What is an investigational drug?
An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.
To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.
What is lexgenleucel-T?
Lexgenleucel-T is an investigational gene therapy product. Gene therapy is an experimental technique that uses genes (short sections of genetic material) to treat or prevent disease. Lexgenleucel-T is a gene therapy product that involves adding an anti-HIV gene (called an “antisense gene”) into CD4 T cells. (CD4 T cells are a type of immune cell that HIV attacks and destroys.)5,6
The antisense gene is delivered into the CD4 T cell by a vehicle called a “vector.” Once the antisense gene has been delivered by the vector and incorporated into the CD4 T cell, the gene becomes a permanent part of that cell’s genetic material. Then, when HIV infects a CD4 T cell that has the antisense gene and HIV starts to replicate itself, the antisense gene becomes activated. The activated antisense gene prevents the production of an HIV protein (called an envelope protein) that’s needed for HIV to successfully replicate. Without the envelope protein, HIV cannot multiply.5-8
Lexgenleucel-T is being studied for its ability to help restore the immune system and as a possible strategy to cure HIV.6,7,9
How is lexgenleucel-T made?
Lexgenleucel-T is made by first collecting CD4 T cells from an HIV-infected person. The cells are sent to a laboratory where they are genetically modified, by way of a vector, to incorporate the antisense gene. The cells are then stimulated to produce many more CD4 T cells with the antisense gene. Finally, the modified CD4 T cells are returned to the person’s body and can multiply in the body. It is hoped that this treatment may provide someone with a population of CD4 T cells that can permanently inhibit HIV replication.6,7,10
How are clinical trials of investigational drugs conducted?
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.11
- Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
- Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
- Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.11
In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.11
In what phase of testing is lexgenleucel-T?
Lexgenleucel-T is being studied in Phase II clinical trials.3,4
What are some studies on lexgenleucel-T?
Study Names: Protocol 802456; NCT00295477
Location: United States
- HIV-infected adults who had taken HIV medicines before entering the study (also called treatment-experienced) and who were taking antiretroviral therapy (ART) at the time of study entry.
- Participants had viral load levels (the amount of HIV in a blood sample) that were undetectable (usually less than 20 copies/mL) and CD4 counts of more than 450 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function. The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm3.)
Purpose: The purpose of this study was to evaluate the safety and effects of multiple lexgenleucel-T infusions on viral loads and CD4 counts. (An infusion is a method to deliver a drug or other fluids, typically into a vein, over a period of time.)
Participants received either 1 or 2 cycles of lexgenleucel-T infusions. A cycle consisted of 3 separate infusions given 2 weeks apart from each other. If a participant received 2 cycles of treatment, then there was a 4-week period between the cycles during which the safety of lexgenleucel-T was assessed.
Four or 5 weeks after their last infusions, participants who had detectable amounts of lexgenleucel-T in their bodies underwent an analytical treatment interruption of ART. (An analytical treatment interruption of ART is a planned break from ART to evaluate how well an investigational drug can maintain control of a participant’s viral load during a clinical trial.)
All participants in this study are still being followed long-term to monitor for any side effects related to lexgenleucel-T. The follow-up period is for 15 years from the date of a participant’s last infusion.
- In the majority of participants who underwent an analytical treatment interruption, lexgenleucel-T treatment appeared to have a “modest” effect on decreasing their viral set points. (The viral set point is the viral load that the body settles at within a few weeks to months after infection with HIV in the absence of antiretroviral drug control. It reflects a balance between the amount of virus being produced and the amount of virus being cleared by the immune system.)
- Most participants’ viral loads rose to detectable levels within 2 to 4 weeks after starting the treatment interruption. One participant, however, was able to maintain control of her viral load below detectable levels and had a CD4 count greater than 1200 cells/mm3 for 14 weeks during the treatment interruption.
- All participants had increases in their CD4 counts after receiving lexgenleucel-T infusions.
