Celcuity - Gedatolisib Phase 3 Results
- rspace2
- Apr 15
- 7 min read
Updated: Apr 20
Executive Summary
Celcuity has a phase 3 readout upcoming for gedatolisib, a dual pan-PI3K/mTOR inhibitor. Phase 1b/2 results look promising, but the side effect profile is concerning. The development history of this class of drugs is littered with failure, primarily due to massive toxicity and intolerance. On the positive, gedatolisib seems to have the most effective dosing schedule, best efficacy results, and the fewest side effects of any drug in the class developed thus far. The most concerning side-effect seen in the phase 2 trials is neutropenia; the rest can be managed. The FDA has approved several isoform-specific PI3K inhibitors and have use in specific cancers with specific mutations. Eli Lilly recently bought a PI3Ka inhibitor from Scorpion Therapeutics for $2.5B.
Celcuity is currently worth about $400M. I think there will be some fireworks to the upside if the drug works. I slightly favor a positive result in the trial, and I think the upside here is potentially very large, so I am long some calls and stock. However, this one is a gamble.
Background Information
ER+/HER2- Breast Cancer
ER+ HER2- (Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative) breast cancer is a subtype of breast cancer characterized by the presence of estrogen receptors (ER) and the absence of HER2 protein overexpression. This means that cancer cells grow in response to estrogen but do not have excess HER2 receptors.
Prevalence
ER+ HER2- is the most common subtype of breast cancer, accounting for about 70% of all breast cancers.
It is more prevalent in postmenopausal women but can occur at any age.
Biological Features
Hormone-Driven Growth: Since these cancer cells have estrogen receptors, they rely on estrogen to grow.
Lower Aggressiveness: Compared to HER2-positive and triple-negative breast cancers, ER+ HER2- cancers tend to grow more slowly and have a better prognosis.
Recurrence Risk: While treatment is effective, there is a risk of late recurrence, sometimes many years after initial treatment.
Diagnosis is typically done through a combination of a mammogram and biopsies. An initial mammogram screens the breasts for potentially cancerous tissue. If suspect tissue is detected, the tissue is biopsy to either confirm or deny the presence of breast cancer.
The treatment course is highly dependent on the stage of the disease.
Early-Stage Disease: Disease is localized and operable.
Surgery
Mastectomy or lumpectomy
Hormone Therapy for at least 5 years
Tamoxifen
Aromatase Inhibitors (Post-menopausal women or premenopausal women with ovarian suppression)
Radiation Therapy (if needed after surgery)
CDK4/6 Inhibitors
Abemaciclib + Hormone Therapy
High-Risk Early Stage defined as:
1. Tumor size ≥5 cm
2. Lymph node involvement
3. High tumor grade (more aggressive cells)
a. Graded by pathologists on a scale of 1-3
4. Ki-67 score is high (indicating fast-growing cancer)
a. Higher proportion of Ki-67 protein indicates a more aggressive and recurrent cancer
5. Genomic Testing (Oncotype DX, Mammaprint) Suggests High Recurrence Risk
Treatment:
Surgery
Chemotherapy
Anthracyclines
Taxanes
Capecitabine
Hormone Therapy
CD4/6 Inhibitors
Radiation Therapy
Metastatic ER+ HER2- Breast Cancer
First-Line: Hormone Therapy + CD4/6 Inhibitors
Palbociclib
Ribociclib
Abemaciclib
Aromatase Inhibitors or Fulvestrant
Second-Line: PI3K/mTOR Inhibitors
For patients with PI3KCA Mutation:
Alpelisib + Fulvestrant
For patients with hormone therapy resistance:
Everolimus + Exemestane
Third-line Chemotherapy
Capecitabine
Paclitaxel
Eribulin
Development History
Gedatolisib is a pan-PI3K/mTOR inhibitor. This means it inhibits all the isoforms of PI3K and both mTOR complex 1 and complex 2. These drugs have an extensive development history in all types of cancers, albeit far from successful. Both pathways are heavily implicated in cancer. Unfortunately, these pathways are also extremely prevalent throughout the body for normal function, so adverse effects and toxicities are common.
Pan/PI3K Inhibitors
1. Buparlisib
2. PX-866
3. Pictilisib
4. Apitolisib
5. Dactolisib
Buparlisib
Buparlisib was tested in advanced HR+/HER2- breast cancer with moderate success. BELLE-2 tested buparlisib in combination with fulvestrant against fulverstrant alone. The PFS in the treatment group was 6.9 months vs 5 months in the fulvestrant alone group. BELLE-3 tested buparlisib with fulvestrant against fulvestrant alone in patients that had already failed an mTOR inhibitor. The treatment group had a PFS of 3.9 months vs 1.8 months on fulvestrant alone.
Despite moderate efficacy, the trials were plagued by horrible neuropsychiatric side effects. Around 25% developed depression, 20% anxiety, and 6% had to be hospitalized. It is hypothesized that buparlisib, a very lipophilic molecule, was able to cross into the brain and wreak havoc. Development of the drug was discontinued after these trials.
PX-866
This drug was tested in solid tumor diseases, but failed due to bad pharmacokinetics, limited bioavailability, and extensive GI side effects. Development was halted after early stage trials.
