I was lucky enough to be an attendee of an exceptional event focused on optimizing drug performance hosted by the great team of experts from Charles River. It was an all-day discussion about best practices of toxicology approaches in early discovery, preclinical and development. The event was opened by Keynote speaker Elizabeth Stoner, MD/MS of MPM Capital who discussed "Speeding drugs across "the abyss": Creating value for partners". She offered an optimistic approach to building new companies by echoing the thought to "Dream Big" and also plan with the END in mind. It was refreshing to hear her takes on how to build value from her perspective as both a decorated industry veteran and venture capital expert. Really it came down, in her opinion, to doing the right experiments and building a vision to Exit. Companies have to realize early the value and market for their products and maximize the strategy and value associated with their niche. She also greatly recommends pre-IND meetings with the FDA and involving the agency early to understand what to address and not guess and hope it will all work out. She also gave insights on testing and recommended finding the maximum dosage early on in your testing. She also outlined all the new venues companies have to enter the market with accelerated filing strategy, breakthrough status, fast track, orphan, and other fast to clinic/patient strategies that can lessen the burn rate. In closing she also stressed that VC is far more sophisticated these days in partnering and developing value in their ventures in biotech which helps build value and invests not only capital but long term partnerships with their venture companies.
Dr. John MontanaThe next speaker was Dr. John Montana of Charles River from their U.K. site. He offered first his insights on "Avoiding the screeching halt: Ensuring the supply of drug product in early development." And later in the panel covered "How do we prove a drug action is "selective"? In vitro assays on-target and off-target." He stressed the Drug Product "stability, solubility and bioavailability" understandings. There are many decisions to make and you need to know when to test stability before or after Proof of Concept? He offered that learning from your partners at CROs like Charles River can help growing companies to understand these issues early and offered that you can learn from their breadth of experience. Don't underestimate the value of your partners, utilize them. His second discussion focused more on proving drug action is "selective" utilizing in vitro assays. He used an example of a morning-after pill that was being repurposed for CNS since it had prior approval and regulatory blueprint. The problem however was the product was a "GR Modulator" and selectively tuning the hormone responses. They had to adapt to find a more selective approach and by using target engagement early on for biomarker evaluation, was an example of an excellent tool for assessment and translation of on target efficiency and toxicology from cell to animals to man.
Eric Tien, PhDThe next speaker was Eric Tien, Ph.D., DABT of Biogen and he brought a very entertaining approach to his discussion of "Industry perspective on drug selection and optimization". He was very good at relating the process of assessing toxicity and outlined that in general companies should really assess which models to use and how far to go with tests before they invest in toxicology studies. He also gave the recommendation that, "As a Toxicologist it is your job to seek toxicity not avoid it." It is important to remember the FDA requires rodent and non-rodent models. It can be tricky so you have to select your non-rodent models carefully to ensure your size, species, and dosage plans are appropriate given your drugs unique properties. You also have to remember your purpose is to HELP people.
Examples-of-bluners-in-toxicityThe panel was capped off by Steve Bulera, Ph.D., Executive Director of Global Toxicology for Charles River. He gave an overall history of toxicology in an informative timeline. He outlined some of the cases that lead to the industry standards we have today in GLP and FDA standards. Two of the biggest reasons the standards exist are the missteps of two companies Searle and IBT. Gross mismanagement of vivarium and lab facilities lead to an internal standard which eventually became the industry standards of GLP we know today.
Steve BuleraSteve offered three areas of focus for any company to complete and successfully get their products through the regulatory process. #1) Do early discovery & PK work to save on GLP issues down the line or formulation issues. #2) Don't just check the boxes on the regulatory studies that are required, use your data and maybe you can get away with only running half the studies vs. the whole list. #3) Do your due diligence using less costly screening assays and ensure your molecule is pure enough to pursue into the clinic and development stages. #4) Don't Panic! Look at all the relevant data before making decisions and jumping ship. Don't go Cheap either; he's seen on numerous occasions where a company went cheap and didn't take the advice of their CRO partners on the best studies to get the most out of their investment in their studies. He recommends overall that everyone adhere to the 3R's: Reduce, Refine, Replace. It now takes 7 studies to IND where it previously took 15!