Progress brings cures into sight
Since taking office in January, President Biden has referred to cancer, or "the C word", as the most frightening word in the English language. This sentiment comes from the personal experience of losing his son to a glioblastoma brain tumor. But the macro data also supports this view. According to the American Cancer Society, approximately 608,570 Americans are expected to die of cancer in 2021, which translates to 1,670 deaths per day. Cancer is the second most common cause of death in the US, exceeded only by heart disease. The financial burden of cancer is also severe. Cancer-related direct medical costs in the US were around US$200 billion in 2020, and are projected to increase to US$246 billion by 2030, based only on population growth and aging.
That said, the five-year relative survival rate for all cancers combined has increased substantially in US since the early 1960s, from 39% to 68% among white people, and from 27% to 63% among the black population. Such a transformation in outcomes has arrived through a combination of public-health measures, such as smoking education, improved healthcare such as earlier diagnosis, and novel pharmaceutical therapies. This trifecta has turned select diagnoses, once considered terminal, into chronic conditions. For example, most patients now diagnosed with multiple myeloma or prostate cancer will have mortality tied to conditions other than their cancer.
Because of the widespread pain the disease causes and enormity of its market size, oncology is a declared focus area for the 10 largest pharmaceutical companies, with an estimated 1,700 clinical compounds in development. This amounts to approximately one-third of the global clinical pipeline across all therapeutic areas.
One of the hottest areas of development in recent years has been in the immuno-oncology (I-O) space. Immunotherapies have transformed cancer treatments in the last decade, and that transformation is led by a class of drugs known as checkpoint inhibitors. In particular, Merck's Keytruda and OPDIVO from BMS are both considered checkpoint inhibitors, and they work by taking the so called brakes off the immune response. These drugs are incredibly successful, with Keytruda selling a billion dollars in monthly revenue. They are getting approved in multiple different types of solid tumors, which comprise about 90% of all cancers. However, they only work in a minority of the patients that receive them. The reason is that their tumors are immunologically cold.
OncoSec has set out to solve this problem by introducing IL-12, a pro inflammatory signaling cytokine, contextually into the tumor microenvironment. This method has the ability to confirm if that tumor is immunologically suppressed, immunologically activated or active. They do this by coding IL-12 onto a DNA plasmid. By putting DNA plasmids into the tumor coded for IL-12 they get that DNA inside of cancer cells and other cells in the tumor. This process is done via gene electrotransfer. In outlining the benefits of this technique, OncoSec Medical president and CEO Daniel J. O’Connor explained: "We are not using an antibody or virus or bacteria to deliver DNA into cancer cells, we are using energy. As such, we do not have an issue with systemic toxicity… We do not want to supplant chemotherapy or radiotherapy side effects with immunotherapy side effects. We want to have a natural immune response that avoids cytotoxic consequences for the patient experience, and our way of delivering IL-12 is getting a lot closer to that big idea.”
Many investors favor OncoSec’s approach because, in comparison to other new therapies, it is cost effective. “If you look at autologous treatments that require the extraction of cells from a patient, manipulation of those cells in a cGMP facility, and then a one-to-one reintegration from treatment to patient it costs US$100,000. It can work, but it is expensive, and those costs must be paid eventually. That is why I favor our plasmid-based approach. Plasmids are very cost effective to make,” said O’Connor.
Scientists have long known that cell therapy, which replaces diseased, faulty or missing cells with healthy versions, could open new horizons in medicine. Now, following a string of regulatory approvals and positive clinical trial data, there is growing optimism that they can be applied to a wide range of diseases. Blood cancers, specifically lymphoma and leukemia, are cell therapy’s first breakthrough domain, thanks to innovations in Car-T therapy, which alters a patient’s immune cells to make them better at fighting cancer. Building off of the earlier success of Gilead and Novartis, in March 2021, BMS and Bluebird Bio jointly received FDA approval for Abecma to treat patients with multiple myeloma who are unresponsive to four or more previous lines of therapy.
Although these cell and gene therapies will undoubtedly have a large impact on the market, cost and manufacturing pose a serious challenge. For example, Abecma will cost US$419,500 per dose. As Eric Ostertag, CEO of Poseida Therapeutics, described: “Right now, (CAR-T cell therapy) is mostly done by autologous or individualized therapies. If somebody gets cancer, you manufacture their cells and put them back into the patient. Consequently, it is a very expensive process; it is time consuming and the clinical trials are expensive and time consuming as well.”
