Seeking Alpha: Bright Prospects for Micromet (Part 2)
by: Ohad Hammer April 24, 2009
Regulation and competition
Micromet (MITI) intends to launch a pivotal study for blinatumumab as consolidation therapy in ALL patients next year, starting from Europe with a likely expansion to North America. Due to the small market size and the aggressive nature of the disease, the trial should be relatively small and short. For example, Genzyme’s (GENZ) Clolar, which is approved for the treatment of pediatric ALL, got approved based on a single arm 49 patient trial, with objective response rate as the primary endpoint. Although it is common to see approvals based on tumor response in settings where there are no available treatments, the situation with blinatumumab is more complex.
The blinatumumab trial is unique since it has MRD conversion as the primary endpoint. MRD is a surrogate for risk of relapse, but it is not as well recognized as reduction in tumor burden. Since the patients who enter the trial have minimal tumor burden, it is still unclear whether regulators will be willing to accept MRD conversion as a basis for approval. Ironically, MRD was shown to be the most important predictive factor for ALL patients, but according to the company’s CEO, approval based on MRD conversion is unlikely. This means that Micromet will have to pick another endpoint such as time to progression or disease free survival rate after 6 months. The aggressive nature of the disease, especially in this specific patient subset might lead to results and subsequent approval already in 2011 and 2012, respectively.
The road to approval in NHL will be more challenging and complex, due to the large size and the availability of multiple lines of therapy. Even if blinatumumab gets approved in some NHL indications, it may face fierce competition from many agents that are currently in advanced clinical testing. In particular, blinatumumab might face competition from other CD19 targeting agents such as Sanofi-Aventis’ (SNY) SAR3419, which is an antibody drug conjugate powered by Immunogen’s (IMGN) technology. Other companies, including Seattle Genetics (SGEN) and Medarex (MEDX) are also developing anti CD19 ADCs that are expected to enter the clinic in the coming years. When I asked Itin about future competition, he answered that there are likely to be other anti-CD19 therapies in the market, but as a BiTE antibody, blinatumumab will have a different clinical profile than that of antibody drug conjugates.
BiTE antibodies may have certain advantages, as well as disadvantages compared to other antibody based drugs, in particular antibody drug conjugates. Before going over the potential differences between BiTE antibodies and ADCs, it is important to understand that each approach has its merits and it is impossible to predict which class of drugs proves superior for any given condition. Nevertheless, there are two basic differences between BiTE antibodies and antibody drug conjugates: Mechanism of action and size.
BiTE Vs. ADC
BiTE antibodies work by activating and redirecting a specific type of immune cells called T cells to attack tumors. Upon activation, T cells start to multiply rapidly at the site of activation. In addition, T cells are known to be “serial killers”, since each T cell can kill many cancer cells one after the other. These two characteristics, which make T cells the most potent immune cells in our body, may lead to a strong amplification effect. Antibody drug conjugates do not have this kind of amplification effect, since their potency is derived solely from the drug payload they carry. To put things in clinical context, a single antibody drug conjugate can kill only the cancer cell it binds, and perhaps one or two nearby cells. A single BiTE antibody, on the other hand, could potentially kill a group of cancer cells.
Another potential advantage BiTE antibodies have is that they do not require internalization into the cancer cells. Antibody drug conjugates, on the other hand must get into the cells in order to release their toxic payload. As a result, BiTE antibodies could prove superior for antigens that do not get internalized efficiently, such as CD20, Rituxan’s target. Another type of targets where the BiTE mechanism of action could be advantageous over antibody drug conjugates is in cases where the target is not densely expressed on cancer cells, such as the case of CD19, blinatumumab’s target.
In many senses, the activity of a BiTE agent could be complementary to that of an ADC, as cancer cells could develop resistance to both drugs through different mechanisms. Tumors could present or secrete factors that suppress the immune response in order to block the effect of BiTE antibodies. In the case of antibody drug conjugates, tumors can develop a plethora of resistance mechanisms, depending on the type of drug payload used. In addition, different cells in the same tumor could react differently to each antibody. For example, current ADCs are considered highly effective against dividing cells but less effective against quiescent cells in the core of solid tumors. A BiTE antibody might do better job with non dividing cells.
On the safety front, BiTE antibodies might be more problematic because they manipulate the immune system in such a potent manner, as I explained in a previous article. Until now, blinatumumab safety profile has been surprisingly good, and according to Micromet, it might be further improved with better dosing schedules and patient selection. Nevertheless, it is impossible to predict the safety profile at higher doses or in the case of additional BiTE agents. There could be a situation where the difference between an effective dose and a toxic dose will be too small for the drug to be given to people.
