Investing in Brain Cancer - Part 3b
Strategic Investor Perspective
Executive Summary
Strategic Investors (e.g. Biopharma, Medical Device and Diagnostic companies) conduct much of the same investment analysis and due diligence that one sees with Institutional Capital, but because the Strategic Investor must live with the investment and develop it into an approved product, other considerations become important. Market opportunity, clinical development strategy and cost, regulatory interaction, manufacturing, market access and payer dynamics come to the forefront. It is a Big Money game requiring lots of capital and often the better part of a decade of investment before any product revenue can be collected. There will inevitably be setbacks, delays and surprises…any of which can derail the successful launch of a product, or its acceptance by the marketplace.
At the end of the day, strategic investment decisions depend on an Expected Value Analysis, which is influenced by the Probability of Success (PoS) of the investment in terms of getting a product approved and embraced by patients, healthcare providers and payers.
As we outlined in Parts 1 and 2 of this Series, the PoS in brain cancers has historically been low. When combined with the significantly smaller market sizes for brain cancers relative to other more frequently occurring non-brain cancers, the barrier to making a strategic investment in brain cancer is high.
Some Lessons from Strategic Investment in Brain Cancers
The full spectrum of brain cancer strategic investment is broad and cannot be fully covered in a MissionGBM post of modest length. So, we have chosen to highlight a few successes and some high profile misses to illustrate a few key points.
BioPharma Experience
Temozolomide. Merck & Company successfully developed and registered the DNA alkylator temozolomide (Temodar®; TMZ) in 1999 for anaplastic astrocytoma patients who were refractory to other chemotherapeutic agents in use at the time. Several more labeled indications were subsequently added based on RCTs, and today TMZ is the workhorse drug used in the SoC chemo-radiation protocol under which just about all newly diagnosed HGG patients are initially treated. The drug has long since become generic, but nonetheless commands a premium price owing to its small overall market potential despite the approval of many (S)NDAs in the US. Key Point: The modest size of the HGG market supports a premium price for TMZ despite multi-source drug availability.
Bevacizumab. Genentech achieved approval of bevacizumab (Avastin®) in 2009 for GBM patients who had progressive disease following prior therapy. As was noted in Part 1 of this Series, the post-approval bevacizumab experience has not demonstrated an enhanced mOS benefit in GBM patients despite apparent advantages in mPFS largely due to pseudo-response phenomena on imaging. It is useful to note that bevacizumab was initially approved for use in non-brain cancers (colon cancer 2004; lung cancer 2006; metastatic breast cancer 2008) and then further registered for treatment of GBM. Key Point: The strategy of gaining earlier approvals in non-brain cancer indications and then following up with brain cancer trials and approvals was discussed in Part 2 of this Series, and is illustrated by bevacizumab.
Immune Checkpoint Inhibitors. Both Merck and Bristol Myers Squibb studied anti-PD-1 medicines on top of SoC in GBM in the 2010s soon after initial approvals in other cancer indications (see here for Merck, and hereand here for BMS). BMS even tried nivolumab (Opdivo®) in combination with ipilimumab (Yervoy®), which yielded high levels of irAEs (see here). In all cases, the studies did not provide an overall mOS advantage versus the control arms, but in a few cases an OR signal was observed (which, frankly, is true for just about any therapeutic agent that is trialed). These studies were conducted in the early “Land Grab” days of immuno-oncology during which the Sponsors threw their I-O drugs against just about every oncology indication often without the benefit of subsequent insights regarding the importance of the inflammatory status of the TME (i.e. a “Hot” TME) or access to the TME by the I-O agent. Key Point: Even very successful immune-oncology medicines can produce modest results as monotherapies in brain cancer. Combination approaches (Drug/Drug and Drug/Device) and patient selection criteria will be required to gain approvals based on enhanced mOS.
