Targeting Pruritus with Novel Peripherally-Restricted Kappa Agonist Therapeutics - May 2020 - Cara Therapeutics
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Targeting Pruritus with Novel Peripherally-Restricted Kappa Agonist Therapeutics May 2020
Forward Looking Statements
This presentation contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of
1995. In some cases, you can identify forward-looking statements by the words “anticipate,” “believe,” “continue,” “estimate,”
“expect,” “objective,” “ongoing,” “plan,” “propose,” “potential,” “projected”, or “up-coming” and/or the negative of these terms, or
other comparable terminology intended to identify statements about the future. Examples of these forward-looking statements in
this presentation include, among other things, statements concerning plans, strategies and expectations for the future, including
statements regarding the expected timing of our planned clinical trials and regulatory submissions; the potential results of ongoing
and planned clinical trials; future regulatory and development milestones for the Company's product candidates; the size of the
potential markets that are potentially addressable for the Company’s product candidates, including the pruritus market and the
potential commercialization of Korsuva™.
These statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of
activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking
statements. Although we believe that we have a reasonable basis for each forward-looking statement contained in this presentation,
we caution you that these statements are based on a combination of facts and factors currently known by us and our expectations of
the future, about which we cannot be certain. Factors that may cause actual results to differ materially from any future results
expressed or implied by any forward-looking statements include the risks described in the “Risk Factors” section of the Company’s
Annual Report on Form 10-K for the year ended December 31, 2019, as well as those set forth from time to time in the Company’s
other SEC filings, available at http://www.sec.gov. Any forward-looking statements speak only as of the date of this presentation.
The Company undertakes no obligation to publicly update any forward-looking statements, whether as a result of new information,
future events or otherwise except as required by law.
2
Pruritus: Large Opportunity Across Different Disease Areas
Chronic Kidney Disease (CKD)
Pruritus occurs in both patients on hemodialysis ~40 to 50%
and those with CKD not yet on dialysis.
Chronic Liver Disease (CLD)
Patients with CLD, especially cholestatic
~20% to 30%
liver disease experience significant pruritus
. U.S. Patients
Treated for Pruritus:
Atopic Dermatitis (AD)
Pruritus is a defining symptom of AD
~100% 20 Million
. SCRIPTS ANNUALLY #
3 # IQVIA Analysis, 2013
KORSUVA™ (Difelikefalin) Directly Blocks Pruritus Sensory Neurons
Macrophages Keratinocytes Mast Cells Tissue Injury T cells
KORSUVA
TNFR RTK
ETA 5HTR IL-31RA TGR5
PAR2 H1 TRPV1 TRPA1 Mrgprs TLR3/7 OSMR
Kappa
Pruritus Receptor
4 Source: Adapted from Pflugers Arch . 2013 December ; 465(12): . doi:10.1007/s00424-013-1284-2
Development Pipeline
STAGE OF DEVELOPMENT
Commercial Rights
Program Indication Preclinical Phase 1 Phase 2 Phase 3 (ex-Japan and S. Korea)^
KORSUVA™ US- Cara
Pruritus CKD-HD** EU/Other- VFMCRP#
Injection
Oral Pruritus CKD
Cara
KORSUVA™ (III-V)
Oral
Pruritus CLD Cara
KORSUVA™
Oral Pruritus Atopic
Cara
KORSUVA™ Dermatitis
The FDA has conditionally accepted KORSUVA™ as the trade name for CR845 / difelikefalin for pruritic indications. CR845 / difelikefalin
is an investigational drug product, and its safety and efficacy have not been fully evaluated by any regulatory authority.
