Following the guest speakers (click here to view that recap), several representatives from companies conducting clinical trials of TB drug candidates presented brief updates on progress made in the clinical development of their candidates.
Click the presentation name to download and view a .pdf of the individual presentations.
PNU-100480 (Pfizer, Robert Wallis)
Emerging data indicates promising activity of oxazolidinones against XDR-TB, but, at least for linezolid, prolonged treatment is still required, and toxicities (hematologic and neurologic) can be substantial. The goals of the PNU-100480 program are to show superior safety and effectiveness vs. linezolid. Phase 1 trials of the oxazolidinone PNU-100480 have been completed and results reported in JID (Sept) and AAC (Nov). Results showed:
- Safety: No hematologic safety signals in healthy volunteers given PNU-100480 at 600 mg BID for 28 days; expected long-term toxicity due to inhibition of mitochondrial protein synthesis should be similar to linezolid 300 mg QD (one-quarter dose).
- Efficacy: Cumulative whole blood bactericidal activity of PNU-100480 at 600 mg BID is 2-3X that of linezolid regardless of dose; synergy seen in the whole blood model when PNU is combined with pyrazinamide.
The mouse and whole blood models give conflicting predictions as to the relative efficacy of once vs. twice daily dosing. For this reason, both schedules will be studied in Pfizer’s first study in TB patients, scheduled to start in 2011. The development program includes studies in M/XDR and drug sensitive TB.
SQ109 (Sequella, Lisan Parker presented on behalf of company)
Results from a Phase 1b trial of SQ109 showed no serious adverse effects. There was mild nausea in 2 individuals with one of those person’s symptoms caused by alcohol intake and not as a result of SQ109. Another Phase 1b trial will start in first quarter of 2011 examining the maximum dose of 300 mg. Sequella is working with the EDCTP on planning for an extended EBA trial. There is also a planned Phase 2 double-blind comparison of SQ109 and Ethambutol (EMB) targeting the acute treatment phase.
AZD5847 (AstraZeneca, Jacques Dumas)
The AZ Bangalore Facility currently houses > 100 scientists and provides a full TB platform with BL2 and BL3 laboratories. AZ recently initiated a discovery collaboration with the TB Alliance, and would welcome other partnerships. AZD5847, an oxazolidinone antibiotic, was originally developed for staphylococcal infections, and is currently in Phase 1 trials. The single ascending dose (SAD) and multiple ascending dose (MAD) are complete and awaiting data publishing. The clinical development plan involves external collaboration for EBA and Phase 2 multi-drug resistant (MDR) studies.Although no specific data was shared, Jacques commented that the Phase 1 trial had completed dosing, which was well tolerated for 14 days in healthy volunteers. Both once a day and twice a day dosing were investigated, and the predicted therapeutic range was reached.
PA-824 (TB Alliance, Ngozi Erondu)
Currently, PA-824 is in Phase 2 testing. Some interesting updates from the field showed that there was a food effect at different doses with a high fat, high calorie meal showing a 2-fold effect at the 200 mg dose and a 1.4 fold effect at the 50 mg dose. The clinical dose used is expected to be 200 mg. The drug-drug interaction was investigated with the 400 mg and no serious inhibition or induction was observed. The geometric mean ratio (GMR) ranged from 0.84 to 1.14.The dosage selection was accomplished in two 14-day EBA studies at two sites in South Africa enrolling patients with newly diagnosed, drug-sensitive pulmonary TB. The doses included in the first study were 200 mg, 400 mg, 600 mg, and 1200 mg. The 200 mg dose was as effective as the 1200 mg dose. In the second study, 50 mg, 100 mg, 150 mg, and 200 mg doses were tested with all doses showing similar results with some falloff at the 50 mg dose. There were consistent results with 200 mg so this dose will be used moving forward.The first combination EBA study (NC-001) is in progress with enrollment to be completed in the first quarter of 2011 and data available by the second quarter of 2011. The double blind, randomized trial will test TMC207/PZA synergy and PA-824/PZA synergy at these 2 clinical research sites. There are 5 treatment arms: PA-824/PZN, PA/Moxifloxacin/PZA, TMC207, TMC207/PZA, Rifafour (standard of care).
TMC-207 (Tibotec, Tina De Marez)
TMC-207 is a diarylquinoline active against MDR and XDR tuberculosis. It is currently in Phase 2 development for MDR indication. There are two double-blind, randomized Phase 2 trials (8 weeks and 24 weeks) in process. Results from the first Phase 2 study (TMC201-C208) shows reduction in median time to culture conversion compared to placebo with 11 weeks for TMC207 and 18 weeks for placebo. The compound was safe and well-tolerated over the 8 week period that the drug was administered. In the second Phase 2 trial (TMC207-C209), patients with newly and non-diagnosed sputum smear positive pulmonary MDR-TB enrolled. At present, enrollment has concluded with 231 patients and data to be available in 2011. Additional data was presented at The Union meeting.
