Interim results from an ongoing phase 2, randomized, placebo-controlled trial of the investigational drug TMC207 for the treatment of multidrug-resistant tuberculosis (MDR-TB) were published in the New England Journal of Medicine. TMC207 is being developed by Tibotec BVBA. The data show that the addition of TMC207 for eight weeks to a 5-drug background regimen, in patients with multidrug-resistant tuberculosis (MDR-TB), resulted in a significant increase in the proportion of patients achieving a negative sputum culture and a shorter time to sputum culture conversion compared with the background regimen alone.

“The results of this study are highly encouraging news for the treatment of tuberculosis,” said Peter Donald M.D., Professor Emeritus, Stellenbosch University in Capetown, South Africa. “Not only is this an agent with a radically different means of action, but it shows potential to shorten the treatment of tuberculosis in the foreseeable future, something the tuberculosis community has been hoping for years.”

Treatment of TB is protracted and burdensome. MDR-TB is currently responsible for an estimated 490,000 incident cases of TB and 110,000 fatalities worldwide each year1. MDR-TB requires extended treatment for at least 18 months with second-line drugs that are less effective and associated with more side effects than first line regimens2. This underscores the need for effective drugs with the potential to shorten and improve MDR-TB treatment outcomes.

TMC207 is being investigated as part of a combination therapy for the treatment of MDR-TB. The results reported are from the first stage of a two-stage Phase II randomized placebo-controlled trial. Forty-seven hospitalized patients with newly diagnosed multidrug-resistant pulmonary TB were randomized to receive TMC207 (400 mg daily for 2 weeks, followed by 200 mg three-times weekly for 6 weeks) (n=23) or placebo (n=24) in combination with a standardized 5-drug background second-line antituberculosis regimen. Six subjects (3 in each treatment group), discontinued the study prematurely. This first stage was conducted in South Africa, where the prevalence of MDR-TB is particularly high.

The results of bacterial culture of sputum showed more patients were TB culture-negative at 8 weeks in the TMC207 group, 47.6% versus 8.7% in the placebo group. In addition TMC207 reduced the time to culture conversion. The probability of becoming culture negative on any given day within the 8-week treatment period was 11.8 times higher in the TMC207 group, versus in the background regimen alone hazards ratio (95% CI): 11.8 (2.26, 61.3); p=0.003 by Cox regression analysis. Mean sputum colony-forming units (CFU) count declined more rapidly in the TMC207 than in the placebo group. Most adverse events were mild to moderate and only nausea occurred more frequently with TMC207 than with placebo (26% vs. 4 %). One subject in each treatment group experienced a serious adverse event, neither of which was considered to be related to the study medication. The data obtained validate ATP synthase as a viable target for the treatment of TB.

“The nearly half a million estimated new cases of MDR-TB annually highlights the urgent need for a paradigm shift in the way this disease is being tackled,” said Roger Pomerantz, President, Tibotec Research & Development. “The development of TMC207 is a tribute to the dedication of our scientists, to innovation and to the commitment of our company to accelerating the development of new drug regimens for tuberculosis.”

TMC207 is a diarylquinoline that offers a novel mechanism of action by specifically inhibiting mycobacterial ATP-synthase3, responsible for the cell’s energy production. In vitro, TMC207 potently inhibits both drug-sensitive and drug-resistant M. tuberculosis isolates and is bactericidal against both actively replicating tubercle bacilli and non-replicating bacilli4. The safety and efficacy of TMC207 are being further evaluated in ongoing and future trials. The second stage of the study, which will evaluate efficacy following 24 weeks of treatment, is currently ongoing with active recruitment in South Africa, Peru, Latvia and Russia. Results from the second stage of the study are expected to be available in 2010.

Notes:

1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. Geneva, WHO, 2007

2. Matteelli A, Migliori GB, Cirillo D, Centis R, Girard E, Raviglion M. Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control. Expert Rev Anti Infect Ther 2007; 5: 857-71
3. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223-7
4. Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed homeostasis. J Biol Chem 2008; volume 283, number 37, pages: 25273-80

Source:
Karen Manson, Tibotec

Porter Novelli

The online edition of The Lancet has published results from a forty-eight week Phase III study of previously untreated (treatment-naïve) HIV-infected patients which showed that ‘Isentress’® (raltegravir), Merck Sharp & Dohme Limited’s (MSD) first-in-class integrase inhibitor, was found to be as effective as efavirenz at suppressing viral load to undetectable levels (less than 50 copies/mL) when used in combination therapy.1

Additionally, at Week 48, patients taking raltegravir had significantly fewer side effects compared to the efavirenz group and there were greater increases in mean CD4 cell count recorded for the raltegravir group, although this was not statistically significant.1 Both raltegravir
and efavirenz were administered in combination with two other anti-HIV medicines, tenofovir and emtricitabine.1 The use of raltegravir in treatment-naïve patients is investigational and the product is not currently licensed in this patient group in Europe.

