Full Press Release Details
We are a clinical-stage
biopharmaceutical company focused on developing therapeutics that treat serious illnesses driven by inflammatory and immunologic processes and direct cellular damage. Our product candidates act upon calcium release-activated calcium
( CRAC ) channels, and would constitute a new class of drugs.
We are a company focused on the discovery and development of CRAC channel
inhibitors. Clinical and preclinical data have demonstrated that the inhibition of CRAC channels may have a therapeutic effect based on a dual mechanism involving both anti-inflammatory and tissue cell protective activities. Our work has shown
compelling evidence of the involvement of CRAC channels in a broad spectrum of both acute critical illnesses and chronic diseases that have the common thread of inflammation or immunologic activity in their pathogenesis. We intend to leverage our
CRAC channel inhibitor platform to develop therapeutics for indications where this dual mechanism of action has the potential for clinical benefit. .
lead product candidate is Auxora, a potent and selective intravenous ( IV ) formulated small molecule CRAC channel inhibitor containing the active compound zegocractin (formerly referred to as CM4620) that, in animal models, reduced
acute epithelial and/or endothelial cell injury and inflammation in organs, such as the pancreas, lungs and kidneys. Multiple Phase 2 clinical trials with Auxora have been conducted: an open-label trial in acute pancreatitis ( AP ),
an investigator led open label trial in asparaginase induced pancreatic toxicity ( AIPT )(which we also refer to as CRSPA ) in which the first cohort of patients has been completed, a placebo-controlled
double-blind trial in severe COVID-19 pneumonia (which we also refer to as CARDEA ) and an investigator led open-label trial in COVID-19 pneumonia
patients with acute respiratory distress syndrome ( ARDS ). We observed in all of these trials that patients treated with Auxora experienced a reduced time to recovery and a reduction of organ damage. We believe the consistency of
the results we observed from these trials in two different acute critical care conditions are mutually supportive and reinforce our plans to further pursue the use of Auxora in several additional acute critical illnesses.
In a Phase 2a trial conducted in the United States in patients with AP and accompanying systemic inflammatory response syndrome ( SIRS )
along with hypoxemia (low concentration of oxygen in blood), a greater proportion of patients treated with Auxora compared to standard of care ( SOC ) alone experienced resolution of persistent SIRS (SIRS lasting 48 hours or more)
and tolerated solid food at 72 hours, an indicator of disease resolution. The majority of patients with respiratory failure treated with Auxora did not require mechanical ventilation. This resulted in hospital discharge for patients treated with
Auxora more than two days earlier than those treated with SOC alone. These findings were published in the peer-reviewed journal Pancreas in 2021. We are currently conducting a blinded placebo-controlled Phase 2b trial in the United States in
patients with AP and accompanying SIRS (which we also refer to as CARPO ). We anticipate topline results from the CARPO trial in the first half of 2024.
CRSPA, a Phase 1/2 single arm trial, is currently being conducted in the United States in pediatric patients with acute lymphoblastic leukemia
( ALL ) who have developed pancreatitis as a side-effect of asparaginase or AIPT. AIPT is a particularly severe form of pancreatitis and historical data suggests that over half of the patients will develop pancreatic necrosis or
pseudocysts and may not receive further asparaginase treatments for their ALL, potentially impacting their prognosis, and develop long term health complications including chronic pancreatitis. The first cohort of nine patients in this trial has been
completed, and, based on preliminary, unpublished data, all patients who have received a full course of therapy have had a more rapid resolution of their symptoms as compared to the current standard of care. According to clinical data published by
Mauney, et. al., in the Journal of Pediatric Gastroenterology and Nutrition in March 2022, patients who developed AIPT have a median length of stay in the hospital of 10 days, whereas the median length of stay for patients treated with Auxora was
less than six days consistent with their resolution of symptoms. This is a single arm open-label trial and comparison to a blinded matched historical control group is underway. We expect data from this trial to be published in the fourth quarter of
2023. While initially a single-center trial, this trial is now being expanded to additional sites.
In addition to AP and AIPT, we are preparing for
clinical trials in additional inflammatory diseases such as acute kidney injury ( AKI ). We recently completed a study in a rat model of AKI, which demonstrated that Auxora compared to placebo increased glomerular filtration rate
and decreased infiltrates of mononuclear cells in the kidneys of rats treated after receiving an ischemic injury. These data, along with observations in our Phase 2 trials in both AP and COVID-19 suggesting
Auxora provides kidney protection in acutely ill patients, support that AKI may be a promising indication for Auxora. We plan to submit an investigational new drug ( IND ) application in the second half of 2023 and, if allowed, be
in a position to initiate a Phase 2 clinical trial in this indication in the first half of 2024, subject to receipt of additional funding.
