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 Amendment 2

Identifier

NCT00784147

Link

https://clinicaltrials.gov/study/NCT00784147

Phase

Phase II

Status

Completed

Sponsor

TaiMed Biologics Inc.

More details

Not provided

Purpose

Evalute the Dose-Response of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1 (Amended to 24-Weeks).

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
Not provided

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

Participants are HIV-1 positive individuals who have a viral load of greater than 1,000 copies/mL and documented decreased susceptibility to at least one NRTI, one NNRTI, and one PI, as measured by resistance testing.

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

Not provided

Purpose

Evalute the Safety of Trogarzo® via IV Over a Reduced Interval or as an IM Injection in Clinically Stable HIV-1 Infected Trogarzo® Experienced Patients and Healthy HIV-uninfected Volunteers.

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
Not provided

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): Participants are individuals aged 18 years and over who are currently receiving a stable Trogarzo containing ARV regiment for at least three months. Additionally, they must have a viral load <1,000 copies/mL and a CD4+ T-cell count > 50 cells/mm3 at screening. Inclusion Criteria - Healthy Volunteers (all groups): Participants are healthy individuals aged > 18 and < 50 years as assessed by medical history and physical examination and are willing to comply with the protocol schedule and undergo HIV-1 testing. Participants are required to be HBV surface antigen negative and HCV antibody negative.

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

46

Allocation

Non-randomized

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

Not provided

Purpose

Expanded Access Study of Ibalizumab Plus an Optimized Background Regimen (OBR) in Treatment-Experienced Patients Infected With Multi-Drug Resistant (MDR) 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
Not provided

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

Participants are HIV-1 positive individuals who 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 testing is not provided by the study for qualification purposes). Participants also have a history of at least 6 months on antiretroviral treatment and are currently receiving a failing antiretroviral regimen OR have failed and are off therapy.

Health status

Study type

Interventional (clinical trial)

Enrollment

79

Allocation

Non-randomized

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

Not provided

Purpose

Sequential Dose-Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered Ibalizumab in HIV-Negative, At-Risk Volunteers.

Interventions

Intervention 1

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2011-02-01

Anticipated Date of Last Follow-up
Not provided

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

Participants are healthy male and female individuals aged between 18-40 years, at-risk of HIV infection as assessed by a medical history, physical exam, and laboratory tests. It is required that participants agree 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 contraception, one barrier and one hormonal (e.g., oral contraceptive pill, injectable or implantable contraceptive combined with diaphragm, Intra Uterine Device (IUD), or condoms), must be used if volunteers engage in sexual activity that could result in pregnancy.

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

Not provided

Purpose

Evaluate the safety and effectiveness of ibalizumab in treatment-experienced patients infected 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
2015-08-01

Anticipated Date of Last Follow-up
Not provided

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

Participants are HIV-1 positive individuals who 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. Participants also have a history of at least 6 months on antiretroviral treatment and are either receiving a stable highly active antiretroviral regimen for at least 8 weeks before Screening and are willing to continue that regimen until Day 14, OR (in the past 8 weeks) have failed and are off therapy and are willing to stay off therapy until Day 14.

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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