Eloxx Pharmaceuticals, Inc. (NASDAQ: ELOX), a clinical-stage
biopharmaceutical company dedicated to the discovery and
development of novel therapeutics to treat cystic fibrosis,
cystinosis, inherited retinal disorders and other diseases caused
by nonsense mutations limiting production of functional proteins,
today provided an update on progress in its Phase 2 clinical
programs and its pipeline of novel ERSG (eukaryotic ribosomal
selective glycoside) compounds.
The Phase 2 Cystic Fibrosis clinical trial program
for ELX-02 is actively dosing patients in the U.S. and Israel and
continuing to enroll patients at leading global investigator sites.
We expect full enrollment to be achieved during the first quarter
of 2020 and to report topline results during the first half of
2020. In the U.S., the Cystic Fibrosis Foundation is providing
funding for a portion of the trial.
We continue to progress our ERSG pipeline in inherited retinal
disorders (IRD) and ADPKD. In ocular, we recently reported on a
critical milestone demonstrating that several of our library
compounds successfully reach retinal disorder-relevant tissue
layers and can restore protein production in an animal model. We
plan to present these data at the Association for Research in
Vision and Ophthalmology (ARVO) Annual Meeting May 3-7, 2020 in
Baltimore, MD. There are over 300 IRD associated with nonsense
mutations.
ADPKD is a relatively common inherited genetic kidney disease
occurring in between 1:400 and 1:1000 patients and the 4th leading
cause of end stage renal disease in the United States. Over 25% of
the primary genetic changes that cause ADPKD are nonsense
mutations, where a premature stop codon in the gene leads to a
truncated, often unstable, protein. We have evaluated the three
most relevant ADPKD nonsense mutations in an in vitro read-through
assay and have demonstrated significant levels of read-through for
ELX-02 and several library compounds which is the first step in our
preclinical development toward IND.
In Cystinosis, Eloxx announced positive data from the first
cohort of the Phase 2 study of ELX-02, a novel ERSG, in the
treatment of patients with nonsense mutation-mediated nephropathic
cystinosis. The first cohort enrolled three homozygous W138X male
and female patients ages 23 to 38, with prior kidney transplants
and varying degrees of renal insufficiency. The primary endpoint
for this study was safety. This study also evaluated other
parameters including white blood cell (WBC) cystine levels.
Following completion of the first cohort, an independent Safety
Review Committee met to review the pharmacokinetic and safety
results and approved progressing to the second cohort that would
enable enrolling patients ages 12 and older.
Following one week of treatment, all three patients in dose
group 2 (DG2, nominal dose 1.0 mg/kg/day) had shown a significant
decrease (p < 0.05) in WBC cystine levels. After a three-week
period of no treatment, followed by two weeks of treatment, two of
three patients in dose group 3 (DG3, nominal dose 2.0 mg/kg/day)
also showed reductions in WBC cystine levels. All three patients in
dose group 1 (DG1, nominal dose 0.5 mg/kg/day, 1 week of treatment)
had increases in WBC cystine levels. For cystinosis patients, the
targeted goal of therapy is to reduce WBC cystine levels to below 1
nmol of ½ cystine/mg protein. Across all dose groups, patients had
elevated and uncontrolled pretreatment WBC cystine levels ranging
from 2.2 to 9.5 nmol of ½ cystine/mg protein, representing a
substantial therapeutic challenge. In prior clinical studies of
cysteamine, patients typically had pretreatment WBC cystine levels
less than 2 nmol of ½ cystine/mg protein. Reductions in WBC cystine
were apparent across the 1.0 and 2.0 mg/kg/day doses in the first
cohort but none of these reductions were to levels below 1 nmol of
½ cystine/mg protein. These promising reductions in WBC cystine
provide a clear indication of ELX-02 biologic activity at nominal
doses > 0.5mg/kg/day.