trial, a Phase 2 randomized double-blind, placebo-controlled trial in patients with severe COVID-19 pneumonia and receiving supplemental oxygen, but not on mechanical ventilation, we observed that patients
treated with Auxora experienced a reduced time to recovery and a 56% relative reduction in mortality at 30 days (p=0.0165) and a 33% relative reduction in mortality at 60 days (p=0.1449) compared to placebo. Time to recovery was seven days for
Auxora-treated patients compared to ten days for patients receiving placebo (p=0.098). For additional information regarding p-values, please refer to the section entitled Auxora, a Selective
CRAC Channel Inhibitor P-Values and Confidence Intervals. The results from CARDEA were published in Critical Care in 2022. The CARDEA data, along with data from an ongoing Phase 2 trial
testing Auxora in COVID-19 patients with ARDS receiving invasive mechanical ventilation, may also help inform future trials in broader ARDS and acute hypoxemic respiratory failure ( AHRF )
patient populations.
Finally, we have compiled additional preclinical data supporting the potential to use CRAC channel inhibition for both chronic and
acute inflammatory and immunologic diseases. We have available product candidates in IND-enabling preclinical testing that present different organ bioavailabilities and potential oral dosing. Our first chronic
indication may be chronic pancreatitis as preclinical data in a mouse model of chronic pancreatitis suggest that CRAC channel inhibition can reduce pancreatic fibrosis and restore ductal cell function. We have published data suggesting CRAC channel
inhibition may be useful in treating ulcerative colitis, allergic asthma, and traumatic brain injury.
Calcium is an important regulator of multiple
biological functions, and in electrically non-excitable cells CRAC channel activation plays a critical role in the activation of calcium-dependent pathways that modulate various responses, including
inflammation and vascular permeability. In immune cells, activation of CRAC channels is a key step in initiating the adaptive immune response and the generation of inflammatory cytokines. In addition, in certain acute critical illnesses, CRAC
channels on affected organ tissue cells can become overactivated, resulting in excess calcium entry into cells. This excess calcium can cause cellular injury and necrosis, or activate apoptosis signaling pathways leading to programmed cell death
further exacerbating the damage caused by inflammatory response. We have developed novel cell-based assays for compound screening that enabled us to identify and optimize a portfolio of potent and selective small molecule CRAC channel inhibitors,
including zegocractin (previously referred to as CM4620 ) which is the active ingredient in Auxora, from several different chemical classes. These compounds each have different pharmaceutic and pharmacokinetic properties and comprise our
portfolio of CRAC channel inhibitors.
We are currently developing our lead compound Auxora in several acute critical illnesses. We have a Phase 2b trial ongoing in AP and an investigator led Phase
1/2 trial ongoing in AIPT. We also completed the treatment portion of an Phase 2 biomarker trial in COVID-19 ARDS, which may inform the design of a Phase 2 clinical trial for the treatment of AHRF and/or ARDS
with multiple etiologies. In addition, we are in preclinical development with Auxora in AKI and plan to submit an IND application in the second half of 2023, and, if allowed, be in the position to initiate a Phase 2 clinical trial in this indication
in the first half of 2024, subject to receipt of additional funding.
Our product candidates are summarized in the table below:
Clinical Experience with Auxora
Our clinical experience with Auxora is summarized in the table below:
We have studied Auxora in a number of clinical trials including multiple Phase 2 clinical trials conducted in the United
States, two of which have been in our lead indication, AP. We have published results from an open-label standard of care ( SOC ) controlled Phase 2a trial in AP, and we expect results from treating the first cohort of patients in
CRSPA to be published in the fourth quarter of 2023. We have also published results from CARDEA and the 30-patient open-label part one portion of this same trial. With our investigator, we expect to publish
data from an open-label randomized placebo-controlled Phase 2 biomarker trial conducted in the United States in critical COVID-19 pneumonia patients with ARDS in which we have completed enrollment and
treatment of patients in 2022 and are now completing the biomarker analysis with samples taken from these patients. We observed in all of these trials that patients treated with Auxora experienced a reduced time to recovery and a reduction of organ
damage. In CARDEA, we observed a numerical improvement of 56% relative risk reduction in mortality at 30 days. We believe the consistency of the results we observed from these trials in multiple acute critical care conditions affecting different
primary organs are mutually supportive and reinforce our plans to further pursue the use of Auxora in several additional acute critical illnesses.
