Cara Therapeutics, Inc. (Nasdaq: CARA), a biopharmaceutical company
focused on developing and commercializing new chemical entities
designed to alleviate pruritus by selectively targeting peripheral
kappa opioid receptors, or KORs, today announced topline results
from its KARE Phase 2 dose-ranging clinical trial of Oral KORSUVA™
(difelikefalin tablets) for the treatment of moderate-to-severe
pruritus in mild-to-severe atopic dermatitis (AD) patients. The
trial enrolled 401 patients at multiple clinical sites across the
United States
“We are encouraged to have met the expected
Phase 3 registration endpoint of a 4-point responder analysis in
the mild-to-moderate AD group,” said Joana Goncalves, M.D., Chief
Medical Officer at Cara Therapeutics. “We now have a defined
patient group and active dose range for Oral KORUSVA in which to
design a registration program that we expect to discuss with the
FDA in the coming months .”
“The KARE Phase 2 trial demonstrates the unique
anti-itch effects of KORSUVA in atopic dermatitis, a highly
inflammatory skin disease,” said Dr. Brian Kim, M.D., MTR, FAAD,
Co-Director, Center For The Study of Itch And Sensory Disorders,
Washington University School of Medicine. “This is novel and
promising for a future in which we can treat the central symptom of
AD, especially for patients with mild-to-moderate AD who experience
severe itch.”
KARE Phase 2 Trial Design and
Results
The KARE Phase 2 trial was a randomized,
double-blind, placebo-controlled study designed to evaluate the
efficacy and safety of Oral KORSUVA for moderate-to-severe pruritus
in 401 adult subjects with atopic dermatitis. Patients were
stratified across treatment groups by disease severity. KARE
enrolled 64% of patients characterized as mild-to-moderate
(BSA<10%) and 36% falling into the moderate-to-severe category
(BSA>10%). Subjects were randomized to three tablet strengths of
Oral KORSUVA: 0.25 mg, 0.5 mg and 1 mg taken twice daily (BID)
versus placebo for 12 weeks followed by 4 weeks of an active
extension phase. A prespecified interim conditional power
assessment was conducted after approximately 50% of the originally
targeted patient number completed the designated 12-week treatment
period. Based on the Independent Data Monitoring Committee’s (IDMC)
recommendation, the sample size for the 0.5mg dose and placebo
groups was increased by approx. 60% respectively.
Primary Efficacy
Endpoint
- KARE’s primary efficacy endpoint
was change from baseline in the weekly mean of the daily 24-hour
Itch NRS score at week 12 of the treatment period. Although no dose
group met this endpoint, a statistically significant improvement
from baseline was evident as early as week 1 for the 1 mg dose
group which was sustained through 75% of the treatment period.
- In a prespecified analysis, a
statistically significant change in the primary efficacy endpoint
was observed in the mild-to-moderate (BSA<10%) patient
population (p=0.036, All doses vs placebo) which was evident at
week 1 and sustained through the treatment period.
Key Secondary
Endpoint
- The key secondary endpoint for KARE
was the assessment of the proportion of patients achieving an
improvement from baseline of ≥4 points with respect to the weekly
mean of the daily 24-hour Itch NRS score at week 12 (4-point
Responder Analysis). No dose group met this endpoint for the ITT
population.
- Prespecified analysis by disease
severity indicated a statistically significant improvement in the
4-point Responder Analysis in the mild-to-moderate (BSA<10%)
patient population with 32% of KORSUVA-treated patients achieving a
≥4 point reduction in NRS at Week 12 versus 19% in the placebo
group (p=0.033, All doses vs placebo). A statistically significant
improvement was also achieved for the 0.5 mg dose (p=0.046, 0.5mg
vs placebo).
Oral KORSUVA was generally well-tolerated across
all doses. Overall, the incidence of treatment-emergent adverse
events (AEs) was generally similar across KORSUVA and placebo
groups. The most common treatment-emergent AEs reported in >5%
of patients in any KORSUVA group and greater than placebo were
abdominal pain, nausea dry mouth, headache, dizziness and
hypertension (5/77 patients in 1 mg dose group; 4/5 of patients had
documented prior history of hypertension at
enrollment).About Atopic Dermatitis
AD is a chronic, pruritic inflammatory
dermatosis that affects up to 25% of children and 2-5% of adults
(Eichenfeld et al 2015, Barbarot 2018). Pruritus is an integral
part of AD and can aggravate the disease due to scratching. Itch is
so common in AD that AD is often described as the itch that rashes
(Boguniewicz M (2005). Pruritus prevalence in AD patients is
greater than 80% and greatly impairs the quality of life of AD
patients by causing sleep and psychological disturbance. (Mochizuki
H, Schut 2005; Farmer WS, 2017) Both quality of life and
psychosocial well-being are known to negatively correlate with itch
severity.(Yosipovitch G, 2008)
The cause of AD is multifactorial, including
genetic predisposition, impaired skin barrier, environmental
triggers, and immune dysregulation (Bieber T. 2010; Thyssen JP,
Kezic S; 2014). The sensation of itch in AD is similarly complex.
Chronic itch in AD is mediated by a complex interplay between
keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and
the peripheral and central nervous system (Pavlis J, Yosipovitch G
2018). An imbalance in the epidermal opioid system has also been
described as potentially playing a role in the modulation of
pruritus in AD (Tominaga et al 2007).
Available systemic immunosuppressants have shown
to reduce pruritus, however several factors may limit their use
e.g., these agents are generally reserved for patients with only
moderate to severe AD, safety concerns exist with regards to long
term therapy, there is limited efficacy with some of the treatments
and certain routes of administration (e.g., an injectable route of
administration) may be problematic in some patients.
