Medical Policy

 

Subject: Monoclonal Antibodies to Interleukin-23
Document #: DRUG.00111 Publish Date:    08/29/2018
Status: Reviewed Last Review Date:    07/26/2018

Description/Scope

This document addresses the use of anti-interleukin-23 monoclonal antibodies developed for use in adults for the treatment and maintenance of moderate to severe plaque psoriasis. Currently, there are two FDA approved therapies which specifically target the p19 subunit of interleukin-23 which is implicated as the key regulatory cytokine in the psoriasis inflammatory pathway. Guselkumab (Tremfya®, Janssen Biotech, Horsham, PA) was approved in 2017. Tildrakizumab-asmn (Ilumya™, Sun Pharma Cranbury, NJ) was approved in early 2018.

Note: Please see the following related documents for additional information:

Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in DRUG.00111, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Position Statement

Medically Necessary:

Guselkumab or Tildrakizumab-asmn is considered medically necessary for the treatment of plaque psoriasis when all of the following criteria are met:

  1. Individual is 18 years of age or older with chronic moderate to severe plaque psoriasis with either of the following:
    1. Plaque psoriasis involving greater than 5% body surface area; or
    2. Plaque psoriasis involving less than or equal to 5% body surface area involving sensitive areas or areas that significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia); and
  2. Agent is used for any of the following reasons:
    1. To reduce signs or symptoms; or
    2. To induce or maintain clinical response; and
  3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (such as acitretin, cyclosporine, or methotrexate).

Not Medically Necessary:

Guselkumab and Tildrakizumab-asmn are considered not medically necessary for an individual with any of the following:

  1. When used in combination with other immunosuppressive therapy (such as other biologic drugs or phototherapy); or
  2. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  3. Individual has not had a tuberculin skin test or a Centers for Disease Control and Prevention-recommended equivalent test to evaluate for latent tuberculosis prior to initiating therapy.

Investigational and Not Medically Necessary:

Guselkumab and Tildrakizumab-asmn are considered investigational and not medically necessary when criteria are not met and for the treatment of all other indications.

Rationale

Guselkumab

On July 13, 2017, the United States (U.S.) Food and Drug Administration (FDA) approved guselkumab (Tremfya) for the treatment of moderate to severe plaque psoriasis in individuals who are candidates for systemic therapy or phototherapy. Guselkumab is supplied as a prefilled syringe to be given as a subcutaneous injection which can be self-administered once training has been completed. Guselkumab may increase the risk of infection with the most common adverse reactions reported being upper respiratory infections, headaches, injection site reactions, arthralgias, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections. Individuals should be evaluated for tuberculosis (TB) prior to the initiation of treatment.

In a pivotal, phase III, multicentered, randomized, double-blind, placebo-controlled trial (VOYAGE 1), Blauvelt and colleagues (2016) compared guselkumab with adalimumab (weeks 0-48) and a placebo-controlled period (weeks 0-16). Adults with moderate to severe plaque psoriasis with no symptoms or history of active tuberculosis who had not previously received adalimumab or systemic immunosuppressants were included. In addition, individuals who had received other anti-TNF-a therapy within the previous 3 months; other treatment targeting IL-12/23, IL-17, or IL-23 within the previous 6 months or phototherapy within the previous 4 weeks were excluded. Participants (n=837) were randomized in a 2:1:2 ratio to receive guselkumab (n=329) for 44 weeks, placebo (n=174) for 12 weeks followed by guselkumab up to week 44; or adalimumab (n=334) for 47 weeks. The coprimary endpoints were the proportion of each group who achieved an Investigator Global Assessment (IGA) 0/1 score at week 16 and the proportion of each group who achieved a PASI 90 at 16 weeks in the guselkumab group compared with the placebo group. At 16 weeks, a significantly greater proportion of individuals in the guselkumab group met co-primary endpoints compared to the placebo group (IGA 0/1: 85.1% versus 6.9%, p<0.001; PASI 90 response: 73.3% versus 2.9%; p<0.001; respectively). The placebo group had achieved similar responses to the guselkumab group after crossing over and receiving guselkumab therapy. In addition, the guselkumab group outcomes at week 16 were superior to the adalimumab group outcomes (IGA 0/1: 85.1% versus 65.9%; PASI 90:73.3% versus 49.7%; respectively). By week 24, the guselkumab group maintained better response rates compared to the adalimumab group. Adverse events (AEs) and abnormal laboratory results were equal between the guselkumab and placebo groups by week 16, and between the guselkumab and adalimumab groups at week 48. Serious infections, malignancies, neutropenia, candidiasis, Crohn’s disease and major adverse cardiovascular events were low across all groups. The authors noted that the results demonstrated the superior efficacy of guselkumab therapy compared with adalimumab therapy. Further studies are needed to evaluate guselkumab’s long term efficacy and safety.

