Accelerating peptide therapeutics with Peptilogics
The rise of peptide therapeutics
In the early 1920s, a peptide hormone observed to have an anti-diabetic effect was succesfully isolated from a dog’s pancreas for the first time. Shortly after, the peptide hormone, insulin, would become the first peptide therapeutic – a pivotal and life-changing advance for the therapy and prognosis of diabetes throughout the next 100 years. Over 60 peptide drugs have since been approved in the United States and other major markets for indications ranging from HIV to chronic pain and prostate cancer – and over a hundred more are in clinical trials. While enthusiasm for peptide therapeutics was tempered by certain limitations of native peptides, recent advancements in structural biology and synthetic technologies have given peptide drug development a new lease of life over the last two decades.
Peptide therapeutics present an opportunity to bind previously undrugged targets thanks to their unique characteristics. In contrast to small molecules and antibodies, peptides have the ability to bind to large surface areas and tend to be more specific to their target – providing a safer alternative to small-molecule drugs. While pharmaceutical investment in peptide therapeutics continues to grow, the systems to bring these therapeutics from discovery to clinical use are slow, costly, and fragmented. Discovery is primarily achieved through screening very large libraries rather than designing molecules rationally to achieve an intended outcome, and manufacturing and synthesis are disjointed from discovery, which limits opportunities for rapid optimization and is not cost-effective.
How Peptilogcs set out to modernize peptide therapeutics
Peptilogics was created to revolutionize peptide therapeutics by streamlining the processes from discovery to development. Shifting away from the traditional approach of random screening and iteration, Peptilogics leveraged machine learning and predictive AI to create a platform capable of purposefully designing peptide therapeutic leads with a greater likelihood of clinical success. Beyond peptide design and discovery, Peptilogics has developed more cost and time-efficient manufacturing processes, creating a vertically integrated development platform with the goal of advancing therapies for hard-to-drug targets. Driving these efforts is an extensive team of experts with deep medical and biomedical experience, alongside pharma leaders with skills in multiple therapeutic areas.
One of the key features of Peptilogics’ approach when building their platform, named Nautilus, was to drive discovery by design rather than by screening. Using this method, Peptilogics is able to design optimized candidates with better safety and activity profiles. Starting with a protein target, with or without a determined structure, Nautilus uses deep learning models to generate peptides expected to bind the target. Underlying Nautilus’ deep learning algorithms are pharmaceutical, biological, chemical, and clinical datasets. As the novel candidates generated by Nautilus are synthesized and screened for broad and specific properties, such as toxicity, membrane permeability, binding affinity, and activities, additional proprietary data are generated and fed back into the learning models. This feedback loop enables Peptilogics to design and improve leads continuously.
Alongside the development of Nautilus, Peptilogics began by developing their first program, PLG0206, for the indication of Periprosthetic Joint Infections (PJIs). Through PLG0206, Peptilogics is successfully demonstrating the transformative impact that a vertically integrated platform can have on bringing peptide therapeutics to the clinic. In 2 years, compared to the industry standard of 4.5yrs, PLG0206 has progressed from initial design to entering Phase 1b clinical studies and has obtained orphan drug designation – all with a 77% cost reduction compared to traditional peptide therapeutic development.
Periprosthetic Joint Infections: a very sticky medical burden
Periprosthetic Joint Infections (PJIs) are one of the most devastating complications of total joint arthroplasties – a surgery to replace a damaged joint with an artificial joint made of metal, plastic, or ceramic. PJIs occur when infections develop at the site of the prosthesis, a complication that can arise for as long as two years following the joint arthroplasty. One of the greatest difficulties of dealing with PJIs involves choosing the optimal method to treat the infected joint – several procedures, ranging from extended antibiotic treatments to multiple additional surgeries (some of which involve complete removal of the artificial joint) may be adopted, but all have significant drawbacks and all exhibit considerable variation in outcomes between patients.
The incidence of prosthetic joint infection (PJI) among all prosthesis recipients ranges from 2% to 10%. Despite this relatively low incidence, PJIs of the knee and hip are estimated to exceed $1.85B in hospital costs annually in the US, an economic burden that can exceed the cost of the original arthroplasty by as much as ~4x. For 95% of patients, PJIs are eradicated within one year from the start of treatment. Throughout that period, the average total per-patient cost averages $500,000. These costs are primarily driven by longer hospital stays, additional surgical procedures, laboratory and pharmaceutical prescriptions.
Several unmet medical needs prevail in the treatment of PJIs:
- High rates of re-infection (23%-60% recurrence depending on treatment procedure), leading to increased rates of readmission and reoperations, and a reduction in the quality of life of patients.
- Intense procedures that limit patients’ mobility for an extended period of time and often leads to bone loss.
- Difficult-to-treat infections with limited options of drugs able to eradicate bacteria.
In light of these challenges, Peptilogics set out to design a peptide candidate capable of addressing infections with limited options. The resulting lead candidate, PLG0206, was intentionally designed to be a broad-spectrum anti-infective capable of targeting PJI-specific pathogens and penetrating biofilms. Peptilogics’ aim was to eliminate additional surgical procedures (down from 3 on average, to just 1), reduce recurrence rates, and lower costs as a result. As a condition with a higher mortality rate than many common cancers (5yr mortality of 21%), patients are in dire need of an improved standard of care.
Beyond PJIs, the ability of the Nautilus platform to design peptides across a wide range of biological classes enables Peptilogics to address ‘undruggable’ targets for indications in oncology and inflammation, for which Peptilogics already has multiple active discovery programs. Peptilogics’ second candidate is designed to treat lung infections in cystic fibrosis patients, another orphan condition with high mortality rates.
Looking ahead with Nautilus
When Peptilogics founder Jon Steckbeck set out to harness the power of a design-based approach to peptide discovery in 2013, the methods developed for PLG0206’s discovery and design, while novel, were not scalable. Since then, Peptilogics has created a platform built on the team’s many years of research and experience designing peptides. Today, Peptilogics has a thriving pipeline of clinical-stage candidates demonstrating the drastic impact the Nautilus platform can have on making peptide design more cost-efficient, time efficient, and scalable.