Despite the treatments available to manage
pruritus in AD, there remain limitations in the current modalities
for use in the mild-to-moderate AD population. As ~80% of the
AD population falls within the mild-to-moderate category this
remains the most significant opportunity in the AD market for the
development of effective systemic anti-pruritic agents
References
- Boguniewicz M. Atopic dermatitis:
beyond the itch that rashes. Immunol Allergy Clin N Am.
2005;25(2):333–51
- Dawn A, Papoiu AD, Chan YH, Rapp
SR, Rassette N, Yosipovitch G.Itch characteristics in atopic
dermatitis: results of a web-based questionnaire.Br J
Derm.2009;160(3):642–4.
- Eichenfeld L et al Am Acad
Dermatol. 2014 February ; 70(2): 338–351.
- Barbarot S, Auziere S, Gadkari A, Girolomoni
G, Puig L, Simpson EL, Margolis DJ, de
Bruin-Weller M, Eckert L, Epidemiology of atopic dermatitis in
adults: Results from an international survey. Allergy. 2018
Jun;73(6):1284-1293
- Mochizuki H, Schut C, Nattkemper LA, Yosipovitch G. Brain
mechanism of itch in atopic dermatitis and its possible alteration
through non-invasive treatments. Allergology international :
official journal of the Japanese Society of Allergology.
2017;66(1):14-21.
- Farmer WS, Marathe KS. Atopic Dermatitis: Managing the Itch.
Advances in experimental medicine and biology.
2017;1027:161-177.
- Yosipovitch G, Papoiu AD. What causes itch in atopic
dermatitis? Current allergy and asthma reports.
2008;8(4):306-311.
- Bieber T.Atopic dermatitis. Ann
Dermatol. 2010;22(2):125–37. 7.
- Thyssen JP, Kezic S. Causes of
epidermal filaggrin reduction and their role in the pathogenesis of
atopic dermatitis. J Allergy Clin Immunol. 2014;134(4):792–9
- Janelle Pavlis’ Gil Yosipovitch,
Management of Itch in Atopic Dermatitis; Am J Clin Dermatol (2018)
19:319–332
- Tominaga M, Ogawa H, Takamori K. Possible roles of epidermal
opioid systems in pruritus of atopic dermatitis. J Invest Dermatol.
2007;127(9):2228-2235
Conference Call
Cara management will host a conference call
today at 8:00 a.m. ET to discuss the results of the study.
To participate in the conference call, please
dial (800) 708-4539 (domestic) or (847) 619-6396 (international)
and refer to conference ID 50157934. A live webcast of the call can
be accessed under "Events & Presentations" in the News &
Investors section of the Company's website at
www.CaraTherapeutics.com.
An archived webcast recording will be available
on the Cara website beginning approximately two hours after the
call.
About Cara Therapeutics
Cara Therapeutics is a clinical-stage
biopharmaceutical company focused on developing and commercializing
new chemical entities designed to alleviate pruritus by selectively
targeting peripheral kappa opioid receptors, or KORs. Cara is
developing a novel and proprietary class of product candidates, led
by KORSUVA™ (CR845/difelikefalin), a first-in-class KOR agonist
that targets the body’s peripheral nervous system, as well as
certain immune cells. In two Phase 3 trials, KORSUVA Injection has
demonstrated statistically significant reductions in itch intensity
and concomitant improvement in quality of life measures in
hemodialysis patients with moderate-to-severe chronic kidney
disease-associated pruritus (CKD-aP). The U.S. Food and Drug
Administration (FDA) has accepted and granted Priority Review for
the New Drug Application (NDA) for KORSUVA™ (difelikefalin)
solution for injection for the treatment of moderate-to-severe
pruritus in hemodialysis patients. The PDUFA target action date for
KORSUVA is August 23, 2021. Oral KORSUVA™ has completed Phase 2
trials for the treatment of pruritus in patients with CKD and AD
and is currently in Phase 2 trials in primary biliary cholangitis
and notalgia paresthetica patients with moderate-to-severe
pruritus.
The FDA has conditionally accepted KORSUVA™ as
the trade name for difelikefalin injection. CR845/difelikefalin is
an investigational drug product and its safety and efficacy have
not been fully evaluated by any regulatory authority.
Forward-looking Statements
Statements contained in this press release
regarding matters that are not historical facts are
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995. Examples of these
forward-looking statements include statements concerning ongoing
clinical trials, the future development of Oral KORSUVA for
pruritus in patients with mild-to-moderate atopic dermatitis, the
plans for meeting with the FDA regarding the potential
registrational program for Oral KORSUVA for mild-to-moderate AD and
the timing of such discussions, and the potential for Oral KORSUVA
to treat these patients. Because such statements are subject to
risks and uncertainties, actual results may differ materially from
those expressed or implied by such forward-looking statements.
Risks are described more fully in Cara Therapeutics’s filings with
the Securities and Exchange Commission, including the "Risk
Factors" section of Cara Therapeutics’s Annual Report on Form 10-K
for the year ended December 31, 2020 and its other documents
subsequently filed with or furnished to the Securities and
Exchange Commission. All forward-looking statements contained in
this press release speak only as of the date on which they were
made. Except to the extent required by law, Cara Therapeutics
undertakes no obligation to update such statements to reflect
events that occur or circumstances that exist after the date on
which they were made.
MEDIA CONTACT: Claire LaCagnina6
Degrees315-765-1462 clacagnina@6degreespr.com
INVESTOR CONTACT:Janhavi MohiteStern Investor
Relations, Inc.janhavi.mohite@SternIR.com
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