In the first part of this article we explained why we think Immunogen (NASDAQ:IMGN) is shaping up to become a central player in the antibody for cancer industry. We also discussed the promising prospects of Herceptin-DM1, which is an armed version of Genentech's (DNA) blockbuster antibody, Herceptin®. IMGN has two wholly-owned ADCs (Antibody-drug conjugates) in clinical trials - huC242-DM4 and huN901-DM1. In addition to Herceptin-DM1, there are three compounds in clinical stages that are being developed by Sanofi-Aventis - AVE9633, AVE1642 and SAR3419.
The story behind this compound perhaps explains the considerable skepticism surrounding Immunogen's platform, and should serve as a demonstration for the risks and uncertainties in drug development. huC242-DM4 is comprised of the humanized antibody huC242 , which binds to CanAg, which is expressed on colorectal, pancreatic and gastric cancer cells. The first ADC based on huC242 was huC242-DM1, which is identical to huC242-DM4 with one difference – the linker.
huC242-DM1 entered 2 phase I clinical trials, in which the vast majority of patients had colorectal cancer. Unfortunately, the compound's performance was rather weak, leading to some minor responses but no objective responses (50% regression in tumor burden lasting at least 6 weeks). There were two possible explanations for the disappointing activity. First, it is well known that colorectal cancer is relatively resistant to antimicrotubule agents, such as paclitaxel (Taxol®) and maytansine, (which is the drug Immunogen uses for its compounds). Second, the compound had a rather poor stability in the bloodstream, which led to lower drug concentrations shortly after administration. In parallel to the phase I, the company started evaluating ADCs based on the same antibody, but with a different linker - huC242-DM4. These evaluations revealed that the substitution of the linker led to an increase of more than 2-fold in the ADC's stability in comparison to huC242-DM1.
Subsequently, on October 2004, the company announced that it had decided to replace huC242-DM1 by huC242-DM4. That meant, of course, a new phase I trial must take place, in order to assess the safety of the new compound. The phase I clinical trial was initiated in mid 2005, with results announced in June of 2007. In this trial, the vast majority of patients were also advanced-stage colorectal cancer patients, so the chances didn't look too good in the first place. Although there were no objectives responses, huC242-DM4 indeed proved to be more stable than the earlier version of this ADC. It was quite clear that huC242-DM4 will not be effective against colorectal cancer, so the company decided to assess the compound's activity for the treatment of gastric cancer, as approximately half of all gastric cancer tumors express CanAg. The company recently initiated a phase II trial in advanced gastric cancer patients, who have failed front-line chemotherapy. During the second half of the 20th century, the incidence of gastric cancer has dramatically decreased in developed countries, but it is still a leading cause of death, responsible for over 11,000 deaths annually in the US alone. Just like many other types of cancer, gastric cancer is curable in its early stages, however, unfortunately, in many cases it is diagnosed in its advanced stages, where the only option is chemotherapy treatments. The company takes pride in the fact that gastric cancer has been found to be highly sensitive to huC242-DM4 in preclinical studies, but we also know that was the case for several colorectal cancer cell lines. Fortunately, last year, the antimicrotubule agent, docetaxel (Taxotere®) was approved by the FDA for the treatment of gastric cancer in combination with other drugs. Additional clinical trials, including trials published this year, also support the use of Taxotere for the treatment of gastric cancer. This is in striking contrast to colorectal cancer, for which antimicrotubule agents are not approved. In addition, both Taxotere and Taxol demonstrated clinical activity in gastric cancer as single agents. These are very encouraging news, since this time, huC242-DM4 actually stands a chance of showing some sort of clinical response, especially in light of the higher potency of DM4 relatively to Taxotere. Nevertheless, although Taxotere was the first FDA approved drug to demonstrate a survival advantage in gastric cancer in more than a decade, it did not improve survival dramatically. The fact that patients enrolled to the phase II trial had failed at least one chemotherapy treatment makes it even more challenging.
In order to get a reliable assessment of huC242-DM4's efficacy with minimal allocation of resources, Immunogen will first evaluate only 17 patients, hoping that there will be at least one objective response (50% regression in tumor size lasting at least 6 weeks). Statistically, if no clinical response is observed among these 17 patients, it is likely that the drug won't be very effective for gastric cancer. That means that interim results from this study may be published in the coming months. In our opinion, this trial is the most important one for Immunogen, as even one partial response can open the door for recruitment of additional patients and possibly for a phase III trial already in 2009. The market expectations regarding this compound are pretty low, which will make any positive indication an extremely positive surprise. Bearing in mind this compound is fully owned by Immunogen, clinical success in the huC242-DM4 front, will lead to substantial appreciation in the stock price.
huN901-DM1, which is the second wholly-owned candidate Immunogen is currently evaluating in clinical trials, comprises the huN901 antibody, which targets CD56 and the DM1 cell-killing agent. CD56 is mainly expressed by multiple myeloma, small-cell lung (SCLC) and ovarian cancers. Small-cell lung cancer accounts for ~20% of all lung cancers cases, with 214,000 cases estimated in 2007. While the response rates to chemotherapy are very high, ultimately, the majority of patients will relapse within a year from the treatment start.
huN901-DM1 is currently being evaluated in 3 different clinical trials, prosaically titled 001,002 & 003:
Study 001 is a phase II trial which was designed to evaluate huN901-DM1 for the treatment of SCLC. Recently, the company presented results from this trial in ASCO 2007. The trial started as a dose escalation trial, until Maximum Tolerated Dose (NYSE:MTD) was set at 60mg/m2/week for four consecutive weeks every six weeks.
