Medical Policy

 

Subject: Ibalizumab-uiyk (Trogarzo™)
Document #: DRUG.00096 Publish Date:    08/29/2018
Status: New Last Review Date:    07/26/2018

Description/Scope

This document addresses the uses for ibalizumab-uiyk (TrogarzoTM; TaiMed Biologics, Irvine, CA). Ibalizumab-uiyk is a humanized monoclonal antibody (mAb) that belongs to the class of human immune deficiency virus (HIV) drugs known as entry and fusion inhibitors which prevent HIV from attaching to and entering human cells. This action hampers replication of HIV and can reduce the viral load in the body.

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

Position Statement

Medically Necessary:

Ibalizumab-uiyk is considered medically necessary for the treatment of multidrug-resistant HIV in combination with other antiretroviral(s), when all of the following criteria are met:

  1. Individual is 18 years of age or older; and
  2. Has a viral load of > 1000 copies/mL; and
  3. Has a history of at least 6 months on antiretroviral treatment; and
  4. Is receiving a failing antiretroviral regimen or has failed and is off therapy; and
  5. Documented resistance to at least one antiretroviral medication from each of the following three named classes as measured by resistance testing
    1. non-nucleoside reverse transcriptase inhibitors (NNRTIs); and
    2. nucleoside reverse transcriptase inhibitors (NRTIs); and
    3. protease inhibitors (PIs); and
  6. Documentation of full viral sensitivity/susceptibility to at least one antiretroviral agent, other than ibalizumab-uiyk, as determined by resistance tests.

Investigational and Not Medically Necessary:

Ibalizumab-uiyk is considered investigational and not medically necessary when the criteria above are not met and for all other indications, including but not limited to:

  1. Individuals who have received immunomodulating therapy within the 12 weeks preceding initiation of treatment with ibalizumab-uiyk (for example, interferon, systemic steroids or systemic chemotherapy);
  2. Individuals being treated for an acute infection secondary to HIV infection.
Rationale

On March 6, 2018, ibalizumab-uiyk received Food and Drug Administration (FDA) approval, in combination with other antiretrovirals, for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection who are failing their current antiretroviral regimen. Ibalizumab-uiyk received breakthrough and orphan drug status for this indication (Product Information [PI] Label, 2018).

The safety and effectiveness of ibalizumab-uiyk was primarily evaluated in a 24-week, Phase III, open-label, single-arm clinical trial in which 40 participants were enrolled. Study enrollees were required to have been on antiretroviral therapy (ART) for at least 6 months and failed the regimen within 8 weeks of study screening. Inclusion criteria included, no acquired immunodeficiency syndrome (AIDS)-defining events in the previous 3 months other than Kapsoi’s sarcoma or HIV wasting syndrome, a viral load of > 1000 copies/mL, documented resistance to at least one antiretroviral medication from each of three drug classes as measured by resistance testing (approved drug classes: non-nucleoside reverse transcriptase inhibitors [NNRTIs], nucleoside reverse transcriptase inhibitors [NRTIs], or protease inhibitors [PIs]), as well as full viral sensitivity/susceptibility to at least one antiretroviral agent, other than ibalizumab. Individuals who were being treated for an acute infection secondary to HIV, were previously exposed to ibalizumab-uiyk or had received immunomodulating therapy within the most recent 12 weeks, were not eligible for enrollment. The individuals enrolled were a heavily treatment-experienced population, with 53% reporting a treatment history of 10 or more antiretroviral drugs. Participants continued their failed ART regimen (or no regimen if they were not currently being treated) and received a single loading dose of intravenous (IV) ibalizumab-uiyk on day 7. Beginning on day 14, through week 23, participants entered the maintenance period and received ibalizumab-uiyk every 2 weeks. Preliminary results show that 82.5% (33 out of 40) of participants enrolled in the study met the primary endpoint of a decrease of ≥ 0.5 log10 in viral load (FDA specified end-point based on historical viral load reduction needed to improve clinical outcomes in this population) from the beginning to the end of the “Functional monotherapy period” (day 7-13) as compared to the proportion of subjects achieving a ≥ 0.5 log10 decrease from the beginning to the end of the “Control period” (day 0-6). At study-end, only 31 of 40 participants remained enrolled in this study (23% [n=9] discontinuations); 4 died, 3 withdrew consent and 2 were lost to follow-up. At Week 25, viral load < 50 and < 200 HIV-1 RNA copies/mL was achieved in 43% and 50% of subjects, respectively (considered an undetectable viral load). The most commonly reported adverse events were rash, diarrhea, headache, and nausea. Most events were mild to moderate. A total of 9 individuals experienced 16 serious adverse events (SAEs), including 10 SAEs that were reported in subjects who died. None of the deaths were attributed to ibalizumab-uiyk; causes were determined to be: 1) respiratory arrest secondary to Kaposi’s sarcoma; 2) hepatic failure secondary to cirrhosis due to hepatitis C infection; 3) lymphoma and; 4) presumed HIV wasting syndrome. The 6 SAEs experienced by subjects who survived included: diplopia, pulmonary hypertension, progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS), cytomegalovirus viremia, fever, and squamous cell carcinoma of the anus and rectum. The only event considered to be related to ibalizumab-uiyk (per investigator) was IRIS manifested as an exacerbation of PML. One participant was found to have low-levels of anti-ibalizumab-uiyk antibodies (PI Label, 2018). Trial limitations include a lack of comparator group, lack of long-term follow-up and only 77% of participants (n=31) remained enrolled at study-end. Furthermore, the safety and efficacy of ibalizumab-uiyk has not yet been established in individuals with a viral load of < 1000 copies/mL. Future studies assessing the long-term impact of ibalizumab-uiyk on survival in the setting of a randomized-controlled trial would contribute greatly to fully understanding the drug’s efficacy and safety profile.

