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
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.
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.
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
CR011-vcMMAE is an ADC currently being developed by Curagen (CRGN), based on Seattle Genetics’ ADC technology. The ADC comprises of an antibody against GPNMB, a protein on the surface of melanoma cells linked to a drug payload. Both the drug and the linker in this case are identical to those used by Seattle Genetics in SGN-35. The story behind this agent demonstrates the need of ADC technology and the high value it has in today’s drug development market. It also demonstrates that going after one of the most challenging indication with a relatively new platform, may not be the best way to validate it.
SGN-35, which is Seattle Genetics’ lead ADC, is comprised of SGN-30 and Seattle Genetics’ highly toxic chemo drug – MMAE. SGN-35 is, in fact, the company’s flagship ADC candidate, since it was its first wholly owned ADC to utilize the company’s new ADC technology, including its peptide-based linker and auristatin-based drug. Having both a naked antibody and an ADC based on the same antibody simultaneously in the clinic is quite unusual, but more than anything, this situation is fascinating because it can clearly exhibit the advantages ADCs have over naked antibodies. In that sense, SGN-35 is similar to Genentech’s Herceptin-DM1, which is currently being developed with Immunogen (IMGN). Herceptin-DM1 served as a validation for Immunogen’s ADC technology since it showed very encouraging results among breast cancer patients, who do not respond to naked Herceptin. Hence, if Seattle Genetics can show that SGN-35 succeeds where SGN-30 fails (hint- Hodgkin’s Lymphoma), without causing substantial side-effects, it should be a very strong proof-of-concept.
SGN-30 entered phase I in 2002, for the treatment of HL and ALCL. In addition to a good safety profile, SGN-30 managed to show clinical activity, mainly among ALCL patients. The antibody was advanced to a phase II trial which later turned into 2 phase II trials, one for the evaluation in HL and the other in ALCL. Results from the two phase II trials emphasized the trend that had been observed in the phase I trial, as SGN-30 demonstrated great activity among ALCL patients but very modest activity in HL. Of the 35 evaluable HL patients, there was no objective response (decrease of 30% in the tumor load), whereas, 14 out of 46 evaluable ALCL patients (30%) had a response, three of which were durable complete responses. This is quite impressive considering the poor prognosis of these heavily pretreated patients. Although SGN-30 could not beat HL, Seattle Genetics still had several options at its disposal, including an armed version of SGN-30, in which the antibody is conjugated to a drug payload.
Although it is very important to get data about an antibody as a single agent, the activity it shows in combination with existing treatments is where most of the potential lies. A typical strategy with antibodies for cancer includes initial evaluation as a single agent in patients who have no other alternatives, followed by multiple trials in combination with existing treatments and/or in early stage patients, who have better prognosis. Ideally, any drug company would like to see its drug being administered as early and in as many combinations as possible, in order to achieve maximal market share. This is indeed the case with SGN-30, which is currently being evaluated in 3 phase II combination trials.
The first study was initiated in 2006 and is evaluating SGN-30 in combination with chemotherapy for the treatment of recurrent HL. This is a relatively large, comparative trial aimed at discovering whether SGN-30 can enhance chemo’s efficacy. The second study, also initiated in 2006, is evaluating SGN-30 in combination with chemotherapy among ALCL patients. A third study of SGN-30 combined with chemotherapy is recruiting pediatric ALCL patients. These trials are financed by the NCI, which enables Seattle Genetics allocating resources to other clinical programs. Despite the promising clinical activity among ALCL patients, the addressable market for ALCL is rather limited, making its clinical development attractive but not too exciting. Obviously, as long as someone else is paying the bills, Seattle Genetics will be more than happy to see SGN-30 advance towards commercial availability, but unless there are stellar results from the HL combination trial, we expect SGN-30 to remain on the backburner, as far as Seattle Genetics is concerned. The real star in the company’s CD30 program is SGN-35.
