Ibalizumab

Associated long-acting platforms

Recombinant humanized monoclonal antibody

Administration route

Subcutaneous, Intramuscular, Intravenous

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Ibalizumab is a humanised IgG4, κ monoclonal antibody produced in a NS0 cell line. The successful scale-up of therapeutic monoclonal antibody (mAb) products involves achieving favourable pharmacokinetic profiles, maintaining formulation stability and ensuring consistency of the overall product quality. However, industrial bioprocessing steps can potentially introduce additional complexities regarding mAb solution viscosity and aggregation propensity.

Tentative equipment list for manufacturing

Industrial bioreactor vessel with a production volume capacity of between 5-25kL. Continuous disc stack centrifuges for bioreactor harvesting with subsequent membrane and depth filtration for supernatant clarification. Recombinant protein-A chromatography or other suitable affinity capture apparatus followed by two chromatographic polishing steps such as cation- and anion-exchange. Ultrafiltration membrane system to concentrate and formulate the final product.

Manufacturing

Store in a refrigerator at 2˚C to 8˚C (36˚F to 46˚F). Protect from light until use. Do not freeze. Ibalizumab is supplied in a single 2 mL (200mg/1.33 mL) glass vial with a rubber stopper and aluminum flip-off seal. MAbs are highly dependent on their structural, chemical and conformational stability for biological activity. Chemical degradation of mAbs during manufacture can lead to the generation of product variants and complex impurity profiles. Additionally prior to packaging, the final product requires close monitoring for the presence of residual contaminants such as endotoxins.

Specific analytical instrument required for characterization of formulation

Formulation characterisation steps for therapeutic mAb products include (but are not limited to): (1) Identification of post-translational modifications using ion-exchange chromatography and capillary isoelectric focusing. (2) Measurement of concentration dependent aggregation rates via thermal differential scanning calorimetry, sub-visible particle quantitation and size-exclusion chromatography. (3) Antibody clipping and fragmentation detection by capillary electrophoresis.

TMB-202

Identifier

NCT00784147

Link

https://clinicaltrials.gov/study/NCT00784147

Phase

Phase II

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

The investigational product, ibalizumab, is a humanized IgG4 monoclonal antibody administered via intravenous infusion at 800 mg every 2 weeks or at 2000 mg every 4 weeks. In addition to study drug, all patients will receive an optimized background regimen (OBR), which is a standard-of-care regimen selected by the investigator prior to randomization that is comprised of 2-4 antiretroviral agents. These agents must have been approved by the local regulatory agency or be available through expanded-access programs for treatment of human immunodeficiency virus (HIV).

Purpose

Dose-Response Study of Ibalizumab (Monoclonal Antibody) Plus Optimized Background Regimen in Patients With HIV-1

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2008-08-01

Anticipated Date of Last Follow-up
2014-04-17

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2011-04-01

Actual Completion Date
2011-04-01

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: 1. Are capable of understanding and have voluntarily signed the informed consent document 2. Have documented HIV-1 infection by official, signed, written history (eg, laboratory report), otherwise an HIV-antibody test will be performed 3. Have no acquired immunodeficiency syndrome (AIDS)-defining events in the 3 months before screening, other than cutaneous Kaposi's sarcoma or wasting syndrome due to HIV 4. Are able and willing to comply with all protocol requirements and procedures 5. Are 18 years of age or older 6. Have a life expectancy that is \>6 months. 7. Have a viral load \>1,000 copies/mL and documented decreased susceptibility to at least one NRTI, one NNRTI, and one PI, as measured by resistance testing 8. Are receiving a stable highly active antiretroviral

Health status

Study type

Interventional (clinical trial)

Enrollment

113

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

TMB-302

Identifier

NCT03913195

Link

https://clinicaltrials.gov/study/NCT03913195

Phase

Phase III

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

This study is designed to assess the safety and pharmacokinetic profile of 800 mg Trogarzo once every two weeks administered via "IV Push" or intramuscular injection. An initial "Sentinel Group" of 5 participants will begin receiving 800mg Trogarzo on a gradual schedule of increasing concentration and decreasing administration time until undiluted IV Push over 30 seconds is achieved, while safety and pharmacokinetics are evaluated. If no safety signals are seen, the Core Group of 15 participants will be enrolled. The Core Group will receive 800mg Trogarzo via undiluted IV Push over 30 seconds while safety and pharmacokinetics are monitored. After completion of the IV Push portion of the study, a second group of 20 participants will be enrolled to evaluate the safety and pharmacokinetics of

Purpose

Study of the Safety of Trogarzo™ Administered as an Undiluted "IV Push" or an Intramuscular Injection