The second pivotal phase III VOYAGE 2 clinical trial conducted by Reich and colleagues (2017) was comprised of 992 individuals randomized to receive guselkumab (n=496), placebo (n=248) or adalimuab (n=248). The coprimary endpoints were the proportion of each group who achieved an IGA 0/1 score at week 16 and the proportion of each group who achieved a PASI 90 at 16 weeks in the guselkumab group compared with the placebo group. Participants (n=992) were randomized in a 2:1:2 ratio to receive guselkumab (n=496) for 20 weeks, placebo (n=248) for 12 weeks followed by guselkumab up to week 23; or adalimumab (n=248) for 23 weeks. At 16 weeks, a significantly greater proportion of individuals in the guselkumab group met coprimary endpoints compared to the placebo group (IGA 0/1: 84.1% versus 8.5%, p<0.001; PASI 90 response: 70.0% versus 2.4%; p<0.001; respectively). Comparison between the two active treatment groups showed that the guselkumab group outcomes at week 16 were superior to the adalimumab group outcomes (IGA 0/1: 84.1% versus 67.7%; PASI 90:70.0% versus 46.8%; respectively). By week 24, the guselkumab group maintained better response rates compared to the adalimumab group. In adalimumab non-responders (n=112) who initiated guselkumab 5 weeks after last adalimumab dose, the PASI 90 response rate was 66.1% at week 48. The most commonly reported adverse effects between the guselkumab and placebo groups included nasopharyngitis, headache, and upper respiratory tract infections. Serious infection, malignancies and major adverse cardiovascular events (MACE) were low across each group. There were two cases of tuberculosis with adalimumab and five malignancy cases with guselkumab. Limitations to this study included subject withdrawal due to an adverse event before 28 weeks affecting study populations, and the comparison of guselkumab with adalimumab for a 24-week duration was insufficient to detect rare events.

The authors indicated that both studies, VOYAGE 1 and VOYAGE 2, yielded similar results and validated the conclusion that guselkumab had greater efficacy than adalimumab when the 100 mg dose injection was administered at 0, 4 and every 8 weeks . This conclusion may suggest that guselkumab is an important treatment modality for psoriasis. However, it should be acknowledged that data in 71 clinical trials including randomized controlled, open label and long extension studies provided evidence of adalimumab long-term safety. These trials studied six different immune-mediated inflammatory diseases including psoriasis, conducted in several continents, spanning 12 years demonstrating that adalimumab has produced no new safety signals (Burmester and colleagues (2013).

