Summary

Name:

Trogarzo™

Synonyms:

Ibalizumab; Ibalizumab-uiyk; TNX-355; TNX355; TNX 355; Hu5A8; TMB-355; TMB355; TMB 355

Sponsor:

TaiMed Biologics (Taiwan, USA)

Co-Sponsor:

Tanox (acquired by Genentech; USA)

Type of product:

Antibodies

Viral family:

Retroviridae

Status:

Market
Orphan Drug status; Fast track status; Breakthrough Therapy Designation (Feb. 2015); Priority Review status granted by FDA (Jun. 2017), and FDA approval for US market granted on Mar. 06, 2018; See Remarks

Trogarzo™ 

Synonyms:Ibalizumab; Ibalizumab-uiyk; TNX-355; TNX355; TNX 355; Hu5A8; TMB-355; TMB355; TMB 355       Sponsor:TaiMed Biologics (Taiwan, USA)       Co-Sponsor:Tanox (acquired by Genentech; USA)       Type of product:Antibodies       Mode of action:EI       Viral family:Retroviridae       Virus:HIV (Human Immunodeficiency virus)      

Details

Characteristics:
Humanized monoclonal IgG4 antibody directed against domain 2 of CD4 cell receptor;
TMB-355 does not inhibit HIV-1 gp120 attachment to CD4 domain 1, but rather inhibits a post-attachment step required for cell entry;
No effect on normal immune function of CD4 receptor and no depletion effect on CD4-expressing cells;
 
Contains an IgG4 Fc domain that does not trigger antibody- and complement-dependent cytotoxicity;
 

Antiviral activity against all HIV-1 clades tested, CCR5- and CXCR4-tropic strains

 

Ref.: Zhang et al., Antimicrob Agents Chemother. 2006 Jun;50(6):2231-3; Dimitrov A, Curr Opin Investig Drugs. 2007 Aug;8(8):653-61

PK Data, Dosage or Route of Administration:

Administration by IV infusion;

Also developed separately for IM administration (less advanced stage)

 

Trogarzo™ is administered IV once every 14 days and used in combination with other antiretroviral medications; Pts should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks (FDA announcement of product approval, Mar. 2018)

Resistance:

In a pt with advanced immunodeficiency and high-level five-class ARV resistance, further treated with Ibalizumab along with some ARVs, one missed infusion of Ibalizumab at week 32 led to rapid loss of virologic response and decreased susceptibility to the remainder of the pt’s salvage therapy regimen;
The HIV-1 envelope gp120 region of the resulting variants showed the acquisition of a Thr to Ile mutation (July 2010 isolate) and a Thr to Ile or Leu mutation (October 2010 isolate) which resulted in the disruption of a potential N-linked glycosylation site (N-X-S/T-X (PNGS) in the HIV-1 envelope V5 loop;
Post-Ibalizumab treatment gp120 sequences from July 2010 and October 2010 exhibited 8 and 13 amino acid differences, respectively, from the pre-Ibalizumab treatment sequences from June 2009 (GenBank Accession numbers JF701703 to JF701706);
Other analyses also showed that HIV-1 can acquire loss of susceptibility to Ibalizumab via mutations that disrupt potential N-linked glycosylation sites (PNGS) in the V5 loop of HIV-1

Ref.: Fessel et al., Antiviral Res. 2011 Dec; 92(3): 484–487; Toma et al., J. Virol. 2011; 85:3872–3880

In vivo and clinical data:
Antiviral activity in SIV-infected macaques; after multiple exposure to TNX-355, some monkeys developed antibodies that blocked drug activity;
 
In clinical trials, drug was administered by intravenous infusion, once or twice-weekly;
Good safety profile with no significant adverse events reported in human trials;
 
Phase Ib results were published in Antimicrob. Agents Chemother. 53, 450-457, 2009 (Jacobsen et al.):
  • HIV-infected pts were divided in 3 arms who received either 10 mg/kg weekly during whole trial, 10 mg/kg as a starting dose and then 6 mg/kg every two weeks for 9 weeks, or 25 mg/kg every two weeks for 5 doses
  • Pts were off ARV medication during the trial or remained on a failing ARV regimen
  • Reduction in HIV RNA levels were observed in 20 of 22 subjects who receive TNX-355, varying from 0.5 to 1.7 log10
  • In most pts, viral load decreased to nadir after 1 to 2 weeks of treatment and then increased again to reach baseline levels, even if treatment was pursued
  • Viral isolates resistant to TNX-355 remained CD4-dependent and were susceptible to T-20 in vitro
  • TNX-355 was not immunogenic and did not induce SAEs

Final Phase IIa results showed significant reduction of viral load in highly treatment-experienced pts receiving TNX-355 (10 and 15 mg/kg) with optimized background therapy (OBT) for 48 weeks, along with increased CD4 counts
 
