DGAP-News: RedHill Biopharma Ltd. / Key word(s): Scientific publication
RedHill Biopharma Ltd.: RedHill Biopharma Announces Interim Results from
Phase IIa Proof-of-Concept Study Supporting Therapeutic Potential of RHB-104
in Multiple Sclerosis
05.04.2016 / 09:00
The issuer is solely responsible for the content of this announcement.
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Press Release
RedHill Biopharma Announces Interim Results from Phase IIa Proof-of-Concept
Study Supporting Therapeutic Potential of RHB-104 in Multiple Sclerosis
- The ongoing CEASE-MS Phase IIa proof-of-concept (PoC), single-arm,
open-label study was designed with a series of exploratory endpoints to
evaluate the safety and potential efficacy of fixed oral dose RHB-104
as add-on therapy to interferon beta-1a in 18 patients treated for
relapsing-remitting multiple sclerosis(RRMS)
- Interim results after completion of the 24 week treatment period of the
study demonstrated positive safety and clinical signals and support
further clinical development based on encouraging preliminary data
- Annualized relapse rate (ARR) at 24 weeks was 0.288 in the modified
intent-to-treat (mITT) population and 0.0 in the per-protocol (PP)
population, comparing favorably with previously reported pivotal
studies of interferon beta-1a therapies Avonex(R) (0.67) and Rebif(R)
(0.87-0.91)
- 88% of the mITT patient population and 100% of the PP patient
population were relapse free at 24 weeks, comparing favorably with
previously reported pivotal data on the use of Rebif(R) (75%) in
comparison with Avonex(R) (63%) as standalone first line therapies; No
patients in the CEASE-MS study relapsed after week 8 of treatment
- Expanded Disability Status Scale (EDSS) scores, a standard measure of
MS disability, indicate the disease was stable during the treatment
period and there was a signal of improvement; No increase in total EDSS
was observed in any of the patients in the study
- With only a single active T1 post gadolinium lesion noted among all
patients followed, combined unique active lesions (CUAs) - the primary
outcome measure in the study - were almost entirely MRI T2 lesions;
Although not powered for efficacy, a reduction in total MRI T2 lesion
volume was observed at 24 weeks as compared to baseline, suggesting a
decreased burden of disease and comparing favorably with previously
reported Avonex(R) and Rebif(R) data
- No clinically significant change was observed for total CUA lesions at
week 24, which is supportive of a stable disease state
- RHB-104 was found to be safe and well tolerated, with no drug-related
serious adverse events or other clinically relevant or unexpected
adverse events
- 2015 U.S. and worldwide sales of multiple sclerosis therapies were
estimated to exceed $12 billion and $17 billion, respectively
- RHB-104 is also undergoing a Phase III clinical study for Crohn's
disease (the MAP US study), with interim data and safety monitoring
board (DSMB) analysis expected in the second half of 2016
TEL-AVIV, Israel, April 05, 2016 RedHill Biopharma Ltd. (NASDAQ; RDHL)
(TASE: RDHL) ("RedHill" or the "Company"), a biopharmaceutical company
primarily focused on the development and commercialization of late
clinical-stage, proprietary, orally-administered, small molecule drugs for
inflammatory and gastrointestinal diseases, including cancer, today
announced encouraging top-line interim results from its ongoing CEASE-MS
Phase IIa proof-of-concept (PoC) clinical study evaluating fixed oral dose
RHB-104 in patients treated for relapsing-remitting multiple sclerosis
(RRMS).
Ira Kalfus MD, Medical Director of RedHill and the CEASE-MS study said: "We
are very pleased with the interim results from the ongoing CEASE-MS Phase
IIa proof-of-concept study with RHB-104 for relapsing-remitting multiple
sclerosis (RRMS). The initial findings from the study, including safety,
clinical and MRI, support the therapeutic potential of RHB-104 as add-on
therapy in RRMS." Dr. Kalfus added: "Although designed as an exploratory
proof-of-concept study in a very small patient population and not powered
for efficacy, the study interim results demonstrate positive safety data
and clinical signals, supporting additional studies to better investigate
the therapeutic potential of RHB-104 in RRMS. 88% of the mITT patient
population and 100% of the per-protocol population were relapse free at 24
weeks of treatment. Importantly, a positive efficacy signal was seen in
reduction of total T2 lesion volume at 24 weeks compared to baseline.
Moreover, EDSS scores were stable with suggestion of improvement. Notably,
no patients experienced an increase in total EDSS, further underscoring the
therapeutic potential of RHB-104 for the treatment of RRMS. RHB-104 was
observed to be safe and well-tolerated with no clinically relevant or
unexpected adverse events, further reinforcing our confidence in this
therapeutic candidate as we continue to advance the ongoing Phase III MAP
US study with RHB-104 for Crohn's disease. We are looking forward to
further analyses of the data upon completion of the 48 week CEASE-MS study.
Patients are now completing their 24 week follow up treatment period, off
RHB-104, and final results of the completed 48 week study are expected
during the second half of 2016. Analysis of the completed study will drive
next steps in the development path of RHB-104 for MS including
identification of the patient population, comparator and clinical endpoints
to be investigated in the next study. We would like to thank the patients,
investigators and clinical support staff who are participating in this
important ongoing study."
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of
the central nervous system (CNS) with an unknown etiology, believed to be
multifactorial. Thought to be autoimmune, the MS inflammatory process is
also consistent with persistent infection. RHB-104 is a proprietary, orally
administered, potentially groundbreaking antibiotic combination therapy
with potent intracellular, anti-mycobacterial and anti-inflammatory
properties. The ongoing CEASE-MS Phase IIa clinical study is a single-arm,
open-label PoC study evaluating fixed oral dose RHB-104 as add-on therapy
to interferon beta-1a for the treatment of RRMS. This study follows
positive pre-clinical research findings and provides clinical evidence of
RHB-104's potential as a treatment for MS. The study was designed as an
uncontrolled, non-powered, single-arm, open-label PoC study with the
objective of evaluating the safety and potential efficacy of RHB-104 using
a series of exploratory measures. Eighteen RRMS patients were enrolled in
two clinical centers in Israel. The patients received 24 weeks of treatment
with RHB-104 and the interim data are presented in this press release. The
patients are currently being evaluated for an additional follow-up period
of 24 weeks after completing treatment with RHB-104. Independent third
parties provided RedHill with the interim data sets and analysis, which
remain subject to finalization and completion of the study.
Dr. Radi Shahien MD of Ziv Medical Center in Safed, Israel, Principal
Investigator of the CEASE-MS study added: "RRMS is a devastating disease
with no known cure, limited treatment options and unknown cause, hence the
importance of the development of RHB-104, an intracellularly acting,
anti-mycobacterial, anti-inflammatory and orally administered drug
candidate. CEASE-MS is a small, open-label, exploratory study intended to
investigate the groundbreaking hypothesis that a bacterial induced
dysregulated immune system plays a critical role in the pathogenesis of MS.
RedHill's CEASE-MS study with RHB-104 is the first clinical study to
evaluate the therapeutic potential of a triple antibiotic combination
therapy, and specifically these intracellularly acting antibiotics, as
add-on therapy in RRMS. The initial analysis of the study's interim results
provides encouraging clinical signals as well as important and reassuring
safety data. In particular, the reduction of total T2 lesion burden over
baseline, a key MS disease burden measurement, as well as relapse-free and
stable EDSS data, are positive and meaningful signals, particularly given
the small patient population in the study and the early time point of the
data generated to date. I find the interim results very promising and am
encouraged by the potential efficacy of RHB-104 in treating MS. I look
forward to the completion of the study, further analyses and presentation
of the final data at the appropriate international medical and academic
forums."
"We are very encouraged by these findings which further reinforce the
potential role of RHB-104 in the field of auto inflammatory diseases. We
are conducting the Phase III MAP US study for Crohn's disease with RHB-104,
with interim DSMB analysis expected in the second half of 2016, and the
CEASE-MS study adds important information to the body of knowledge about
the drug," stated Dror Ben-Asher, RedHill's Chief Executive Officer. "With
a strong balance sheet and three ongoing Phase III programs in
gastroenterology with planned data points in 2016 - RHB-104 for Crohn's
disease, RHB-105 for H. pylori infection and BEKINDA(TM) for acute
gastroenteritis - RedHill is well positioned for continued growth in 2016
and beyond."
