Cassava Sciences Profile
Cassava Sciences, Inc. operates as a clinical-stage biotechnology company. The company is in the business of new drug discovery and development.
The company's lead therapeutic drug candidate, simufilam, is under clinical evaluation for the proposed treatment of Alzheimer's disease dementia in Phase 3 clinical studies.
The company's strategy is to leverage its unique scientific/clinical platform to develop a first-in-class program for treating neurodegenerative diseases, such as Alzheimer's-a degenerative disease of the brain, where a patient's cognition and health functions decline over time as the disease progresses and the patient moves from mild to moderate to, eventually, severe Alzheimer's disease.
The company has two biopharmaceutical assets under development: the company's lead therapeutic product candidate, called simufilam, is a novel oral treatment for Alzheimer's disease dementia; and the company's lead investigational diagnostic product candidate, called SavaDx, is a novel way to detect the presence of Alzheimer's disease from a small sample of blood.
The company's lead product candidate, simufilam, is a proprietary small molecule drug. Simufilam was discovered and designed in-house and was characterized by the company's academic collaborators during research activities that were conducted from approximately 2008 as of December 31, 2023.
Simufilam targets an altered form of a protein called filamin A (FLNA) in the Alzheimer's brain. Published studies have demonstrated that the altered form of FLNA causes neuronal dysfunction, neuronal degeneration and neuroinflammation. Specifically, simufilam disrupts amyloid binding to the ?7 nicotinic acetylcholine receptor (?7nAChR), which underlies the company's drug's primary mechanism of action in Alzheimer's disease. More recent data also suggest a meaningful impact of simufilam on mTOR signaling. Because mTOR contributes to age-related cellular changes, simufilam's suppression of mTOR overactivation, concurrent with improved insulin sensitivity, may slow certain aging processes and attenuate this pathological feature, potentially benefiting brain function and memory in Alzheimer's disease and in aging.
The company owns exclusive, worldwide rights to the company's drug and diagnostic assets and related technologies, without royalty obligations to any third party. The company's patent protection with respect to simufilam and use of simufilam for Alzheimer's disease and other neurodegenerative diseases runs through 2039 and includes nine issued U.S. patents. Corresponding foreign filings have been made for each of the U.S. filings.
The company is conducting two randomized placebo-controlled Phase 3 clinical trials of oral simufilam in patients with Alzheimer's disease dementia. Both trials are fully enrolled. The trials have randomized a total of approximately 1,900 patients with mild to moderate Alzheimer's disease at baseline. All efficacy data from the company's Phase 3 program remain blinded. There are no interim analyses on efficacy outcomes.
The company's first Phase 3 study, called RETHINK-ALZ, is designed to evaluate the safety and efficacy of simufilam 100 mg tablets versus placebo over 52 weeks (NCT04994483). Top-line results of the company's 52-week Phase 3 study are anticipated approximately year-end 2024.
The company's second Phase 3 study, called REFOCUS-ALZ, is designed to evaluate the safety and efficacy of oral simufilam 100 mg and 50 mg tablets versus placebo over 76 weeks (NCT05026177). Top-line results of the company's 76-week Phase 3 study are anticipated approximately mid-year 2025.
Simufilam Drug Development
IND submission to FDA, Drug Safety in Early Clinical Studies
The company conducts basic research, in vitro studies and preclinical studies in the support of a successful Investigational New Drug (IND) submission to FDA for simufilam, including requisite studies around safety pharmacology, toxicology, genotoxicity and bioanalytical methods. In 2017 the company filed an IND with FDA for simufilam.
