Experts debate how to develop drugs specifically for MDR TB

Some of the drugs in clinical development for tuberculosis (TB) could get to market faster by taking a page from the history of AIDS drug development —if they prove useful in the treatment of multidrug-resistant TB (MDR-TB) — according to an article in the recent issue of PloS Medicine. And from reports made at a Treatment Action Group (TAG) and Stop TB Partnership Satellite Workshop held just a few days before the 38th World Lung Health Conference this week in Cape Town, at least a couple of companies are first trying to prove that their drugs are safe and effective for patients who have no treatment options.This could qualify the drugs for some form of accelerated regulatory approval.

However, this approach may be quite challenging — because testing drugs at centres that treat people with MDR-TB hasn’t really been tried before. And without reliable drug sensitivity tests for second-line TB drugs, some experts fear that pairing new drugs with weak or poorly effective second line drugs could quickly lead to resistance to the new and novel compounds.

There are seven potential TB drugs in human studies now.

The two furthest along in development, gatifloxacin and moxifloxacin, are ‘third-generation’ fluoroquinolone antibiotics, similar — though perhaps somewhat more potent — than related drugs like levofloxacin and ofloxacin, which are used in regimens to treat MDR-TB.

Ongoing studies are trying to determine whether the drugs could replace ethambutol or, in the case of moxifloxacin, isoniazid as well in the first line TB regimen, and potentially shorten the duration of first-line treatment from six to four months. Some of the phase II study results have indeed been quite promising while other studies didn’t quite demonstrate a significant difference from the standard regimen.

One challenge in evaluating new TB drugs quickly is that there are no agreed surrogate markers that reliably predict long-term significant clinical benefit in TB, as viral load does for HIV disease. So at present, studies must measure clinical endpoints — which can take time because a person with TB may appear to be cured and yet suffer a relapse within 18 months of treatment discontinuation.

Another challenge is that the standard regimen usually cures a high percentage of patients. So these studies have to be quite large to show a significant difference and last a couple of years to convincingly demonstrate to regulatory authorities that substituting the new drug for an older one in the regimen improves the response to first line treatment. Currently, the phase III study of gatifloxacin is halfway accrued, while the 2400 patient phase III study of moxifloxacin should be getting underway before the end of this year.

Although their safety has yet to be established for this use (and there are some concerns about risks related to diabetics on gatifloxacin), there is little doubt that these fluoroquinolones will prove effective based upon their use in second-line therapy. If their use in second line therapy does in fact shorten the time people have to take first-line TB therapy, many believe it would translate to better adherence, improving outcomes and thus reduce the development of MDR-TB.

But there are questions about whether this is the really the best way to use these particular drugs, as noted by Dr Ruth McNerney of the London School of Hygiene and Tropical Medicine at the TAG Workshop. After first stressing that her focus of research is TB diagnostics rather than drug therapy, she said:

“Fluoroquinolones are very important for second line treatment, and yet we are spending millions of pounds trying to see if they’ll improve first-line treatment. That doesn’t seem quite right to me. Are we going to use them for first-line treatment or not? If we’re not going to use them, why are we spending all this money on these drug trials? Let’s spend it on doing trials for MDR treatment.”

Indeed, people with MDR- and extensively drug-resistant TB (XDR-TB) are desperately in need of treatment options — and the remaining five drugs in clinical development seem far more interesting for this population. However, according to a timeline presented last year by the TB Alliance (a public private partnership that focuses on TB drug development), these drugs could be at least five or six years away from marketing approval.

But once basic pharmacokinetic/safety and early bactericidal activity studies (short studies that demonstrate anti-TB activity in humans) have demonstrated that a new drug candidate warrants further study (no small feat), it may now be possible to speed their development by testing the drug in those patients without adequate treatment options, according to the recent paper in PLos Medicine by Mitnick et al — and if the drugs are found to improve clinical outcomes, there should be no reason why they would not qualify for accelerated approval.