Study Design and Baseline Characteristics
CEASE-MS is an ongoing study with additional data reads due at week 48 once
all patients who completed the 24 weeks RHB-104 treatment period, will have
completed a 24 week follow-up treatment period with interferon beta-1a,
without RHB-104 add-on. All endpoints will be reassessed at that time using
patients as their own control for analysis of interferon beta-1a with and
without add-on RHB-104 therapy.
18 patients suffering from RRMS were enrolled in the ongoing CEASE-MS study
in two sites in Israel, of which 17 patients who completed dose escalation
were included in the modified intent-to-treat (mITT) data set. One patient
was withdrawn from the study due to prohibited concomitant medication
usage. The patients had been treated with interferon beta-1a for an average
of approximately five years prior to enrollment in the study, experienced
at least one MS relapse within 12 months prior to enrollment or two MS
relapses within 24 months prior to enrollment, and had an EDSS score of 6.0
or less at screening, with a mean of 3.06. The per protocol (PP) analysis
included ten patients, all of whom completed both the dose escalation and
24 week treatment period without any major protocol deviations.
Annualized Relapse Rate (ARR)
Patients in the study experienced an annualized relapse rate (ARR) of 0.288
in the mITT population and 0.0 in the per-protocol (PP) population,
respectively. These results compare favorably with previously reported
values for both interferon beta-1a therapies Avonex(R) and Rebif(R). The
pivotal study of Avonex(R) demonstrated an ARR of 0.67 , and a different
Avonex(R) study reported ARRs of 0.53 and 0.31 in patients with and without
previous history of disease modifying therapy, respectively . The pivotal
study of Rebif(R) demonstrated an ARR of 0.87 - 0.91 (a relapse rate of
1.73 - 1.82 over 2 years, 44 mcg or 22 mcg dose dependent), respectively .
In separate studies, reported ARR for Rebif(R) have ranged from 0.72 in the
PRISMS-4 Long Term Efficacy Study and 0.39 as first line therapy in the
CARE-MS I study.
Relapse During the Study
88% of the mITT patient population and 100% of the PP patient population
were relapse free at 24 weeks of treatment with RHB-104. This data compares
favorably with previously reported pivotal data on the use Rebif(R) (75%)
in comparison with Avonex(R) (63%) as standalone first line therapies .
Notably, no patients in the CEASE-MS study relapsed after treatment week 8
and there was also marked improvement over historical self-control of the
CEASE-MS patients.
Expanded Disability Status Scale (EDSS)
The EDSS scale is a standard for monitoring MS patients. EDSS scores in the
study were stable at 24 weeks and were suggestive of improvement.
Importantly, no increase in total EDSS was observed in any of the patients
in the study.
T2 Lesion Volume and MS Disease Burden
Burden of disease is defined as the total volume of all MRI T2 lesions. T2
lesion load, expected to increase by approximately 11% per year in RRMS if
untreated , is accepted as an indicator of response and progression in
RRMS. Although not powered for efficacy, and conducted over a short period
of time in a small number of patients, the CEASE-MS study interim results
indicate a reduction in T2 lesion volume at 24 weeks of treatment with
RHB-104 as compared to baseline, suggesting reduction in MS disease burden
and comparing favorably with previously reported Avonex(R) and Rebif(R)
data: In a previous study with Rebif(R), administered for 24 months as
first line treatment of RRMS, median T2 lesion burden was noted to decrease
by 6.5% at 24 months , while patients treated with RHB-104 as add-on
therapy in the CEASE-MS study had a 3.37% decrease in median T2 lesion
burden at 24 weeks. Mean T2 lesion burden decreased by 7.56% at 24 weeks in
the CEASE-MS study with RHB-104 as add-on therapy, compared with a 10.4%
increase in Avonex(R) treated patients at 12 months.
Combined Unique Active Lesions (CUA)
MRI is useful in monitoring MS progression and MRI findings are generally
accepted as a surrogate endpoint in MS trials. Combined unique active
lesions (CUAs) are defined as active lesions on T1 post-gadolinium, T2
sequences, or both, avoiding double counting. A T2 lesion in this context
is defined as a new or enlarging lesion or a lesion reappearing at a site
of previous lesion resolution. CUAs served as the primary outcome measure
of the CEASE-MS study and among all patients followed, only a single active
T1 post gadolinium lesion was noted. Combined unique active lesions (CUAs)
in the study were almost entirely driven by changes in T2 lesions, and
changes in total CUA lesions at week 24 were not clinically significant. An
increase in the average percent change from baseline was observed for total
CUA lesions at week 24 yet, as noted above, a positive efficacy signal was
seen in reduction of total T2 lesion volume at 24 weeks as compared to
baseline. This apparent discrepancy between the average percent change from
baseline and the reduction of total T2 lesion volume is best explained by a
combination of statistical fluctuation and definitional bias in this small
study. Importantly, these MRI findings, along with the presence of only a
single active T1 post gadolinium lesion, are consistent with stable
radiological and clinical disease.