In a randomized, double-blind, Phase III (NAVIGATE trial), Langley and associates (2017) evaluated the safety and efficacy of guselkumab in individuals who had an inadequate response to ustekinumab. Clinical efficacy was measured evaluated using the IGA scores with the primary endpoint set as the number of visits at which randomized individuals achieved IGA 0/1 and ≥ 2 grade improvement (from week 16) from week 28-40. Individuals with moderate or severe plaque psoriasis (n=871) received open-label ustekinumab. Those with an inadequate response to ustekinumab (an IGA of 2 or greater) at week 16, were randomized to receive either ustekinumab (n=133) or guselkumab (n=135). Individuals with an adequate response (n=585) continued on open-label ustekinumab (n=585). A total of 18 individuals discontinued treatment during the open-label treatment period.  Individuals who received guselkumab had a significantly higher mean number of visits with an IGA score of 0 or 1 and at least a 2-grade improvement relative to week 16 from week 28 through week 40 compared to those who received ustekinumab (1.5 versus. 0.7; p<0.001). In addition, the proportion of individuals with an IGA score of 0 or 1 and ≥ 2-grade improvement relative to week 16 at week 28 was significantly greater in the guselkumab group compared to the ustekinumab group (31.1% versus 14.3%, p=0.001). AEs were slightly higher in the guselkumab group compared to the ustekinumab group, primarily due to higher reported rates of musculoskeletal and connective tissue disorders (eg, back pain and psoriatic arthropathy), general disorders and administration site conditions such as injection site reactions. Infections were the most common type of AE reported, with the rate of incidence similar between both randomized groups. Serious AEs were reported in 6.7% (n=9) of the guselkumab-treated group and 4.5% (n=6) of the ustekinumab-treated group.

Guselkumab (Tremfya) 2017 FDA Product Information label includes the following warnings and precautions:  

Tildrakizumab-asmn

On March 21, 2018, the FDA approved tildrakizumab-asmn (Ilumya) to treat adults with moderate to severe plaque psoriasis who are candidates for systemic or phototherapy. Tildrakizumab-asmn is administered by subcutaneous injection every 12 weeks, after the initial loading doses. The approval was based on two pivotal trials (reSURFACE 1 and reSURFACE 2) which evaluated tildrakizumab-asmn against placebo or etanercept in individuals with chronic plaque psoriasis.

Reich and associates reported on the results of both pivotal trials (Reich, 2017) which involved individuals aged 18 years or older with moderate to severe chronic plaque psoriasis. Moderate to severe disease was defined as having body surface area involvement (BSA) of 10% or greater, Physician’s Global Assessment (PGA) score of 3 or greater, and Psoriasis Area and Severity Index (PASI) score of 12 or greater. The co-primary endpoints for both studies were noted as the proportion of individuals achieving PASI 75 and a PGA response defined as a score of 0/1 with a 2 or greater grade improvement from baseline through week 12. In reSURFACE 1, 772 participants were randomly assigned to receive either tildrakizumab-asmn 200 mg, tildrakizumab-asmn 100 mg or placebo. ReSURFACE 2 (n=1090), included a fourth arm in the study in which individuals received etanercept. Both trials included a second part (following 12 weeks) in which those in the placebo group were re-randomized to receive either tildrakizumab-asmn 200 or 100 mg. Finally, in part 3 of both trials, responders and partial responders in either tildrakizumab-asmn group were re-randomised at 28 weeks to continue the same treatment, receive a different dose of tildrakizumab-asmn, or to the placebo group. At week 12, both studies reported a significantly higher proportion of individuals achieving PASI 75 in the tildrakizumab-asmn groups than in the placebo groups (p<0.0001). In addition, in reSURFACE 2, there was a significantly higher proportion of individuals achieving PASI 75 in the tildrakizumab-asmn 200 mg group compared to the etanercept group (66% versus 48%; 17·4% difference; p<0.0001). Individuals who were initially assigned to placebo and were re-randomized to receive tildrakizumab-asmn reported similar response rates by week 28 as those who had received tildrakizumab-asmn throughout the study. AEs were similar across both studies and all groups. In reSURFACE 1, one or more AEs were reported in 40 to 48% of all participants with serious AEs reported in 1 to 3% of all participants. ReSURFACE 2 reported one or more AEs in 43 to 57% of all participants with serious AEs reported in 1 to 5% of all participants.

