Aadi Bioscience Breakthrough Therapy nab-Sirolimus (ABI-009) Preliminary Data Released from the AMPECT Registration Trial in Advanced PEComa

Highlights:

• 42% investigator-assessed ORR achieved in patients with advanced PEComa – a rare sarcoma with no currently approved therapy
• First prospective clinical study in advanced PEComa shows durable responses with nab-sirolimus with a manageable safety profile
• 62% of all responding patients continue to remain on therapy
• American Society Clinical Oncology (ASCO) Oral Presentation highlighted efficacy, safety and mutational analysis data from pivotal AMPECT study
• US FDA New Drug Application expected to be submitted late 2019 or early 2020
• nab-Sirolimus leverages proven nanoparticle albumin-bound (nab) technology

PACIFIC PALISADES, Calif., June 3, 2019 /PRNewswire/ -- Aadi Bioscience, Inc (Aadi), a privately held clinical stage biopharmaceutical company, today released preliminary data on the ongoing nab-sirolimus (ABI-009) registration trial (AMPECT) for Advanced (metastatic or locally advanced) Malignant PEComa (perivascular epithelioid cell tumor) - a rare form of sarcoma for which there is no currently approved therapy.

Nanoparticle albumin-bound sirolimus (nab-Sirolimus), an mTOR inhibitor, received Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) in Dec 2018, "for the treatment of patients with advanced (metastatic or locally advanced) malignant perivascular epithelioid cell tumor (PEComa)."

The AMPECT trial was conducted at 9 U.S. sites and enrolled 34 adult patients, with 31 confirmed as PEComa by a central pathology laboratory.  PEComa origin sites in these patients included the uterus, pelvis, retroperitoneum, lung, kidney, liver, brain, muscle, ovary, aorta and small bowel.

These data, demonstrating a 42 percent confirmed investigator-assessed objective response rate (ORR) across advanced PEComas originating in various tissues, were released in an oral presentation at the American Society of Clinical Oncology (ASCO) 2019 annual meeting in Chicago (abstract 11005). AMPECT Principal Investigator Andrew Wagner, M.D., Ph.D., from the Dana Farber Cancer Institute, said nab-sirolimus had delivered consistent and durable responses in advanced PEComa patients.  "These responses were achieved with a manageable safety profile," Dr. Wagner said. "We saw a majority of the responding patients achieving a response by their first assessment at 6 weeks following initiation of therapy. Cytotoxic chemotherapies and other drugs approved for treatment of advanced sarcomas show only marginal benefit in PEComas. Activation of the mTOR pathway is common in PEComa and case reports have shown activity of mTOR inhibitors ^[1].  We are encouraged by the outcomes in this first-ever prospective clinical trial in advanced PEComa."

"The Aadi Bioscience team is proud to have contributed to this important study presented at ASCO," said Neil Desai, Ph.D., Chief Executive Officer of Aadi Bioscience. "We are grateful to the patients, families, and clinical trial teams who help push the boundaries of available care through their participation in clinical trials. These results are an important milestone in the ongoing development of nab-sirolimus across a wide range of diseases and therapeutic indications that are driven by mTOR activation and for which there is a need for new therapies."  Dr. Desai added: "Results from the AMPECT study will serve as the basis for the ABI-009 New Drug Application (NDA) for nab-sirolimus, which the company expects to submit to the FDA in late 2019 or early 2020. The primary analysis for the NDA will rely upon central, independent radiology review, which will be performed in the second half of 2019. The company plans to release these data at a scientific meeting, which will also include additional patient follow-up, before the end of 2019."

Key Data Presented at ASCO

The primary efficacy outcome measure for the analysis presented at ASCO is investigator-assessed objective response rate (ORR) as measured by RECIST v 1.1. Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), PFS rate at 6 months (PFS6) and safety. The data presented at ASCO employed a May 10, 2019 data cut-off, summarized below, was based on response assessments as performed by each respective clinical trial site (local, investigator-assessed radiology). A separate response assessment performed by independent radiologists, not yet completed, will be required to support global regulatory filings.

Consistent with agreements with the FDA, advanced PEComa patients enrolled in the Phase 2 trial (AMPECT) contributed to the efficacy analysis. The data presented are based on 34 patients evaluable for safety and 31 patients evaluable for efficacy per defined criteria in the protocol. 

Sixty-two percent of patients (8/13) with responses are continuing on treatment which include 3 patients on therapy for more than 1 year and 3 patients on therapy for more than 2 years.  Median DOR has not been reached; median time to response is 1.4 months (95% CI: 1.3, 2.7).  Median PFS is 8.4 months (95% CI: 5.5, --), PFS rate at 3 months (PFS3) is 80% (95% CI: 60%, 90%), PFS6 is 61% (95% CI: 41%, 76%), and 32 percent of all patients enrolled remain on treatment.

