Alpelisib

“We have two phase 3 studies in the frontline population, and that\'s a big $20 billion tent,” Celcuity CEO Brian Sullivan told Fierce.\n While Revolution Medicines dominated this year’s American Society of Clinical Oncology annual meeting by conquering the “undruggable” RAS pathway, another up-and-coming biotech hopes to do the same with a different vexing target that drives a plethora of cancers.Celcuity, a Minnesota biotech founded by CEO Brian Sullivan in 2012, announced today that its PAM pathway inhibitor, called gedatolisib, about doubled average progression-free survival in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The analysis focused on patients in the phase 3 VIKTORIA-1 trial with a mutation in the PIK3CA gene, which controls production of a key enzyme in the PAM pathway.Celcuity had previously announced that gedatolisib won out over Novartis’ PI3K inhibitor Piqray in the trial, but today’s ASCO presentation is the first time the numbers behind the victory have been shared.Patients treated with Piqray and the hormone therapy fulvestrant lived without disease progression for a median of 5.6 months, compared to 11.3 months for those given gedatolisib and fulvestrant and 11.1 months for those given that doublet plus Pfizer’s Ibrance.The gedatolisib doublet and triplet also hit objective response rates of 35.7% and 48.9%, respectively, Celcuity reported today. These results are “the highest reported in this setting,” Sullivan told Fierce on the sidelines of ASCO.Even so, the numbers came in below expectations forecasted by analysts from Leerink Partners ahead of the conference. The analysts said experts anticipated the doublet notching a PFS of around 12 months, with the triplet even higher at between 14 and 15 months.Sullivan told Fierce that he’s heard a lot of enthusiasm from experts he’s spoken to about the data.“It\'s not often you can double outcomes for patients, so we\'re very excited about the data,” he said.Sullivan also sees gedatolisib’s safety profile as a key advantage. As an intravenous infusion, the molecule is given three times a month instead of the 28-day monthly regimens required of current oral medicines. Less frequent dosing means less exposure to the drug, which Sullivan said is much more potent than its competitors.“The real bugaboo in this class of drugs has been hyperglycemia,” Sullivan said. “We report nominal hyperglycemia lower than has ever been reported for drugs in this class.”The most significant adverse events for gedatolisib were a drop in white blood cells, known as neutropenia, and stomatitis, which involves inflammation of the mucous membranes in the mouth.One patient in the gedatolisib triplet group died, which was attributed to Ibrance, while two patients died in the group given Piqray and fulvestrant. “Both gedatolisib regimens were well-tolerated with very few VIKTORIA-1 patients discontinuing treatment due to an adverse event,” Celcuity’s chief medical officer, Igor Gorbatchevsky, M.D., said in today’s release. “These safety results compare very favorably to those from the patient group treated with alpelisib and fulvestrant, which we believe reflects the benefit of gedatolisib’s multi-target mechanism of action, pharmacokinetic profile and intravenous administration.”Celcuity has already filed gedatolisib with the FDA for approval in breast cancer patients without PIK3CA mutations, with a decision expected by July 17. With this fresh data in hand, the biotech plans to submit a supplemental new drug application to the regulator in the third quarter, Sullivan said.Celcuity licensed gedatolisib from Pfizer in 2021 for just $10 million in a mixture of cash and stock—a good deal, as Sullivan put it. After first focusing on building a cellular analysis program, Celcuity hit upon PAM as a particularly important pathway for numerous cancers, including those of the breast and prostate. But though well-known, it was considered too tough to drug, much like RAS.While RAS has been described as a “greasy ball,” the PAM pathway is more like a “spider with many legs” or a Rubik’s cube, Sullivan said. PAM stands for PI3K/AKT/mTOR, the pathway’s three key components, and it is essential for regulating cell growth and division.While other drugs hit just one piece at a time, gedatolisib shuts down the entire pathway all at once.If gedatolisib is approved and proves effective in ongoing frontline efforts, too, Sullivan thinks it will set Celcuity on a path to becoming a $10 billion company.“We have two phase 3 studies in the frontline population, and that\'s a big $20 billion tent,” the CEO said. “You almost don\'t want to say it out loud.”

Two regimens containing Celcuity's multi-target PAM inhibitor gedatolisib halved the risk of disease progression or death versus Novartis' PI3Kα inhibitor Piqray (alpelisib) in adults with hormone receptor (HR)-positive, HER2-negative, PIK3CA mutated, locally advanced or metastatic breast cancer. The statistically significant and clinically meaningful findings come from the Phase III VIKTORIA-1 trial, which were presented Tuesday at the American Society of Clinical Oncology (ASCO) annual meeting. “By comprehensively blocking the PI3K/AKT/mTOR, or PAM, pathway, gedatolisib…showed it can offer these patients two times the likelihood of survival without disease progression or death relative to a single-target inhibitor of  the PAM pathway," said co-principal investigator Sara Hurvitz. "With these results, the gedatolisib regimens, if approved, represent a new potential standard of care for patients with HR+, HER2-negative, PIK3CA mutant advanced  breast cancer whose disease progressed on or after treatment with a CDK4/6 inhibitor.”   VIKTORIA-1 already produced positive results in the PIK3CA wild-type cohort, with a progression-free survival (PFS) benefit of 76% for gedatolisib compared to fulvestrant — the FDA is set to decide on approval in this patient population by July 17. And last month, Celcuity said that the study, which enrolled participants who progresed on, or after, treatment with a CDK4/6  inhibitor and an aromatase inhibitor, also hit its primary endpoint against Piqray in the PIK3CA-mutant cohort. Results presented at ASCO showed that a triplet regimen of gedatolisib, fulvestrant and Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) reduced the risk of disease progression or death by 50% versus Piqray plus fulvestrant. Median PFS in the two arms was 11.1 months and 5.6 months, respectively. Meanwhile, the dual regimen of gedatolisib plus fulvestrant reduced the risk of disease progression or death by 49% compared to Piqray plus fulvestrant, with median PFS of 11.3 months. Celcuity added that the gedatolisib triplet regimen demonstrated an objective response rate of 48.9%, which it was 35.7% for the dual regimen, compared to 26% for Piqray plus fulvestrant. Further, the median duration of response was 15.7 months for the gedatolisib triplet regimen, versus 24.2 months for the doublet regimen and 7.5 months for Piqray plus fulvestrant. “Both gedatolisib regimens were well-tolerated with very few VIKTORIA-1 patients discontinuing treatment due to an adverse event," said Igor Gorbatchevsky, Celcuity's chief medical officer. Treatment-related adverse events that led to the discontinuation of study treatment occurred in 2.6% of patients in the gedatolisib-triplet group, 3.8% in the gedatolisib doublet group, and 7.1% in the Piqray plus fulvestrant group. While there was one grade 5 TRAE in the  gedatolisib-triplet group, the company noted that this was related to Ibrance — there were no similar events in the gedatolisib-doublet group, versus two in the Piqray plus fulvestrant arm.