Auxora for the Treatment of AP
Auxora for the Treatment of AIPT: Pancreatitis as a Side Effect of Treatment for Pediatric ALL
Auxora for the Treatment of Acute Kidney Injury
Auxora for the Treatment of Acute Respiratory Failure
Potential Additional
We are a company focused on the discovery and development of CRAC channel inhibitors. We intend to develop therapeutics to treat acute critical illnesses and
chronic inflammatory and immunologic diseases including AP, AKI, ARDS or ARHF, and chronic pancreatitis. Our strategy to achieve this as follows:
Our executive team is led by A. Rachel Leheny,
Ph.D., our chief executive officer, who has more than 30 years of experience in the life sciences industry as a scientist, venture capital investor and investment banking research analyst. Kenneth Stauderman, Ph.D., a
co-founder and our chief scientific officer with more than 30 years of experience in drug discovery and development, is a leading expert in CRAC channels and led the discovery of some of the foundational work
in this field. Sudarshan Hebbar, M.D., our chief medical officer, has more than 15 years of clinical development and product development experience and was previously a practicing nephrologist and critical care physician. Raven Jaeger, MS, our chief
regulatory officer, who has over 20 years of regulatory affairs experience with several marketing approvals in serious diseases with high-unmet medical need.
Essential Roles of Calcium Signaling
Calcium serves as an essential messenger for intracellular signals and plays diverse and important roles in biological systems. The major
storehouse for calcium in a cell is a compartment called the endoplasmic reticulum ( ER ). Calcium is found there at average concentrations that are 1,000 to 5,000-fold higher than in a
cell s interior or cytoplasm. When an outside signal stimulates a cell in a particular way, the stored calcium is rapidly and periodically released from the ER into the cell interior, resulting in activation of a number of key cellular
processes affecting synthesis and release of other signaling molecules, cell growth, differentiation and division. These processes include, for example, gene transcription and protein kinase signaling. In response to sufficient external stress on
the cell, release of calcium from these intracellular stores can trigger cell death.
A specific set of calcium-transporting ion channels known as CRAC channels are responsible, among other things, for replenishing the calcium stores in the ER.
The two principal proteins that comprise CRAC channels are the ER calcium-sensing protein Stomal Interaction Molecule 1 ( STIM1 ) and the cellular membrane calcium channel protein Orai1. When cells are stimulated in particular
physiological ways, intracellular messengers are generated that cause the periodic release of calcium from the ER. The release of calcium from the ER is then sensed by STIM1, which unfolds and activates, or opens, the Orai1 calcium channel
triggering an influx of calcium into the cell. In certain pathological conditions, however, CRAC channels can be activated in non-physiological ways, such as by a toxin that can cause excessive release of
calcium from the ER, leading to overactivation of CRAC channels.
Depending upon the extent of activation and the cell or tissue involved, calcium influx
through CRAC channels can regulate calcium-dependent inflammatory pathways or can activate cell injury pathways. For example, in immune cells like T lymphocytes, activation of CRAC channels plays a key role in initiating the adaptive immune response
and the generation of inflammatory cytokines. In certain acute critical illnesses such as AP, CRAC channels on affected organ tissue cells can become overactivated, resulting in excess calcium entry that is toxic to cells, causing cellular injury or
death that can exacerbate an accompanying inflammatory response.
CRAC channels serve to replenish calcium levels in the ER and to provide calcium for cellular signaling events.
There is strong evidence linking STIM1 and Orai1 to the way the cell replenishes its calcium stores and to the physiological consequences of disrupting these
proteins from both in vitro and in vivo models, including animal gene knock-out or knock-in models, and human genetics. This linkage is true at both the
cellular and phenotypic levels. At the cellular level, manipulating STIM1 or Orai1 activity by genetic inactivation or enhancement has been shown to impact calcium transport. Inactivating STIM1 or Orai1 was shown to decrease calcium entry into
cells, whereas creating mutations in STIM1 or Orai1 that enhance their activity was shown to increase calcium influx. At the phenotypic level, people with homozygous genetic deficiencies in the genes encoding Orai1 or STIM1 develop the
life-threatening condition of severe combined immunodeficiency. Because these individuals lack the ability to mount an effective immune response, they suffer from an extreme risk of contracting life-threatening infections. People with a heterozygous
genotype for the mutated genes encoding Orai1 or STIM1 do not have any notable conditions resulting from or associated with these genetic deficiencies despite a partial reduction in the functional activity of the Orai1 or STIM1 proteins.
In lymphocytes, CRAC channels are critically responsible for controlling the entry of calcium that subsequently initiates calcium-dependent events. Within
minutes of activating CRAC channels, alterations in intracellular calcium levels result in both (a) the inhibition of lymphocyte migration and (b) the activation of immune cell activity. Both of these elements of CRAC channel biology are
central to identifying potential therapies. Effects of prolonged calcium signaling supported by both calcium release from the ER and CRAC channel-mediated calcium entry include stimulation of cell proliferation; expression of immune-activated genes;
production of cytokines and chemokines; and lymphocyte differentiation. These longer-duration effects, too, are central to the backdrop for therapeutic intervention. For example, genes triggered by calcium release and subsequent calcium entry
through CRAC channels include many activators of inflammation. This mechanism involves various signaling proteins, including two in particular, calcineurin and a transcription factor called nuclear factor of activated T cells