Following FDA acceptance of the company's IND in 2017, the company investigated the safety, dosing and pharmacokinetic profile of simufilam in healthy human volunteers. The design of the company's first-in-human Phase 1 study was based on regulatory feedback, clinical and scientific rationale and observations from previously conducted preclinical and in vitro studies. In a Phase 1 study, simufilam was evaluated in 24 healthy human volunteers (18 simufilam, 6 placebo) in a single site in the U.S. for safety, tolerability and pharmacokinetics. Study subjects were administered a single oral dose of 50, 100 or 200 mg of simufilam or placebo. Drug appeared safe and well-tolerated. Importantly, simufilam showed no treatment-related adverse effects and no dose-limiting safety findings. Pharmacokinetic measurements demonstrated that simufilam, a small molecule, was rapidly absorbed. Dose-proportionality was observed over the full dose range of 50 to 200 mg.
Phase 2 Clinical Studies
In 2019, the company completed a first-in-patient, clinical-proof-of-concept, open-label Phase 2a study of simufilam in the U.S., with substantial support from the National Institute on Aging (NIA), a division of the NIH. In this small study of thirteen patients with mild-to-moderate Alzheimer's disease, treatment with simufilam for 28 days significantly improved certain exploratory biomarkers of Alzheimer's pathology, neurodegeneration and neuroinflammation (p<0.001). Drug was safe and well-tolerated. Biomarkers effects were seen in all patients in both cerebrospinal fluid (CSF) and plasma.
In September 2020, the company reported final results of a Phase 2b study with simufilam in Alzheimer's disease. In this clinical study funded by the NIH, Alzheimer's patients treated with 50 mg or 100 mg of simufilam twice-daily for 28 days showed statistically significant (p<0.05) improvements in CSF biomarkers of disease pathology, neurodegeneration and neuroinflammation, versus Alzheimer's patients who took placebo. Simufilam treatment also significantly reduced levels of plasma P-tau181 in sample testing conducted by Quanterix Corporation, a third-party vendor. In addition, Alzheimer's patients treated with simufilam showed improvements in validated tests of episodic memory and spatial working memory, versus patients on placebo. Cognitive improvements correlated most strongly with decreases in levels of P-tau181. Drug was safe and well-tolerated.
Given the absence of observable dose-limiting effects in the company's Phase 1 or Phase 2 studies, and in light of the strong scientific rationale and multiple peer-reviewed publications and research grant awards, the company determined that simufilam demonstrated favorable proof-of-principle for further evaluation as an investigational drug for the treatment of Alzheimer's disease.
24-Month Clinical Safety Study
Much of the strategic value of the company's 24 month clinical safety study is to support simufilam's long-term safety profile in patients. Clinical results may serve to help inform and manage the inherent risks and uncertainties of drug development while the company undertakes a large, expensive Phase 3 clinical testing program.
In March 2020, the company initiated a clinical safety study of simufilam, the company's lead drug candidate, in patients with Alzheimer's disease (NCT04388254). This study was funded in part by a research grant award from NIH. This study was designed to evaluate the long-term clinical safety and tolerability of simufilam in patients with Alzheimer's disease over 24 months. The study included a pre-specified exploratory efficacy endpoint of mean change in ADAS-Cog11 scores, a cognitive scale widely used in Alzheimer's clinical research. This study enrolled over 200 patients with mild-to-moderate Alzheimer's disease ((Mini-Mental State Examination (MMSE) 16-26) who were recruited from 16 U.S. clinical sites. Alzheimer's is a progressive disease, with severity of disease typically assessed by MMSE score. In this study, mild patients are MMSE 21-26, and moderate patients are MMSE 16-20.
The company conducted the 24-month safety study in three continuous phases: a 12-month, open-label treatment phase, followed by a 6-month randomized, placebo-controlled withdrawal phase (previously referred to as the 'Cognition Maintenance Study' or CMS), followed by 6 additional months of open-label treatment.
Study participants received simufilam oral tablets 100 mg twice-daily in the open-label treatment phases, and simufilam or matching placebo during the randomized withdrawal phase. In an open-label study design, both the health providers and the patients are aware of the drug treatment being given.
All study participants who completed 12 months of open-label simufilam treatment were eligible to participate in the 6-month randomized, placebo-controlled withdrawal phase. Likewise, all study participants who completed the randomized, placebo-controlled withdrawal phase were eligible for 6 additional months of open-label treatment.