Background/Overview

n the United States, nearly 1.2 million people are infected with the HIV, the virus that causes AIDS. HIV enters cells by a complex process that involves attachment to the CD4 receptor followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cell membranes. HIV attacks the immune system by destroying CD4 positive (CD4+) T-cells, a type of white blood cell that is vital to fighting off infection. The destruction of these cells leaves people infected with HIV vulnerable to other infections, diseases and serious associated complications.

Today, there are 31 ART drugs approved by the FDA for the treatment of HIV infection. These treatments do not cure HIV or AIDS but suppress the virus. The advent of ART has turned what was once a fatal disease into a manageable chronic illness for many individuals. There are six major classes of drugs used to treat infection with HIV, they are grouped by how they interfere with replication of the virus. However, the emergence of drug resistance to ARTs and the need for simpler regimens that allow better adherence have been an important focus in the research surrounding HIV/AIDS.

Ibalizumab-uiyk is a humanized mAb that belongs to a class of HIV drugs known as entry and fusion inhibitors. Entry and fusion inhibitors block HIV from getting into and infecting certain cells of the immune system which prevents the virus from multiplying and can reduce the viral load. Ibalizumab-uiyk works by attaching to a CD4 receptor on the surface of immune cells which prevents attachment and entry of HIV into the cell. Ibalizumab-uiyk was shown to have significant antiviral activity in the treatment-experienced adults and was well tolerated in clinical studies.

Adverse Events and Warnings

The most common (incidence >5%) adverse reactions listed on the FDA PI Label (2018) include diarrhea, dizziness, nausea, and rash. An additional FDA PI Label consideration highlights immune reconstitution inflammatory syndrome (IRIS) which was reported in individuals treated with ibalizumab-uiyk in combination with other antiretrovirals.

Definitions

Acquired Immunodeficiency Syndrome (AIDS): A disease of the body's immune system caused by the human immunodeficiency virus (HIV). AIDS is characterized by the death of CD4 cells (an important part of the body's immune system), which leaves the body vulnerable to life-threatening conditions, such as infections and cancers.

Antagonist: Block the binding of an agonist (a substance that binds to a specific receptor and triggers a response in the cell) at a receptor site. Coreceptor antagonists prevent the HIV virus from attaching to CD4 coreceptor.