“These findings show that a raltegravir-based regimen was as effective as an efavirenzbased regimen, a standard first-line medication, in reducing viral load to undetectable levels and increasing CD4 cell counts in treatment-naïve patients,” said Mark Nelson, Consultant in HIV Medicine, Chelsea and Westminster Hospital, London. “This study suggests that raltegravir in combination therapy with other antiretroviral treatments may become an important new treatment option for a broader spectrum of patients, including those who have not been previously treated with HIV therapy.”

Raltegravir, the first and only approved integrase inhibitor, is currently approved in more than 80 countries across six continents for use in combination with other ARV agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of HIV-1 replication despite ongoing ARV therapy.2

MSD recently received a positive opinion from the European Union’s Committee for Medicinal Products for Human Use (CHMP) recommending expanded marketing authorisation for raltegravir in combination with other antiretroviral (ARV) medicinal products for the treatment of HIV-1 infection in all adult patients, including treatment-naïve and treatment-experienced patients.3

Raltegravir studied in a Phase III trial of more than 500 previously untreated HIV patients The Lancet reports findings from an ongoing multi-centre, double-blind, randomised, active-controlled Phase III trial of previously untreated HIV-infected patients called STARTMRK. In the study, 563 treatment-naïve, HIV-infected patients received either 400 mg raltegravir (n=281) orally twice daily or 600 mg efavirenz (n=282) orally once daily, in combination with tenofovir and emtricitabine. Suppression of viral load and increase in CD4 cell counts maintained through 48 weeks.

The data showed that HIV viral load was reduced to undetectable levels (less than 50 copies/mL) in 86 percent of patients treated with raltegravir compared to 82 percent of patients treated with efavirenz (p<0.0001). At week 48, patients taking raltegravir had a greater increase
in CD4 cell counts, an average increase of 189 cells/ L, while patients taking efavirenz had an average increase of 163 cells/ L. This difference though was not statistically significant.

Time to virologic response was significantly earlier for patients taking raltegravir compared to those taking the efavirenz regimen (p<0.0001).
Tolerability profile of raltegravir in STARTMRK study Drug-related adverse events of any severity occurred in fewer patients (44 percent vs.
77 percent; p<0.0001) treated with raltegravir. Raltegravir had minimal effect on lipid levels. Mean Changes in Lipid Concentrations from Baseline to Week 48 Raltegravir Mean Change Efavirenz Mean Change P Value
Total Cholesterol +0.55 mmol/L +1.82 mmol/L P<0.0001 HDL Cholesterol +0.23 mmol/L +0.56 mmol/L P<0.0001 LDL Cholesterol +0.33 mmol/L +0.89 mmol/L P<0.0002

Total: HDL -0.02 -0.01 P=.2924
Triglycerides -0.16 mmol/L 2.08mmol/L P<0.0001

In the study, the most commonly ( 2.0 percent in either treatment group) reported drugrelated clinical adverse experiences of moderate or severe intensity in patients receiving raltegravir and efavirenz, respectively, were headache (4 percent vs. 5 percent), nausea (3 percent vs. 4 percent), dizziness (1 percent vs. 6 percent), insomnia (4 percent vs. 3 percent), diarrhoea (1 percent vs. 3 percent), and fatigue (1 percent vs. 3 percent). Central nervous system (CNS) symptoms were reported significantly less frequently through Week 8 with the group receiving raltegravir compared to the group receiving efavirenz (20 percent versus 52 percent; p<0.0001). A significant treatment difference remained with the cumulative incidence of CNS events through Week 48 in the group receiving raltegravir compared to the group receiving efavirenz (26 percent versus 59 percent; p<0.0001).

Cancer was diagnosed in one patient taking the regimen with raltegravir and nine patients taking the regimen with efavirenz.

About Raltegravir

Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity.4 Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells.4 There are drugs
in use that inhibit two other enzymes critical to the HIV-1 replication process - protease and reverse transcriptase - but raltegravir is the only drug approved that inhibits the integrase enzyme.5 Raltegravir is a single 400 mg tablet taken twice daily without regard to food. Raltegravir does not require boosting with ritonavir.2

References

1. Lennox J, DeJesus E, Lazzarin A et al. Safety and Efficacy of Raltegravir-based versus Efavirenz-based Combination Therapy in Treatment-Naive HIV-1 Infected Patients. The Lancet. Early Online Publication, 3 August 2009doi:10.1016/S0140-6736(09)60918-1
2. Summary of Product Characteristics
3. CHMP for human use post-authorisation of positive opinion for ‘Isentress’. Available at:
http://www.emea.europa.eu/pdfs/human/opinion/Isentress_47115109en.pdf [Accessed on 03.08.09]
4 Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and Efficacy of the HIV-1 Integrase Inhibitor Raltegravir (MK-0518) in Treatment-Experienced Patients with Multidrug-Resistant Virus: A Phase II Randomised Controlled Trial. The Lancet 2007; 369:1261-1269.
5. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000; 287:646-50.

Source
Merck & Co