Safety and Tolerability
Overall, RHB-104 was well tolerated. There were no clinically relevant or
unexpected adverse events reported in the study, and none of five serious
adverse events (SAEs) seen in the study were related to the study drug. As
expected, almost all patients experienced chromaturia (abnormal coloration
of the urine). Two subjects withdrew from the study due to adverse events
of metallic taste and nausea/vomiting.
Cytokine Levels
Cytokine analysis contribution was generally difficult to assess due to
absence of control, the very small patient population and heterogeneity in
observed values.
Mycobacterium avium subspecies paratuberculosis (MAP) Status
Development of the RedHill MAP diagnostic is ongoing. It is expected that
evaluation of MAP status, using samples collected and stored as part of the
ongoing CEASE-MS study, will be performed in conjunction with the
development of the diagnostic test.
About Multiple Sclerosis:
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of
the central nervous system with an unknown etiology, believed to be
multifactorial. A dysfunctional immune system in MS patients causes
recurrent inflammatory attacks on the central nervous system (CNS), leading
to neurological disability. Diffuse inflammatory and demyelinating lesions,
also known as plaques, are the main pathological finding in MS neural
tissue. The lesions are primarily found in the spinal cord, optic nerves,
brainstem, and periventricular white matter. The symptoms of MS are
dictated by the location of the lesions within the CNS. Geographic
variation in MS distribution, which cannot be solely explained by
population genetics, supports the notion that environmental factors also
hold etiological importance. There is currently no known cure for MS, and
available treatments are mainly intended to manage or prevent relapses or
reduce symptoms. In 2015, there were estimated to be over 900,000 diagnosed
patients with MS worldwide. Approximately 85% of MS patients initially
exhibit relapse-remitting disease. The 2015 U.S. and worldwide sales of MS
therapies were estimated to exceed $12 billion and $17 billion,
respectively.
About RHB-104:
Currently in a first Phase III study for the treatment of Crohn's disease
(the MAP US study) and a second Phase III study which is being prepared
(the MAP EU study), RHB-104 is a proprietary and potentially groundbreaking
antibiotic combination therapy in oral capsule formulation, with potent
intracellular, anti-mycobacterial and anti-inflammatory properties. RHB-104
is based on increasing evidence supporting the hypothesis that Crohn's
disease is caused by Mycobacterium avium subspecies paratuberculosis (MAP)
infection in susceptible patients. Clinical trials conducted with earlier
formulations of RHB-104 include an Australian Phase III study conducted by
Pfizer. RedHill has conducted several supportive studies with the current
formulation of RHB-104 and a long-term population pharmacokinetic (pop-PK)
study is ongoing as part of the Phase III MAP US study. RHB-104 is covered
by several issued and pending patents. RedHill is also conducting the
CEASE-MS Phase IIa, proof-of-concept clinical study, evaluating RHB-104 as
an add-on therapy to interferon beta-1a in patients treated for
relapsing-remitting multiple sclerosis (RRMS), with top-line interim
results announced.