Tildrakizumab-asmn (Ilumya) 2018 FDA Product Information label includes the following warnings and precautions:

Combination therapy

Combination therapy involves the use of more than one type of agent, which may act synergistically by targeting different steps in the psoriasis pathology pathway. It has been proposed as a potential therapy for recalcitrant psoriasis which has not responded to monotherapy.Currently, there have been no published studies evaluating the use of anti-interleukin-23 monoclonal antibodies in combination with other immunosuppressive agents.

Background/Overview

According to the AAD (2008) plaque psoriasis is a multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. The major manifestation of plaque psoriasis is chronic inflammation of the skin, characterized by "disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritic and may cause significant quality of life issues." Treatments available to help manage the symptoms of plaque psoriasis include topical therapy, phototherapy, systemic therapy, and biologic disease-modifying anti-rheumatic drugs.

There are several types of psoriasis:

Plaque psoriasis is the most common type of psoriasis, approximately 79% of individuals with psoriasis will develop plaque psoriasis (National Psoriassi Foundation [NPF], 2017). Psoriatic arthritis is a condition associated with plaque psoriasis. Psoriatic arthritis is characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons. Symptoms of psoriatic arthritis can range from mild to very severe. Approximately 1 in 3 individuals, or 2.4 million people, with psoriasis develop psoriatic arthritis (NPF, 2017).

Guselkumab and tildrakizumab-asmn are human IgG1 antibodies that bind to the p19 subunit of interleukin (IL)-23, inhibiting its interaction with the IL-23 receptor and suppressing IL-23-mediated inflammation associated with psoriasis. These cytokines are abundant in psoriatic skin and are thought to promote the accumulation of the psoriasis-causing T-cells.  Earlier therapies suppressed both IL-12 and 23, however, subsequent research has shown that IL-23 is the primary inflammatory pathway and it’s inhibition is at least as effective as the inhibition of both IL-12 and 23 (Reich, 2017).

The American Academy of Dermatology (AAD) published a set of evidence-based guidelines, Guidelines of Care for the Management of Psoriasis (Ps) and Psoriatic Arthritis (PsA) (AAD, 2008), intended to assist physicians in managing the complexities of the treatment of individuals with Ps and PsA. The first guideline, Section 1: Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis with Biologics (AAD, 2008) provides an overview of psoriasis classification, co-morbidities, assessment tools, and the use of biologics to treat psoriasis. The work group states that approximately 80% of individuals affected with psoriasis have mild to moderate disease, with 20% having moderate to severe psoriasis, defining the extent of body surface area involvement as:

…affecting more than 5% of the body surface area (BSA) or affecting crucial body areas such as the hands, feet, face, or genitals…The areas of involvement and types of psoriasis should be considered in evaluating severity of disease because the impact of these types of psoriasis may be quite substantial.

Treatment planning for the use of a biologic agent for moderate to severe plaque psoriasis considers this definition of body surface area involvement with plaque psoriasis. In addition, for individuals with plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (for example, palms, soles of feet, head/neck, or genitalia), ≤ 5% body surface area involvement is considered as moderate to severe disease.

Definitions

Conventional therapy: Treatments that are widely accepted and practiced by the medical community.

Dermatology Life Quality Index (DLQI): The effect of skin problems on aspects of daily life during the previous week for an overall score of 0-30 with a higher score indicating severe disease.

Immunomodulator drugs: A class of drugs that modifies or influences the immune system.

Investigator Global Assessment (IGA): Psoriatic lesions are graded for induration, erythema, and scaling on a scale of 0-4: clear (0), minimal (1), mild (2), moderate (3), severe (4).

Monoclonal antibody: A laboratory-produced protein that can locate and bind to specific cells wherever they are in the body. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to their target cell.

Nail Psoriasis Severity Index (NAPSI): A target nail is examined for the presence of nail matrix and nail bed psoriasis on a scale of 0-4 with higher scores indicating severe disease.

Psoriasis Area and Severity Index (PASI): Psoriatic lesions are assessed in the head, trunk, and upper and lower extremities, account for 10%, 20%, 30%, and 40% respectively of the Body Surface Area (BSA), and rated on a scale of 0-4 with a higher score indicating more severe disease.