- The number of modified cells in the body did not increase when 6 infusions were given versus when 3 infusions were given. Also, the number of modified cells in the body decreased after infusions, but persisted in some participants for up to 5 years.
- In terms of safety, no serious or unexpected side effects related to lexgenleucel-T occurred during the study or 5 years of follow-up.12-15
Study Names: (1) VRX496-USA-05-002; NCT00131560 and (2) VRX496-USA-05-002-Rollover; NCT00622232
Location: United States
- HIV-infected, treatment-experienced adults who had experienced either treatment failure or intolerance (because of side effects) to at least one three-drug combination ART regimen. (Treatment failure is when an ART regimen is unable to control HIV infection.)
- Participants may or may not have been on ART at study entry. Those who were receiving ART were willing to continue on their current therapy during the study. Those who were not receiving ART were willing to remain off of therapy during the study.
- At screening, participants had viral loads between 5,000 and 200,000 copies/mL and CD4 counts of at least 150 cells/mm3.
The purpose of this study was to evaluate the safety and activity of multiple infusions of lexgenleucel-T and single infusions of lexgenleucel-T.
Participants were assigned to one of the following five groups:
- A one-dose infusion of lexgenleucel-T every 2 weeks, for a total of 4 infusions.
- A one-dose infusion of lexgenleucel-T every 2 weeks, for a total of 8 infusions.
- A single infusion that contained one dose of lexgenleucel-T.
- A single infusion that contained two doses of lexgenleucel-T.
- A single infusion that contained three doses of lexgenleucel-T.
A roll-over study (called VRX496-USA-05-002-Rollover) allowed participants who had completed the VRX496-USA-05-002 trial to receive one additional infusion containing one dose of lexgenleucel-T.
All participants in this study are still being followed long-term to monitor for any side effects related to lexgenleucel-T. The follow-up period is for 15 years from the date of a participant’s last infusion.3,10-13
- Overall, a small number of participants had increases in CD4 count, but the majority of participants had either no change or a slow decline in CD4 count during the 9- to 12-month period after infusion.
- Three out of 6 participants who could be evaluated from the single one-dose infusion group showed significant and sustained increases in their CD4 counts between 6 and 12 months after their infusions. Two of those participants received an additional one-dose infusion of lexgenleucel-T about 12 months after their prior infusions, and this increased their CD4 counts even further.
- Three out of 6 participants who could be evaluated from the single one-dose infusion group had significant drops in their viral loads between 2 and 6 months after their infusions. However, these reductions were temporary, and viral load levels returned to baseline levels.
- Looking at all groups studied, the average viral load changes from baseline to the end of the study were within the range of the test’s variability and may not have reflected actual viral load changes.
- Investigators concluded that single infusions of lexgenleucel-T rather than multiple infusions of lexgenleucel-T would provide better benefits in terms of immune response in HIV-infected participants in future studies.
- In terms of safety, no serious side effects related to lexgenleucel-T treatment have been reported.3,4,16
What side effects might lexgenleucel-T cause?
In the Protocol 802456 study discussed under the previous question, no safety concerns related to multiple infusions were reported. The most common side effect was a garlic/creamed corn odor occurring during infusions. Other common side effects related to treatment were reactions occurring at the infusion site, such as stinging and cold sensation.13,14
In the Phase II studies (VRX496-USA-05-002 and VRX496-USA-05-002-Rollover), among 27 participants who have completed 3 years of follow-up safety monitoring, there has been no evidence of long-term safety issues.16
Because lexgenleucel-T is still being studied, information on possible side effects of the drug is not complete. As testing of lexgenleucel-T continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying lexgenleucel-T?
More information about lexgenleucel-T-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.
How can I find more information about participating in a clinical trial?
Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.11
Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/1294006-17-9. Last accessed on March 3, 2016.
- Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on March 3, 2016.
- VIRxSYS Corporation. A Phase II, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, and Biological Activity of Single and Repeated Doses of Autologous T Cells Transduced With VRX496 in HIV-Positive Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 16, 2005. NLM Identifier: NCT00131560. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00131560. Last accessed on March 3, 2016.