Interventions

Intervention 1

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2019-05-30

Anticipated Date of Last Follow-up
2023-09-14

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2022-10-17

Actual Completion Date
2022-10-31

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria - HIV-infected participants (all groups): 1. Are capable of understanding and have voluntarily signed the informed consent document 2. Currently receiving a stable Trogarzo-containing ARV regimen for a minimum of 3 months, and no change in background ARVs anticipated over the period of study participation; a stable regimen is defined as having no changes in dose or frequency and no interruptions greater than or equal to 2 weeks during the 3 month period 3. Have no acquired immunodeficiency syndrome (AIDS)-defining events in the 3 months before Screening, other than cutaneous Kaposi's sarcoma or wasting syndrome due to HIV 4. Are able and willing to comply with all protocol requirements and procedures 5. Are 18 years of age or older 6. Have a life expectancy that is \>6

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

46

Allocation

Not provided

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

TMB-311

Identifier

NCT02707861

Link

https://clinicaltrials.gov/study/NCT02707861

Phase

Phase III

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

Ibalizumab is a monoclonal antibody that works by blocking HIV entry into the immune system cells (CD4+ or T-cells) the virus typically infects. Ibalizumab is intended for use in combination with other anti-HIV drugs in people with multi-drug resistant HIV and limited treatment options. This study will collect further information on the safety and tolerability of intravenously administered (IV) ibalizumab combined with an optimized background regimen for treating multi-drug resistant HIV-1 infection, and will provide continuing access to ibalizumab for patients completing a prior ibalizumab clinical trial.

Purpose

Ibalizumab Plus Optimized Background Regimen in Treatment-Experienced Patients With Multi-Drug Resistant HIV-1

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2016-03-01

Anticipated Date of Last Follow-up
2021-02-18

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2018-11-01

Actual Completion Date
2018-11-01

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: (Cohort 1) * Currently receiving ibalizumab via other TaiMed-sponsored or investigator-Sponsored protocol * Are capable of understanding and have voluntarily signed the informed consent document (Cohort 2) * 18 years of age or older * Are capable of understanding and have voluntarily signed the informed consent document * Have documented HIV-1 infection by official, signed, written history (e.g., laboratory report), otherwise an HIV-antibody test will be performed * Are able and willing to comply with all protocol requirements and procedures * Have a viral load \>1,000 copies/mL and documented resistance to at least one antiretroviral medication from each of three classes of antiretroviral medications as measured by previous viral resistance testing (resistance test

Health status

Study type

Interventional (clinical trial)

Enrollment

79

Allocation

Not provided

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

TMB-108

Identifier

NCT01292174

Link

https://clinicaltrials.gov/study/NCT01292174

Phase

Phase I

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

The is a blinded safety study of ibalizumab given by subcutaneous injection in sequentially increasing dose-groups of at-risk, HIV-negative, healthy volunteers. The study involves the administration of four total injections of ibalizumab or matching placebo in each volunteer, given once every week, at one of three dose levels. Drug administration begins at the lowest dose. After 4 of 8 volunteers in the first group have received all study drug injections and have completed 6 additional weeks of follow-up, an independent safety monitoring group will review available data before approving initiation of the next higher dose-group. This process will be repeated prior to initiation of the 3rd and highest dose-group. All volunteers will participate in 2 separate intensive blood sampling periods

Purpose

Safety Study of Ibalizumab Subcutaneous Injection in Healthy Volunteers

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2011-02-01

Anticipated Date of Last Follow-up
2012-12-17

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2012-09-01

Actual Completion Date
2012-09-01

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: 1. At-risk adult males and females, as assessed by a medical history, physical exam, and laboratory tests 2. At least 18 years of age and no greater than 40 years on the day of screening 3. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study 4. In the opinion of the principal investigator or designee, has understood the information provided; written informed consent needs to be given before any study-related procedures are performed 5. Willing to undergo HIV Testing and counseling, and receive HIV test results 6. Agrees to use a barrier form of contraception if engaging in sexual activity at any time throughout the study and the follow-up period (males and females) - two reliable forms of contracepti

Health status

Study type

Interventional (clinical trial)

Enrollment

25

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

TMB-301

Identifier

NCT02475629

Link

https://clinicaltrials.gov/study/NCT02475629

Phase

Phase III

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

This Phase 3, single arm, multicenter study will evaluate the safety and effectiveness of ibalizumab in treatment-experienced patients infected with multi-drug resistant HIV-1.

Purpose

Ibalizumab Plus Optimized Background Regimen in Patient With Multi-Drug Resistant HIV

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2015-08-01

Anticipated Date of Last Follow-up
2020-03-10

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2016-10-01

Actual Completion Date
2016-12-01

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Are capable of understanding and have voluntarily signed the informed consent document * Have documented HIV-1 infection by official, signed, written history (e.g., laboratory report), otherwise an HIV-antibody test will be performed * Have no acquired immunodeficiency syndrome (AIDS)-defining events in the 3 months before Screening, other than cutaneous Kaposi's sarcoma or wasting syndrome due to HIV * Are able and willing to comply with all protocol requirements and procedures * Have a life expectancy that is \>6 months. * Have a viral load \>1,000 copies/mL and documented resistance to at least one antiretroviral medication from each of three classes of antiretroviral medications as measured by resistance testing * Have a history of at least 6 months on antiretrov

Health status

Study type

Interventional (clinical trial)

Enrollment

40

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

Not provided

Residual solvents used

Not provided

Description

Use of ibalizumab for the treatment of HIV-2 infection

Brief description

There are major differences in the susceptibility of human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) to currently available drugs, and novel approaches for the treatment of HIV-2 are needed. The present application relates to a method for treating infection by several HIV-2 strains/isolates, including multidrug resistant (MDR) HIV-2 strains, comprising administering to a subject in need thereof an effective amount of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope, or an overlapping epitope, as ibalizumab.

