Drug Modality Game Changers

Pharmaceutical science on the edge. An update from the 2023 Charles River World Congress 

A Potential Weapon in the Opioid Crisis

Last year, more than 110,000 people in the US died of a drug overdose, driven largely by the illicit spread of the opioid fentanyl. There is a clear public health need to find drugs and strategies beyond naloxone (Narcan), a nasal spray that can reverse an opioid overdose but may not be effective against other products driving the drug overdose deaths.

One experimental approach, described yesterday at Charles River’s Sixth World Congress in Cambridge, MA., by the company Clear Scientific removes narcotics from the bloodstream and brain, in much the same way chelation therapy excretes lead in urine. Clear Scientific says the product works by binding to, inactivating and clearing narcotics with a high degree of specificity.

“Treating a person who has overdosed on fentanyl with naloxone works, but fentanyl stays in the system too long for it to be wholly effective,” Shekar Shetty, Chief Executive Officer of Clear Scientific, told World Congress attendees. For instance, he said that some overdose patients revived with naloxone can re-enter an overdose state because there is residual fentanyl still circulating in the body. 

Clear Scientific, a small Cambridge, Massachusetts biotech with a big mission to help ease the opioid crisis, is injectable and oral forms of their drug. The injectable functions as a sequestrant, cleaning the bloodstream of certain narcotics (namely fentanyl, methamphetamine and cocaine) and helping the body to rapidly clear it in urine in a matter of minutes. The oral medication reduces the absorption of the drug from the GI tract to the blood and brain.

Piercen Oliver, Vice President of R&D at Clear Scientific, said their first-in-class small molecule drug emerged from early work conducted at the University of Maryland and Massachusetts General Hospital. Thus far, animal studies show the therapy works, most recently a large animal study that found the sequestrant cleared methamphetamine via the urine and reversed psychotic effects of the narcotic within five minutes. A radiolabeled study in rats found that the anti-opioid compound prevents absorption of the narcotic in tissue, while resulting in a high removal of meth.

The company plans to submit an Investigational New Drug application soon and hopes to begin a first-in-human study by the end of the year, says Shetty. 

Digital Twins: It’s All About the Data

Look around and you can find examples of how artificial intelligence (AI) is shaking up the pharmaceutical industry. It is being used to support diagnostic decision making in the medical imaging space and driving sustainable histology in preclinical pathology. The complexity of drug development and the massive amounts of data being generated in the process make drug discovery an ideal arena for the application of tools.

But the way Colin Hill, chairman and CEO of Aitia sees it, there are three foundational challenges hanging over AI-driven drug development: How to use AI to design a drug, how to use it to discover the right targets, and how to use it effectively to yield accurate simulations ahead of screenings or clinical drug trials. 

Aitia (formerly named GNS Healthcare), is focusing on the last two foundational challenges by generating digital twins or virtual replicas of patients. Using AI to create virtual models that can simulate drug behavior in the body, and predict efficacy and safety, opens doors that traditional drug development cannot, and hopefully will reduce, if not eliminate, some of the trial and errors that cost time and money, says Hill.

The digital twins being created by Aitia link patient characteristics to drug treatments. Along the way, they reveal complex genetic and molecular mechanisms and pathways driving clinical outcomes. Hill contrasted the work to computer chips, an industry that is ubiquitous today. A computer chip can have millions, even billions of components, but its behavior is entirely predictable. Humans have only thirty-thousand genes and merely hundreds of thousands of pathways. Yet 95% of the circuitry in the human body is not known, says Hill. "We continue to persist and find new drugs, despite this missing circuitry," says Hill. 

Hill said three breakthroughs inspired Aitia’s Digital Twins: cheaper and faster whole-genome sequencing,that led to large-scale data banks; cloud-based supercomputers; and the ability to use causal AI to ask what-if questions. 

Aitia’s Digital Twins are computational representations of a disease that capture genetic and molecular interactions, and that causally drive clinical and physiological outcomes. Hill said they have struck 20 partnerships to develop multiomic data on at least 300 patients. The partnerships span oncology, neurodegenerative diseases, and immunology, including hard-to-crack Alzheimer's disease. 

Three digital twins, two in blood and one in tissue, have been generated to study Alzheimer's. In one of Aitia's blood models, they were able to identify drug targets hiding in plain sight among the tau proteins that are considered one of the potential drivers of AD. Hill says the chances of this happening with conventional drug development tools would be close to zero. 

Getting companies to share data and ensuring that the data is clean and useable are still big obstacles holding AI back, but Hill sees the tide shifting, both within the industry and among regulators. "Clearly, the FDA is signaling an appetite for using these methods,” says Hill, referring to a May 12 paper published by the Food and Drug Administration using AI and machine learning in drug development.  “I believe digital twins of animals and patients will become a standard part of the drug development process,” Hill said.

Charles River Researcher Award

Every year at the World Congress, Charles River gives an award to a researcher, laboratory or organization dedicated to supporting the development of novel therapies. This year the recipient of the US$50,000 award was Terry Pirovolakis, whose son Michael was born with an ultra-rare condition known as SPG50. Terry has worked tirelessly for years to find a treatment for his son. Last year Michael became the first person to receive a gene therapy to treat his disease. 

This April, a clinical trial evaluating the experimental gene therapy in the US got underway. A second trial is expected to open soon in Spain.  This month, Terry launched Elpida Therapeutics, to take five rare disease gene therapy programs from proof-of-concept to approval in time to save the lives of children impacted by these diseases. 

The World Congress also heard from Thomas Whitehead, whose daughter Emily was the first child to be treated with a chimeric antigen receptor (CAR) T cell therapy nearly a decade ago. Today Emily is 18, cancer-free, and headed to Penn State.  

Several past winners of the World Congress Researcher Award also attended the meeting, including the research couple Sonia Vallabh and Eric Minikel, Rich Horgan of Cure Rare Disease, David Hysong of Shepherd Therapeutics, and Becky Schweighardt of the Grace Science Foundation.