Rifapentine (CDC Division of TB Elimination, Elsa Villarino)
The TBTC Study 29 is testing Rifapentine (RPT, 10 mg/kg, Sanofi Aventis) + INH + PZA + EMB versus Rifampin (10 mg/kg) + INH + PZA + EMB. There are 531 patients enrolled with results expected in March 2011.Protocol is being drafted for a TBTC20B/TBTC Study 29 extension which will answer the question of what is the maximal tolerated dose (5/10/15/20 mg/kg) for RPT. The sample size will be 6 subjects per dosing cohort.
Gatifloxacin (WHO/TDR and IRD, Christian Lienhardt)
Gatifloxacin was chosen as a candidate TB drug based on its activity, cost, and generic status. The objective is to shorten treatment to 4 months. The clinical development plan is housed with the WHO/TDR with the Phase 3 (OFLOTUB) trial almost completed. The study is a 4-month randomized, open label, non-inferiority, multi-center controlled trial. There are 5 centers in Africa involved along with the WHO/TDR and other European partners. The study arms are 2 months GRHZ/2 months GRH (experimental) and 2 months ERHZ/4 months RH (control) with a 2 year follow up period with study visits at 1, 2, 4, 6, 9, 12, 15, 18, 24 months after treatment. The last patient completed assigned regimen in April 2009 and preliminary efficacy results are expected in June 2011 once the follow-up period is completed. This Phase 3 study was extensive spanning 10 years from clinical development, required capacity development, pre-study visits, to enrollment and follow-up. There is a definite need for new markers of efficacy!
Moxifloxacin (TB Alliance, Fran Pappas)
The TB Alliance Moxi (REMox) trial is in pivotal Phase 3 registration trial with Moxifloxacin substituted for Isonizid or Ethambutol in standard care regimen with a one year follow-up. There are currently 6 sites in Africa enrolling patients with 2 new sites to start enrollment in 2011, 1 site in malyasia, 3 in Thailand, and there are efforts underway to involve sites in India and China by first quarter of 2011. At present, 1034 volunteers have been screened, 749 participants have been enrolled (72% of targeted enrollment), and 302 have completed the treatment phase of the trial.There are several key challenges of the trial. One, the trial is very complex and has been expanded to 25 sites from the original 3-6 sites proposed. Two, the regulatory and ethical approval process can be overwhelming with approval required from 9 countries. There are different expiry dates for the study drugs in five languages. Also, capacity development is needed at many of the sites due to the unfamiliarity with clinical trials and issues arising with informed consent and participants’ fears. Lastly, additional infusion of funding is necessary to ensure the trial can be completed.
At the conclusion of all of the presentations, all of the speakers took seats at the front of the room and answered questions from the audience. Some of the questions and some answers to these questions are below:
Q: To the drug company specific speakers- What is the commercial vs noncommercial activity for the drugs currently in clinical trials?
A: These are internal discussions for the pharmaceutical companies and depends on which group within the company is assessing the commercial viability of the drug, i.e. emerging markets verses another market, but there are few case examples.
Q: What plans are in place for studying drugs in children?
A: Tibotec in discussion with authorities regarding children – Pfizer no discussions known at present– Bayer plans to discuss
Q: How much money spent on ReMox trial?
A: Expensive trial – $25 million largely because additional clinical sites need to be brought online with training, etc.
Comment: It might be helpful to have a second lab verify initial findings before conducting future trials.
Q: How was the Moxi/PZA/PA regimen for MDR TB decided on?
A: It was tested in mice infected with H37Rv
Comment: Mice do not get necrotic lesion and H37Rv is a drug-sensitive strain.
Q: There is a great need for a biomarker of sterilizing cure, i.e. storing samples collected for biomarkers (e.g. serum) in a depository for future examination. With all of the clinical trial work in progress, are samples being collected for future evaluation?
A: The TB Alliance received a grant from FDA to collect samples to store and begin to look for biomarkers– funding has not been available until now
Q: Increased side effects of drugs and underlying diabetes observed in Japanese clinical trials, how are patients screened to ameliorate potential problems?
A: For the Gati trial, extreme care was taken in the selection of patients- although for other trials monitoring for diabetes not usually part of screening –Pfizer uses finger puncture
Comment: Clinical trials should be double-blinded because open label bias may arise where care givers observing improved patient outcomes in a trial may be inclined to help the patient despite the study design.
Response: Bias is always a challenge – difficulty in finding sites with proper training of healthcare workers.
Comment: Biosampling process should be encouraged– greater need of samples for biomarkers – every trial has to keep sampling
Response: TBTC Study 29 is collecting samples on baseline – all panelists agree that minimum standards for collection of biosamples needs to become routine.
Concluding comments:
- There is a need to keep sites up and in use once trials are completed.
- A suggestion was made to set up database of trial sites for future to avoid loss of resources that have been put in to trials
- Building up capacity is necessary or we will lose people, so it is important to collaborate to work on this.
Please submit your comments/suggestions below. Thank you.