Depatuxizumab Mafodotin (ABT-414; “Depatux-M”). Perhaps, the largest set of clinical trials recently conducted in GBM was sponsored by AbbVie (formerly Abbott) in the 2010s. Depatux-M is an Antibody Drug Conjugate (“ADC”) composed of the EGFRvIII-specific humanized monoclonal antibody (depatuxizumab) linked to the anti-microtubule toxin monomethyl auristatin F (mafodotin). AbbVie stopped the Phase 3 trials in 2019 after an interim analysis showed that ndGBM patients receiving Depatux-M demonstrated no survival advantage versus Placebo when added to the SoC regimen of TMZ + RT. Post-hoc non-clinical studies suggested that one potential reason for the failure of the trials was the limited ability of the macromolecular ADC to cross the BBB in appreciable amounts to cause therapeutic effect (see here). Even if Depatux-M had been able to significantly cross the BBB (by using Focused Ultrasound, perhaps), one must wonder if the ADC would have resulted in an mOS advantage, given (i) that GBM tumors are notoriously heterogeneous (i.e. cancer cells in the GBM would not all be expected to express EGFRvIII); and (ii) that a spectrum of therapeutic agents directed at EGFRvIII have all failed in human clinical trials with post-hoc analyses indicating that the surviving cancer cells are antigen-depleted with respect to EGFRvIII (see here, here and here) likely due to ecDNA mechanisms. Key Point: The Depatux-M case is an important example of an expensive clinical trial failure that surprised many Neuro-Oncologists practicing under the “Clinical Heavy, but Science Lite” philosophy that pervades the field. There is no substitute for high quality, rigorous translational science.
Medical Device Experience
NOTE: If the reader is seeking an overview of emerging medical device approaches to the treatment of brain cancers, see here. We will focus below on a few key concepts as they pertain to approved device therapies for the treatment of brain cancers.
Targeted Radiation. Radiation has served as the foundation of brain cancer therapy for decades. RT is used extensively in SoC regimens for primary glioma as well as brain metastases. Advances in dose fractionation, computer-controlled targeting and local delivery have improved the therapeutic efficacy and reduced the neurotoxic AEs associated with RT. As much as we would like to eliminate RT from brain cancer therapeutic protocols due to the long term neurotoxic AEs, it is difficult to imagine doing so. Instead, a more productive strategy may be to emphasize approaches that minimize the neurotoxic AEs. Numerous researchers and companies are pursuing such a strategy, and we watch the area closely. Why? Because we have plenty of MissionGBM members who, after celebrating ORs, PRs and CRs that allow them to live longer, discover that the long term (>2 years post-RT) effects of RT-induced neurotoxic AEs can compromise quality of life. As new treatment protocols are developed, we believe that the impact of RT neurotoxicity will become an even more important issue. Note: Brachytherapy using radionuclide seeds in an implantable matrix is considered RT, and has been approved for brain cancer (newly diagnosed and recurrent). A review of the literature regarding GammaTile® studies and clinical experience can be foundhere. Key Point: Even long estabished therapies such as RT are ripe for innovative approaches to minimize neurotoxicity, which will become increasingly important as patients live longer under newer treatment protocols.
Tumor Treating Fields (TTF). TTF was approved for rGBM in 2011 (Based on EF-11 study) and ndGBM in 2015 (based on the EF-14 study). In its 3Q2023 earnings release, Novocure reported 3639 patients on therapy globally with the majority being GBM patients. Top line revenue has remained stable around $500 million annually with essentially all sales coming from the GBM market. The company has been pursuing a strategy of expanding the labeled indications beyond GBM to encompass other thoracic and abdominal cancers as well as brain metastases, which makes total sense as these additional markets offer larger patient populations (illustrates the Pan-Cancer approach that we highlighted in Part 2 of this Series). Of particular note are the recent reports of clinical studies in ndGBM and NSCLC in which TTF was combined with anti-PD-(L)1 immuno-oncology agents to produce a compelling level of ORs in both brain and non-brain cancers, presumably via the mechanism described by Dr. David Tran’s lab (see here and here). Novocore has announced that it is pursuing advanced trials utilizing TTF + anti-PD-1 agents in both NSCLC (Keynote B-36 trial) and ndGBM (Keynote D-58 trial). Watch this space. Key Points: (i) Employing a Pan-Cancer strategy is sound clinical and business rationale, if the scientific data support it; (ii) ALWAYS listen carefully to what the data is saying and update clinical development plans as warranted; and (iii) Drug/Device combination strategies will be required, which can represent an execution challenge for Device companies.