Out of the 30 evaluated patients, 13 patients were treated with doses lower than the MTD. 2 patients had a partial response and 5 had stable disease, which is not a spectacular response rate, but definitely justifies additional evaluations.
Study 002 is a phase I trial evaluating huN901-DM1 for the treatment of SCLC and other CD56-expressing solid tumors. The dosing in this trial is somewhat more aggressive in comparison to the 001 trial, as the compound is dosed daily for three days in a 21-day cycle with doses starting at 12 mg/m2 to 225 mg/m2 over three days. The last update from this trial was reported in November of 2006, after evaluating 41 patients. This trial was also a dose-escalation trial, which means that many of the patients were administered with lower doses. Out of the 41 patients, there was one complete response in a patient with relapsed Merkel cell cancer (a rare type of skin cancer) which lasted 21 months (At the time of data presentation), one partial response in a patient with SCLC and 13 patients with stable disease, two of which lasted for 18 weeks. MTD has not been reached, which means there is room for higher doses to be evaluated. This trial's MTD will be much higher than the one achieved in the 001 study, which led the company to give the 002 study priority over study 001. Due to supply constraints, Immunogen is yet to enroll additional patients in the 002 trial, however, the company expects to start additional dosing very soon.
Study 003 is the reason for the delay in patient recruitment for study 002. This study evaluates huN901-DM1 for the treatment of relapsed multiple myeloma, a very common blood cancer that expresses CD56 in 70% of the cases. According to the American Cancer Society, approximately 20,000 new cases of multiple myeloma will be diagnosed in the USA in 2007, and close to 11,000 people will die from the disease. Fortunately for patients, the competitive landscape in the multiple myeloma market has become very tough, with 3 highly effective drugs gaining FDA approval in the past 5 years: bortezomib (Millennium's Velcade®) thalidomide (Celgene's Thalomid®) and lenalidomide (Celgene's Revlimid®). All three have demonstrated substantial activity as single agents as well as in combination regimens for early and advanced stages multiple myeloma.
Since the company sees this trial as the most promising opportunity for huN901-DM1, and is currently limited in the amount of drug it can manufacture, it decided to give it priority over the 001 and 002 trials. So far, only preliminary results were reported from this trial, evaluating only 2 cohorts of 3 patients each, with huN901-DM1 administered weekly for two weeks in a three-week cycle. The lower dose did not demonstrate clinical effect, however the higher dose (60 mg/m2/day) resulted in impressive results. One of the three patients receiving the higher, 60 mg/m2 dose level had an objective response to treatment and the other two patients receiving this dose showed evidence of clinical benefit. More importantly, the patient who achieved a partial response had previously been treated with thalidomide and lenalidomide, among other treatments. The company recruited more patients to be administered with higher doses, up to 112 mg/m2, and will report results at The American Society of Hematology's (NYSE:ASH) annual meeting this December.
The company's management sounds very enthusiastic in regard to the results of that follow on trial. Abstracts for ASH 2007 had to be submitted by August 21, with late-breaking abstract deadline set at October 9, so by now the data has probably been prepared and analyzed by the company. During a presentation at the BIO InvestorForum 2007 that took place on October 10, the company's CFO again expressed a great deal of optimism regarding the evaluation of huN901-DM1 for multiple myeloma, calling it "the fastest route for the market". We specifically see the company's expectations build-up for ASH 2007 as a strong indication for the quality of results involving the 3 additional doses.
This Antibody-drug conjugate was created by ImmunoGen and licensed to Sanofi-Aventis. AVE9633 consists of the huMy9-6 antibody, which binds specifically to the CD33 antigen found on acute myeloid leukemia cells, and Immunogen's DM4 cell-killing agent. There expected to be more than 13,000 new cases of AML this year in the US alone, and around 9,000 americans are expected to die as a result of the disease. Although during the last decade, an increase in survival rates was achieved due to the introduction of new treatments, most patients will die less than 5 years after diagnosis. The high likelihood of disease relapse is especially unsatisfactory, despite the relatively high portion of complete responses achieved by chemotherapy and Wyeth's (WYE) Mylotarg®, the sole approved antibody-drug conjugate to date. CD33 antigen is present in approximately 90% of AML patients, which makes it a very attractive target. More importantly, the concept of targeting CD33 has been validated by the impressive activity of Mylotarg in AML. On he other hand, AVE9633 will have to be show at least the same activity and safety profile in order to be approved. This a relatively high bar, and according to preliminary results, chances are pretty low.
