Regardless of IMGN901’s specific case, the impression I am getting from all the scientific material I come across that deals with Immunogen’s (IMGN) technology, is that IMGN901 will probably be the last ADC (antibody-drug conjugate) powered by the cleavable DM1 linker. There are currently no ADC programs, except from IMGN901, that utilize this specific linker. As I mentioned in one of my SGEN’s (SGEN) pieces, Genentech seems to prefer a noncleavable linker for the majority of its ADCs. Another example may be, Centocor, who licensed Immunogen’s technology for arming a antibodies targeted against alpha integrin and evaluated both DM1 and DM4 cleavable linkers with the same antibody. Results from several animal experiments showed that the cleavable DM4 version was much more stable in the bloodstream and active in inhibiting tumor growth than the cleavable DM1 version.
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At ASH (American Society of Hematology), Immunogen (IMGN) and its partners presented data on several projects including IMGN901(formerly known as HuN901) for Multiple Myeloma and AVE9633 for AML (Acute Myelogenous Leukemia) .
The company presented updated results from its phase I dose escalation study in Multiple Myeloma patients who have failed prior treatments. IMGN901 was administered weekly for 2 consecutive weeks in a 3-week cycle, and the company reported results from 12 patients in 4 cohorts of 3. The evaluated doses were 40 mg/m2/week, 60 mg/m2/week, 75 mg/m2/week, and 90 mg/m2/week. Immunogen had previously published results for the two lower doses, which included one partial response (PR) and 2 stable disease (SD) in the 60 mg/m2/week cohort. In its ASH presentation, the company revealed that among the 6 patients who received the 2 higher doses (75 and 90 mg/m2), there was also one partial response in a patient at the 90 mg/m2/week cohort, although this patient had to drop out of the trial due to unrelated issues. Of note, the patient who responded at 60 mg/m2 is still on the study, after more than 10 months.
I must admit I expected results to be somewhat better, based on management’s remarks in several investor conferences. I wrongly concluded that if a company gets a partial response in 1 out of 3 patients who were dosed at 60 mg/m2, and claims to be very excited about the 2 higher doses, there would be at least one partial response in each cohort to generate a response rate of 33%. Nevertheless, these results are quite positive for two reasons. First, all patients who participated in this trial were heavily pretreated patients, who had already received more than four prior therapies. Second, IMGN901 demonstrated excellent safety profile as no severe side effects were documented. This means that additional patients can be recruited and receive higher doses, that might be more effective.
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There are currently 2 ongoing and one planned clinical trials for the evaluation of SGN-33.
The first clinical trial is the extension of the phase I trial, but this time all patients are to receive the highest dose tested in the original phase I (8mg/kg). The company expects to have data from this trial by the beginning of 2009. Typically, these types of trials should result in better performance than the first dose escalation trial, since the highest dose is expected to achieve better results than lower doses. In this case, since clinical activity in the highest dose and in the lower doses was similar, I wouldn’t expect to see a substantial improvement in the rate of CR in the ongoing trial. This can be explained by the fact that even lower doses ( 4 and 2.5 mg/kg) lead to the saturation of the vast majority of CD33 in the bone marrow, so any additional antibodies that enter the bone marrow has no targets left to bind. This is also why the dose was not escalated beyond 8 mg/kg even though there were no dose limiting toxicities.
The second trial (and the more important one) is a randomized double-blind trial where SGN-33 is combined with low-dose araC, the standard therapy for older AML patients. Half of the patients are to receive araC+ placebo with the other half receiving araC+ SGN33. This trial will hopefully shed some light on two crucial issues.
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Chemotherapeutic Drugs in The Clinic – Competitors or Potential Partners?
Obviously, SGN-33 was not directly compared to any other agent, so insight gained from comparing SGN-33 to other agents from different clinical trials is far from being conclusive. In addition, a comparison of a naked antibody (that will likely be given in combination with other drugs), to other chemo and combination regimens is not a fair one. Nevertheless, these comparisons are the only means researchers and investors alike have when evaluating the prospects of SGN-33.
The efficacy/safety ratio of SGN-33 is very impressive when compared to available treatments as well as other treatments currently evaluated in clinical trials. The cornerstone treatment for older AML patients is low-dose araC which has less than 20% complete response rate as a single agent (compared with 29% for SGN-33 in the current trial). araC is typically administered with other agents and is currently evaluated in combination with some novel drug candidates. These combinations result in a much better response rate, in the range of 30-60% among a variety of patient populations.
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Seattle Genetics (SGEN) recently published clinical data from a phase I which evaluated SGN-33 for the treatment of elderly AML (Acute Myelogenous Leukemia) patients. AML is a common type of blood cancer, with around 13,000 new cases and 9000 deaths expected to occur during 2007 in the US alone. Prognosis of the disease is very poor, especially among elderly patients (over 60 years old), who have a long term survival rate of 5%, compared to 20% in the case of patients who are under 60. The dismal prognosis elderly AML patients have can be attributed to their inability to tolerate aggressive chemotherapy or stem cell transplant. Moreover, AML among elderly patients is inherently more resistant to standard chemotherapy due to several factors. Therefore, there is a unique challenge in developing better treatments for elderly AML patients, because these treatments must be very safe in addition to being effective. Antibodies, as well as other targeted therapies are regarded as excellent candidates, as they have an excellent safety profile and can be usually co-administered with other treatments. The market opportunity for such treatments is substantial, due to the high incidence of AML among elderly patients, so naturally there are multiple treatments currently being evaluated. The majority of these treatments are chemo agents but there are several targeted therapies, the most promising of which is SGN-33.
