D-peptides have the potential to become an important new class of drugs. Navigen has assembled a team of outstanding scientists with extensive experience in D-peptide discovery and optimization. Our team is committed to establishing Navigen as the industry leader in bringing important new D-peptide therapies forward. We have validated the benefits of D-peptides as drugs with our novel viral entry inhibitor for the treatment and prevention of HIV. This compound, CPT31, has been shown to be safe, potent, and efficacious in non-human primates. Navigen plans to initiate Phase 1 human studies for CPT31 in 2018. We also have strong pre-clinical programs for D-peptides for respiratory syncytial virus (RSV) as well as TNFα for treatment of inflammatory diseases.
CPT31 for Treatment and Prevention of HIV
Navigen’s clinical candidate, the viral entry inhibitor CPT31, is a D-peptide designed to both treat patients with HIV infection and prevent contraction of the disease in healthy individuals. Based on the unique properties of D-peptides and extensive pre-clinical data in non-human primates, CPT31 is expected to have:
- Efficacy as both a preventative and therapeutic;
- High potency against all major circulating HIV clades;
- Strong barrier to resistance resulting from an exceptionally high binding affinity to a highly conserved region of HIV;
- Low immunogenicity;
- Minimal side effects due to highly selective targeting of an HIV-specific binding site; and,
- A pharmacokinetic profile that allows convenient long-acting dosing to support improved patient compliance.
In collaboration with the National Institutes of Health (NIH), we have generated strong efficacy data for CPT31 in a non-human primate (NHP) HIV model. In this model, CPT31 monotherapy was shown to both prevent infection and maintain virus levels below levels of detection in infected NHPs with controlled virus.
CPT31 prevents HIV from entering cells by targeting gp41, a protein essential for viral entry. Gp41 has long been recognized as a promising target for HIV treatment and prevention. An L-peptide drug that binds gp41, Fuzeon®, was approved for HIV treatment. However, as an L-peptide, Fuzeon is rapidly degraded by the body, thus it requires large and frequent dosing (twice daily injection). Furthermore, development of drug resistance is a significant problem for Fuzeon. These factors limit its commercial viability.
A region of gp41 known as “the pocket” is highly conserved (i.e. mutates less frequently than other regions of HIV). Thus, it takes much longer for the virus to develop resistance to drugs targeting the pocket (Fuzeon does not bind the pocket). Many attempts have been made to develop pocket-binding small molecules and antibodies that would be more effective therapies than Fuzeon. However, small molecules were not potent enough to block the large protein-protein interface partly formed by the pocket during HIV entry. Antibodies are too large to access the space in which the pocket resides. Navigen’s CPT31 binds the pocket with extraordinarily high affinity and has succeeded against this target when all other types of molecules have failed. As expected by specifically targeting the conserved pocket, CPT31 is much less susceptible to drug resistance than Fuzeon.
CPT31 Addresses Many Unmet Needs in the Treatment and Prevention of HIV
While recent advances in the treatment of HIV have led to significant improvements in health and quality of life for millions of people around the world, there are still unmet needs in both treatment and prevention. Approximately 25-30% of patients on treatment are not achieving viral suppression. Three critical factors contribute to the challenge of suppressing the virus in treated patients: 1) serious side effects of current therapies; 2) lack of compliance driven by side effects and inconvenient daily dosing schedules; and 3) development of drug-resistant virus. Most HIV drugs on the market today are known to present a risk of long-term toxicity as well as unpleasant side effects including GI discomfort, insomnia, and depression, among others. These factors contribute to high rates of treatment non-compliance that in turn contributes to development of drug resistance. Many patients have developed resistance to one or more of the currently used classes of HIV drugs. A safe and effective therapy with more convenient dosing and high barriers to resistance would represent a major advance in HIV patient care. We believe CPT31 will be that major advance.
Navigen has received significant funding support for the CPT31 development program from the National Institutes of Health (NIH), including a $300K Phase I SBIR, a $3MM, three-year Phase II SBIR, and a $500K R56 award, with additional applications for grant funding pending.
