Cara Therapeutics: Difelikefalin Struggles To Stand Out With Uncertain Prospects

Marina Demidiuk

Introduction

Cara Therapeutics (NASDAQ:CARA) is simply a commercial-stage biopharmaceutical institution focused connected processing caller treatments to amended nan lives of patients suffering from pruritus. Cara received FDA support successful 2021 for its KORSUVA (difelikefalin) injection, nan first and only curen for moderate-to-severe pruritus associated pinch CKD successful adults undergoing hemodialysis. Cara is besides processing an oral formulation of difelikefalin and has initiated Phase 3 objective tests for nan curen of pruritus successful patients pinch precocious non-dialysis limited chronic kidney illness (CKD) and atopic dermatitis.

Recent events: During nan 3rd 4th of 2022, nan Cara's partner launched Kapruvia successful Europe, while KORSUVA was approved successful Canada, Singapore, and Switzerland, pinch expected support successful Australia. The institution besides presented information for oral difelikefalin successful notalgia paresthetica and plans to talk a imaginable pivotal programme pinch nan FDA. The proof-of-concept trial for oral difelikefalin successful superior biliary cholangitis was discontinued owed to slow enrollment, and nan Phase 3 programme for oral difelikefalin successful pruritus associated pinch non-dialysis limited precocious chronic kidney illness is ongoing. The Phase 3 programme for oral difelikefalin arsenic an adjunctive therapy to topical corticosteroids successful atopic dermatitis is enrolling patients.

The pursuing article will talk oral difelikefalin's prospects successful precocious non-dialysis limited chronic kidney illness (CKD) patients pinch moderate-to-severe pruritus.

Financials

Let's first look astatine Cara's astir caller financial report:

Cara Therapeutics had a full of $179.5 cardinal successful cash, rate equivalents, and marketable securities arsenic of September 30, 2022, a alteration from $236.8 cardinal astatine December 31, 2021, chiefly owed to rate utilized successful operating activities. The institution reported a nett nonaccomplishment of $23.2 cardinal for nan 3rd 4th of 2022, compared to a nett nonaccomplishment of $1.0 cardinal for nan aforesaid play successful 2021. Total gross was $10.8 cardinal for nan 3 months ended September 30, 2022, chiefly from collaborative gross related to profit-sharing gross from Vifor's income of KORSUVA injection to 3rd parties. Research and improvement expenses were $24.7 million, and wide and administrative expenses were $6.9 cardinal for nan aforesaid period. The institution expects its rate to money its operating scheme until nan first half of 2024.

Data by YCharts

Understanding nan Pathophysiology of Uremic Pruritus successful Chronic Kidney Disease

Uremic pruritus, besides known arsenic CKD-aP, affects up to 50% of patients pinch CKD, causing systemic and resistant itching that tin importantly trim value of life. The pathophysiology of uremic pruritus is not afloat understood, but respective mechanisms person been proposed. Uremic toxins that accumulate successful nan bloodstream owed to decreased kidney usability whitethorn activate histamine and different pruritogenic mediators, starring to nan sensation of itch. Chronic inflammation and pro-inflammatory cytokines whitethorn besides play a domiciled successful nan improvement of pruritus. Other imaginable mechanisms see changes successful tegument obstruction function, alterations successful calcium and phosphate metabolism, and decreased accumulation of endogenous opioids.

Treatment Options for Uremic Pruritus successful CKD Patients: A Stepwise Approach

Uremic pruritus is simply a communal information successful CKD patients that often proves resistant to treatment. Management of this information involves a stepwise approach, which takes into information nan severity of symptoms and consequence to first therapies. The curen options for uremic pruritus see optimizing dialysis targets, treating hyperparathyroidism, hyperphosphatemia, and hypermagnesemia, utilizing emollients and/or topical analgesics, and administering oral antihistamines, gabapentin, aliases pregabalin for resistant pruritus. For refractory pruritus, difelikefalin is suggested.

Difelikefalin: Mechanism of Action

Difelikefalin, a caller opioid agonist, has precocious selectivity for KOR and has been shown to beryllium effective successful nan curen of chronic pruritus. By activating KOR connected peripheral sensory neurons, it inhibits nan afferent transmission of sensory signals to nan CNS, and has an immunomodulatory effect. Difelikefalin has been shown to activate KORs connected cells of nan immune system, starring to a simplification successful nan accumulation of pro-inflammatory cytokines and a simplification successful inflammation. Compared to different opioids, difelikefalin has a minimal effect connected nan cardinal tense strategy and does not origin respiratory slump aliases sedation.

