We are a clinical-stage biopharmaceutical company developing novel, small
molecule product candidates designed to modulate the ribosome and promote
readthrough of premature stop codons induced by nonsense mutations (“NMs”) to
enable the production of full-length proteins. Targeting ribosome subunits
provides a therapeutic approach to addressing a number of genetic diseases.
According to the Human Gene Mutation Database, NMs account for approximately 10%
to 12% of patients with a given genetic disease. There are over 7,000 inherited
genetic diseases that collectively affect 350 million people worldwide. Our
immediate focus is to advance the clinical development of our product candidate,
exaluren, for the treatment of rare kidney diseases. We have also exclusively
licensed our product candidate, ZKN-013, to Almirall, S.A. (“Almirall”), who is
developing it for the treatment of rare skin diseases.
Exaluren is a novel eukaryotic ribosome-selective glycoside product candidate
that is designed to induce premature termination codon (“PTC”) readthrough in
the presence of NMs and promote the restoration of full-length proteins. We
believe this mechanism has the potential to apply to all genetic diseases caused
by NMs. We are initially developing exaluren to induce full-length Collagen IV
protein for the treatment of Alport syndrome (“AS”) with NMs (“NMAS”). NMAS, a
subset of AS, is a genetic kidney disorder that is caused by the loss of one of
three Collagen IV subtypes, Collagen IV alpha 3 (“COL4A3”), alpha 4 (“COL4A4”),
or alpha 5 (“COL4A5”), and the resulting loss of the Collagen IV alpha 3,4,5
trimer. This trimer is made in podocyte cells and required for the functioning
of the filtration structure of the kidney comprising the glomerular basement
membrane (“GBM”), foot processes and slit diaphragms.
We estimate that NMAS affects roughly 7% of AS patients or approximately 4,200
patients in the United States and approximately 11,000 patients worldwide. NMAS
is characterized by hematuria and proteinuria, or blood and protein,
respectively, in the patient’s urine and results in progressive kidney disease,
hearing loss and eye abnormalities. The median age to kidney failure in patients
with NMAS is 20 years and 30 years for patients with NMs in the COL4A3/4 genes
and the COL4A5 gene, respectively. Although angiotensin converting enzyme
inhibitor and angiotensin receptor blocker therapies can slow progression to
end-stage kidney disease, they do not prevent kidney failure, and there are no
therapies approved by the U.S. Food and Drug Administration (“FDA”) specifically
indicated to address the underlying genetic cause of AS. Exaluren has received
Orphan Drug Designation for the treatment of AS from the FDA.
We have evaluated exaluren in eight clinical trials, including four Phase 1
studies in healthy volunteers, one Phase 2a study in NMAS, two Phase 2 studies
in cystic fibrosis (“CF”) patients with NMs, and one Phase 2 study in
nephropathic cystinosis patients with NMs. In total, 145 subjects have received
at least one dose of exaluren during these clinical trials with 89.4
subject-months exposure. In these studies, no dose-limiting toxicities were
reported and no serious adverse events were attributed to exaluren.
Between January 2023 and April 2024, we conducted a proof-of-concept Phase 2a
open-label trial in the United Kingdom in three patients with autosomal
recessive AS and a NM in the COL4A4 gene. The primary endpoint of this study was
to assess the number of participants with adverse events associated with
administration of exaluren. The secondary endpoints were change from baseline in
proteinuria, measured by the urine protein-to-creatinine ratio (“UPCR”) in a
patient’s urine samples, and hematuria, and change in baseline in Collagen IV
expression. All three patients showed a reduction in podocyte foot process
effacement (“FPE”), which is the flattening and loss of specialized kidney cell
structures that form the filtration barrier and attach to the podocytes and GBM,
in transmission electron microscopy (“TEM”) images. FPE is a hallmark of kidney
diseases, including AS, and the severity of FPE has historically been associated
with time to kidney failure. TEM images of biopsy samples also showed an
improvement in the GBM width in all treated patients. FPE was also measured as a
50% increase in the filtration slit density (“FSD”). These results were
consistent with exaluren’s proposed mechanism of functional full-length protein
restoration as reflected by improvements in GBM architecture and FPE observed in
kidney biopsies. At the end of treatment, UPCR had decreased for one patient and
increased for two patients. We received clearance to proceed with a Phase 2b
clinical trial for exaluren in NMAS patients (without kidney biopsies in U.S.