About RedHill Biopharma Ltd.:
RedHill Biopharma Ltd. (NASDAQ/TASE: RDHL) is a biopharmaceutical company
headquartered in Israel, primarily focused on the development and
commercialization of late clinical-stage, proprietary, orally-administered,
small molecule drugs for the treatment of inflammatory and gastrointestinal
diseases, including cancer. RedHill's current pipeline of proprietary
products includes: (i) RHB-105 - an oral combination therapy for the
treatment of Helicobacter pylori infection with successful results from a
first Phase III study; (ii) RHB-104 - an oral combination therapy for the
treatment of Crohn's disease with an ongoing first Phase III study and an
ongoing proof-of-concept Phase IIa study for multiple sclerosis; (iii)
BEKINDA(TM) (RHB-102) - a once-daily oral pill formulation of ondansetron
with an ongoing Phase III study in the U.S. for acute gastroenteritis and
gastritis and a planned Phase II study for IBS-D; (iv) RHB-106 - an
encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v)
YELIVA(TM) (ABC294640) - an orally-administered first-in-class SK2
selective inhibitor targeting multiple oncology, inflammatory and
gastrointestinal indications with a Phase I/II study initiated for
refractory/relapsed diffuse large B-cell lymphoma (DLBCL); (vi) MESUPRON(R)
- a Phase II-stage first-in-class uPA inhibitor, administered by oral
capsule, targeting gastrointestinal and other solid tumors; (vii) RP101 -
currently subject to an option-to-acquire by RedHill, RP101 is a Phase
II-stage first-in-class Hsp27 inhibitor, administered by oral tablet,
targeting pancreatic and other gastrointestinal cancers; (viii)
RIZAPORT(TM) (RHB-103) - an oral thin film formulation of rizatriptan for
acute migraines, with a U.S. NDA currently under discussion with the FDA
and marketing authorization received in Germany in October 2015; and (ix)
RHB-101 - a once-daily oral pill formulation of the cardio drug carvedilol.
This press release contains "forward-looking statements" within the meaning
of the Private Securities Litigation Reform Act of 1995. Such statements
may be preceded by the words "intends," "may," "will," "plans," "expects,"
"anticipates," "projects," "predicts," "estimates," "aims," "believes,"
"hopes," "potential" or similar words. Forward-looking statements are based
on certain assumptions and are subject to various known and unknown risks
and uncertainties, many of which are beyond the Company's control, and
cannot be predicted or quantified and consequently, actual results may
differ materially from those expressed or implied by such forward-looking
statements. Such risks and uncertainties include, without limitation, risks
and uncertainties associated with (i) the initiation, timing, progress and
results of the Company's research, manufacturing, preclinical studies,
clinical trials, and other therapeutic candidate development efforts; (ii)
the Company's ability to advance its therapeutic candidates into clinical
trials or to successfully complete its preclinical studies or clinical
trials; (iii) the extent and number of additional studies that the Company
may be required to conduct and the Company's receipt of regulatory
approvals for its therapeutic candidates, and the timing of other
regulatory filings, approvals and feedback; (iv) the manufacturing,
clinical development, commercialization, and market acceptance of the
Company's therapeutic candidates; (v) the Company's ability to establish
and maintain corporate collaborations; (vi) the Company's ability to
acquire products approved for marketing in the U.S. that achieve commercial
success and build its own marketing and commercialization capabilities;
(vii) the interpretation of the properties and characteristics of the
Company's therapeutic candidates and of the results obtained with its
therapeutic candidates in research, preclinical studies or clinical trials;
(viii) the implementation of the Company's business model, strategic plans
for its business and therapeutic candidates; (ix) the scope of protection
the Company is able to establish and maintain for intellectual property
rights covering its therapeutic candidates and its ability to operate its
business without infringing the intellectual property rights of others; (x)
parties from whom the Company licenses its intellectual property defaulting
in their obligations to the Company; (xi) estimates of the Company's
expenses, future revenues capital requirements and the Company's needs for
additional financing; (xii) competitive companies and technologies within
the Company's industry; and (xiii) the impact of the political and security
situation in Israel on the Company's business. More detailed information
about the Company and the risk factors that may affect the realization of
forward-looking statements is set forth in the Company's filings with the
Securities and Exchange Commission (SEC), including the Company's Annual
Report on Form 20-F filed with the SEC on February 25, 2016. All
forward-looking statements included in this Press Release are made only as
of the date of this Press Release. We assume no obligation to update any
written or oral forward-looking statement unless required by law.
<pre>
Company contact: IR contact (U.S.):
Adi Frish Marcy Nanus
Senior VP Business Development & Senior Vice President
The Trout Group
Licensing +1-646-378-2927
RedHill Biopharma Mnanus@troutgroup.com
+972-54-6543-112
adi@redhillbio.com
</pre>
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451083 05.04.2016
DGAP-News: RedHill Biopharma Ltd.: RedHill Biopharma Announces Interim Results from Phase IIa Proof-of-Concept Study Supporting Therapeutic Potential of RHB-104 in Multiple Sclerosis
| Source: EQS Group AG