Study Results for the 12-month, Open-label Treatment Phase
In January 2023, the company announced positive top-line results for the 12-month, open-label treatment phase of the safety study. The pre-specified, exploratory efficacy endpoint was change in baseline on ADAS-Cog11, a cognitive scale widely used in Alzheimer's clinical research. Other exploratory endpoints included the Mini-Mental State Examination (MMSE) to assess disease stage by cognitive impairment; the Neuropsychiatric Inventory (NPI) to assess dementia related behavior; and the Geriatric Depression Scale (GDS). Endpoints were measured at baseline (study entry) and month 12.
Study Results for the 6-month, Randomized Withdrawal Study Phase ('Cognition Maintenance Study')
In May 2021, the company initiated the randomized, withdrawal phase of the 24 month safety study, which has been previously referred to as the 'Cognition Maintenance Study' or CMS. The CMS has a randomized, withdrawal study design.
The design of randomized, withdrawal phase of the study was intended to evaluate simufilam's effects on cognition and health outcomes in Alzheimer's patients who continue with drug treatment versus patients who discontinue drug treatment. This was a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer's disease. Study patients were randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. Final enrollment was 157 patients.
Study Results for the 24-Month Safety Study
In February 2024, the company reported top-line results of the 24-month clinical safety study.
End-of-Phase 2 (EOP2) Meeting with FDA
In January 2021, the company held an End-of-phase 2 (EOP2) meeting for simufilam with the U.S. Food and Drug Administration (FDA). The purpose of this EOP2 meeting was to gain general agreement around key elements of a pivotal Phase 3 program to treat Alzheimer's disease dementia.
In February 2021, the company announced the successful completion of the company's EOP2 meeting. Official meeting minutes confirm that the company and FDA are aligned on key elements of a Phase 3 clinical program for simufilam. FDA agreed that the completed Phase 2 program, together with an ongoing and well-defined Phase 3 clinical program, are sufficient to potentially show evidence of clinical efficacy for simufilam in Alzheimer's disease. There was also agreement that the use of separate clinical scales to assess cognition (ADAS-cog1) and function (ADCS-ADL2) are appropriate endpoints of efficacy. iADRS3 is an efficacy endpoint that combines scores for ADAS-cog and ADCS-ADL, and thereby provide a single composite measure of cognition and health function. Other endpoints include the NPI4.
Special Protocol Assessments
In August 2021, the company had reached agreement with FDA under a Special Protocol Assessment (SPA) for both Phase 3 studies. These SPA agreements document that FDA has reviewed and agreed upon the key design features of the company's Phase 3 study protocols of simufilam for the treatment of patients with Alzheimer's disease.
An SPA agreement indicates concurrence by the FDA with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, etc.). These elements are critical to ensure that the company's planned Phase 3 studies of simufilam in Alzheimer's disease can potentially be considered adequate and well-controlled studies in the support of a future regulatory submission and marketing application.
The first clinical study protocol under the SPA is titled 'A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 52-Week Study Evaluating the Safety and Efficacy of One Dose of Simufilam in Subjects with Mild-to-Moderate Alzheimer's Disease.'
The second clinical study protocol under the SPA is titled 'A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 76-Week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects with Mild-to-Moderate Alzheimer's Disease.'
Phase 3 Clinical Program
The company's Phase 3 program consists of two large, double-blind, randomized, placebo-controlled studies of simufilam in patients with mild-to-moderate Alzheimer's disease dementia. Both studies are designed to measure changes in cognition and function during their treatment period.
Premier Research International is the CRO supporting the conduct of the company's Phase 3 clinical program. The company's Phase 3 clinical sites are located in the United States, Canada, Puerto Rico, Australia, and South Korea.
RETHINK-ALZ and REFOCUS-ALZ
In Fall 2021, the company announced initiation of two Phase 3 studies of simufilam in mild-to-moderate Alzheimer's disease dementia. In November 2023, the company had announced the completion of patient enrollment in both Phase 3 studies. A total of approximately 1,900 patients are randomized into these studies. Approximately 70% of randomized patients entered the company's Phase 3 studies with mild Alzheimer's disease (MMSE 20 to 27).