pediatric patients) under an Investigational New Drug application (“IND”) from
the FDA and we plan to initiate this trial in the third quarter of 2026. We
anticipate topline data from the initial 16-week placebo-controlled part of the
study by mid-2027 with the final readout by the end of 2027.
Our pipeline also includes a preclinical program evaluating exaluren for the
treatment of autosomal dominant polycystic kidney disease (“ADPKD”) in patients
that have NMs (“nmADPKD”). ADPKD is the most common monogenic kidney disease
based on genetic diagnosis, affecting approximately 160,000 to 200,000 patients
in the United States. The PKD1 gene encodes polycystin-1 (“PC1”) and the PKD2
gene encodes polycystin-2 (“PC2”), these are proteins that regulate cell growth
and fluid secretion in kidney tubules. Loss of functional PC1 or PC2 protein
leads to uncontrolled cyst formation. Approximately 26% of ADPKD patients have
NMs in the PKD1 and PKD2 genes resulting in a prevalence of approximately 40,000
to 50,000 patients in the United States and over 90,000 in developed markets
outside of the United States. Patients experience hypertension, kidney stones,
urinary tract infections, heart valve abnormalities, hematuria and increased
probability of aortic aneurysm. Formation of these cysts eventually leads to
nephromegaly (kidney enlargement) and end-stage renal disease. The only approved
therapy for ADPKD, tolvaptan, does not address the underlying genetic cause and
carries significant tolerability limitations. Preclinical organoid and cellular
models have shown increased PC1 and PC2 gene expression following treatment with
exaluren. We plan to initiate enrollment in a Phase 2 trial of exaluren for the
treatment of nmADPKD in 2027 following protocol finalization and clearance of an
Investigational New Drug application by the FDA. We anticipate topline data from
this trial by mid-2028.
We have also exclusively licensed ZKN-013, an oral ribosome modulating agent
with structural similarity to azithromycin that induces PTC readthrough, to
Almirall. In March 2024, we entered into an exclusive global rights agreement
with Almirall (the “Almirall License Agreement”) for Almirall to develop and
commercialize ZKN-013 for the use in all indications. Through the Almirall
License Agreement, Almirall is developing ZKN-013 for the treatment of recessive
dystrophic epidermolysis bullosa (“RDEB”) and junctional epidermolysis bullosa
(“JEB”) with NMs. RDEB and JEB are rare skin diseases characterized by mutations
in the Collagen VII (RDEB) and LAMB3 (JEB) proteins. We estimate that there are
approximately 4,000 patients with NMs in these diseases in the major markets of
the United States, Japan and Western Europe. Patients with these diseases suffer
from severe skin bruising, wounds and internal lesions resulting in increased
risk of skin cancer and severe malnourishment. Under the Almirall License
Agreement, we received an upfront payment of $3 million and a development
milestone payment of $3 million in 2024. Almirall is responsible for development
and commercialization of ZKN-013 and we are eligible to receive up to
approximately $470.0 million in additional development, regulatory and
commercial milestone payments as well as tiered royalties based on global sales.
The agreement may be terminated under specified circumstances, including for
convenience by Almirall, in which case rights may revert to us.
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We were incorporated under the laws of the State of Delaware. Effective as of
June 30, 2024, we became a remotely headquartered company and we do not maintain
a principal executive office. For purposes of compliance with applicable
requirements of the Securities Act of 1933, as amended, and the Exchange Act,
the address of our principal executive offices is P.O. Box 274, Arlington, MA,
02476. Our phone number is (781) 577-5300. Our website address is
www.eloxxpharma.com.
