Eoganacht wrote: ...is less than 30 cents, the company has struggled with funding, and the fully diluted share count is 313,010,080.
According to Drs. Lilge and Mcfarland:
Notwithstanding fifty years since its first oncological application, PDT has not become a mainstream modality for treating any type of cancer. At a molecular level, it may come down to oxygenation, tissue penetration, and metastasis. The absolute requirement for oxygen is a fundamental limitation of PDT so far. Oxygenation of tumors is highly variable and difficult to measure, and this presents a challenge in predicting which patients are most likely to benefit from PDT. Paradoxically, the PDT treatment itself can render the target tissue hypoxic and thus resistant to PDT. Poor tissue penetration by both light and photosensitizer can also limit the effectiveness of PDT. For larger, solid tumors, penetration of both throughout the tumor volume is crucial for achieving effective tumoricidal activity. Finally, PDT is viewed as a local treatment despite its ability to invoke antitumor immunity.34–37 Approved protocols are optimized for local tumor ablation rather than for antitumor immunity. Gollnick and coworkers have demonstrated the importance of a two-step PDT protocol that would combine an immune-enhancing regimen to be followed by a tumor-ablating regimen; the parameters are not the same.36–38 It is estimated that metastasis is responsible for about 90% of cancer deaths,39 and it is impossible to deliver light to widely disseminated disease. For PDT to make an important contribution to improving survival rates in the most aggressive cases, the immune-enhancing facet of PDT must be exploited.
The poor adoption of PDT can be blamed on the clash of philosophy and pragmatism, which is responsible for the unfruitful photosensitizer-centered approach outlined earlier. In the pragmatic approach, an independent academic chemist synthesizes a new compound, and then studies its interactions with biological macromolecules and its photodamaging capacity in cell-free environments. In vitro testing is not available in most chemistry laboratories, and in vivo testing is rarer still. The very narrow and linear approach to characterizing the performance of these new photosensitizers is done most often in the absence of any specific clinical cancer indication target. New photosensitizers are rarely assessed alongside existing, clinically-approved photosensitizers, and the multidimensional complexity of PDT precludes a meaningful comparative analysis even when in vitro and in vivo screening is accessible to the chemist. This situation is further complicated by most academic laboratories not being able to purchase Photofrin® due to cost and the difficulties of procuring a “drug” by a non-physician. Without critical collaborations and partnerships — and an intellectual property (IP) strategy—, chemists are trapped in a bottom-up approach to photosensitizer design, and most photosensitizers languish, untested in the pre-clinical animal studies that precede translation and commercialization. At the same time, cancer biologists interested in PDT are stuck in a linear top-down approach, without access to new and better photosensitizers. The result is that very few new photosensitizers have both the physiological properties and the economic potential to reach extremely expensive human clinical studies. We posit that significant progress in the field of PDT demands a lateral approach, where chemists develop new photosensitizers from a tumor-centered approach, alongside partners and investors, with a sound IP strategy (Figure 2). Multidisciplinary and multi-dimensional relationships are crucial; the traditional model of the lone research chemist in academia is outdated.
Pragmatically, the problems with photosensitizer distribution and dosimetry warrant a personalized approach to PDT delivery and robust clinical investigations. A number of reviews note that there is a lack of randomized controlled clinical trials of adequate power. The equipment and expertise required for PDT is not standard clinical infrastructure. Where PDT studies are possible, different treatment protocols used in different small studies at different centers make comparison of clinical results difficult. There is generally a lack of commitment from the venture capitalists and government organizations that are able to fund large, multi-center trials. In addition, for ethical reasons, clinical trials have largely focused on PDT as an adjuvant, or on patients with advanced cancers that have failed other therapies (which leads to inherent bias towards poor outcomes). The number of variables to be optimized for clinical PDT with new photosensitizers means that the time in clinical trials could be longer than other standard therapies, which adds significant cost and risk. All of these challenges underscore the importance of developing the photosensitizer, light parameters, and protocol together for a specific clinical indication from the very beginning of the drug discovery process. There is merit in considering panchromatic photosensitizers that could be optimally activated with any wavelength of light from visible to NIR given the difficulty in getting new photosensitizers approved. A panchromatic photosensitizer that is safe and well-tolerated in humans might enable the light parameters and protocol to be optimized so that treatment depth matches tumor invasion depth for personalized medicine. Ultimately, this may reduce cost, facilitate regulatory approval, and also position the photosensitizer to be developed simultaneously as part of an immunotherapeutic PDT package.
While PDT experts on the clinical side are aware of these issues, reports of new photosensitizers in the primary literature generally do not acknowledge the shortcomings of PDT research and the tenuous position of PDT as an anticancer modality. PDT runs a real risk of being completely dismissed if new photosensitizers and new approaches are not introduced in a timely manner. As with any innovative technology that depends on investment for commercialization, PDT is at a critical point on the Gartner hype cycle (Figure 3). If we do not bring PDT to the forefront for some clinical indication as mainline or adjuvant therapy soon, certainly it will become increasingly more difficult to find support for its development.
Dr. McFarland and Lilge's article underscores the crucial importance of good results in Theralase's phase 2 trial. Great results leading to the displacement of Merck's Keytruda as the new preferred treatment for BCG-unresponsive non-muscle-invasive bladder cancer could finally convince "venture capitalists and government organizations" to loosen the purse strings and adequately fund research on photodynamic therapy for cancer.