The first Phase 3 study, called RETHINK-ALZ, is designed to evaluate the safety and efficacy of oral simufilam 100 mg over 52 weeks (NCT04994483). Details of the RETHINK-ALZ Phase 3 study include:
Approximately 800 patients are randomized into this study.
Patients are randomized (1:1) to simufilam 100 mg tablets or matching placebo twice daily.
Patients are treated for 52 weeks.
Efficacy endpoints are ADAS-Cog12, a cognitive scale, and ADCS-ADL, a functional scale and iADRS, (which is a combination of scores from ADAS-Cog & ADCS-ADL). All three clinical measurements are standard psychometric assessment tools in trials of Alzheimer's disease.
Other endpoints include plasma biomarkers of disease and NPI, a clinical tool that assesses the presence and severity of dementia-related behavior.
No interim analyses on efficacy are planned.
The company's second Phase 3 study, called REFOCUS-ALZ, is designed to evaluate the safety and efficacy of oral simufilam 100 mg and 50 mg over 76 weeks (NCT05026177). Details of the REFOCUS-ALZ Phase 3 study include:
Approximately 1,100 patients are randomized into this study.
Patients are randomized (1:1:1) to simufilam 100 mg tablets, 50 mg tablets, or matching placebo twice daily.
Patients are treated for 76 weeks.
Efficacy endpoints are ADAS-Cog12, a cognitive scale, and ADCS-ADL, a functional scale and iADRS, (which is a combination of scores from ADAS-Cog & ADCS-ADL). All three clinical measurements are standard psychometric assessment tools in trials of Alzheimer's disease.
Other endpoints include biomarkers of disease, MRI imaging and NPI, a clinical tool that assesses the presence and severity of dementia-related behavior.
No interim analyses on efficacy are planned.
Phase 3 Entry Criteria
In the company's Phase 3 clinical studies, eligibility criteria are the requirements that patients must meet to be included in a study. These requirements help make sure that study participants are substantially and closely matched as a group in terms of specific factors such as age, disease or stage of disease, general health, and other key factors. Eligibility criteria can consist of inclusion criteria, which are required for a person to participate in the study, or exclusion criteria, which prevent a person from participating.
Use of Plasma Phosphorylated-tau181 (p?tau181)
Plasma p?tau181 is a biomarker qualifier of Alzheimer's neuropathology. RETHINK-ALZ and REFOCUS-ALZ Phase 3 studies use a 'research use only', non-safety related exploratory p-tau181 plasma assay to qualify mild-to-moderate Alzheimer's patients. The plasma assay the company uses does not rely on age, APOE-gene status or complex algorithms to provide a result. P-Tau181 testing was performed by an independent commercial laboratory.
Data and Safety Monitoring Board (DSMB)
In September 2023, the company announced that a routine, scheduled meeting of a DSMB recommended that both of the company's Phase 3 studies continue as planned, without modification. This DSMB only reviewed patient safety. It did not assess drug efficacy.
Interim MRI Safety Data
In October 2023, the company announced a potentially significant safety finding based on interim magnetic resonance imaging (MRI) brain data from Alzheimer's patients who are enrolled in a Phase 3 clinical trial of simufilam. These MRI data suggest simufilam is not associated with treatment-emergent amyloid-related imaging abnormalities, or ARIA. MRIs were all analyzed for ARIA by independent, board-certified neuroradiologists.
ARIA is a medical term used to describe a spectrum of brain MRI imaging abnormalities, such as brain swelling and brain bleeds. ARIA is a known risk factor for Alzheimer's patients taking the class of drugs known as monoclonal antibodies directed against amyloid. In contrast to that class of drugs, simufilam is a small-molecule (oral) drug candidate.