Patient |
% Change in White Blood Cell Cystine Levels |
Dose Group 11-week
treatment(nominal dose 0.5
mg/kg/day) |
Dose Group 21-week
treatment(nominal dose 1.0
mg/kg/day) |
Dose Group 32-week
treatment(nominal dose 2.0
mg/kg/day) |
1 |
+ 32.2 |
-23.7 |
+16.3 |
2 |
+ 126.4 |
-38.0 |
-13.7 |
3 |
+20.5 |
-24.6 |
-20.5 |
The pharmacokinetics of ELX-02 administered daily were
consistent with those expected based on the prior SAD, MAD and
renal impairment studies and the emerging safety profile of ELX-02
in patients supports continued development. In this study, ELX-02
was generally well tolerated with no deaths, nephrotoxicity,
ototoxicity or serious adverse events potentially related to
ELX-02. The only reported adverse events related to ELX-02 were
injection site reactions that were mild in severity. Consistent
with the absence of meaningful changes or negative trends in serum
creatinine or eGFR, kidney function was preserved in these
post-transplant patients. In other clinical trials, changes in
serum creatinine and eGFR have been used as important study
endpoints.
Patient |
Lab Test |
Screening |
DG1 Pre-dose |
DG2 Pre-dose |
DG3 Pre-dose |
4-Week Safety Follow Up |
Day1 |
Day 7 |
Day 1 |
Day 7 |
Day 1 |
Day 7 |
Day 14 |
1 |
Serum Creatinine µmol/L |
132 |
117 |
126 |
128 |
138† |
128 |
120 |
116 |
136 |
2 |
180 |
126 |
110 |
122 |
113 |
128 |
115 |
129 |
130 |
3 |
167 |
145 |
124 |
129 |
131 |
146 |
143 |
140 |
150 |
1 |
eGFR mL/min/ 1.73m2 |
44 |
51 |
47 |
46 |
42† |
46 |
49 |
52 |
43 |
2 |
45 |
69 |
81 |
72 |
79 |
68 |
77 |
67 |
66 |
3 |
49 |
58 |
70 |
67 |
66 |
58 |
59 |
61 |
56 |
† Day 5 value |
Eloxx is reviewing these data with a panel of cystinosis
scientific and clinical experts to determine if protocol
modifications would be appropriate before initiating cohort 2 of
this study.
The clear indications of biologic activity at nominal doses >
0.5mg/kg/day provide human clinical proof of concept for ELX-02 and
de-risk other clinical applications of our ERSG library using this
dosage range. These encouraging results also provide a basis for
expansion to studies of additional kidney diseases caused by
nonsense mutations such as ADPKD.
This study was conducted with the support of nondilutive funding
from Genome Quebec and Genome Canada.
About Cystinosis
Cystinosis is a rare autosomal recessive lysosomal storage
disease characterized by the abnormal accumulation of the amino
acid, cystine, in lysosomes which eventually leads to intracellular
crystal formation throughout the body. Nephropathic cystinosis
presents in infancy and is the most common and severe form. Early
detection and prompt treatment are critical in slowing the
development and progression of symptoms associated with cystinosis.
The kidneys and eyes are the two organs most often affected.
Individuals with nephropathic or intermediate cystinosis ultimately
require a kidney transplant by age 10. With treatment this may
be delayed into the patient’s teens or 20s. Other signs and
symptoms that may occur in patients include muscle deterioration,
blindness, inability to swallow, impaired sweating, decreased hair
and skin pigmentation, diabetes, and thyroid and nervous
system problems. In 1994, the Food and Drug Administration (FDA)
approved cysteamine bitartrate (Cystagon®) for the treatment of
individuals with cystinosis. In 2013, the FDA approved Procysbi®,
an extended release form of cysteamine. Cysteamine is a
cystine-depleting agent that can greatly lower cystine levels
within cells, but compliance with these agents is often
poor.