^ Commercialization rights to CR845 in defined indications - Japan: Maruishi Pharma; South Korea: CKD Pharma
** Breakthrough Designation for IV CR845 for Pruritus CKD-HD
# VFMCRP and Cara have rights to promote in Fresenius Medical Care dialysis clinics in the US under a profit share agreement
5 CKD-HD: Chronic Kidney Disease- Hemodialysis; CLD: Chronic Liver DiseaseKORSUVA™ Injection
for Dialysis Patients
6US Market Opportunity for KORSUVA™ Injection in Dialysis Patients
60%
of ESRD patients have pruritus2,3
>500K ~40%
patients on dialysis have moderate to severe pruritus
Per NKF, >500K patients undergoing KORSUVA™ granted Per Nov. 2018 CMS rule:
dialysis in the US1 Breakthrough Therapy within the ESRD Prospective
Designation for CKD-aP Payment System all new
• ~60% have some form of pruritus2,3 dialysis drugs eligible for
• Itching severity associated with worsening • Significant unmet need reimbursement at ASP for 2
Quality of Life (QoL) Sleep disturbance, • No FDA approved yrs under TDAPA, effective
depressed mood/anxiety, socialization therapies Jan. 1, 20204
• Increased mortality risk
1. National Kidney Foundation
2. Pisoni RL, Wikstrom B, Elder SJ, et al. Nephrol Dial Transplant. 2006;21:3495-3505.
3. Ramakrishnan et al. International Journal of Nephrology and Renovascular Disease. 2014:7 1–12
7 4. https://www.govinfo.gov/content/pkg/FR-2018-11-14/pdf/2018-24238.pdfKORSUVA Injection in CKD-HD: Phase 3 Program
KALM-1 trial (US): KALM-2 trial (Global): Open label safety studies:
Positive Data Readout Positive Data Readout Closing Q2, 2020
• Met Primary and • Met Primary and Key • > 1500 total exposures
Secondary Endpoints Secondary Endpoints • > 500 at 6 months
• Topline Data: • > 300 at 1 year
Q2, 2020
8
8KALM-1/2: General Pivotal Study Design
SCREEN 1:1 RANDOMIZATION END OF TREATMENT Endpoints: Week 12
Primary
RUN-IN INTRAVENOUS BOLUS TREATMENT
• Proportion of subjects achieving ≥3
point improvement from baseline in
KORSUVA 0.5 mcg/kg weekly mean of daily worst itching
after each hemodialysis session 52 Week intensity NRS (WI-NRS)
Open-Label Secondary
Extension
Ongoing • Proportion of subjects achieving
Placebo ≥4 point improvement in WI-NRS
after each hemodialysis session
• Change from baseline in itch-
related Quality of Life as measured
by Skindex-10 and 5-D Itch
7 Days 12 Weeks
questionnaires
Subjects Undergoing Hemodialysis Safety assessments
With Moderate-to-Severe Pruritus
(WI-NRS ≥ 4 or 5)
9Primary Endpoint: ≥3 point improvement WI-NRS (Week 12)
U.S. KALM-1 Trial Global KALM-2 Trial
P = 0.00002 60%
P = 0.020
60%
54%
51%
40% 40%
42%
20% 28% 20%
0% 0%
Placebo (N = 189) KORSUVA (N = 189) Placebo (N = 236) KORSUVA (N = 237)
10 Estimated percentage & P-value based on a logistic regression model with terms for treatment group, baseline WI-NRS score, region and strata
Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumptionKey Secondary Endpoint: ≥4 point improvement WI-NRS (Week 12)
U.S. KALM-1 Trial Global KALM-2 Trial
P = 0.00003 60%
P = 0.010
60%
40% 40%
41%
39%
20% 20%
28%
18%
0% 0%
Placebo (N = 189) KORSUVA (N = 189) Placebo (N = 236) KORSUVA (N = 237)
11 Estimated percentage & P-value based on a logistic regression model with terms for treatment group, baseline WI-NRS score, region and strata
Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumptionChange from Baseline in WI-NRS Over Time
Significant differences observed in WI-NRS starting at Week 1 and sustained through treatment period
0
U.S. KALM-1 Trial 0
Global KALM-2 Trial
Change from Baseline
-1 -1
*
* Placebo (N=189) Placebo (N=236)
* *
-2 -2
** *
** *
** * *
-3 -3 * * * *
** ** **
** * * * *
** ** ** *
KORSUVA (N=189) KORSUVA (N=237)
-4 -4
Baseline 1 2 3 4 5 6 7 8 9 10 11 12 Baseline 1 2 3 4 5 6 7 8 9 10 11 12
Weeks in Double-blind Treatment Period Weeks in Double-blind Treatment Period
LS Means over time LS Means over time