Author is long SGEN
As we previously explained, the market for lymphomas, targeted by Rituxan is huge, and attracts many companies. There are, however, several lymphomas for which Rituxan is not effective since Rituxan’s target, the CD20 receptor, is not expressed by these cancers. These conditions, expected to be diagnosed in more than 15,000 Americans in 2007, can be divided into two groups: Hodgkin’s lymphoma [HL] and T-cell NHL [T-NHL]. Patients diagnosed with such conditions are treated with similar regimens that are used for NHL, however, Rituxan is omitted because it has no effect. Combining chemotherapy and radiotherapy with antibodies is a well validated concept, since antibodies can increase a regimen’s efficacy without substantial side effects. As there are currently no approved antibodies for the treatment of non CD-20 lymphomas, there is a great rational behind developing such antibodies that can be co administered with existing treatments. Although market opportunity for treatments for these “non Rituxan” lymphomas is substantially smaller than the Rituxan opportunity, it is still a viable niche which is poorly addressed by most players in the field. Seattle Genetics’ CD30 program is aimed specifically at that niche.
CD30 is a well known marker for Hodgkin’s Lymphoma [HL], expressed by certain malignant cells that are present in the patient’s lymph nodes. Interestingly, these cells (Reed-Sternberg cells), represent only a small portion of the tumor but are considered to be the driving force in the creation and development of the disease. In addition, CD30’s expression in normal tissues is very limited, making it ideal for antibody-based therapy. HL is one of the most curable cancers, as historical data shows that patients have a 75% chance of achieving complete remission with a combination of several chemo drugs. However, up to 40% of patients will relapse, some of which will develop chemo-resistant tumors. The most viable option for patients whose disease has relapsed is bone marrow transplant, an aggressive treatment that is associated with high incidence of mortality and low success rates in this type of patients. Interestingly, CD30 presence has been associated with aggressive disease, making anti-CD30 antibodies a very reasonable path for treating advanced stage patients. The market for HL will never become as gigantic as the NHL market, with “only” 8190 cases of HL and 1,070 HL-related deaths are expected in 2007 in the US.
CD30 is also expressed on 30% of T-NHL, most consistently on a subtype of T-cell lymphoma called anaplastic large cell lymphoma [ALCL]. Many T-NHL lymphomas, in contrast to HL, are characterized by very poor prognosis and new treatments are desperately needed. It is hard to estimate the market opportunity on this front, but it seems like it is in the scale of several thousand cases per year in the US. Seattle Genetics is currently evaluating 2 anti-CD30 platforms: SGN-30, which is a naked antibody and SGN-35 which is an antibody-drug conjugate [ADC].
Seattle Genetics’ lead product is SGN-40, an antibody targeting CD40 which is a very common receptor expressed on various hematological malignancies such as non-Hodgkin lymphoma [NHL], chronic lymphoid leukemia [CLL] and Multiple myeloma [MM]. Surprisingly, CD40 is also expressed on solid tumors such as breast and ovarian cancers, which may broaden SGN-40’s spectrum of application. Although everybody is smiling at the moment, the company has undergone quite a rollercoaster with this candidate, lasting more than 8 years and involving 3 different names for the same antibody.
The capability of developing antibodies for cancer can be found at most pharma companies’ R&D centers, either as a result of internal R&D efforts or M&A activity, such as the acquisitions of Cambridge Antibody Technology and Abgenix by AstraZeneca (AZN) and Amgen (AMGN), respectively. Therefore, there is nothing unique about a company that can develop cancer antibodies, even though there are many other differentiating factors between the companies. The crucial element in developing an ADC is linking the antibody to the drug payload. As simple as this concept may sound, its realization is highly complex and challenging, and in our opinion represents the main entry barrier to the field. As ADCs are also termed “armed antibodies”, companies like Seattle Genetics can be viewed as the arms merchants of the antibody industry.
As an arms merchant, the company focuses on two areas: Technologies for conjugating antibodies to toxic drugs and potent toxic compounds that will be attached to the antibodies. The ability to develop highly potent drugs and conjugation technologies is Seattle Genetics’ main asset, since this is the ideal way to differentiate itself and to broaden the company’s pipeline through partnership deals. In an industry where the vast majority of candidates fail, it is imperative for companies like Seattle Genetics to have as many candidates as possible, even if eventually most of the revenues go to the partners. At this stage, with the limited resources Seattle Genetics has, betting on few wholly owned candidates is statistically unfeasible. Although the company has had its share of failures over the years, we believe the advances made both in terms of linkers and drugs will finally enable it to generate a constant flow of candidates into the clinic, whether independently or in collaboration with partners. In order to look at the progress that has been made so far, the best place to start is the failure of Seattle Genetics’ flagship product, SGN-15, an antibody linked to the chemo agent Doxorubicin, whose development was discontinued in mid 2005 after a series of discouraging clinical trials. On top of the usual uncertainties related to drug development, there were probably two main factors that severely sabotaged this candidate’s prospects.