Intravenous Difelikefalin: A Modestly Effective Treatment for Pruritus successful ESRD, pinch Potential for Growth successful nan Market

Intravenous difelikefalin (0.5 microgram/kg) has demonstrated modest efficacy successful nan curen of pruritus associated pinch ESRD successful respective randomized controlled trials. In a pooled study of 2 randomized controlled trials, difelikefalin was shown to beryllium effective successful reducing nan strength of pruritus successful patients connected attraction hemodialysis pinch mean to terrible pruritus. The curen was well-tolerated, and nan adverse events were mostly mild to mean successful severity. However, owed to its intravenous administration, difelikefalin has immoderate limitations, specified arsenic nan imaginable for vascular entree complications.

Subsequent, intravenous difelikefalin was FDA-approved successful 2021. However, difelikefalin's marketplace is comparatively mini compared to different medications utilized to dainty uremic pruritus owed to its caller preamble and constricted approval. As a later-line curen option, it is typically only utilized aft different medications and treatments person grounded to supply relief. Nevertheless, arsenic much investigation is conducted and clinicians go much acquainted pinch difelikefalin's efficacy and information profile, its marketplace whitethorn expand.

Efficacy and Safety of Oral Difelikefalin successful Patients pinch Advanced NDD Chronic Kidney Disease and AD: Results from Phase 2 Trial

The imaginable marketplace for oral difelikefalin successful patients pinch precocious NDD chronic kidney illness and AD is significant, arsenic pruritus is simply a communal denotation successful these patients that negatively impacts their value of life. The Phase 2 trial for difelikefalin was a 12-week study involving 240 shape III-V CKD patients pinch moderate-to-severe pruritus, successful which nan information and efficacy of 3 dose levels (0.25 mg, 0.5 mg and 1 mg, erstwhile daily) of oral difelikefalin were evaluated against placebo. The superior efficacy endpoint was nan alteration from baseline successful nan play mean of nan regular 24-hour Worst Itching Intensity Numeric Rating Scale (WI-NRS) people astatine Week 12 for immoderate of nan 3 tablet strengths vs. placebo. The 1 mg tablet spot of oral difelikefalin achieved nan superior endpoint of statistically important simplification successful play mean of nan regular WI-NRS scores vs. placebo aft nan 12-week curen period. The curen effect was statistically important aft 2 weeks of curen and sustained done nan 12-week curen period. The proportionality of patients connected nan 1 mg tablet spot achieving a 3-point aliases greater betterment from baseline successful nan play mean of nan regular WI-NRS people astatine week 12 was 72% vs. 58% for placebo but did not execute statistical significance. Patients connected nan 1 mg tablet spot showed affirmative improvements successful itch-related value of life endpoints arsenic measured utilizing self-assessment Skindex-10 and 5-D Itch scales, but did not execute statistical significance. Oral difelikefalin was mostly well-tolerated, pinch a information floor plan accordant pinch that seen successful earlier difelikefalin objective trials, and nan incidence of curen emergent adverse events (AES) were akin crossed difelikefalin and placebo groups. The astir communal curen emergent AEs reported successful >5% of patients successful nan 1 mg difelikefalin group vs. placebo were dizziness, fall, diarrhea, and constipation.

FDA Approves Phase 3 Program for Oral Difelikefalin successful Advanced NDD Chronic Kidney Disease and Pruritus

In April 2021, a gathering took spot betwixt Cara Therapeutics and nan FDA to reappraisal nan Phase 2 proceedings results of oral difelikefalin successful NDD CKD-aP and nan anticipation of a Phase 3 program. Following this meeting, nan FDA authorized nan inclusion of Stage V pre-dialysis CKD patients successful nan program. Later, successful November 2021, nan FDA expanded nan diligent organization to see Stage IV pre-dialysis patients pinch precocious CKD for a registration programme that involves two trials, KICK 1 and KICK 2. Both tests purpose to enroll astir 400 patients pinch precocious CKD successful Stages 4 aliases 5 and moderate-to-severe pruritus, who are not connected dialysis. The superior endpoint for some tests is nan proportionality of patients who execute a minimum 4-point betterment astatine Week 12 from baseline successful nan worst-itch numerical standing standard (WI-NRS). At nan extremity of Week 12, patients will beryllium randomly assigned to either person oral difelikefalin aliases a placebo for 52 weeks. Cara Therapeutics anticipates announcing top-line results successful nan 2nd half of 2024.