D-Peptides for Treatment and Prevention of Human Respiratory Syncytial Virus (RSV)
RSV is a leading cause of severe respiratory tract infections primarily affecting infants, young children, and seniors. RSV infection leads to over 250,000 hospitalizations and 14,000 deaths each year in the U.S. Worldwide, each year RSV is responsible for 200,000 deaths of children under five years old.
Currently, there are no vaccines to prevent RSV and no safe and effective RSV therapeutics available for all RSV patients. A partially effective RSV preventative, Synagis®, is available but only for high-risk premature infants and young children with chronic heart and lung disease.
Navigen is developing anti-RSV D-peptides that have the potential to both prevent and treat RSV infection. Like our anti-HIV drug candidate, these D-peptides target a region of RSV essential for entry into host cells. We have shown via structural biology that our lead, CR32T, forms a highly specific interaction with its RSV target, and we have demonstrated it has potent anti-viral activity (mid nM IC50) in vitro.
The RSV program has benefited from a $600K, two-year NIH Phase I SBIR award and a $3MM, three-year NIH Phase II SBIR grant awarded in 2016.
Targeting Inflammatory Diseases: Anti-TNF D-peptides
Navigen is developing a D-peptide antagonist of tumor necrosis factor (TNF) for inflammatory diseases including inflammatory bowel disease and rheumatoid arthritis. Currently available anti-TNF antibodies are widely used but have high rates of non-response among patients. For example, up to 50% of inflammatory bowel disease and rheumatoid arthritis patients develop antibodies that render these drugs ineffective. D-peptides are minimally immunogenic, reducing or eliminating the risk of a significant anti-drug antibody response.
In addition, anti-TNF antibodies are systemically delivered to patients, resulting in a risk of immunosuppression. D-peptides are stable in the gut when taken orally, but they are not systemically absorbed. Therefore, they can potentially treat inflammatory bowel disease locally without immunocompromising patients.
Targeting Cancer: Anti-SIRPα D-peptides
Phagocytic cells, such as macrophages, initiate anti-tumor immune responses by engulfing cancer cells and priming T lymphocytes to attack tumors. Normal cells are not engulfed, because they display the protein CD47 on their cell surface. CD47 transmits an anti-phagocytic ("don't eat me") signal to macrophages by binding to the signal regulatory protein-alpha (SIRPα) protein on these cells. CD47-SIRPα is an important innate immune checkpoint regulating immune surveillance, and cancer cells subvert this checkpoint by overexpressing CD47. This enables tumor cells to simultaneously evade both direct phagocytic killing (innate immunity) as well as priming of an anti-tumor cytotoxic T-cell response (adaptive immunity).
Blocking CD47 has shown dramatic enhancement of antibody immunotherapy (tumor-targeted antibodies) in preclinical models, and experiments combining CD47 blockade with adaptive checkpoint modulators (e.g. PD-1/PD-L1) demonstrate 60-100% survival in rodents. However, due to ubiquitous CD47 expression, anti-CD47 immunotherapies must overcome a large antigen sink (reduced bioavailability), and are limited by on-target/off-tumor toxicity, such as thrombocytopenia and anemia. In contrast, the receptor SIRPα is mainly expressed on myeloid cells, such that inhibitors targeting SIRPα will have reduced toxicity and increased bioavailability.
Using our innovative mirror-image phage display platform, Navigen is developing D-peptide blockers targeting SIRPα to inhibit CD47-SIRPɑ anti-phagocytic signaling. Combining immunotherapy and chemotherapy is becoming the standard of care for many cancers, and targeting both adaptive and innate immune cells is considered to be a promising strategy to generate robust and durable antitumor immunity. We anticipate developing our D-peptide SIRPα blockers for use in combination with other immunotherapies (adaptive checkpoint modulators or tumor-targeted antibodies) and/or standard chemotherapy to achieve synergistic anti-tumor activity without the limitations observed for CD47 blockers. In addition, D-peptides are much smaller than antibodies, which should lead to more rapid and extensive tissue penetration, making them ideally suited for intratumoral delivery.