- VIRxSYS Corporation. A Rollover Study to Evaluate Safety and Therapeutic Effect of Re-infusing Subjects Who Completed Participation in the VRX496-USA-05-002 Trial With Autologous T Cells Transduced With VRX496. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 11, 2008. NLM Identifier: NCT00622232. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00622232. Last accessed on March 3, 2016.
- Horn T. VIRxSYS gene therapy makes progress—Researchers have reported encouraging results from a clinical trial of a gene therapy approach to treat HIV. On European AIDS Treatment Group website. Available at: http://www.eatg.org/news/163817/VIRxSYS_gene_therapy_makes_progress. Last accessed on March 3, 2016.
- VIRxSYS Corporation. FDA Biological Response Modifiers Advisory Committee Meeting Briefing Package—Autologous T Cells Transduced with VRX496, an HIV-1 Based Lentiviral Vector for the Treatment of Patient-Subjects Infected with HIV-1; October 26th, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3794b3_13_sponsor.pdf. Last accessed on March 3, 2016.
- Sheehy J, Zack J, Kiem HP, Handibode J. Cell/Gene Therapy—HIV Cure Research Training Curriculum. Located on the AVAC website (http://www.avac.org/cure-curriculum/module3), under PowerPoint. Available at: http://www.avac.org/sites/default/files/u16/Gene_Cell_Therapy_July.pptx. Last accessed on March 3, 2016.
- Stan R and Zaia JA. Practical Considerations in Gene Therapy for HIV Cure. Curr HIV/AIDS Rep. 2014; 11(1): 11–19. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929767/. Last accessed on March 3, 2016.
- Hartman TL and Buckheit RW Jr. The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets. Mol Biol Int. 2012; 2012: 401965. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400388/. Last accessed on March 3, 2016.
- Humeau LM, Binder GK, Lu X, et al. Efficient Lentiviral Vector-mediated Control of HIV-1 Replication in CD4 Lymphocytes from Diverse HIV+ Infected Patients Grouped According to CD4 Count and Viral Load. Mol Ther. 2004 Jun;9(6):902-13. Available at: http://www.nature.com/mt/journal/v9/n6/full/mt2004118a.html. Last accessed on March 3, 2016.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on March 3, 2016.
- University of Pennsylvania. A Phase I/II, Open-label, Single Center Study to Evaluate the Tolerability, Trafficking and Therapeutic Effects of Repeated Doses of Autologous T Cells Transduced With VRX496 in HIV Infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 21, 2006. NLM Identifier: NCT00295477. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00295477. Last accessed on March 3, 2016.
- Tebas P, Stein D, Binder-Scholl G, et al. Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. Blood. 2013 Feb 28; 121(9): 1524–1533. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587318/. Last accessed on March 3, 2016.
- Tebas P, Stein D, Zifchak L, et al. Prolonged Control of Viremia After Transfer of Autologous CD4 T Cells Genetically Modified with a Lentiviral Vector Expressing Long Antisense to HIV env (VRX496). 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2010. Available at: http://www.natap.org/2010/CROI/croi_182.htm. Last accessed on March 3, 2016.
- Penn Medicine: News Release, dated February 18, 2010. Penn Researchers Present Phase II HIV Gene Therapy Trial Data at CROI 2010. Available at: http://www.uphs.upenn.edu/news/News_Releases/2010/02/hiv-gene-therapy/. Last accessed on March 3, 2016.
- Rebello T, Stein D, Blick G, et al. Safety and Efficacy of Autologous CD4+ T cells Transduced with a Lentiviral Vector Delivering Anti-HIV RNA Antisense env in HIV+ Subjects Failing One or More HAART Regimens. Mol Ther. 2010 May; Vol 18, Supplement 1: S251 (Abstract 646). Available at: http://www.nature.com/mt/journal/v18/n1s/pdf/mt201087a.pdf. Last accessed March 3, 2016.
Last Reviewed: March 3, 2016