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.
MT-103 is an antibody which is evaluated for the treatment of several blood cancers, including NHL (Non-Hodgkins Lymphoma). Similar to other antibodies evaluated for the treatment of cancer, MT-103 utilizes an antibody’s ability to specifically and selectively target cancer cells, however, it also represents a very different approach to targeting them. If we try to classify MT-103, it can be described by two primary factors: It is a (i) bi-specific antibody and a (ii) single-chain Fv antibody.
In the last decade, researchers have evaluated countless bi-specific antibodies as well as countless single-chain Fv antibodies. The vast majority of these candidates failed to show the slightest clinical activity, and consequently, the antibody industry decided to focus on more “conventional” antibody types. I must admit that when I first heard about MT-103, I was sure it would be a complete flop. I remember thinking to myself, “these guys take two niches of the antibody field that have been a clinical graveyard for years, combine them, and expect to get an effective drug – not going to happen”. Well, it happened big time. I will try to elaborate more about bi-specific antibodies and single-chain Fv antibodies later, but for now the most important thing to understand is that the combination of the two “underperforming” approaches is probably the reason for the astounding anti-cancer activity demonstrated by MT-103.
Even more astounding are the low doses of MT-103 that showed such an impressive clinical activity. This trial was a dose escalation trial, so it involved multiple doses with the intention of finding the highest possible dose that can be administered without causing unbearable side-effects. Although the research team has yet to identify the maximum tolerated dose, the 3 highest evaluated doses showed very promising results.
Among the 18 patients who received the 3 highest doses (0.015 to 0.06 mg/m2 per day), three had a complete response and four had a partial response, which leads to a response rate of 39%. This response rate is very impressive especially in light of the fact that most participants were heavily pre-treated patients in advanced stages of the disease. Moreover, all three patients who received the highest dose (0.06 mg/m2 per day) had a clinical response. These dose levels are substantially lower than those used for any other antibody-based therapy I have ever seen. A comparison to Rituxan, an approved antibody for the treatment of NHL might clarify that point.
Rituxan, which is the best selling antibody in history and is used to treat similar patient population, is generally dosed at 375 mg/m² per week. MT-103 was dosed every day, so in order to compare MT-103 doses to that of Rituxan, doses should be multiplied by 7. In addition, because MT-103 is much smaller than a typical antibody like Rituxan, the dose should be further multiplied by 3 to get an apples-to-apples comparison. Therefore, MT-103 was dosed at 0.315-1.26 mg/m2 per week, which are more than 300 fold lower than the typical dose of Rituxan. Historical clinical data shows that Rituxan leads to a response rate of 40-50% in relapsed patients, which makes the 39% response rate achieved by the extremely low doses of MT-103 very impressive.
Finally, a few words of caution. Investing in a tiny company such as Micromet, with an early-stage candidate such as MT-103 bears a very high risk, no matter how impressive preliminary clinical results are. The fact that MT-103 is a very unusual antibody platform certainly adds more uncertainty. Nevertheless, the impressive results among heavily pretreated lymphoma patients, the “homeopathic” doses, and the sheer size of MT-103’s addressable market all lead to the conclusion that Micromet represents a very attractive investment opportunity.
Author is long MITI