Representative patent

WO21062546

Category

Use

Patent holder

Taimed biologics inc.

Exclusivity

Not provided

Expiration date

October 1, 2040

Status

Not provided

Description

Ibalizumab and homologues ( anti-CD4 antibodies blocking HIV-induced syncytia)

Brief description

Anti-CD4 antibody homologs, DNA sequences and recombinant DNA molecules encoding them, prophylactic, immunotherapeutic and diagnostic compositions comprising those antibody homologs, and methods for preventing or treating diseases in mammals, including humans, caused by infective agents whose primary targets are CD4+ lymphocytes. Such diseases include acquired immune deficiency syndrome ('AIDS'), AIDS related complex, and human immunodeficiency virus infection.

Representative patent

WO1992009305

Category

Compound patent broad claims and CDR

Patent holder

Biogen

Exclusivity

Not provided

Expiration date

November 27, 2011

Status

Expired

Publications

Chahine EB, Durham SH. Ibalizumab: The First Monoclonal Antibody for the Treatment of HIV-1 Infection. Annals of Pharmacotherapy. 2021;55(2):230-239. DOI:10.1177/1060028020942218

Objective:

To review the efficacy and safety of ibalizumab (IBA) in the treatment of HIV-1 infection.

Data Sources:

A literature search was performed using PubMed and Google Scholar (2010 to mid-June 2020) with the search terms TMB-355, TNX-355, and ibalizumab. Other resources included abstracts presented at recent conferences and the manufacturer’s website and prescribing information.

Study Selection and Data Extraction:

All relevant English-language articles of studies assessing the efficacy and safety of IBA were included.

Data Synthesis:

IBA is a monoclonal antibody that blocks HIV-1 from infecting CD4+ T cells. IBA is approved by the Food and Drug Administration, in combination with other antiretrovirals (ARVs), for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1 infection failing their current ARVs. IBA demonstrated significant and sustained antiviral activity in patients with MDR HIV-1 infection who had advanced disease and limited treatment options. It carries a warning regarding the development of immune reconstitution inflammatory syndrome. Common adverse reactions include diarrhea, dizziness, nausea, and rash.

Relevance to Patient Care and Clinical Practice:

IBA represents an attractive option for treatment-experienced adults with advanced HIV-1 infection who are no longer able to achieve viral suppression on oral ARV therapy alone and who are able to adhere to an infusion therapy every 2 weeks. As with other biologics, there is a potential for the development of antibodies to IBA that can compromise its efficacy and safety.

Conclusion:

IBA provides a needed treatment option to achieve and maintain viral suppression in heavily treatment-experienced adults with MDR HIV-1 infection.

Bettiker, Robert L.a; Koren, David E.d; Jacobson, Jeffrey M.a,b,c. Ibalizumab. Current Opinion in HIV and AIDS 13(4):p 354-358, July 2018. DOI: 10.1097/COH.0000000000000473

Purpose of review 

Antiretroviral options for patients infected with multiclass resistant HIV-1 warrant the development of new agents with unique mechanisms of action and modes of delivery. Here we review one such agent, ibalizumab, a parenteral CD4 postattachment inhibitor that has demonstrated efficacy as part of combination antiretroviral therapy in the treatment of HIV-1.

Recent findings 

In a phase III clinical trial in HIV-infected participants with multiclass antiretroviral drug resistance, the intravenous administration of ibalizumab led to declines in plasma HIV-1 RNA more than 0.5 log in 83% of participants at 1 week. An optimized background antiretroviral regimen was then added, and plasma HIV-1 RNA became less than 50 copies/ml in 43% of participants at 24 weeks. Adverse effects of ibalizumab were uncommon and generally low grade. Ibalizumab was approved by the US Food and Drug Administration on March 16, 2018, under the trade name Trogarzo.

Summary 

Ibalizumab has demonstrated both safety and efficacy in the treatment of HIV-1 infection. Its primary use will be in the setting of multidrug resistant virus as part of combination antiretroviral therapy. Further enhancements of ibalizumab to prolong its clearance and broaden its activity are in development.

Additional documents

No documents were uploaded

Useful links

• FDA PRODUCT QUALITY REVIEW(S) - IBALIZUMAB

• FDA PRODUCT SUMMARY REVIEW - IBALIZUMAB

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