Psoriasis Symptoms and Signs Diary Symptoms (PDDS): Signs and symptoms of psoriasis are graded on a scale of 0-10 scale in a daily diary with a higher score indicating more severe symptoms.

Physician Global Assessment of Hands and/or Feet (hf-PGA): The severity of psoriasis plaques on the palms and soles is scored on a 5-point scale: clear (0), almost clear (1), mild (2), moderate (3), and severe (4).

Scalp-Specific Investigator Global Assessment (ss-IGA): Scalp lesions are assessed in terms of clinical signs of redness, thickness, and scaliness and are scored on a 5-point scale: absence of disease (0), very mild disease (1), mild disease (2), moderate disease (3), severe disease (4).

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

C9029

Injection, guselkumab, 1 mg [Tremfya]

J3490

Unclassified drugs [when specified as guselkumab (Tremfya) or tildrakizumab-asmn (Ilumya)]

J3590

Unclassified biologics [when specified as guselkumab (Tremfya) or tildrakizumab-asmn (Ilumya)]

 

 

ICD-10 Diagnosis

 

 

L40.0

Psoriasis vulgaris

 

L40.1

Generalized pustular psoriasis

 

L40.2

Acrodermatitis continua

 

L40.3

Pustulosis palmaris et plantaris

 

L40.4

Guttate psoriasis

 

L40.8

Other psoriasis

 

L40.9

Psoriasis, unspecified

 

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above, for the situations described in the Position Statement section as not medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Blauvelt, A, Papp, KA, Griffiths, CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo-and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017; 76(3):405-417.
  2. Burmester GR, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and crohn’s disease. Ann Rheum Dis. 2013; 72(4):517-524.
  3. Farahnik B, Patel V, Beroukhim Ket al. Combining biologic and phototherapy treatments for psoriasis: safety, efficacy, and patient acceptability. Psoriasis (Auckl). 2016; 6:105-111.
  4. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, Phase 3 NAVIGATE trial. Br J Dermatol. 2018; 178(1):114-123.
  5. Papp K, Thaçi D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015; 173(4):930-939.
  6. Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017; 76(3):418-431.
  7. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017; 390(10091):276-288.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Dermatology (AAD). American Academy of Dermatology Association (AADA). Guidelines of care for management of psoriasis and psoriatic arthritis. May 2008. Available at: http://www.aad.org/education-and-quality-care/clinical-guidelines. Accessed on July 9, 2018.
  2. Guselkumab (Tremfya) [Product Information Label]. Janssen Research & Development, LLC, Spring House, PA. July 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761061s000lbl.pdf. Accessed on July 9, 2018.
  3. Tildrakizumab-asmn (Ilumya) [Product Information Label]. Merck & CO., Whitehouse Station, NJ. March 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761067s000lbl.pdf. Accessed on July 9, 2018.
  4. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2017; 12:CD011535.
Websites for Additional Information
  1.  National Psoriasis Foundation (NPF). Available at: https://www.psoriasis.org/. Accessed on July 9, 2018.
  2. U.S. National Library of Medicine. Health Topics. Available at: http://www.nlm.nih.gov/medlineplus/healthtopics.html. Accessed on July 9, 2018.
Index

CNTO 1959
Guselkumab
Ilumya
MK-3222
Tildrakizumab-asmn
Tremfya

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.  Updated Rationale and References sections.

Revised

05/03/2018

MPTAC review. Revised title from Guselkumab (Tremfya™) to Monoclonal Antibodies to Interleukin-23. Add tildrakizumab-asmn to the medically necessary, not medically necessary and investigational and not medically necessary position statements. Updated Discussion, Rationale, Background, References and Index sections.

 

12/27/2017

The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes; added C9029.

 

10/01/2017

Updated Discussion adding note referring to CG-ADMIN-02.

New

08/03/2017

MPTAC review. Initial document development.

Preliminary Discussion

05/04/2017

MPTAC review. Pre-FDA approval review.