AVE9633 entered phase I in 2005, where the compound was dosed once per three weeks at doses up to 260 mg/m2, without encountering dose-limiting toxicities. Since there was no substantial clinical activity, Sanofi-Aventis decided to launch 2 additional phase I trials where AVE9633 is dosed more frequently. Although data is yet to be reported from this trial, the company defines results "encouraging". Clinical findings from this trial are expected to be presented in ASH 2007 as well. The comparison to Mylotarg is inevitable, since both compounds are ADCs that target CD33. In pre-clinical trials, AVE9633 was found to be more active than Mylotarg, however, a quick glance at the dosing profile of the two agents reveals a staggering difference. Mylotarg is dosed twice at 9 mg/m2, with 14 days between the first and the second dose, and achieves impressive clinical response, including 20-30% complete responses. AVE9633 could not achieve an objective response at a single dose of 260 mg/m2. What is even more discouraging is the fact that according to several trials, Mylotarg reaches complete saturation of CD33 sites present in the bloodstream and 42% to 90% saturation in the bone marrow at a dose of 9 mg/m2. In other words, there is no use to administer additional amount of drug since it has no target to bind. Therefore, unless there is something we are totally missing here, something went very wrong with AVE9633.
AVE1642 is a "naked" antibody that binds insulin-like growth factor (IGF-1R). It is currently evaluated in a phase I clinical trial that started in October of last year. Interestingly, this antibody is not attached to a drug payload, and is most likely intended to be used in combination with chemotherapy.
IGF-1R is postulated to be a very important target in several types of cancers such as colorectal, lung and breast cancers. This receptor has been shown to contribute to the development and progression of tumors, as its activation triggers a cascade of signals ultimately leading to survival and proliferation. An antibody targeted at IGF-1R may serve as an anticancer agent by preventing the growth factors from binding the receptor or by inducing an immune response against cells that express IGF-1R. IGF-1R is also expressed by normal cells, including blood vessels, which offers an explanation to why Sanofi-Aventis decided not to arm AVE1642 with a deadly payload. This is a good example for cases where ADCs cannot be used, because they will probably lead to unbearable side effects.
Since targeting IGF-1R by monoclonal antibodies seems very promising, several other companies, including Pfizer (NYSE:PFE) and Imclone (OTCQB:IMCL) are actively pursuing this pathway. Both companies have already published results from phase I clinical trials, showing some clinical activity and a very good safety profile, which makes Sanofi Aventis a little late to the party, but eventually, demonstrating clinical activity is the top priority for AVE1642.
SAR3419, which entered clinical trials just recently, is an ADC comprised of an antibody that targets CD19 and the toxic agent DM4. CD19 is broadly expressed through many types of B-lymphoid malignancies but not on normal B cells. To date, several anti CD19 antibodies were evaluated pre-clinically as well as in clinical trials but did not show a great deal of clinical effect. In addition, CD19 was shown to internalize after an antibody binds it, which makes it a suitable target for Antibody-drug conjugates.
SAR3419 is being developed by Sanofi-Aventis for the treatment B-cell hematological malignancies, including non-Hodgkin's lymphoma [NHL] and acute lymphoblastic leukemia [ALL]. The huge potential in this market can be demonstrated by the success of Genentech's Rituxan®, which had worldwide sales of just under 4$ billion in 2006. Since Rituxan's target (CD20) is different than SAR3419's, these agents are not necessarily competitors, but even may have a synergistic effect. Even if SAR3419 is found to be clinically active, it might face a tough competition from Micromet's (NASDAQ:MITI) promising anti CD19 bispecific antibody, MT103, which has already showed promising results among NHL patients.
In addition to these five candidates, Immunogen expects to have 1-3 additional compounds in clinical stages by June of 2008. Potential candidates may be compounds which are being developed in partnership with Biogen Idec, Centocor, and of course Genentech and Sanofi-Aventis. 2 promising compounds that have demonstrated great pre-clinical results have been discussed in recent scientific publications. The first is an anti CD79 ADC, based on immunogen's DM1, which is developed by Genentech for the huge market of NHL treatment. Interestingly, the DM1-based compound was compared head to head with a compound based on Seattle Genetics' (NASDAQ:SGEN) technology and there were no substantial differences between the two compounds regarding their activity in mice. It remains to be seen, whether Genentech decides to advance any of the compounds into clinical trials. The second article was published by Centocor and evaluated 3 different ADCs based on Immunogen's technology that target ανintegrins, which are present on several tumors including lung cancer and melanoma. One of these ADCs, CNTO 365, showed the most promising results.
In summary, we believe that not only does Immunogen have an impressive and diverse pipeline, they also have an attractive platform for developing new ADCs, either independently or via its partnerships. This platform will hopefully lead to a constant flow of candidates into the clinic in the coming years, without putting too much pressure on the company's expense line. Even after acknowledging that statistically, the majority of its evaluations will probably fail, we view Immunogen as a very attractive long-term play.
Disclosure: Author has a long position in IMGN