Gedatolisib Shatters Phase 3 Goals and Scales For Breast Cancer Breakthrough
By Katie Anderson, Chief Editor, Pharmaceutical Online
Decades ago, the dysregulation of the PI3K/Akt/mTOR (PAM) pathway was linked to the rapid progression of advanced breast cancer; however, efforts to inhibit it have since seen only moderate success without being able to completely shut it down. The result has been HR+/HER2- advanced breast cancer (ABC) treatment with minimal improvements to survival rates.
The future is shining a bit brighter today for those with ABC, due to unexpectedly impressive results from a phase 3 clinical trial of Celcuity’s gedatolisib (Viktoria-1). Celcuity CEO and Co-Founder Brian Sullivan anticipated successful phase 3 results, but the unprecedented outcome had him elated not only for validation of his team’s hard work but also mostly for the patients with ABC that now had more hope.
What Make’s Gedatolisib Different?
The Celcuity team identified how important the PAM pathway was to slowing the progression of breast cancer and made that pathway its focus. Gedatolisib shuts down the four PI3K and two mTOR targets to completely inhibit the PAM pathway. Though others had developed PAM pathway drugs, they did not shut down all three pathways.
“You have 3 pathways that essentially are interconnected and somewhat act as a circuit. If one pathway is inhibited and the others aren't, you can increase the activity in the other pathways. Our hypothesis was the optimal way to treat HR+/HER2- ABC was to shut down all 3 pathways simultaneously,” explained Sullivan.
Sullivan emphasized that the success of gedatolisib to inhibit the pathway and slow cancer progression shows that the pathway is a fundamental driver of the disease irrespective of a PIK3CA mutation. By inhibiting the PAM pathway, gedatolisib is essentially pulling the energy source of the tumor cells to prevent them from proliferating, according to Sullivan.
Phase 3 Test Results
Phase 3 clinical testing involved a combination of gedatolisib with estrogen receptor inhibitor fulvestrant and palbociclib to inhibit the CDK4/6 pathway. Also tested was gedatolisib and fulvestrant.
Compared to a two-month median progression-free survival (PFS) of just fulvestrant, the trio of drugs produced a 9.3 month-median PFS and a hazard ratio of .24. Similarly, the two drug combination produced a 7.4 month-PFS with a hazard ratio of .33.
Sullivan added that the .24 hazard ratio is the lowest that’s ever been reported for any study in HR+/HER2- ABC. “We felt pretty optimistic about having positive results given how good our early phase study results were, but you would never project results like this. And you don't forecast those. You're just obviously thankful when you get them,” furthered Sullivan. He added that this is establishing a new standard in care, where previously patients after progressing with CDK4/6 and lack a PIK3C mutation only can expect 2–4-month median PFS with standard care depending on their ESR-1 status.
Not only did gedasolisib achieve impressive efficacy data, but it also saw favorable safety data. In fact, less than 4% of clinical trial participants had to cease treatment because of side effects. “The treatment discontinuation rate due to adverse events for both of the regimens we tested was lower than has been reported for any drug combination ever in HR+/HER2- ABC.
FDA Breakthrough/Fast Track Status
Based on early data, gedatolisib was granted breakthrough status by the FDA. To achieve that status, the clinical and regulatory team had to create a detailed briefing book. The status was imperative to keeping the drug’s progression on track. However, according to Sullivan, equally as important was Celcuity’s collaboration with the FDA.
“The more closely you can collaborate with the FDA, the better. We always believe that you should think of them as a partner to successfully develop a drug,” added Sullivan.
That status allowed Celcuity to ask the kind of questions that oftentimes aren't addressed until you get to a pre-NDA meeting. His team gathered information from their partnership on necessary toxicity data, clinical pharmacology data and CMC data so they weren’t in doubt at the last minute. They worked with the FDA on their trial design to make sure it satisfied its expectations, and he believes the collaboration ultimately will result in much less work in the long run.
“We're better prepared now for a new drug application. “We've anticipated what the agency requires for data to support the review, and we are in a position to quickly submit a new drug application with confidence,” he noted.
With the new voucher system, more sponsors will no doubt be seeking breakthrough status. Sullivan continued that while the status is helpful, it is important to be pragmatic about it. It is worth it for a true breakthrough.
Transition to Commercialization
Gedatolisib has impressive clinical results and favorable safety data, so what does scale-up look like once approved to reach all these patients? It’s already well underway, according to Sullivan. “In this business you have to assume success, because the lead times for doing all this work can in some cases be years,” added Sullivan.
The Celcuity team simultaneously developed the process at scale so they had sufficient drug at the time of approval. And with a targeted launch date in 2026, that work needed to already be done. The team had to determine what volume of drug they would need and then figure out how frequently they would need to run the batch. “It's impractical to run too many batches. You just can't schedule the logistics, and so you have to make sure that your process has high enough volume from a batch, so you don't have scheduling challenges. Then, you have to develop a realistic long-term forecast and then project accordingly,” he added.
Gedatolisib is a small molecule, but it is a tricky molecule, according to Sullivan. Though its scale up process had its own challenges, its manufacturing team developed a robust process that is consistent.
“To anticipate success, you have to do the registration, validation of batches, etc. ahead of time, so that you're ready to roll at launch. Sullivan worked backwards from its launch date to ensure scale-up was ready. Therefore, they are in a good position, with a commercial supply to support the demand for the next few years.
At the same time, while the company is evaluating other indications for gedatolisib such as prostate and endometrial cancer, it anticipates success there and incorporates those needs into its long-term supply chain forecast.
Future Steps for Gedatolisib
While the company prepares its NDA, it is also assessing the long-term needs for gedatolisib and started considering second sources for greater volume. “We've optimized our primary sources, and we have drug that will meet our needs for the next couple of years at least. At the same time, it's important that you have backup supply, and so that's the work that you start now. We've already begun that work in terms of valuation of alternatives,” explained Sullivan.
The Celcuity team is hoping for a launch in 2026, but it still has to wait on the FDA’s approval pathway. After that, it plans to create awareness of the drug among oncologists and present the data at major medical conferences. One thing is for certain——gedatolisib for the treatment of HR+/HER2- ABC has so far exceeded expectations, and the breast cancer community is abuzz with hope of a standard of care. With breakthrough status and positive clinical data already under its belt, getatolisib’s approval seems imminent but, as we know, not always guaranteed.