About ELX-02
Our lead investigational compound, ELX-02, is a eukaryotic
ribosomal selective glycoside (ERSG) designed to increase the
read-through activity in patients with nonsense mutations and
enable the production of sufficient amounts of full-length
functional protein to restore activity. Currently ELX-02 is in
Phase 2 clinical trials in cystic fibrosis and nephropathic
cystinosis patients with diagnosed nonsense mutations on one or
both alleles. These patients have a high unmet medical need, a high
burden of disease and few, if any, treatment options. Our Phase 2
clinical trial in cystinosis is enrolling 6 patients with the
support of the Genome Canada Genomic Applications Partnership
Program. Our Phase 2 program in cystic fibrosis will enroll up to
24 patients in the US, Europe and Israel. The Cystic Fibrosis
Foundation is providing funding for a portion of the U.S. trial.
The protocol has been sanctioned by the Cystic Fibrosis
Therapeutics Development Network (“TDN”) and the study will be
conducted at TDN member sites. In Europe, our Phase 2 program has
been given a score of “high priority” by the European Cystic
Fibrosis Society-Clinical Trial Network (ECFS-CTN).
About Eloxx Pharmaceuticals
Eloxx Pharmaceuticals, Inc. is a clinical-stage
biopharmaceutical company developing novel RNA-modulating drug
candidates (designed to be eukaryotic ribosomal selective
glycosides) that are formulated to treat rare and ultra-rare
premature stop codon diseases. Premature stop codons are point
mutations that disrupt protein synthesis from messenger RNA. As a
consequence, patients with premature stop codon diseases have
reduced or eliminated protein production from the mutation bearing
allele accounting for some of the most severe phenotypes in these
genetic diseases. These premature stop codons have been identified
in over 1,800 rare and ultra-rare diseases.
Read-through therapeutic development is focused on extending
mRNA half-life and increasing protein synthesis by enabling the
cytoplasmic ribosome to read through premature stop codons to
produce full-length proteins. Eloxx’s lead investigational product
candidate, ELX-02, is a small molecule drug candidate designed to
restore production of full-length functional proteins. ELX-02 is in
the early stages of clinical development focusing on cystic
fibrosis and cystinosis. ELX-02 is an investigational drug that has
not been approved by any global regulatory body. Eloxx’s
preclinical candidate pool consists of a library of novel drug
candidates designed to be eukaryotic ribosomal selective glycosides
identified based on read-through potential. Eloxx recently
announced a new program focused on rare ocular genetic disorders.
Eloxx is headquartered in Waltham, MA, with operations in Rehovot,
Israel. For more information, please visit www.eloxxpharma.com.
Forward-Looking Statements
This press release contains forward-looking statements, which
are generally statements that are not historical facts.
Forward-looking statements can be identified by the words
"expects," "anticipates," "believes," "intends," "estimates,"
"plans," "will," "outlook" and similar expressions. Forward-looking
statements are based on management's current plans, estimates,
assumptions and projections, and speak only as of the date they are
made. We undertake no obligation to update any forward-looking
statement in light of new information or future events, except as
otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to
predict and are generally beyond our control. Actual results or
outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, including: the development of the Company’s read-through
technology; the approval of the Company’s patent applications; the
Company’s ability to successfully defend its intellectual property
or obtain necessary licenses at a cost acceptable to the Company,
if at all; the successful implementation of the Company’s research
and development programs and collaborations; the Company’s ability
to obtain applicable regulatory approvals for its current and
future product candidates; the acceptance by the market of the
Company’s products should they receive regulatory approval; the
timing and success of the Company’s preliminary studies,
preclinical research, clinical trials, and related regulatory
filings; the ability of the Company to consummate additional
financings as needed; as well as those discussed in more detail in
our Annual Report on Form 10-K and our other reports filed with
the Securities and Exchange Commission.
Contact:
Barbara Ryan 203-274-2825barbarar@eloxxpharma.com
SOURCE: Eloxx Pharmaceuticals, Inc.
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