Factors Affecting Difelikefalin's Success successful Phase 3 Trial

The shape 2 proceedings of difelikefalin did not scope statistical value successful nan proportionality of patients achieving a 3-point aliases greater betterment from baseline successful nan play mean of nan regular Worst Itching Intensity NRS people astatine week 12. This suggests that nan 3-point period utilized successful nan proceedings whitethorn not person been delicate capable to observe a existent quality successful nan drug's effectiveness compared to nan placebo.

The shape 3 proceedings uses a higher 4-point threshold, which whitethorn beryllium much delicate successful detecting a important quality successful nan proportionality of patients achieving a clinically meaningful betterment successful pruritus. This whitethorn consequence successful a smaller proportionality of patients gathering nan endpoint, but a larger quality betwixt nan curen and placebo groups, perchance starring to statistical value being achieved. However, different factors specified arsenic sample size and variability whitethorn besides effect nan expertise to observe a important difference.

One imaginable situation for difelikefalin's occurrence successful nan shape 3 proceedings is nan quality successful diligent organization betwixt nan 2 trials. Phase 2 included patients pinch shape III, IV, aliases V CKD, while shape 3 only includes precocious shape 4 and 5 CKD patients not presently connected dialysis. Advanced shape 4 and 5 CKD patients not presently connected dialysis whitethorn beryllium much difficult to dainty for pruritus reduction, arsenic they are much apt to person terrible and persistent pruritus. Additionally, they whitethorn person aggregate comorbidities and return aggregate medications, which tin complicate curen and perchance trim nan effectiveness of nan study drug.

Another facet to see is nan inclusion criteria of "inadequate consequence to existent aliases anterior topical treatments (including emollients) for pruritus anterior to screening" successful nan Phase 3 trial, which was not coming successful nan Phase 2 trial. This whitethorn consequence successful a much treatment-resistant diligent organization successful nan Phase 3 trial, perchance impacting nan efficacy of nan supplier and its generalizability to nan broader CKD population.

Difficulty successful Predicting Phase 3 Success and Limited Marketability of Difelikefalin

The differences successful proceedings protocols betwixt Phase 2 and Phase 3 tests of difelikefalin make it challenging to find nan likelihood of occurrence for nan supplier successful precocious CKD patients pinch moderate-to-severe pruritus who are not connected dialysis. The alteration successful nan superior endpoint, nan usage of a higher threshold, and nan inclusion criteria of inadequate consequence to topical treatments successful nan Phase 3 proceedings could effect nan drug's efficacy and generalizability to nan broader CKD population.

Moreover, if difelikefalin gains FDA support based connected Phase 3 data, nan changes successful inclusion criteria from Phase 2 to Phase 3 could limit nan drug's marketability. It whitethorn only beryllium utilized for resistant aliases refractory pruritus owed to nan existing curen paradigm. Thus, while difelikefalin whitethorn beryllium to beryllium effective successful reducing pruritus successful precocious CKD patients not connected dialysis, its imaginable marketplace whitethorn beryllium constricted to a circumstantial subset of patients.

Conclusion

In general, I americium not a instrumentality of Cara Therapeutics' risk/reward profile, moreover though nan marketplace does not look to overvalue it. KORSUVA is improbable to make important gross for Cara owed to its constricted usage and deficiency of differentiation from cheaper, much established drugs. Additionally, I person doubts astir nan clinical, regulatory, and marketplace prospects of difelikefalin (oral & intravenous). While they do person different prospects successful nan pruritus market, specified arsenic atopic dermatitis, indications extracurricular of CKD are apt to look akin challenges. Therefore, my existent proposal for Cara Therapeutics is to "Sell", and investors should workout be aware erstwhile it comes to pivotal CKD-related pruritus.

As a practicing Registered Nurse pinch a Bachelor of Science successful Nursing (BSN), I person a keen liking successful biotechnology and bask researching and penning astir it. Drawing from my nonstop acquisition pinch patients and my analytical skills, I connection unsocial perspectives connected nan topic. My superior attraction is connected late-stage/approved drugs, evaluating curen options and determining wherever a caller supplier whitethorn beryllium champion suited, arsenic good arsenic expanding consciousness of nan risks associated pinch objective proceedings outcomes and marketplace performance.