CD4 cells: A type of infection-fighting white blood cell that carries the CD4 receptor on its surface; also known as helper T cell or CD4 lymphocyte. CD4 cells coordinate the immune response, which signals other cells in the immune system to perform their special functions. The number of CD4 cells in a sample of blood is an indicator of the health of the immune system. HIV infects and kills CD4 cells, which leads to a weakened immune system.

Chemokine receptor 5 (CCR5): A protein on the surface of some immune system cells. Along with CXCR4, it is one of two coreceptors that HIV can use along with the CD4 receptor to bind to and enter host cells.

Coreceptor: A protein on the surface of a cell that serves as a second binding site for a virus or other molecule. Although the CD4 protein is HIV's primary receptor, the virus must also bind to either the CCR5 or CXCR4 coreceptor to get into a host cell.

Human Immunodeficiency Virus (HIV): The virus that causes Acquired Immunodeficiency Syndrome (AIDS). HIV is in the retrovirus family and is responsible for most HIV infections throughout the world.

Immune Reconstitution Inflammatory Syndrome (IRIS): An exaggerated inflammatory reaction to a disease-causing microorganism that sometimes occurs when the immune system begins to recover following treatment with antiretroviral (ARV) drugs; it may be mild or life-threatening.

Treatment-experienced: A term used to describe HIV-infected individuals who are currently being treated with anti-HIV drugs or who have taken anti-HIV drugs in the past.

Treatment failure: A broad term that describes failure of an anti-HIV treatment to adequately control HIV infection. The three types of HIV treatment failure are virologic, immunologic, and clinical failure. Factors that contribute to treatment failure include poor adherence, drug resistance, and drug toxicity.

Viral load (VL): The amount of HIV RNA in a blood sample, reported as number of HIV RNA copies per milliliter of blood plasma; also known as HIV RNA. The VL provides information about the number of cells infected with HIV and is an important indicator of HIV progression and of how well treatment is working. 

Virologic failure: The inability of anti-HIV drug treatment to reduce viral load or to maintain suppression of viral load. Virologic failure is the most common type of treatment failure and may lead to immunologic and clinical failure.

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

 

J3490

Unclassified drugs [when specified as ibalizumab-uiyk (Trogarzo)]

J3590

Unclassified biologics [when specified as ibalizumab-uiyk (Trogarzo)]

 

 

ICD-10 Diagnosis

 

 

B20

Human immunodeficiency virus [HIV] disease

 

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. Jacobson JM, Kuritzkes DR, Godofsky E, et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother. 2009; 53(2):450-457.
  2. Lewis S, Fessel J, Emu B, et al. Long-acting ibalizumab in patients with multi drug-resistant HIV-1: A 24-Week study. Conference on Retroviruses and Opportunistic Infections. February 2017. Abstract Number: 449LB. Available at: http://www.croiconference.org/sessions/long-acting-ibalizumab-patients-multi-drug-resistant-hiv-1-24-week-study. Accessed on June 21, 2018.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Department of Health and Human Services (DHHS). AIDSinfo. Ibalizumab. Updated on September 01, 2016. Available at: https://aidsinfo.nih.gov/drugs/511/ibalizumab/0/professional.  Accessed on June 21, 2018. 
  2. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Updated on May 30, 2018. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.  Accessed on June 21, 2018.
  3. Ibalizumab. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated March 16, 2018. Available at: http://www.micromedexsolutions.com. Accessed on June 21, 2018.
  4. TrogarzoTM [Product Information Label], Irvine, CA. TaiMed Biologics, Inc. Revised March 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761065lbl.pdf. Accessed June 21, 2018.
  5. Theratechnologies Inc. Ibalizumab plus optimized background regimen in patients with multi-drug resistant HIV. NLM Identifier: NCT02475629. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02475629. Accessed on June 21, 2018. 
Websites for Additional Information
  1. Department of Health and Human Services (DHHS). AIDSinfo Glossary. Available at: https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/199/department-of-health-and-human-services.  Accessed on June 21, 2018.
  2. DHHS. HIV/AIDS medical practice guidelines. Available at: http://aidsinfo.nih.gov/guidelines. Accessed on June 21, 2018.
Document History

Status

Date

Action

New

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development.

Preliminary Discussion

11/03/2016

MPTAC Pre-FDA approval review.