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A lot of clinical data was published at the American Society of Hematology (ASH) meeting, some of it quite impressive. Naturally, established drugs such as Millennium Pharmaceuticals‘ (MLNM) Velcade, Genentech’s (DNA) Rituxan and Celgene’s (CELG) Revlimid got most of the attention. In my opinion, the real star of the conference is MT-103 which is being co-developed by Micromet (MITI) and MedImmune, the biologics division of AstraZeneca (AZN). I won’t go too deep into describing the mechanism of action and the platform based on which MT-103 is built (I intend to do that in a review I hope to publish next week). However, the clinical data presented by Micromet is so impressive and so groundbreaking from several perspectives, that it must not be ignored.
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Japan is considered as one of the most advanced telecom markets in the world, especially in terms of average bandwidth allocated per each subscriber. Although there are many European countries with higher broadband penetration, subscribers in these countries can get up to several Mbps, while the standard in Japan is at least several tens of Mbps. This is thanks to years of infrastructure buildout mainly by the country’s leading incumbent, NTT, which has deployed a massive fiber network that covers the majority of population in Japan. The high fiber penetration and population density made Japan Ikanos’ (IKAN) largest market. Accounting for more than 35% of the market, there were more than 10 million FTTH subscribers in Japan in mid 2007, with the remaining of the broadband market dominated by DSL. During recent years, there is a clear trend among Japanese subscribers who migrate from DSL services (mainly ADSL) toward FTTH services. In fact, the number of FTTH subscribers is expected to surpass the number of DSL subscribers somewhere in 2008. In Q1 of 2007, for instance, more than 800k subscribers signed up for FTTH services, in contrast to a 200k drop in the number of DSL subs.
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Ikanos is a chip company which specializes in access and media gateways. For the past several years the small company has been the undisputed leader of the VDSL (Very High Speed DSL) market. This market, which originally existed mainly in Japan and Korea, seems to be spreading to the rest of the world, especially to Europe and the US. Although VDSL enables much higher transmission rates, it is still unclear how widely accepted it would become.
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CD70 program
CD70 is a receptor expressed on many types of blood cancers as well as the majority of renal cancer cases. The expression profile of this target is highly restricted to cancer cells, which, combined with its ability to internalize antibodies, makes it a desirable target for ADCs. Seattle Genetics is evaluating a naked antibody as well as an ADC that target CD70, both candidates are based on the same antibody, which was licensed from CLB-Research and Development. The naked antibody, SGN-70, is evaluated for certain blood cancers and is expected to enter phase I during 2008. Another possible use for SGN-70 is for autoimmune diseases, as it is expressed on white blood cells that are involved in the disease, but not on “resting” cells.
SGN-75 is an ADC based on SGN-70, which is currently evaluated pre-clinically for Renal cell carcinoma. This disease, although not as common as prostate and lung cancers, represents a large market opportunity with over 43,000 new cases and almost 13,000 deaths expected in 2007 in the US alone. Although surgical resection of the kidney has high chances to prevent the disease from spreading, nearly one third of patients are diagnosed at advanced stage, where the cancer has spread to additional organs. In addition, more than 30% of patients who undergo resection will eventually develop metastatic disease, for which very few therapeutic options exist. SGN-75 is expected to enter the clinic only in 2009.
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The partnership with MedImmune, which dates back to 2005, is probably Seattle Genetics’ second most important partnership. On the scientific side, now that MedImmune has been merged with Cambridge Antibody Technology [CAT] to form AstraZeneca’s (AZN) biologics division, Seattle Genetics has a real antibody powerhouse on its side. On the financial side, Seattle Genetics could benefit from another pharma giant on its partner list, equipped with the 8th largest R&D budget in the industry and consequently the ability to support multiple clinical programs simultaneously. Looking at Immunogen’s partnership with Sanofi-Aventis, which has thus far led to 3 clinical programs, is making us hope that AstraZeneca will be to Seattle Genetics, what Sanofi is to Immunogen.
The cooperation with MedImmune originally revolved around one target – EphA2. This intriguing target is highly expressed in numerous solid cancers including breast, prostate and colorectal, which makes the potential opportunity immense. In addition, there is a growing body of scientific evidence that expression of EphA2 is associated with aggressiveness and poor survival, which makes its targeting very reasonable in advanced stages of the disease. The specific targeting of EphA2 looks particularly promising since MedImmune’s scientists discovered that there are several regions within EphA2 which become exposed and consequently accessible for antibodies only on cancer cells.
MedImmune views Epha2 as a very important target. In fact, it has such high hopes for it, that there it is currently evaluating multiple approaches to targeting this promising antigen. One of these approaches is Micromet’s (MITI) Bite (stands for: Bi-Specific T cell Engager) platform, which is being co-developed with Medimmune for several targets, one of which is EphA2. The Bite Platform, a very interesting technology (that deserves an article of its own being so different from other antibody-based platforms) consists of two small antibodies that link between a tumor and specific immune cells in order to manipulate them to attack the tumor. It has demonstrated very impressive potency in mice, and even more impressive results among heavily pre-treated NHL patients, mainly due to the very low doses that showed a clinical effect. The Bite platform hasn’t been evaluated in solid tumors yet, but clinical trials are expected to be announced in the future, one of them is for a Bite agent that targets Epha2. Due to its unique characteristics that present both advantages and disadvantages, it is very hard to predict Bite’s efficacy in these settings. Although some consider Bite an immunotoxin, it differs from immunoconjugates in that it does not contain any drug or toxin payload, so it is reasonable to expect that MedImmune will explore it in parallel to Seattle Genetics’ platform. Although Bite is not necessarily a direct competitor, I bet the folks at Seattle Genetics are following that program closely. Nevertheless, MedImmune seems pretty happy with Seattle Genetics’ platforms, as it has recently licensed Seattle Genetics’ ADC technology for a second undisclosed target.
Author is long SGEN