The new safety finding is based on an independent, interim neuroradiological evaluation of brain MRIs taken at week 40 in a blinded sub-study of 180 Alzheimer's patients enrolled in REFOCUS-ALZ, the company's on-going 76-week Phase 3 clinical trial of simufilam in mild-to-moderate Alzheimer's. Final MRI data is expected at the conclusion of this Phase 3 study.
Status of Phase 3 Clinical Program
The company's Phase 3 trials have randomized a total of approximately 1,900 patients with mild to moderate stages of Alzheimer's disease at baseline (MMSE 16-27), with approximately 800 patients randomized in the 52-week study (RETHINK-ALZ) and approximately 1,100 patients randomized in the 76-week study (REFOCUS-ALZ).
Approximately 70% of patients enrolled in the company's Phase 3 trials are diagnosed with mild Alzheimer's disease (MMSE 20-27), with remaining patients entering the study with moderate disease (MMSE 16-19). Since the distribution of patients randomized in these trials is numerically skewed towards mild patients, the company expects to rely predominantly on outcomes from mild patients to evaluate drug safety and efficacy.
Over 340 patients have completed the 52-week RETHINK-ALZ study. Over 215 patients have completed the 76-week REFOCUS-ALZ study, for a total of over 555 completers.
All efficacy data from the company's Phase 3 program remain blinded. There are no interim analyses on efficacy outcomes.
The company anticipates top-line data readout for the company's 52-week study (RETHINK-ALZ) approximately year-end 2024.
The company anticipates top-line data readout for the company's 76-week study (REFOCUS-ALZ) approximately mid-year 2025.
The company has initiated a discussion with the FDA to finalize a statistical analysis plan (SAP), which is a formal document defining the detailed analysis that the company's independent biostatisticians will undertake as to efficacy data collected in the company's Phase 3 trials. The SAP includes in-depth technical details and descriptions on the intended clinical trial analysis, the statistical methods and models that will be used, the population being analyzed, the data variables that will be analyzed, how missing data will be accounted for, descriptions of covariates to be included in the statistical model, and other statistical factors, all of which will be prospectively defined, documented and finalized prior to unblinding of any efficacy outcomes.
Open-label Extension Study for the Phase 3 Program
In October 2022, the company announced the initiation of an open-label extension study for the company's Phase 3 program. This study is designed to provide no-cost access to oral simufilam for up to one year to Alzheimer's patients who have successfully completed a Phase 3 study of simufilam and who meet other entry criteria.
The company expects the open-label extension study to generate additional long-term clinical safety data for oral simufilam 100 mg twice daily over 52 weeks. There is no obligation for a patient or a physician to participate in the open-label extension study. Each clinical investigational site and each patient chooses whether to participate in this open-label extension study.
Patient enrollment for this study began in November 2022. To date, over 500 patients entered the open-label extension study.
Phase 3 Drug Supply
The company has a drug supply agreement with Evonik Industries AG for simufilam. Under the agreement, Evonik supplies and is expected to continue to supply the company with large-scale, clinical-grade quantities of simufilam. Evonik is one of the world's largest contract development and manufacturing organizations for pharmaceutical ingredients. Other vendors supply excipients, the finished dosage form (i.e., simufilam tablets), drug packaging, package labeling and other critical components of the supply chain for Phase 3 drug supply.
SavaDx
The company's investigational product candidate, called SavaDx, is an early-stage program focused on detecting the presence of Alzheimer's disease from a small sample of blood. For business, technical and personnel reasons, the company continues to prioritize the development of simufilam, the company's novel drug candidate, over SavaDx, the company's novel diagnostic candidate. SavaDx is a research-use only, non-safety related exploratory biomarker.
Working with third parties, the company continues to evaluate the use of mass spectrometry to detect FLNA or other proteins of interest. The data and information generated from these evaluations continues to be under review for potential intellectual property rights.
SavaDx is designed as an antibody-based detection system for altered filamin A (FLNA). Working with third parties, the company is evaluating the use of mass spectrometry to detect FLNA, i.e., without the use of antibodies. These evaluations are on-going.
