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

Highlights:

• Trial meets its Primary Endpoint with 39% ORR (95%CI 22%-58%) in patients with advanced PEComa – a rare sarcoma with no currently approved therapy
• First prospective clinical study in advanced PEComa shows durable ongoing responses with half the responders having ongoing response duration of 15.3 months or longer
• Manageable safety profile with no new or unexpected toxicities
• Connective Tissue Oncology Society (CTOS) Oral and Poster Presentations highlight efficacy, safety, and mutational analysis data from pivotal AMPECT study
• 67% of all responding patients continue to remain on therapy
• 90% of patients achieve a PR or SD
• Exploratory mutational analysis shows an 89% confirmed response rate in TSC2 mutated tumors
• US FDA New Drug Application expected to be submitted in the first-half of 2020
• nab-Sirolimus leverages proven nanoparticle albumin-bound (nab) technology

November, 14 2019, Aadi Bioscience, Inc. (Aadi), 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.

Results of the primary analysis were released in an oral presentation (abstract 3206452) at the CTOS 2019 annual meeting in Tokyo, Japan, demonstrating a 39% confirmed independent radiology reviewed objective response rate (ORR) in patients with advanced PEComas originating in various tissues. Responses were rapid and durable with half the responders having an ongoing response duration of 15.3 months or longer and the majority of responders (67%) are still on treatment. AMPECT Investigator and lead author on the oral presentation, Mark Dickson, M.D., from Memorial Sloan Kettering Cancer Center, said “nab-sirolimus delivered highly durable responses in advanced PEComa patients. Most of the responding patients achieved a response by their first assessment at 6 weeks following initiation of therapy and these patients have stayed on therapy for extended periods with a manageable safety profile. We are encouraged by the outcomes in this first-ever prospective clinical trial in advanced PEComa.” A second presentation by the principal investigator of the AMPECT trial, Dr Andrew Wagner M.D., Ph.D., from the Dana-Farber Cancer Institute, highlighted the exploratory mutational analysis from the study (abstract 3258096). “Patients having mutations in the TSC2 gene were found to have an 89% confirmed response rate to nab-sirolimus, while patients with TSC1 mutations or no mutations in the TSC1 or TSC2 genes had lower response rates. This is the first prospective study of outcomes vs mutational status of mTOR pathway genes and highlights the relevance of TSC2 mutations in advanced PEComa,” Dr. Wagner said.

Neil Desai, Ph.D., Chief Executive Officer of Aadi Bioscience, said “The Aadi Bioscience team is grateful to the patients, families, and clinical trial teams who help expand 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 New Drug Application (NDA) for nab-sirolimus, which the company expects to submit to the FDA in the first half of 2020.”

Key Data Presented at CTOS

The primary endpoint for the AMPECT study presented at CTOS is independent central radiology reviewed ORR, assessed 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 CTOS represent a May 22, 2019 data cut-off for the primary analysis, with an additional 5.5 months of follow-up (Nov 6, 2019) for the duration of response endpoint.

The data presented are based on 34 patients evaluable for safety and 31 patients evaluable for efficacy per defined criteria in the protocol.

Ninety percent of patients had a best response PR or SD, with disease control (defined as a confirmed response + SD ?12 weeks) achieved in 71% of patients.

As of Nov 6, 2019, 75% (9/12) of responders had been on therapy for more than 1 year and 42% (5/12) for more than 2 years, with 67% (8/12) still on treatment. Median DOR has not been reached (range [5.6 –33.2+ months]) and 50% of the responders have a response duration that is 15.3 months or longer; the median time to response was 1.4 months (95% CI: 1.3, 2.7).

Median PFS is 8.9 months (95% CI: 5.5, –), PFS rate at 3 months (PFS3) is 79%, PFS6 is 70%, and 26% (9/34) 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 [1].

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%, 8 confirmed responses [89%], 1 unconfirmed response [11%]) 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 CTOS 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 (79%), rash (56%), 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. There were no new or unexpected toxicities not previously known for mTOR inhibitor class.

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 at least 30 efficacy evaluable patients with a primary endpoint of independently reviewed ORR, could support the submission of an NDA for approval to treat this rare disease assuming a 30% response rate was observed and the lower bound of the 95% confidence interval of the ORR exceeded 14.7%. These data have not been reviewed by any regulatory agencies.

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.