Birinapant

Summary

Birinapant (TL32711) is a bivalent peptidomimetic SMAC mimetic that antagonizes inhibitor of apoptosis proteins (IAPs). It is being investigated as an intravenous anticancer agent for solid tumours, including ovarian, head‑and‑neck, and various refractory malignancies. The drug is not approved for any indication and remains in early‑phase clinical research.

Mechanism of Action

Birinapant binds to cellular IAPs such as cIAP1 and XIAP, promoting their auto‑ubiquitination and proteasomal degradation. Loss of IAPs releases caspases from inhibition, allowing activation of the intrinsic and extrinsic apoptosis pathways. In tumour cells that produce TNF‑α, IAP loss also amplifies death‑receptor signaling, sensitising cells to cytotoxic agents and radiation.

What the Research Shows

Phase I testing in 50 patients with refractory solid tumours or lymphoma identified a maximum tolerated dose of 47 mg/m² weekly (3 weeks of 4) and a half‑life of 30–35 h. The trial reported target suppression (cIAP1 loss, increased caspase activity) and disease stabilisation in a few cases (non‑small‑cell lung, colorectal, liposarcoma). A phase II study in 11 women with platinum‑resistant ovarian cancer showed consistent down‑regulation of cIAP1 and procaspase‑3 but no objective responses, leading to early termination. Review articles note promising pre‑clinical synergy with chemotherapy, radiation, and immune activation, especially in head‑and‑neck cancer, but emphasize the need for combination strategies and larger trials.

Reported Benefits

Evidence from early trials indicates that birinapant reliably suppresses IAP targets in tumours and peripheral blood cells, and it is generally well tolerated. A subset of patients achieved prolonged stable disease, suggesting potential antitumour activity when used alone or with other therapies. Pre‑clinical models further demonstrate enhanced cell death and immunogenic effects when combined with standard treatments.

Limitations of the Evidence

Monotherapy activity has been modest; the phase II ovarian study showed no objective responses, and overall response rates remain low. Sample sizes have been small, and long‑term efficacy data are lacking. Biomarkers predictive of response are not yet validated, and optimal combination partners are still under investigation.

Safety Considerations

Birinapant has been described as well tolerated in early trials. Common adverse events were grade 2 toxicities; dose‑limiting toxicities at higher doses included headache, nausea, vomiting, and grade 3 lymphopenia. Two cases of grade 2 Bell’s palsy were reported at the highest dose level. No unexpected severe organ toxicities have been observed to date.

How It Is Administered

The drug is administered intravenously. Phase‑I dosing ranged from 0.18 to 63 mg/m² once weekly for three weeks of a four‑week cycle; the recommended phase‑II dose is 47 mg/m² on days 1, 8, and 15 of a 28‑day cycle. The formulation is a sterile solution for infusion.

Routes of Administration

Goals & Uses

• Solid tumor oncologyOncologyModerate
• Solid tumor treatmentOncologyLow
• Sensitization to chemotherapyCombination Oncology TherapyModerate
• Hematologic malignanciesOncologyModerate
• Apoptosis induction in cancer cellsOncologyModerate
• Treatment of myelodysplastic syndromes (MDS)OncologyModerate
• Treatment of acute myeloid leukemia (AML)Hematologic MalignancyModerate

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Active uncontrolled infectionInfectious DiseaseModerate
• Known hypersensitivity to birinapant or its componentsAllergyHigh

Adverse Effects

• ThrombocytopeniaHematologicUncommonLow platelet count
• Facial palsy (Bell's palsy / cranial nerve VII palsy)NeurologicalUncommon
• Nausea and vomitingGastrointestinalCommon
• NeutropeniaHematologicUncommonLow neutrophil count
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• Increased liver enzymes (transaminitis)HepaticUncommon
• Infusion-related reactionsHypersensitivityUncommon

Drug Interactions

• CYP3A4 inhibitorsModerate
• TNF-alpha-inducing agentsModerate
• CYP3A4 inhibitors/inducersLow
• 5-Azacitidine (Azacitidine)Low

Population Constraints

• PregnancyReproductive SafetyAbsolute
• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Pregnant womenReproductiveRelative
• Patients with pre-existing cranial nerve disordersNeurologicalRelative
• PediatricsAgeRelative

Regulatory Status

• European UnionInvestigationalClinical trial authorization in multiple member states.
• United StatesInvestigationalIND for oncology trials.
• United KingdomInvestigationalNot approved by MHRA; available only within clinical trial settings.

Not approved by FDA, EMA, or MHRA; currently holds investigational new drug (IND) status in the United States and equivalent clinical trial authorizations in the EU.

Evidence & Sources

• Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer
  Journal ArticleModerateNoonan AM, et al.2016-01-01T00:00:00.000000Z
• Therapeutic Inducers of Apoptosis in Ovarian Cancer
  Journal ArticleModerateBinju M, et al.2019-01-01T00:00:00.000000Z
• The IAP Protein Family, SMAC Mimetics and Cancer Treatment
  Journal ArticleModeratePhilchenkov A, Miura K2016-01-01T00:00:00.000000Z
• Promises and Challenges of Smac Mimetics as Cancer Therapeutics
  Journal ArticleModerateFulda S2015-01-01T00:00:00.000000Z
• The expanding role of IAP antagonists for the treatment of head and neck cancer
  Journal ArticleModerateKansal V, et al.2023-01-01T00:00:00.000000Z
• A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma
  Journal ArticleModerateAmaravadi RK, et al.2015-01-01T00:00:00.000000Z

Frequently Asked Questions