Diagnostic Development Program
SavaDx is an investigational diagnostic product candidate that has not yet been reviewed by FDA. Early clinical testing consisted of collecting blood samples on a limited scale to test and validate SavaDx using antibodies or mass spectrometry. The company's ability to test such samples and generate accurate results depends on multiple factors, many of which are beyond the company's control.
The company has conducted four early validation tests using SavaDx. In three blinded studies of test samples, SavaDx detected more than a 10-fold separation between Alzheimer's patients and normal healthy control subjects (N=232 test samples). In these three proof-of-concept studies, SavaDx demonstrated nearly 100% accuracy and specificity. The three studies deployed a research grade antibody manufactured by an outside vendor.
A fourth blinded study of SavaDx failed to generate meaningful diagnostic data. The fourth study deployed a faulty research antibody sourced from an outside vendor. Commercially available research antibodies can present certain technical flaws, such as improper validation, significant batch-to-batch variations or inconsistent storage, any of which can jeopardize results of studies and experiments.
In July 2021, the company announced positive clinical data with SavaDx when used to measure plasma levels of altered filamin A before and after simufilam treatment in patients with Alzheimer's disease. In a Phase 2b randomized, controlled trial sponsored by the National Institutes of Health (NIH), simufilam significantly reduced a plasma marker of altered filamin A in Alzheimer's patients treated for 28 days. Plasma levels of p-tau181 also dropped significantly in these same patients, as measured by Quanterix Corporation, a third-party vendor.
SavaDx is designed as an antibody-based detection system for filamin A (FLNA). Working with third parties, the company is evaluating the use of mass spectrometry to detect FLNA, i.e., without the use of antibodies. These evaluations are on-going.
The company has no issued patents in the United States with respect to SavaDx.
Simufilam was discovered and designed in-house and was characterized by the company's academic collaborators during research activities that were conducted from approximately 2008 to date. SavaDx is being developed in-house with outside collaborators. The company owns exclusive, worldwide rights to those drug and diagnostic assets and related technologies, without royalty obligations to any third party. The company's patent protection with respect to simufilam and use of simufilam for Alzheimer's disease and other neurodegenerative diseases runs through 2039 and includes nine issued U.S. patents. In addition, the company has patent protection with respect to simufilam for use in treating certain cancers that runs through 2033. The company's patent estate further includes patents and patent applications for related compounds and treatments. Corresponding foreign filings have been made for each of the U.S. filings.
Strategy
The key elements of the company's business strategy include building a lean company that is narrowly focused on developing innovative product candidates for Alzheimer's disease and other areas of neurodegeneration; validating the company's unique scientific approach with competitive research grants and publishing the company's scientific data in peer-reviewed journals; applying the company's development capabilities to advance the company's product candidates through clinical proof-of-concept studies and beyond; using the company's expertise and experience to continue to focus on discovering new indications and product candidates, validated by experimental evidence and leading experts in the field; and continuing to outsource preclinical studies, clinical studies and formulation development activities in order to allow more efficient deployment of the company's resources. The company also conducts basic research and development in collaboration with academic and other partners.
Research and Development
The company's research and development expenses were $89.4 million for the year ended December 31, 2023.
Manufacturing
Simufilam and any future product candidates must be manufactured for clinical trial use in compliance with current good manufacturing practices (cGMP) regulations.
The company's manufacturing vendors must have facilities to make the company's product candidates in strict compliance with cGMP requirements and the FDA's or comparable foreign regulatory authorities' satisfaction.
The company relies on one non-affiliated contract development and manufacturing organization (CDMO)-Evonik Corporation-to manufacture simufilam and expect to continue to do so. In 2021, the company entered into an agreement with Evonik Corporation to supply large-scale, clinical-grade quantities of drug substance for simufilam.
History
The company was founded in 1998. It was incorporated in Delaware in 1998 as Pain Therapeutics, Inc. and changed its name to Cassava Sciences, Inc. in 2019.
