Today it is clear that treating cancer with monoclonal antibodies is one of the greatest advancements in oncology. Just over a decade ago, the approval of Rituxan marked the birth of a multi-billion dollar market, as 8 additional antibodies have since joined Rituxan. The market is currently dominated by a specific flavor of antibodies termed “naked” antibodies, which represent a fraction of the large amount of different antibody flavors. In contrast to naked antibodies, other flavors have yet to reach maturity, although some of these are making their way steadily to the center stage. All these approaches have one thing in common: They rely on antibodies’ exquisite ability to recognize and bind a target in a very specific manner. One of these approaches, represented by Immunogen (IMGN) and Seattle Genetics (SGEN), deals with Antibody-drug conjugates (ADCs), which are constructed by linking antibodies to a drug-payload. The antibody serves as a guiding system by guiding the drug to tumors, and releases it inside cancer cells. In addition, there is a lot of activity in developing additional antibody-based therapies that involve linking other types of substances to antibodies. For example, one possibility for boosting an antibody’s potency is linking it to a radioactive molecule like in GlaxoSmithKline’s (GSK) Bexxar case.
In biotech, just like in other investment fields, it is important to recognize market trends, and identify emerging technologies and concepts. The problem with such cutting-edge technologies is that, regardless of how promising they seem, there is always an unknown period of incubation, in which the technology migrates from basic research to the industry. If we take the whole antibody industry as an example, it took almost a quarter of a century from the scientific breakthrough that gave rise to monoclonal antibodies, to the approval of Rituxan. In the case of ADCs, several encouraging results may imply that the incubation period is finally over, although drug development is always characterized with a high level of uncertainty. As someone who has been following the antibody market for quite some time now, I assumed that ADCs such as T-DM1 will represent the majority of clinical breakthroughs in the coming years. However, preliminary results from a small clinical trial that were published in ASH three months ago, showed that there is a unique platform which can generate highly potent antibodies, without even linking them to drugs or other effector molecules. In fact, this platform gave rise to one of the most potent antibodies ever tried on human beings - Micromet’s (MITI) MT103.
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Rosetta Genomics (ROSG) represents one of the most exciting revolutions in biology in recent decades. The company is a pioneer in the field of microRNAs (miRNAs), a group of recently discovered genes that may serve as a novel class of diagnostic markers and drug targets. Unlike “traditional” genes we were familiar with, miRNA genes are not expressed as proteins, but as small RNA fragments that regulate the expression of many proteins. Rosetta Genomics’ impressive pipeline, unparalleled discovery capabilities and intellectual property make it one of the most exciting biotech companies out there.
The field of miRNA have captured the scientific community’s attention only in recent years, and is expected to become an important field in the drug development industry. The ultimate proof for how hot miRNAs are is the increase in the number of published scientific articles that focus on this new gene family. Using the Pubmed database, I looked for articles that contain the term “miRNA” in their title or abstract. There were only 38 such articles in 2003 but the number increased more than fourteen-fold in 2007. Even more striking is the diverse list of medical areas in which miRNAs are investigated, from oncology to cardiovascular diseases, from tissue engineering to women’s health.
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Although the North American market is viewed by Ikanos (IKAN) only as the third in its importance, there may be some positive surprises from that region in 2008. In addition, since the company has only negligible sales in the US, every deployment they can get represent a completely new revenue stream for the company, who is still struggling to reach profitability.
Similarly to what happened in Europe, Ikanos was left out of the flagship VDSL project in North America- AT&T’s FTTN deployment. This deployment is, without a doubt, the largest FTTN deployment in the world, as AT&T expects to pass 17 million homes by the end of 2008. It certainly does not mean that it expects to have an actual subscriber number that is even close to that figure, but the long term potential is huge. This time it was Conexant (CNXT) who got the lion’s share of the project mainly through Alcatel (ALU) on the CO side and 2Wire on the CPE side. It remains to be seen whether Ikanos will manage to get into this lucrative deployment, although so far there is no indication of that.
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Ikanos (IKAN) sees the European market as the most promising market for 2008, with several carriers evaluating VDSL platforms powered by Ikanos’ technology. There are several factors which make Europe so attractive for Ikanos.
First, fiber penetration in Europe is not as deep as in Japan and Korea, where fiber is typically pushed very close to the customer’s home or building. In Europe, the loop lengths are substantially longer, ranging from several hundreds to several thousands feet, which calls for ADSL2+ and FTTC/N rather than FTTH/B, assuming that carriers want to minimize capex. Second, European telcos are not pressured by cable operators, as cable companies in Europe are inferior to the large European carriers such as Deutsche Telekom and Telefonica. In the US, cable companies have a very strong position and are planning to fight Verizon’s and AT&T’s triple play offers by massive upgrades, including Docsis 3.0 that can potentially deliver 160Mbps, setting a very high bar. Third, the European market is characterized by strong regulation, which forces carriers to share their infrastructure and provide unbundled access to alternative carriers. This has led numerous carriers to a direct clash with the EU regulatory body regarding network unbundling and the feasibility of network upgrades in light of existing policies. The most familiar of these clashes is DT’s dispute with the European Commission (EC) about its VDSL buildout. DT refuses to provide alternative service providers such as Hansenet and Arcor access to its VDSL network despite harsh criticism and threats from the EC. Fourth, Ikanos has a very strong partnership with Alcatel–Lucent (ALU), the most dominant access vendor in Europe. Ikanos expects most of its future sales in Europe to be derived from the partnership with Alcatel, who is currently shipping its VDSL systems based on Ikanos’ chipset to 3 customers, with additional 4-5 carriers who are in field trials. Ikanos has particularly high hopes for Alcatel’s 48-port VDSL2 line card, which was launched in the first half of 2007.
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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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