What Is BBP-398?
BBP-398 is an investigational medication currently being studied in clinical trials. It is also known by its former name, IACS-15509. BBP-398 works as a potent, selective, orally active allosteric inhibitor of SHP2. SHP2 is a protein (a tyrosine phosphatase) that plays a key role in the RTK-MAPK signal transduction pathway. This pathway is essential for cell growth and survival, involving components such as the small GTPase RAS, RAF, MEK, and ERK. By blocking SHP2, BBP-398 aims to disrupt these signals, potentially slowing the growth of cancer cells.
This drug is being investigated for its potential use in treating various cancers. Clinical trials are exploring BBP-398 for conditions such as non-small cell lung cancer and different types of advanced or metastatic solid tumors.
Uses and Conditions Under Study
BBP-398 is currently being studied in 5 clinical trials for various cancer conditions. These trials have enrolled a total of 132 participants, with the first trial starting in 2020 and the latest in 2023. The main conditions under investigation can be grouped into two categories:
- Non-Small Cell Lung Cancer (NSCLC): This is a common type of lung cancer. BBP-398 is being studied for NSCLC, metastatic NSCLC, and advanced or metastatic non-small cell lung cancer. The drug's mechanism of action, which involves inhibiting SHP2 to disrupt cell growth pathways, suggests it could be a potential treatment for these cancers.
- Solid Tumors: This category includes cancers that form a solid mass. BBP-398 is being investigated for advanced solid tumor, metastatic solid tumor, solid tumor, solid tumor in adults, and general solid tumors. Similar to NSCLC, the drug's ability to interfere with critical cell signaling pathways makes it a candidate for treating a range of solid tumor types.
Dosing
BBP-398 is administered orally, typically as oral capsules. In clinical trials, it has been administered once a day (QD). The specific dosage forms and regimens studied are investigational and are being evaluated to determine the safest and most effective treatment plan.
Clinical trials have explored various dosing strategies for BBP-398, both as a single agent and in combination with other medications. For example, BBP-398 has been studied in combination with osimertinib and with sotorasib. These studies included different dose escalation levels (such as Level 1, Level 2, and Level 3) and dose expansion phases. The purpose of these phases is to identify the optimal dose and regimen for patients. Specific dose regimens (like Regimen 1 and Regimen 2) have also been explored during dose expansion and optimization studies.
Side Effects
In clinical trials, patients taking BBP-398 experienced side effects. The most common side effects were generally gastrointestinal in nature.
For patients with Irritable Bowel Syndrome with Constipation (IBS-C) in a placebo-controlled study (NCT04008272), the most frequently reported side effect was diarrhea. 13.7% of patients taking BBP-398 experienced diarrhea, compared to 4.7% on placebo. Other common side effects included:
- Nausea: 6.9% of patients taking BBP-398 experienced nausea, compared to 3.3% on placebo.
- Abdominal pain: 5.6% of patients taking BBP-398 experienced abdominal pain, compared to 4.0% on placebo.
- Headache: 4.7% of patients taking BBP-398 experienced headache, compared to 4.3% on placebo.
- Flatulence: 3.0% of patients taking BBP-398 experienced flatulence, compared to 2.0% on placebo.
In a separate open-label study (NCT04500123) involving patients with hyperphosphatemia undergoing dialysis, where no placebo comparison was available, the most common side effects included:
- AV fistula complication: 12% of patients.
- Hyperkalemia: 9% of patients.
- Diarrhea: 8% of patients.
- Nausea: 7% of patients.
- Vomiting: 6% of patients.
Clinical Trial Results
Clinical trials have evaluated BBP-398 for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) and hyperphosphatemia in patients undergoing dialysis.
IBS-C Results (NCT04008272)
A 12-week, Phase 3 study (NCT04008272) involving 599 patients with IBS-C compared BBP-398 to placebo. The primary goal was to determine the percentage of "Overall Responders," defined as patients who experienced at least a 30% reduction in weekly worst abdominal pain score and an increase of at least one complete spontaneous bowel movement (CSBM) per week for at least 6 of the 12 treatment weeks.
- Overall Responders: 44% (135 out of 307) of patients taking BBP-398 met this primary endpoint, compared to 33% (99 out of 300) of patients on placebo.
Key secondary endpoints also showed positive results:
- Abdominal Pain Responders: 55% (168 out of 307) of patients on BBP-398 achieved at least a 30% reduction in weekly worst abdominal pain for at least 6 of 12 weeks, compared to 40% (120 out of 300) on placebo.
- CSBM Responders: 60% (184 out of 307) of patients on BBP-398 experienced an increase of at least one CSBM per week for at least 6 of 12 weeks, compared to 49% (147 out of 300) on placebo.
- Average Weekly CSBM Frequency: Patients taking BBP-398 saw an average increase of 2.1 CSBMs per week, while those on placebo saw an average increase of 1.2 CSBMs per week.
- Average Weekly Abdominal Pain Score: Patients on BBP-398 experienced an average reduction of 1.8 points in their abdominal pain score, compared to a 1.0-point reduction for those on placebo.
Hyperphosphatemia Results (NCT04500123)
An 8-week, Phase 2 open-label study (NCT04500123) involving 100 patients undergoing dialysis evaluated BBP-398 for the treatment of hyperphosphatemia, a condition characterized by high phosphate levels in the blood. Lowering phosphate levels is a key treatment goal.
- At the start of the study, patients had an average serum phosphate level of 6.8 mg/dL.
- By Week 4, BBP-398 reduced average serum phosphate levels to 4.5 mg/dL, representing an average reduction of 2.3 mg/dL.
- By Week 8, average serum phosphate levels were further reduced to 4.2 mg/dL, an average reduction of 2.6 mg/dL from baseline.
- By Week 8, 75% of patients achieved the target phosphate level of less than 5.5 mg/dL.
- Additionally, 50% of patients achieved a more stringent target phosphate level of less than 4.5 mg/dL by Week 8.