Life to Years
Never before has science made such revolutionary progress in advancing our understanding of cancer, with new treatments approved every year. Yet we still face an uphill battle to save the lives of patients suffering from cancer and prevent relapse due to drug resistance. Why are the mainstays of treatment for most advanced cancers still toxic recipes that deprive patients of their quality of life?
At FogPharma, we believe we have the answer; a new and unique drug modality that is better for patients, bringing them life to years and years to life. FogPharma is pioneering the discovery and development of cell-penetrating miniproteins (CPMPs), which are specifically designed to target cancer-causing proteins inside cancer cells and neutralize them.
FogPharma was born from the scientific and entrepreneurial vision of founder Greg Verdine, a pioneer in the discovery and development of new drug classes that “drug the undruggable.” FogPharma’s cell-penetrating miniproteins (CPMPs) are a broad new class of medicines that can drug targets beyond the reach of conventional therapeutics. Together with world-leading experts and collaborators in cancer biology and therapy, our team is building a drug discovery powerhouse having passion, knowledge, and creativity to develop fundamentally new cancer treatments.
FogPharma derives financial support from a unique syndicate of extraordinary private and institutional investors. FogPharma’s network of friends includes our founders, employees, investors, advisors, collaborators, and cancer patients; all working together to pioneer a unique approach toward conquering cancer.
We are laser-focused and unstoppable in our mission to deliver the new class of medicines to patients and their families to bring them years to life and life to years.
Limitations of Current Drug Modalities
The two well-established drug modalities, small molecules and biologics, have saved tens of millions of lives, but they are not a universal solution to all drug discovery challenges. Biologics strongly engage targets, but are too large and polar to cross the outer cell membrane, making them useful to less than 10 percent of extracellular human targets. Similarly, small molecules can access intracellular targets but are limited by their surface area and engage only about 10 percent of all targets.
What FogPharma’s CPMPs Do
Cell-penetrating miniproteins (CPMPs) combine the target-engagement power of biologics with the cell-entry ability of small molecules and therefore have the potential to be a game-changing new-modality solution to the challenge of drugging refractory disease drivers.
Our CPMP Platforms
Drugging the Undruggable in Cancer with CPMPs
“Undruggable” targets are especially problematic in cancer, because all three of the most prevalent drivers of cancer – Ras, Myc and β-catenin – have thus far eluded all efforts to be drugged. Mutationally deranged Ras proteins together account for
35 percent of all cancers, gene amplifications in Myc for
25 percent and mutational activation of β-catenin for
15 percent. Research began in the Verdine Lab at Harvard and further developed at FogPharma has clearly demonstrated that Ras and β-catenin are targetable by CPMPs.
CPMPs are polypeptides that have been rendered pharmacologically effective by introduction of a structural brace. This brace locks the peptide into its bioactive three-dimensional structure and can engage the target directly, giving the CPMP high affinity for targets that cannot be bound tightly by small molecules. The brace also confers cell-penetrating ability on the CPMP, dramatically increasing in vivo stability and circulating half-life.
Our 3 Distinct CPMP Platforms
Second-generation stapled peptides: The original hydrocarbon-stapled peptide platform and dual Hdm2/x antagonists, invented in the Verdine lab, have given rise to the first stapled peptide to achieve proof-of-concept in humans, with ALRN 6924 in Phase II clinical development. The second-generation system builds on the original system, enabling extensive structural variation of the staple itself to optimize physical and pharmacologic properties.
Pro-locked peptides: This system affords peptides of 8-11 amino acids with a designed N-terminal capping system. Pro-locked peptides have been shown to exhibit significant levels of oral bioavailability in rats.
Bi-helical CPMPs: These molecules consist of two tightly paired α-helices, and can engage even the most challenging targets with extraordinarily high affinity and specificity. For example, a bi-helical CPMP has been discovered that targets all Ras isoforms with an affinity below 200 pM.
FogPharma’s key program aims to discover and develop direct-acting antagonists of β-catenin. β-catenin is a key signaling hub in the Wnt pathway, which is activated by pathway mutations in nearly all colorectal cancers and a significant number of cancers of the liver, breast, prostate, endometrium and lung, among others. In these cancers, the activations are all upstream of or in β-catenin; our antagonists are expected to block all Wnt-driven cancers, irrespective of their specific pathway mutation.
Recently, the laboratory of our scientific advisory board member Dr. Thomas Gajewski showed that Wnt pathway activation also plays an important role in tumors going “cold”, avoiding invasion by cytotoxic T lymphocytes. β-catenin antagonist might be useful in two distinct and potentially synergistic ways; as an anti-oncogene to block tumor cell proliferation and as an immuno-oncology drug to promote tumor clearance by cytotoxic T cells. FogPharma is actively pursuing both of these indications in pre-clinical models.
β-catenin has multiple interacting partners and interference with any one of them may be therapeutically beneficial. FogPharma is developing multiple series of drugs, each of which binds β-catenin at a unique site and blocks a particular interaction. These series will be developed initially as single agents, but the company’s long-term goal is to use them in combination to stave off the emergence of resistance.
The role of β-catenin in tumor evasion of the immune response: Spranger, S, Bao, R, Gajewski, TF, Melanoma-intrinsic β-catenin signaling prevents anti-tumor immunity. Nature 2015, 523, 231-235.
Targeting an ultra-undruggable target, the transcription factor Notch: Moellering, RE, Cornejo, M, Davis, TN, Del Bianco, C, Aster, JC, Blacklow, SC, Kung, AL, Gilliland, DG, Verdine, GL, Bradner, JE, Direct inhibition of the NOTCH transcription factor complex. Nature 2012, 462, pp 182-188.
Targeting β-catenin: Grossmann, TN, Yeh, JTH, Bowman, BR, Chu, Q, Moellering, RE, Verdine, GL, Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin. Proc. Natl. Acad. Sci. USA 2012, 109, 17942-17947.
First demonstration of efficacy in an animal model: Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004, 305. pp 1466-70.