In response to these challenges, companies like Poseida are focusing on a fully allogeneic process, which means they will take cells from a healthy donor, manufacture them and then potentially give them “off the shelf” to many patients. That drops the cost of manufacturing while greatly expanding patient access.
One of the key issues is that most companies with CAR-T right now are only able to make somewhere between six to 12 doses from a single manufacturing run. With Poseida’s “booster molecule” this process holds the potential to be much more scalable. “We have shown we can make hundreds of doses from a single manufacturing run and that takes the cost of manufacturing CAR-T from well over US$100,000 to just a few thousand dollars, putting it in the same range as a monoclonal antibody or a bispecific therapy,” Ostertag affirmed.
“We see an opportunity for miRNAs as they can bind to several mRNAs at the same time to induce mRNA cleavage or inhibition of translation to functional proteins. What you see if you do transcriptomic analysis is that these small miRNAs bind to mRNAs across different signaling pathways… By intervening across different pathways at the same time and through dysregulation of multiple mRNAs at the same time, you potentially make it much more difficult for the tumor cell to develop resistance.”
Roel Schaapveld, CEO, InteRNA Technologies
From genetics to epigenetics
Surrounding the DNA in all our cells are molecular systems that tell genes when to turn on or off. As researchers learn more about these so-called epigenetic mechanisms, they are increasingly looking to use them to modify problematic genes. Foghorn Therapeutics, which was incubated and funded by Flagship Pioneering, targets one aspect of epigenetics — chromatin winding — to try to treat first cancer, and then other disorders. Foghorn Therapeutics, based in Cambridge, Mass., was co-founded in 2016 by Cigall Kadoch, whose research into chromatin regulation defects in a rare childhood cancer laid the groundwork for the company’s drug approach.
They soon brought on Adrian Gottschalk as president and CEO, who took the company public in a US$120 million IPO in October 2020. When asked what compelled him to leave Biogen to join Foghorn, Gottschalk replied: “50% of cancers have some sort of mutation or breakdown associated with the chromatin regulatory system, meaning this biology is playing a central role in the disease state. I found it profound that you had a system that was orchestrating gene expression, got hijacked by cancer cells and could potentially be corrected in some way. It could have a big impact on cancer patients.”
The company now has IND clearance for FHD-286 in both relapsed and refractory AML and metastatic uveal melanoma, and is currently initiating its first two clinical studies with initial data possible by the end of 2021.
Constellation Pharmaceuticals is another company incubated by a group of venture capital firms: The Column Group, Third Rock Ventures and Venrock, and is focused around epigenetics. They recognized that the potential for small molecule inhibitors to control gene expression through epigenetic mechanisms can be powerful in combating disease, and built their drug discovery engine to develop a pipeline around that thesis. While the company’s lead candidate Pelabresib is indicated for Myelofibrosis, it also is developing a second generation EZH2 inhibitor called CPI-0209 and CPI-482, which is an LSD1 inhibitor. Constellation president and CEO Jigar Raythatha commented: “Discovery is our lifeblood. Everything that we have progressed into the clinic has been homegrown. This underscores our strategy to invest in translational science. CPI-482 has a significant effect on myeloid biology, which could help us move into adjacencies and complimentary spaces.”
“Nearly 70% of human cancer genes are conserved in flies. Despite this, fruit flies had not been successfully used as a drug screening tool until Tosk perfected the process. We have harnessed this animal to yield a new technology to identify drugs that might not be discovered using traditional methods such as target discovery and high throughput screening.”
Brian Frenzel, President & CEO, Tosk
Despite the vast potential of new therapies and diagnostics in development, the reality is that cancer rates are expected to spike substantially as a result of disruptions in research, screening, diagnosis and treatments. The priority for the medical battle against Covid-19 has necessarily been to tackle the crisis caused by the virus itself. But other aspects of human health face collateral damage on a huge scale from the pandemic, which will require governments to increase health spending even faster than previously planned for several years to come.
As Lancet Oncology said in its editorial on COVID one year on: “Covid-19 has had devastating effects on patients with cancer, with huge numbers of missed diagnoses and delayed treatments due to health systems under pressure and patients’ reluctance to seek medical care.” Michael Kauffman, CEO of Karyopharm Therapeutics, confirmed this observation via the impact of his company’s rollout of XPOVIO for patients with multiple myeloma. He noted “Estimates are that between 30-70% of appointments in patients with active cancers were missed. When the history is written on this pandemic, I think we are going to see a lot of excess morbidity and mortality because of these missed appointments”
With this in mind, the next decade will be defined by continued effort to push the boundaries of what conditions are deemed “treatable.”
Image courtesy of Regeneron Pharmaceuticals