The first factor was the use of an approved chemotherapy drug such as Doxorubicin as the conjugated drug. Chemotherapy agents that are conventionally administered to patients are distributed across the body and affect healthy cells as well as cancer cells, leading to the so typical side effects of chemo. Consequently, approved chemo drugs represent a fine balance between two needs: They must be strong enough in order to kill cancer cells, but not too strong, so the damage caused to normal tissues is acceptable. In contrast, when chemo drugs are linked to an antibody, they can be targeted to tumors specifically, since the antibody guides them. This enables the use of much more potent drugs, otherwise impossible to use in conventional administration. Furthermore, since only a small fraction of the administered antibodies eventually accumulate in cancer cells, it is critical that the few antibodies that do reach the tumors carry a very potent payload. This can be accomplished by two approaches: The antibody must either be loaded with a large amount of drug molecules or a small amount of very potent drug molecules. Although there are efforts on both fronts, the latter approach is more practical, at least for now. Bottom line, in order to have an effective ADC, drug developers should use chemo drugs that are too toxic to be generally administered. This approach was validated by the only FDA-approved ADC, Mylotarg, which utilizes Calicheamicin, a drug that is too toxic on a stand alone basis. Both Seattle Genetics and Immunogen (IMGN) are currently using such compounds as the basis for their ADC platforms: Seattle Genetics picked auristatin, while Immunogen focuses on maytansine. The second disadvantage in SGN-15 is linker instability. An ideal linker should be very stable in the bloodstream but also readily degradable once inside cancer cells, so it would release the free drug only inside target cells. For SGN-15, Seattle Genetics uses an acid-labile linker, which is relatively stable in neutral environment (bloodstream) and very unstable in acidic environment (present in certain compartments inside cells). This kind of linker is used very successfully in Mylotarg for the treatment of acute myelogenous leukemia [AML], making Seattle Genetics’ pick very reasonable at the time. However, SGN-15’s stability in patients proved to be pretty low, mainly as a result of premature linker degradation in the bloodstream, before reaching the tumors. Mylotarg had a great success despite being based on an acid-labile linker because it attacks a blood-borne malignancy and the antibody can find its target quickly, before linker degradation and drug release. In contrast, the dense mass of solid tumors makes them far less accessible compared to blood cancers. Therefore, the ADC must be present in the bloodstream for longer periods at higher concentrations, necessitating highly stable linkers.
By the time SGN-15 was scrapped, Seattle Genetics already had its next generation of ADC technology up and running. On the drug front, the company licensed a potent drug called auristatin E from Arizona State University, which was found to be almost 200-fold more potent than Doxorubicin, and used it as a basis for its own proprietary drug, MMAE. This drug is a very potent anti-tubulin inhibitor that can be synthesized cheaply in very large quantities and subsequently be conjugated to a virtually unlimited number of different antibodies. Another appealing attribute of Seattle Genetics’ conjugation technology is the highly homogeneous population of ADCs, as oppose to other methods, including that of Immunogen. On the linker front, Seattle Genetics chose a peptide-based linker which is cleaved by enzymes that are present inside cells but not in the bloodstream. Upon cancer cell binding, ADCs are trafficked to a special compartment called lysosome, where there is an abundance of enzymes that cleave the linker and release the drug inside the cell. Seattle Genetics’ peptide linker has demonstrated an increase of more than 3-fold in stability in the bloodstream, which, combined with the high potency of MMAE, puts the company’s candidates in a better starting point.
It is crucial to understand that ADCs are not commodity products, but highly complex systems that require a great deal of customization and optimization. Multiple factors, including (but not limited to) cancer type, the target on cancer cells, exact binding site, type of linker, efficiency of drug release, mechanism of conjugation, type of drug and amount of drug payload affect the performance of each candidate. The number of variations for each ADC is high but it is impossible to predict the optimal combination in advance. Thus, the exact antibody-linker-drug combination should be tailored specifically for each ADC candidate, perhaps even for each condition the candidate is aimed at treating. In order to stay relevant, Seattle Genetics must constantly develop new linkers and drugs, in addition to developing antibodies and identifying attractive cancer related targets. It is not surprising though, that the company is currently developing next generation linkers and drugs that will possibly be employed in future projects.
Author is long SGEN
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