ACER-801 (osanetant) for induced Vasomotor Symptoms (VMS)

ACER-801 (osanetant) is a novel, non-hormonal, neurokinin 3 receptor (NK3R) antagonist that could offer a potential treatment option with meaningful improvement of Vasomotor Symptoms (VMS) by blocking the stimulatory signaling of neurokinin B (NKB) on the KNDy neurons. NK3R is the main receptor for NKB, a tachykinin peptide primarily found in the arcuate nucleus (ARC) of the hypothalamus. In December 2018, we entered into an exclusive license agreement with Sanofi to acquire worldwide rights to ACER-801.

Hot flashes, flushing, and night sweats are known as vasomotor symptoms (VMS), and most often occur in women who are entering or in menopause. VMS are caused by low estrogen levels leading to increased stimulatory signaling of neurokinin B (NKB) on the KNDy neuron in the hypothalamus. The lack of estrogen alters neurotransmitter activity, especially in the serotonergic and noradrenergic pathways.

VMS can also be induced (iVMS) by anti-androgen and anti-estrogen cancer therapies and surgical procedures that can lead to treatment non-compliance.^1,2 VMS are caused by low estrogen levels leading to increased stimulatory signaling of NKB on the KNDy neurons in the hypothalamus. A non-hormonal treatment to manage iVMS is needed as estrogen is contraindicated for the management of VMS in patients with hormone-positive tumors, including breast and prostate tumors.

Rationale for ACER-801 Treatment for VMS
NKB/NK3R is implicated in a variety of human functions and affects the hypothalamus-pituitary-gonadal axis, which plays a critical part in the development and regulation of a number of the body’s systems, such as the reproductive and immune systems. Clinical proof of concept studies with other NK3R antagonists have demonstrated rapid and clinically meaningful improvement in vasomotor symptoms and polycystic ovarian syndrome.

ACER-801 was originally developed by Sanofi as osanetant (SR142801) for the treatment of symptoms associated with schizophrenia. Development was discontinued in 2005. Direct human safety evidence is available from 23 completed Phase 1 and 2 studies in which approximately 387 healthy subjects and 821 patients were treated with osanetant for schizophrenia, depression, and other indications. Data from these studies indicated no major safety concerns after single-dose and repeat-dose administration.³ ACER-801 is orally bioavailable⁴ and readily crosses the blood-brain barrier⁵. We believe that several disorders involving the hypothalamus-pituitary-gonadal axis could benefit from treatment with an NK3R antagonist.

ACER-801 Registration Plan (VMS)
In March 2022, we announced the enrollment of the first patient in our Phase 2a randomized, double-blind, placebo-controlled, dose-ranging trial evaluating the efficacy, safety, and pharmacokinetics (PK) of ACER-801 at different doses, compared to placebo, for the treatment of moderate to severe VMS associated with menopause.

The trial enrolled forty-nine postmenopausal women aged 40-65 who experienced moderate to severe hot flashes, were randomized 1:1:1:1, and received either twice daily 50 mg, 100 mg, 200 mg of ACER-801 or placebo over a 14-day treatment period, followed by a 14-day safety follow-up assessment. Primary endpoints were safety and pharmacokinetics, with efficacy compared to placebo as a secondary endpoint. In March 2023, we announced that topline results from the Phase 2a proof of concept clinical trial to evaluate ACER-801 (osanetant) as a potential treatment for moderate to severe Vasomotor Symptoms (VMS) associated with menopause showed that ACER-801 was safe and well-tolerated but did not achieve statistical significance when evaluating ACER-801’s ability to decrease the frequency or severity of hot flashes in postmenopausal women. As a result, we are pausing the ACER-801 program until we have conducted a thorough review of the full data set. More information can be found in the press release issued on March 17, 2023.

ACER-801 is an investigational drug in the U.S. and is not currently FDA approved for any indication. There is no guarantee that this product candidate will receive regulatory authority approval in any territory or become commercially available for any indications.