinically meaningful, SAR3419 must have a response duration of at least 6 months on average.
SAR3419 is carefully watched by investors in Micromet, who will also be presenting updated results from a phase I NHL study at ASH. Micromet’s blinatumomab demonstrated exceptional activity in a small number of NHL patients, with a response rate of ~92% at the highest dose tested. Micromet’s technology (BiTE) can be viewed as a competitor of Immunogen’s technology and at ASH it will be the first time the two can be evaluated for the same target, even though in different trials that cannot be directly compared.
SAR3419 may offer an advantage in its dosing schedule. Micromet’s blinatumomab is given as a continuous infusion for 4-8 weeks while Sanofi’s SAR3419 is given once every 3 weeks until disease progression. On the other hand, it will be very hard to match blinatumomab’s activity, even though it should be noted that the larger a trial gets, the lower the performance usually is. I addressed the advantages and disadvantages of the two technologies in a previous article on Micromet.
It is very hard to predict which candidate will be more successful, and assuming both agents show good efficacy, physicians and patients will choose treatment based on a combination of factors including anti-tumor activity, response duration, safety profile and patient convenience. At the end of the day, the market is big enough for more than one anti-CD19 drug.
Additional presentations to watch at ASH are phase I results for IMGN901 (wholly owned by Immunogen) and Biotest’s BT-062. The two ADCs are evaluated in two different trials for the treatment of multiple myeloma, the primary indications of the blockbusters Revlimid and Velcade. In contrast to T-DM1 and SAR3419, the data for these compounds will be less mature, with up to 30 patients in each trial. Since both studies are dose escalation trials, the results may understate the drugs’ efficacy, although it is clear both have some level of activity in this disease.
Data from the IMGN901 phase I trial will probably demonstrate a low level of activity and a good safety profile. Based on the abstract, IMGN901 led to a partial response in one of 23 patients, but the dose used for this patient turned out to be too toxic. 3 additional patients derived benefit from this compound in the form of minor responses. Immunogen will present data for additional patients, but based on Immunogen’s announced plans to start a phase II trial of IMGN901 in combination with Revlimid, it appears that IMGN901 is not potent enough to be developed as monotherapy.
IMGN901 will eventually be outlicensed in order to support late stage development. Fortunately, antibodies for multiple myeloma are in high demand and the bar for activity is rather low. A recent example is the 2008 outlicensing of Facet Biotech’s (FACT) (Formerly PDL Pharmaceuticals) elotuzumab to BMS. When the deal was signed, BMS knew that elotuzumab did not achieve objective responses as a single agent , but it did not prevent it from paying an upfront payment of $30M and committing $510M in milestones. IMGN901 is being evaluated in additional cancers, which could affect its value in a partnership deal.
Biotest’s BT-062 is an antibody-drug conjugates (ADC) targeted against CD138, a protein well known in the context of multiple myeloma. Based on the abstract, of the 20 evaluable patients, one had a partial response with an additional patient showing a strong anti-tumor effect. Several patients showed prolonged disease stabilization as well. Additional patients are being accrued at the maximum tolerated dose, so it will be interesting to see if more responses are achieved.
Interestingly, Biotest announced its plans to launch an 80 patient phase II study for BT-062 as monotherapy. This is quite unusual for antibodies for multiple myeloma, which are usually evaluated in combination with other drugs in phase II trials. It remains to be seen whether this decision was based on additional positive data.
Another intriguing property is BT-062’s circulation time. According to the abstract, BT-062 gets cleared from the bloodstream at a very fast rate when given in low doses, but in patients receiving higher doses it had a better circulation time. The reason is still unclear, but this profile may imply very efficient internalization of the ADC, which might play out in Biotest’s favor, assuming that the drug exposure with the higher doses is sufficient.
In summary, Immunogen concludes 2009 as its best year ever, armed with not only a product on the verge of potential approval, but with a broad pipeline and a validated platform technology. During 2009, no new drugs entered clinical trials, but the company’s partnered pipeline matured nicely, with two compounds achieving proof of concept. On top of the clear activity, Immunogen’s technology has overcome the safety issues of earlier generation ADCs, as all of its compounds had a mild side effect profile. From a business development standpoint, the most important event was the two licenses given to Amgen. Although the timelines are not clear for these projects, having someone of Amgen’s caliber is another validation for Immunogen’s technology.
In 2010, Immunogen is looking at several important events. Investors can expect additional licensing deals with attractive financial terms as well as at least two new agents in clinical trials. In June, results from two additional ADCs based on Immunogen’s technology (IMGN388 and BIIB015) will be presented at the ASCO meeting. These compounds, which entered the clinical trials in mid-2008, should have enough data for evaluating their merit. Finally, the second half of 2010 could see the approval of T-DM1 for advanced breast cancer, triggering a substantial milestone payment to Immunogen.
Together with its competitors, Seattle Genetics (SGEN) and Micromet, Immunogen is leading the paradigm shift in the biotech industry towards next generation antibodies. For more on this trend and its implications, click here.