A BiTE antibody is three fold smaller than a standard antibody, which results in a very high clearance from the body. Antibodies such as Herceptin and Rituxan are present in the blood stream several weeks after administration. ADCs stay in the bloodstream for several days whereas blinatumumab is gone by approximately 24 hours. As a result, to get a prolonged exposure to blinatumumab, patients must receive continuous infusions for a period of one month, every treatment cycle. Currently the treatment is administered with a pump the size of a BlackBerry that continuously delivers the drug into the blood stream.
This is a huge drawback in terms of patient convenience and may deter patients, especially in settings where prolonged treatment is needed, such as the adjuvant setting. Antibody drug conjugates such as Genentech’s T-DM1 or Curagen’s (CRGN) CR011 are given every three weeks. Although until now, no compliance issues have arisen in the blinatumumab trials, the company is well aware of this issue and intends to evaluate subcutaneous administration instead of the standard injection currently used.
The small size of BiTE antibodies could also confer an advantage over conventional antibodies in terms penetration. Small antibodies are believed to have better penetration properties, so they can reach areas that are less accessible for normal antibodies, especially the inner compartments of solid tumors or bone marrow. This might, in part, explain blinatumumab’s ability to purge patients’ bone marrow so efficiently. The better penetration could also be important in solid tumors, where the core of the tumor is less accessible.
2009 events
Micromet is looking at a busy 2009, with three important value creation points.
The first event will occur this June, with the update from the phase II ALL study. The results may show two important features. The first one is blinatumumab’s ability to clear disease remnants from additional patients’ bone marrow, while the second feature is response duration. Positive results will set the stage for a registration trial next year.
The second event will occur at the European Cancer Organization (ECCO) meeting in September. Micromet expects to present data for a second BiTE antibody, MT110. Although little to no value is ascribed to this agent, a good data set could have a huge impact. Apart from being the second BiTE antibody to generate clinical data, MT110 is the first BiTE antibody that targets solid tumors. Solid tumors have always been more difficult to treat and they are characterized by lower success rates, particularly due to accessibility and drug penetration issues.
Theoretically, BiTE antibodies are ideal for eradicating solid tumors because they have better tumor penetration and a mechanism of action that involves amplification. Solid tumors typically require higher doses compared to blood cancers, so in this trial Micromet might have to dose escalate all the way to the maximum tolerated dose for a therapeutic effect. Therefore, the trial might provide more data with respect to the toxicity of BiTE antibodies. MT110 targets a protein called EpCAM, which is expressed in some of the most common tumor types, including lung and colorectal cancer, so it represents a huge commercial opportunity. In contrast to blinatumumab, Micromet owns 100% of the rights to MT110, so the upside potential, as well as the risk in this program is substantial.
Lastly, the third event should be at least one new licensing deal for a BiTE product. The company stated it expects to announce at least one deal but refused to provide additional details. In the first half of 2010, Micromet will probably launch a pivotal trial in ALL with potential approval in 2012, but at the moment, the company has cash reserves that will finance operations through the second half of 2010. Therefore, Micromet must find an additional source of capital already this year, in order to have more than a year’s worth of cash.
MT110 could turn out to be a huge value creator, but data is expected only towards year end, and of course, the nature of the data is unpredictable. This leaves Micromet with two options to get a meaningful cash infusion. The first option is doing another equity placement, which could be relevant only at higher price levels. Another option is finding a new partner for blinatumumab. According to the amended agreement with Medimmune, the US rights for blinatumumab cannot be partnered until the drug is approved, which leaves only the international rights on the negotiation table. Micromet will probably want to keep the European rights, so it should try to do what Arqule (ARQL) did in 2007 and license the commercialization rights for the Japanese market, the second largest oncology market in the world. The Japan based pharmaceutical companies have been very active on the M&A and licensing front, especially in the oncology field, so Micromet might find a bidder within several months. The financial terms of the deal will depend primarily on the data Micromet will present at the EHA meeting this summer.
In summary, despite Medimmune’s decision to abandon blinatumumab, its prospects are as bright as ever. During 2009, Micromet will have several important events, including at least one licensing deal and two potential proof of concept events in ALL and solid tumors. On the financial front, the recent development turned 2009 from an originally worriless period into a more challenging year, as Micromet will have to raise at least $30M through licensing deals or other means in order to make it to the finish line. |