* P < 0.05, ** P < 0.001
LS Means from MMRM with terms for treatment group, week, week by treatment interaction, baseline score, region and strata
12 Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumptionKALM-2 & KALM-1 Pooled: Most Commonly Reported TEAEs
TEAEs at ≥5% frequency Placebo KORSUVA
(N= 424) (N= 424)
Diarrhea 20 (4.7) 37 (8.7)
Dizziness 14 (3.3) 26 (6.1)
Vomiting 20 (4.7) 25 (5.9)
Nausea 19 (4.5) 21 (5.0)
Fall 17 (4.0) 21 (5.0)
13 KALM-1 KALM-2 Pooled AEsKORSUVA™ Injection NDA and U.S. Commercial Launch
NDA Submission – 2H, 2020: U.S. Commercial Launch– 2021:
Breakthrough Designation 40% of Hemodialysis Patients:
& Priority Review Eligible moderate-severe CKD-aP
60% of population experiences pruritus
40%
moderate-severe CKD-aP
Total patient population in U.S. = 500k
14Established Commercial Agreements: KORSUVA Injection
Tiered Royalty By Sales: EU
$440 million Commercial Milestones
Maruishi Tiered Royalty By Sales: Japan
Pharmaceutical Co., Ltd. ~$10 million Commercial Milestone#
Tiered Royalty By Sales: S. Korea
15 • # 1 Billion YenOralKORSUVA™
Development Programs
16Development Programs for Oral KORSUVA™
Phase 2 Trial Complete Phase 2 Trial Phase 2 Trial
CKD-aP (Stage III-V) Atopic Dermatitis- Chronic Liver Disease-
associated Pruritus associated Pruritus
~25 to 30% experience pruritus ~87% to 100% experience pruritus ~30% experience pruritus
17Oral ™
KORSUVA for
CKD-associated Pruritus
18US Market Opportunity in CKD-aP: Non-Dialysis
~7.3 million 33%
diagnosed with CKD (IQVIA est) receive pruritus tx
Per NKF, CKD is a significant No FDA approved therapies – Oral KORSUVA™, if
under-recognized US public large unmet medical need approved for pre-dialysis
health issue • Commonly used medications:
patients, would not fall
• ~30 million people affected anti-histamines, corticosteroids, under ESRD bundle
gabapentin, anti-depressants etc. payment system
19Oral KORSUVA™ for CKD-aP: Phase 2 Trial Design
SCREEN
RANDOMIZE END OF Endpoints: Week 12
(N = 240; 1:1:1:1) TREATMENT
Primary
RUN-IN TREATMENT (Once Daily) • Change from baseline in weekly mean
of daily Worst Itching Intensity NRS
Difelikefalin: 0.25 mg (WI-NRS) score
Difelikefalin: 0.5 mg Secondary & Additional
• Change from baseline in itch-related
Difelikefalin: 1.0 mg QoL
✓ Skindex-10
Placebo ✓ 5-D Itch
• Proportion of subjects achieving >3
points improvement from baseline in
7 Days 12 Weeks
weekly mean of daily WI-NRS score
Baseline Mean Change WI-
• WI-NRS complete responder; patient
Mean WI-NRS > 5 NRS at Week 12
global impression of change
20Primary Endpoint: Change from Baseline to Week 12 for WI-NRS
Significant difference in WI-NRS in patients treated with 1 mg oral KORSUVA™ compared to placebo
Difelikefalin
Placebo 0.25 mg 0.50 mg 1.00 mg
0
-1
Change from Baseline
-2
-3
-4
-5 p=0.018
LS Mean from MMRM with terms for treatment group, week, week by treatment interaction as fixed effects; baseline score and strata as covariates; patient as a repeated measures
Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption
21Change in Worst Itching Intensity NRS Over Time
0
Significant differences Placebo (N = 67)
-1
between 1mg oral
KORSUVA and placebo
Change from Baseline
DFK 1.00 mg (N = 67)
-2
observed in WI-NRS *
starting at week 2
-3 **
**
**
** *
-4 * *
* P < 0.05, ** P < 0.01
*
*
-5
Weeks in Double-blind Treatment Period
LS Means over time
LS Mean from MMRM with terms for treatment group, week, week by treatment interaction as fixed effects; baseline score and strata as covariates; patient as a repeated measures
22 Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumptionAdditional Endpoint: Complete Responder
NRS Complete Responder*
50
p=0.006
40
p=0.027 p=0.037
% of Subjects
30
20 33% 32% 39%
10
14%
0
Placebo 0.25 mg 0.5 mg 1.0 mg
Difelikefalin
*80% of NRS scores at Week 12 equal to 0 or 1.