 
On May 25, 2016, TaiMed announced preliminary results of ongoing Phase III study NCT02475629 (TMB-301):
  • Phase III NCT02475629 was single arm, 24-week study of Ibalizumab plus optimized background regimen in treatment experienced pts infected with multi-drug resistant HIV-1; Primary objective was to demonstrate antiviral activity of Ibalizumab 7 days after first dose, defined as the proportion of pts achieving a ≥ 0.5 log10 decrease in HIV-1 RNA 7 days after initiating Ibalizumab therapy, day 14 of the study
  • Treatment consisted of 2000 mg Ibalizumab administered IV (loading dose) on Day 7 followed in 14 days (on Day 21) by 800 mg IV Ibalizumab administered once every two weeks, plus an optimized background regimen beginning on Day 1; Ibalizumab was continued at doses of 800mg IV every two weeks through 24 weeks on study treatment
  • Preliminary results announced in May 2016 indicated that 82.5% of pts (33/40) enrolled in the study have met primary endpoint; This result was statistically significant (p <0.0001)
  • Administration of Ibalizumab was well tolerated during first week of treatment

 

Results of clinical Phase III NCT02475629 (TMB-301) and NCT02707861 (TMB-311) at 48 weeks were reported by Emu et al. at IDWeek™ 2017, Oct. 4-8, San Diego, CA:

  • Clinical trial TMB-301 was an open-label study in which highly treatment-experienced pts with Multi-Drug Resistant (MDR) HIV-1 received Ibalizumab with an optimized background regimen (OBR) through 48 weeks of treatment;
    Pts first received an IV loading dose of 2000 mg followed by 800 mg doses every 2 weeks for 24 weeks; 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study
  • Following completion of the 24-week TMB-301 study, pts continued to receive Ibalizumab at 800 mg every 2 weeks under TMB-311 for up to 48 weeks, with safety and efficacy assessed until 48 weeks
  • A total of 31 pts enrolled in TMB-301 completed the 24-week treatment period; Of those 31 pts, 27 entered study TMB-311
  • Ibalizumab plus OBR was well tolerated; Of the 27 pts, 24 (89%) continued to receive treatment until Week 48; The 3 pts discontinued early due to non Ibalizumab-related reasons; No new or unexpected safety concerns emerged between Week 24 and 48
  • The potent suppression of viremia observed at Week 24 was sustained through Week 48; Median viral load (VL) reduction from baseline was 2.5 log10 at both Week 24 and 48
  • 16 of 27 pts (59%) had VL < 50 copies/mL and 17 (63%) pts had VL < 200 copies/mL; All 15 pts with VL < 50 copies/mL at Week 24 maintained viral suppression to Week 48
  • Authors concluded that Ibalizumab plus OBR continued to achieve high rates of virologic suppression through Week 48, supporting durable efficacy and long-term safety of Ibalizumab in highly treatment-experienced MDR pts

Development status

Market
Orphan Drug status; Fast track status; Breakthrough Therapy Designation (Feb. 2015); Priority Review status granted by FDA (Jun. 2017), and FDA approval for US market granted on Mar. 06, 2018; See Remarks

Remarks

Attachment inhibitor of HIV, targets CD4 receptor, potentially blocking viral adsorption and entry;
 
Fast track status granted by FDA in Oct. 2003;
 
Tanox received exclusive license to the cpnd from Biogen and completed Phase IIa trial;
 
Additional dose-finding study was requested by FDA in Aug. 2006;
 
Tanox was acquired by Genentech (merged completed in Aug. 2007), and product was licensed to TaiMed Biologics the same year;
 
TaiMed has collaboration with WuXi PharmaTech/Wuxi Biologics (China) for large-scale production of sterile Ibalizumab;
 
On May 2, 2014, WuXi PharmaTech and TaiMed Biologics announced that FDA has approved the first batch of Ibalizumab manufactured at WuXi’s biologics facilities for ongoing treatment/ Compassionate use in pts under investigator-sponsored IND's (no longer available as of Dec. 2016);
 
Product was granted FDA's Breakthrough Therapy Designation in Feb. 2015;
 
On Mar. 18, 2016, Theratechnologies and TaiMed announced a 12-year collaboration agreement to market and distribute Ibalizumab in USA and Canada; Pursuant to the terms of the agreement, Theratechnologies received exclusive rights to commercialize Ibalizumab in USA and Canada, while  TaiMed continued to be responsible for development of Ibalizumab; TaiMed will seek approval from the FDA whereas Theratechnologies will be responsible to obtain approval from Health Canada;
 
Trogarzo was FDA-approved on Mar. 06, 2018, for IV use in combination with other antiretroviral medications, for treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen