When CRO Selection Went Sideways, Ashvattha Therapeutics Did This To Recover

A conversation with Ashvattha Therapeutics CEO Jeff Cleland, Ph.D.

Running a clinical trial is tough enough work. But complicate things with CRO troubles, a competitive therapeutic environment, and reluctant investigators, and you get a trial that’s trending toward failure.

But that wouldn’t be the fate for Ashvattha’s subcutaneous (subQ) MGB dosing Phase 2 study for the treatment of wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME) —and CEO Jeff Cleland was going to make sure of it.

Back in 2023, Ashvattha began its Phase 2 journey with a two-stage adaptive trial meant to be more efficient thanks to its single clinical trial agreement, single process for site activations, and rapid IRB review of straightforward amendments. The company intended to move quickly because, as we’ll learn, time and cash were not in great supply.

In this Q&A, Cleland details when things went sideways with their CRO and explains how he and his team rebounded as they prepare to take their drug candidate into Phase 3 trials.

Clinical Leader: What innovative approaches did Ashvattha utilize in the execution of the Phase 2 trial to ensure data quality, minimize bias, and optimize patient recruitment and retention, and which of these will be prioritized in larger, multi-center studies?

Jeff Cleland, Ph.D.: We initiated the trial with a CRO that did not adequately oversee the project. After taking over the trial, our team diligently cleared queries and completed monitoring activities to ensure data quality and patient retention as well as investigator engagement.

I've done almost 17 development projects in the last 30 years, and it's the first time I've seen a CRO that — and our team is accountable as well — didn't go out to the clinical sites to launch the study. We activated sites, but then no sites enrolled for six months. And I was asking, what's going on? This is a very large indication. It's not like this is a rare disease where you expect delays. So, we held a meeting with all the investigators in San Diego in the fall of 2023. Then we started to finally enroll patients, driven by our company and not by the CRO.

The CRO was just not doing much to help with enrollment; they weren't engaging with the sites and the sites really didn't have any interaction with them, and yet they were charging us for a part-time person what they would charge for a full-time person.

When you think about the economics, does it really make sense to pay somebody part-time when we can just hire somebody to do the work ourselves, where we have control over it and they're more invested in the outcome?

The challenge is if you bring everything in-house, you have to have all those SOPs, the quality checks, the data integrity, and the trial master file. As a small company, it was a heavy lift to get everything set up. But once we got it set up, the execution was much better.

The problem is, private companies like ours live hand to mouth. You don't get cash until you execute and create value with a clinical trial, assuming it's positive. So here we are, having to stretch our cash because nobody was going to give us more. We ended up in this really vicious cycle; we couldn't get data, and we were running out of cash. It was a really tough situation to be in.

Looking back at your CRO selection process, what did you learn from the experience?

The challenging thing for a lot of small companies, and I've seen this before in my previous companies, is working with a very large CRO. When we selected them, they weren't part of a large CRO, but soon after, they were acquired, so, they took on all this bureaucracy. Larger CROs are used to working with pharma, and the mindset of pharma is very different from that of a startup. We are not used to bureaucracy. We want to move fast, we want to be nimble, and we want to be able to be cost-effective. Pharma doesn't seem to care. Slow and expensive is fine for them, but it doesn't work for us.

When picking the CRO for the next study, it’s going to be somebody who's more focused on helping our type of company and very experienced and focused in our therapeutic area. We had a lot of people from that CRO that weren't ever in ophthalmology. They had to be trained; it's kind of like starting from scratch.

To recover, we hired a person to lead clinical operations who had experience bringing programs in-house. We also leveraged external consulting experience from someone else who left that CRO, and he was able to help us navigate and bring on the right consultants. We hired a consultant group for the monitoring, and they were experienced in ophthalmology trials.

As for your interactions with patients, investigators, or regulatory bodies, what lessons did you learn from them?

We learned that detailed site training on the clinical protocol and procedures is critical to ensuring robust data outcomes. Our future plans will include more site engagement from start to finish, including frequent contact with principal investigators.

At my previous two companies, either myself or the CMO would go to each site along with the clinical operations person to teach the site about the drug, how it works, and get them engaged about why this is different and they should be excited about it. And then we would make sure they understand all the details of the protocol, especially inclusion/exclusion and trial conduct.

Some sites weren't great at following those. That obviously led to some issues at the end with quality, and we had to go back and look into it and make sure we cleaned it up. Doing that up front more rigorously and building your relationships is really critical, especially having investigators interact with your company and not only with a CRO. I've heard stories where a certain CRO is coming into the site, and the site just cringes because they've had bad interactions with other representatives from that CRO.

 You’ve detailed a few challenges so far, but which was the most significant? And how did you address it?

We faced enrollment challenges as a first-in-patient study, especially with competing trials. We believe that our positive clinical data and novel approach will facilitate better patient enrollment going forward.

When I worked at Genentech in the ’90s, we were developing a drug called Lucentis, and the retinal ophthalmologists really didn't want to inject the eye, but that's the only way we could get the drug to the target. With that, everyone gets an injection (for the two indications that we’re talking about), and they have to do that as often as once a month. You get a needle stuck in your eye to treat your disease, or you go blind — that's the other option. If you have it in both eyes, you have to make two visits. So that gets to be a really huge treatment burden on the patients.

We differentiate ourselves by giving our drug subcutaneously once a month. So, it's not that dramatic needle-in-the-eye process. It can even be done at home in the future. We're competing with companies that are still doing injections in the eye, and those carry ocular adverse events that we don't have.

But when we were just starting, investigators thought it wasn’t going to work if you gave it any other way than an injection in the eye. Now that we have data and positive results — we're seeing effects in both eyes from one subQ injection — it gets rid of the needle and will be much more enticing and competitive.

People have tried systemic administration, and it didn't work. It was toxic. But we have no safety issues. Now that we have the data, it's easier. Back then, we had to compete with the tried-and-true approaches of injecting in the eye.

 About The Expert:

Jeff Cleland, Ph.D., has 30 years of industry experience in research and development, including more than a decade at Genentech, Inc. He is currently the chairman, CEO, president, and co-founder of Ashvattha Therapeutics, Inc., a private clinical-stage company developing novel nanomedicines in ophthalmology, neurology, and inflammation. His experience in startups includes major roles in obtaining more than $500 million in capital at stages from Series A through D and exit via IPO, including over $400 million in capital raised as CEO. He holds a BS in chemical engineering from the University of California, Davis and a Ph.D. in chemical engineering from the Massachusetts Institute of Technology. Dr. Cleland has authored more than 100 articles and four books and holds several issued patents. He also serves on the boards of BIO, Elixirgen Therapeutics, and Syncromune, and has advisory roles with small emerging biotechnology companies.