Developing oncology drugs is getting harder and harder. The rising regulatory hurdles, the constant flow of new agents and competition for trial participants all make getting a drug to market a formidable challenge. This is particularly true in drugs for blood cancers, a field that saw tremendous progress in the past decade and is becoming very crowded. As a result, even highly effective drugs require long and expensive studies with active regimens in the control arm and survival as an endpoint.
These challenges can be coped with, to some extent, by identifying settings where it is possible to get a drug to market quickly and cost-effectively. These settings should include a small, well-defined patient population with limited therapeutic options and an agent with a robust activity that could persuade regulators to grant accelerated approval based on a small single-arm trial. Micromet’s (MITI) lead agent, blinatumomab (Bmab), is a perfect example of how creative clinical planning can differentiate a product by facilitating quick approval.
Although Bmab has potential across many types of blood cancers, the company focused on specific patient populations and treatment settings that enabled it to avoid the classic development route. Bmab is about to be in two small pivotal phase II trials in ALL (Acute lymphoblastic leukemia), both could generate data in the 1st half of 2013 and potentially support filing. The indications Micromet is going after are certainly not the largest opportunity for Bmab, but they are probably the safest and quickest way to market. Following approval, Micromet will be able to generate cash via commercial sales as well as a licensing deal, which could support expansion into larger indications such as NHL.
Last week Micromet announced that based on feedback from the FDA, a small single-arm phase II study could be enough to get accelerated approval in relapsed/refractory ALL. Of course, there is no obligation from the regulator’s end, but the fact Micromet is pursuing this path implies the FDA is willing to consider approval, providing results are compelling. Micromet is already recruiting patients in another pivotal phase II trial in ALL where Bmab is given to patients who still have disease remnants in their bone marrow (minimal residual disease or MRD) after conventional therapy.
The new pivotal phase II trial will include 65 ALL patients from the US and Europe, all of whom will receive Bmab. The primary endpoint is complete remission (CR), with response duration and survival as secondary endpoints. This design is extremely favorable for Micromet based on recent results in a similar patient population which included a CR rate of 75%. Although the dataset included only 12 patients, this level of activity in such an advanced population is unprecedented.
Bmab is an anti-CD19 antibody that can redirect the immune system to attack cancer cells very efficiently. Originally, Bob’s main competitors were other antibodies targeting CD19. The most advanced of these is Sanofi-Aventis’ (SNY) SAR3419, an antibody-drug conjugate (ADC) based on Immunogen’s (IMGN) technology. Initial data from this program was presented last year with clear activity in other blood cancers but it did not include ALL patients. Sanofi just started a phase II in ALL with SAR3419, which should trigger a $4M milestone to Immunogen (expected to be announced shortly).
Since Micromet shifted its focus to ALL, with two ongoing registration-enabling phase II trials, Micromet’s main competitor is now Pfizer (PFE). Following the Wyeth acquisition, Pfizer got inotuzumab ozogamicin, an antibody-drug conjugate targeting CD22 that has strong activity in ALL. Data at ASCO 2011 included a 56% response rate in 40 patients. Investigators concluded the data stating that inotuzumab is “likely the single most active single agent tested so far in relapsed/refractory ALL”.
It is too early to pick a winner between Bmab and inotuzumab due to the limited available data. One clear advantage inotuzumab has is its convenient administration (one injection every 3 weeks) in contrast to Micromet’s Bmab which is given as a continuous infusion over 4 weeks. Although Pfizer’s inotuzumab is clearly active and has a more extensive data set, the responses it induces are not necessarily as deep (the criteria to reach bone marrow response in the Micromet study was more stringent) and prolonged as those observed with Bmab to date. In the long run, the two drugs could be combined or used in tandem, as each agent binds a different target.
Another potential competitor is Genentech, who also has a CD22 ADC, powered by Seattle Genetics’ (SGEN) technology. It is currently in phase I alone and in combination with Rituxan. The phase I does not include ALL patients but focuses on NHL, however, expanding into ALL is an obvious step based on data with Pfizer’s anti-CD22 ADC. Based on the superiority of Seattle Genetics’ technology compared to Wyeth’s older technology, Genentech’s ADC might be an even stronger contender.
Data flow during 2017
The pivotal trial in relapsed/refractory ALL will join another pivotal study Micromet is running in MRD-positive ALL. The latter could support registration in Europe but probably not in the US. Although the company has not provided specific timelines, both studies should complete enrollment towards the end of 2012. As the primary endpoints in both trials require short follow-up (CR rate and MRD conversion rate, respectively), top-line results could be available in the 1st half of 2013. It remains to be seen whether regulators demand more matured data from both studies for submission. Since both trials are single arm open-label studies, Micromet will have a constant flow of data it may or may not choose to share with investors during 2012.
Micromet’s strategy of targeting ALL as a lead indication enables it to pursue regulatory approval in two treatment lines with minimal time and cost. The two pivotal trials cost several tens of millions of dollars and could open up a market of ~$400M for Micromet in ALL, assuming a certain degree of off-label use. Eventually, Bmab will surely face competition but thanks to Micromet’s strategy, it will be the first to get approval for ALL.
3 years after inception, the biotech portfolio managed by Ran Nussbaum and myself is up 90%, which compares favorably to general and healthcare related indices and ETFs (see tables below). We feel comfortable with the three positions in Micromet (account for 10% of portfolio) going into ASH this December.