For the first part of this article click here.
Synta launched a phase I trial in 2004 for the evaluation of elesclomol in combination with paclitaxel in advanced solid tumors. The trial enrolled 35 highly-pretreated patients, who received paclitaxel in combination with escalating doses of elesclomol. There were two partial responses (5.7%), one patient with kaposi’s sarcoma and another patient with ovarian cancer in addition to 15 patients who achieved stable disease. Because this was a combination trial, there was no way of knowing whether elesclomol had a synergistic effect with paclitaxel. Nevertheless, there was evidence that elesclomol can sensitize tumors to chemotherapy, as some of the patients who responded to the treatment had previously progressed during treatment with paclitaxel alone. Another important observation was that elesclomol and paclitaxel can be safely co-administered. Elesclomol then entered three phase II trials in melanoma, non-small-cell lung cancer (NSCLC) and soft tissue sarcoma. Both the NSCLC and the sarcoma trials failed to show a benefit from adding elesclomol to paclitaxel. The melanoma trial, on the other hand, produced a very impressive set of data.
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Synta Pharmaceuticals (SNTA) may look like the typical American biotech company: A promising phase III compound, which is, of course, partnered with a pharma giant, two agents in early clinical stages, a list of failed trials, and an alarming cash burn rate. Nonetheless, the story behind the company’s lead product, elesclomol, is shaping up as one of the most interesting events in oncology in recent years. Elesclomol is currently in a registrational phase III trial for metastatic melanoma, a major achievement by itself, however, if successful, this trial will mark two events on a historical scale.
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On the previous article , I discussed the importance of microRNAs (miRNAs) and the great attention they have been receiving in the scientific industry. With every day that goes by, miRNAs gain more momentum and their cardinal role in biology is constantly being elucidated. Due to their importance and presence in such a wide range of creatures and medical conditions, from plants to humans, from cancer to women’s health, miRNA are making the migration from a scientific sensation to a huge commercial opportunity. This is great news for a company focused purely on miRNA such as Rosetta Genomics (ROSG), as after years of wandering alone in the desert, it may find itself at the heart of one of the hottest segments in the pharmaceutical industry.
The rationale behind miRNA-based drugs and diagnostics is straight forward. miRNAs are a group of genes which are involved in almost every biological process, as they control over a third of our genome. This central role makes them obvious “druggable” targets, which can be manipulated in order to treat diseases. Their central role might also make them ideal bio-markers for early-detection and diagnosis purposes, due to several advantages that will be described later on. The key in commercializing miRNA-based products is finding the relevant ones which are associated with a specific medical condition. The process starts by looking at the miRNA profile of healthy cells and compare it to that of cells with the particular condition or disease. The miRNAs that may serve as diagnostic markers or drug targets are those which have a different expression profile in the particular condition compared to normal cells.
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BiTE Antibodies
A BiTE (Bispecific T Cell Engager) antibody is a bi-specific antibody (bsAb) which directs T-cells to attack cancer cells, by simultaneously binding the two cells. Upon binding, a physical link is created between the two cells, which in turn triggers the T cell to attack the target cell. Every BiTE antibody has two binding arms, the first binds the CD3 receptor present on T-cells and the second binds a specific element on a cancer cell. The T-cell binding arm provides the activity while the cancer binding arm provides the specificity. By changing the cancer binding arm, the BiTE antibody can be adapted not only from one type of cancer to another, but also from one target to another in the same type of cancer. Therefore, BiTE represents a universal and modular platform for producing bsAbs for an unlimited number of targets.
As previously stated, bi-specific antibodies are aimed at recruiting immune cells against cancer. Therefore, one of the first decisions to be made concerns the type of immune cells to be recruited. The first attempts to develop bi-specific antibodies, mainly included recruiting T-cells, which are considered the most potent cells of the immune system. T cells play a critical role in the body’s efforts to eliminate malfunctioning cells such as cancer or virally infected cells, making them even more obvious candidates. Read the rest of this entry »
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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