Estimated percentage and P-values are based on a logistic regression model with terms for treatment group, baseline WI-NRS score, and renal disease status
23 Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumptionExecutive Summary & Next Steps
• Oral KORSUVA met the primary endpoint:1mg dose advancement to Phase 3
- Primary: Change from baseline in weekly mean WI-NRS score
- Dose-dependent statistically significant improvement in Complete Responders
• Oral KORSUVA was generally well-tolerated: safety profile similar to Phase 3
KORSUVA Injection studies
Projected End-of-Phase 2 FDA meeting/Phase 3 start: 2H,2020
24Oral KORSUVA™:
Additional Pruritus
Development Programs
Atopic Dermatitis
Chronic Liver Disease
25Atopic Dermatitis Associated Pruritus: Phase 2 Trial Ongoing
END OF END OF
Study
RANDOMIZE
SCREEN (N=320) TREATMENT EXTENSION 320 adult patients with AD
(80/arm) and moderate to severe
RUN-IN TREATMENT EXTENSION
pruritus
KORSUVA: 0.25 mg BID Primary Endpoint:
• Change from baseline in the weekly
KORSUVA: 0.5 mg BID mean of the daily 24-hour WI-NRS
score at Week 12
KORSUVA: 1 mg BID
Secondary Endpoints:
• Responder analysis (Week 12):
Placebo: BID Change from baseline in I-NRS
score of >4 points
7 Days 12 Weeks 4 weeks • Change in itch related QoL:
Skindex-10, 5-D Itch scales & Sleep
Baseline: Interim Statistical Assessment Mean Change WI-
Q2, 2020 NRS at Week 12 Quality Assessment at week 12
Mean NRS > 5
• Safety assessments
26Pruritus Associated with Primary Biliary Cholangitis (PBC): Phase 2
END OF Study
SCREEN 1:1 RANDOMIZATION TREATMENT A 16-week, double blind, randomized,
PBO-controlled study in PBC patients
RUN-IN TREATMENT
with moderate to severe pruritus
Oral KORSUVA 1 mg BID (N=30)
Primary Endpoint:
• Change from baseline in the weekly
mean of the daily 24-hour WI-NRS score
at week 16
Placebo BID (N=30)
Secondary Endpoints:
• Change in itch related QoL:
Skindex-10 & 5-D Itch scales at week 16
7 Days 16 Weeks
• Responder analysis (Week 16): Change
from baseline in weekly main of daily
worst NRS score of >3 points
• Safety assessments
27Financial Cash/marketable securities
Highlights (March 31, 2020)
$179.8M
Net loss
(March 31, 2020)
($28.9M)
Shares outstanding
~46.7M
28Projected Milestones –2020
Pruritus / KORSUVA™ Injection Pruritus / Oral KORSUVA™
Top-line data: KALM-2 Ph 3 Interim statistical analysis
2Q,2020 trial (CKD-aP in dialysis pts) Phase 2 Atopic Dermatitis
Top-line data Ph2 trials:
2H,2020 NDA submission Atopic Dermatitis
Chronic Liver Disease
Complete EoPII meeting:
2H,2020 Phase 3 Program
CKD-aP (Stage III-V CKD)
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