For reference, per a meta-analysis of 10 years of phase 2 trials in advanced soft tissue sarcomas (STS) published by the EORTC STS and Bone Sarcoma Group ^[2], the  PFS3 and PFS6  are widely accepted as a meaningful measure of activity of drugs in STS and may be utilized to determine acceptable criteria of benefit. Drugs yielding a PFS rate of ≥40% at 3 months and ≥14% at 6 months are considered to be 'potentially active' in advanced STS ^[2].

A protocol prespecified exploratory mutational and biomarker analysis was available for 25 patients on the AMPECT trial.  Mutational status of the suspect genes TSC1 or TSC2 in the mTOR pathway were analyzed for association with patient response outcomes. Mutation or deletion of TSC1 or TSC2 (no overlap) occurred in 5 (20%) and 9 (36%) patients respectively, while 11 (44%) patients had no alterations in TSC1 or TSC2. Responses occurred in 9/9 (100%) patients with TSC2 mutations, 1/5 (20%) patients with TSC1 mutations and 1/11 (9%) of patients with no mutations in TSC1 or TSC2. 

The safety data presented at ASCO was available for all 34 patients treated on the AMPECT trial. The most common treatment-related hematologic adverse events of any grades included anemia (47%) and thrombocytopenia (32%) and the most common nonhematologic treatment-related adverse events of any grades included mucositis (74%), rash (65%), fatigue (59%), nausea (47%), and diarrhea (38%). Most of these events were grade 1 and 2, were manageable with dose modifications and no grade 4 events were observed. Twelve patients (35%) required dose reductions due to adverse events. Two patients (6%) discontinued nab-sirolimus due to an adverse event.

The AMPECT Phase 2 registration trial for Advanced Malignant Perivascular Epithelioid Cell Tumors completed enrollment in late 2018.  Aadi previously received agreement from the FDA that this open label study in approximately 30 efficacy evaluable patients with a primary endpoint of independently reviewed objective response rate could support the submission of an NDA for approval to treat this rare disease.    

About Aadi Bioscience and nab-sirolimus (ABI-009)

Aadi is a clinical stage biopharmaceutical company led by Dr. Neil Desai, an inventor of ABRAXANE  and the albumin-based technology platform.  Aadi's lead product nab-sirolimus (sirolimus albumin-bound nanoparticles for injectable suspension, ABI-009) is an mTOR inhibitor complexed with human albumin that has significantly higher tumor accumulation, mTOR target suppression and improved efficacy over other mTOR inhibitors in preclinical models. mTOR as a therapeutic target is well recognized in oncology, however Aadi aims to develop the full potential of albumin-bound sirolimus in therapeutic areas and diseases that are driven by mTOR activation and where the mTOR inhibitors have not or cannot be effectively exploited due to problems of pharmacology, effective drug delivery, safety or effective targeting to the disease site. These indications include oncology, cardiovascular, CNS, mitochondrial disease and diseases of ageing. Aadi's ongoing and planned clinical trials include Oncology (first-line treatment of advanced  colorectal cancer with respect to PTEN status, pediatric tumors, advanced sarcoma, newly diagnosed and recurrent glioblastoma, advanced neuroendocrine tumors), Cardiovascular indications (pulmonary arterial hypertension), CNS indications (surgically refractory epilepsy) and Mitochondrial disease (Leigh Syndrome).

About PEComa

Perivascular epithelioid-cell tumors (PEComa), defined by the World Health Organization as 'mesenchymal tumors composed of distinctive cells that show a focal association with blood-vessel walls and usually express both melanocytic and smooth muscle markers,' are a rare subset of soft-tissue sarcomas, with an undefined cell of origin. Malignant PEComas may arise in almost any body site (typically the uterus, retroperitoneum, lung, kidney, liver, genitourinary, and gastrointestinal tract) and can have an aggressive clinical course including distant metastases and ultimate death. Cytotoxic chemotherapies typically used for sarcoma show minimal benefit and there are currently no drugs approved for this disease. Malignant PEComas have been shown to frequently harbor mutations in the TSC1 and/or TSC2 genes that result in the activation of mTORC1 pathway. Therefore, mTORC1 signaling is a promising therapeutic target for malignant PEComa.

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Aadi Contact:
Nancy Jorgesen
Email: [email protected]
website: www.aadibio.com

References:

[1] Wagner et al. 2010. J Clin Oncol 28(5): 835-840
[2] Penel et al. 2011. Ann Oncol 22(6): 1266-1272

The AMPECT study was funded in part by a grant from the FDA Office of Orphan Products Development (OOPD).

ABRAXANE is a registered trademark of Celgene Corporation

SOURCE Aadi Bioscience, Inc