Pictilisib
Pictilisib was also tested in HR+/HER2- breast cancer. Efficacy was minimal at best, with the FERGI trial showing a PFS difference of 6.2 months vs 5.0 months in the treated vs control groups. Trials were halted due to adverse effects. 61% experienced grade three or above AEs compared to 28% in the placebo group. 16% experienced serious AEs related to treatment. The most common AEs were GI related and rash.
Apotolisib
Apotolisib is a pan-PI3K/mTOR inhibitor, the same MOA as gedatolisib. The story is similar here to the other molecules. In advanced HR+/HER2- breast cancer, the molecule showed an increase in PFS of 1.4 months from placebo (4.8 vs 3.4 months).
Significant AEs caused development to discontinue. In the two P2 trials, 75-80% experienced a grade three or above AE. The most common significant AEs were hyperglycemia, rash, liver dysfunction, pneumonitis, and GI issues.
Dactolisib
Like apotolisib, dactolisib is also a pan-PI3K/mTOR inhibitor. However, it did not show efficacy in HR+/HER2- breast cancer, but experienced significant AEs like the others.
Dose reductions were common, and the most significant AEs were GI events, hyperglycemia, and fatigue. In my opinion, the trial designs were also highly questionable. They tested the drug with Everolimus, another mTOR inhibitor, which served to only increase side effects without increasing efficacy. It is also pretty clear that these class of drugs should be combined with fulvestrant or AI.
There are also a slew of drugs that inhibited specific isoforms of PI3K with moderate success. Many centered on specific types of cancers and resulted in similar, but lessened, AE profile compared to the pan-PI3K inhibitors. Most recently, it is worth highlighting that Eli-Lilly purchased STX-478, a mutant-selective PI3Ka inhibitor, for $2.5B. Frankly, the data appears mediocre in terms of efficacy but does have a reduced AE profile compared to the pan-PI3K inhibitors. For reference, Celcuity has a market cap of close to $400M.
Gedatolisib
Like dactolisib and pictilisib, gedatolisib is a pan-PI3K/mTOR inhibitor. Despite the earlier failures of dactolisib and pictilisib, gedatolisib looks far more promising. It was granted fast-track designation by the FDA in 2L/3L advanced HR+/HER2- breast cancer. Phase 3 topline results are due in late Q1 2025 or early Q2 2025. The trial design is below:
The trial design essentially throws the kitchen sink at the drug to detect any type of difference between the placebo and the treatment groups. Based on their earlier phase 1B/2 results, I have high confidence the drug will be effective versus placebo. However, there are concerns about the AEs seen in the trial combined with the significant AEs seen in similar molecules.
Phase 1b/2
An excellent article was posted in The Lancet reviewing their phase 1B/2 results titled “Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.”
I highly recommend reading the full article, as it contains much of the nuance that will be discussed here. However, if it is not possible for you to access the article, the results are shown below in Celcuity’s presentation.
The subgroup analysis presentation is more relevant for the P3 trial.
The key arm here is expansion group D as that is a similar patient population to the P3 trial. The median PFS in this group ended up being 12.9 months. For reference, fulvestrant alone in this late-stage of disease has a median PFS of about 3.5-4 months if lucky.
In patients with a PI3Ka mutation who took Piqray (albelisib), the median PFS was about 11 months. The results seen in treatment group C are far more common in this late-stage of disease. Although the Lancet article noted that the patients in treatment group C were likely less sick compared to treatment group D, there is a mechanistic explanation for treatment group D having superior results. Typically, mTOR inhibitors, such as Everolimus, are dosed in a pulsating manner. Chronic, high-dose Everolimus is used as an immunosuppressant for organ rejection. Conversely, low-dose, pulsating Everolimus was shown to increase the immune response to a flu vaccine in older people. There is a good body of evidence to suggest that dosing mTOR inhibitors in a pulsating manner is superior to a chronic dosing schedule in most people, with the exception of organ transplant recipients.
Although not relevant to this treatment population, the results in expansion group A were also very impressive versus the standard of care. The PFS was about 46 months, compared to about half that for the current standard of care of the AI + CDK4/6 inhibitor.
I don’t think there is much doubt we will see a difference in efficacy versus the control arms. However, the prevalence of AEs is something worth discussing further.
80% of participants had a grade 3 or above AE. Dose reductions were required in 18/27 patients in group D. The most common grade 3 or grade 4 event was neutropenia. 53% had grade 3 neutropenia; 10% had grade 4 neutropenia. However, gedatolisib monotherapy is not associated with myelosuppression, but the study protocol required dose reductions for grade 3 or above neutropenia. The neutropenia was likely a result of the palbociclib.
The other common grade three AEs were stomatitis or mucosal inflammation (common in mTOR inhibitors), rash, and fatigue. GI AEs, although prevalent, were not deemed grade 3 or above. Apart from neutropenia, the side effect profile appears to be manageable. However, this could worsen in phase 3. The FDA is no doubt aware of the risks and gave the green light to the trial, despite 80% of study participants having a grade 3 or above AE. The biggest risk to this trial is the side effect profile.
Conclusion
Gedatolisib likely works and will meet several primary endpoints in the P3. However, the side effect profile is a huge risk here. The development history is not promising, although gedatolisib appears to be more effective and has fewer side effects than previous treatments. Additionally, they seem to have stumbled upon a much better dosing schedule, which makes sense mechanistically with what is known about mTOR inhibitors. This one is a gamble, but there is a lot of money to be made on the upside if the trial is successful. The topline results are due in Q2 2025.
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