At one time, it might have been difficult to find enough patients to enrol into such a study, but as Mitnick et al. point out, the magnitude of the MDR-TB epidemic and the expanding capacity of MDR-TB treatment programmes may now allow for randomized controlled studies to be conducted in people with MDR-TB.

Furthermore, experience in HIV drug development has shown that it is possible to give a person the best possible available second-line or salvage regimen (with components selected by drug sensitivity testing) and still be able to evaluate the safety and effectiveness of the new drug when added to the optimized background therapy.

Even so, since treatment responses to the background regimens are still rather poor — particularly in people with HIV — it shouldn’t take great numbers of people to show whether the new drug works or not. In addition, running studies in this population should enhance the knowledge base about how best to treat people with MDR-TB.

Dr David McNeeley, Director of Global Clinical Development of Tibotec, described how his company is utilising this strategy to expedite the clinical development of TMC207. TMC207 is a diarylquinoline which has a novel mechanism of action and that lacks cross-resistance to any of the current TB drugs.

Although a seven-day study was able to demonstrate early bactericidal activity, some other problems have emerged during TMC207’s early clinical development. Since it is metabolised by CYP3A4, it has a drug interaction with rifampicin, which lowers levels of TMC207 by 50% — and it is not yet clear whether this can be overcome by dosing adjustments.

So rather than going into large studies in first line regimens, Dr McNeeley said the company decided to study the drug in patients with MDR-TB — and address a high unmet medical need.

“The MDR patients have a great need for new therapy, the alternative drugs that they are using are toxic, unpleasant to take and require a long term of treatment,” he said. He said that they discussed this with the FDA who encouraged them to file an IND.

“The study that we are undertaking now, which started in June in South Africa, is I believe, the first placebo controlled double blind randomised trial in MDR-TB. It is being conducted in two phases, the current phase one of this study will involve eight weeks of treatment in 50 subjects, and will evaluate pharmacokinetics, anti bacterial activity, safety and tolerability of TMC207 compared to placebo. Once a dose is confirmed, and they find a good safety profile, the company will move into the second phase of the study, in 150 people with newly diagnosed smear positive MDR-TB."

The study will also investigate whether there are any drug-drug interactions between TMC207, its active metabolite and the other drugs in the background regimen The primary endpoint is time to sputum conversion (defined as two consecutive negative cultures at least 28 days apart).

The study is taking place at six centres in South Africa and Dr McNeeley notes that a high number of people who screen don’t get into the study. Although people with HIV are allowed in the trial, they are asked not to join if they expect be going on ART during the course of the study because the company has not yet done drug interaction studies between TWC207 and antiretrovirals. “However, if someone with HIV should need to go on to ART treatment during the course of the study, we ask them to inform the investigator so he can keep a close eye on that patient,” he said.

Dr McNeeley says that running the study has not been easy.

“There’s a lack of historical precedence for this kind of trial so, we feel like we’ve kind of had to invent the wheel on this. The TB world will learn a lot from our trial, whether we wind up being successful or not. With all the other drugs that the person is taking, how do you sort out which drug is causing toxicity? What is your drug doing? What is its profile?”

“We are working in MDR-TB hospitals in this community. Those hospitals are overwhelmed with patients. There is a lack of clinical trial experience in these hospitals — there’s a lack in TB centres in general of clinical trial experience — but there’s a lack especially in MDR-TB hospitals because not many people have looked into doing a study there before. Not many people have looked to do MDR drug development.”

The protocol is complex; the data collection has to be very precise. The length of the trial is difficult, Finally, there are a lot of complex health and social issues with the patient which makes the study difficult.”

On the positive side, there have yet to be any serious adverse events reported in the 44 enrolled subjects. The first stage of the study should be completed by January at which point an independent data safety and monitoring board will review the data and give the company the go-ahead to proceed into phase II. At that point, the company will consider expanding the study into sites in Peru, India and potentially other places.

Otsuka Pharmaceutical has adopted a similar approach for their nitroimidazole compound OPC 67683 versus placebo in combination with background second-line TB therapy.

The new compound has been evaluated in a number of dose-ranging studies and has demonstrated encouraging early bactericidal activity. However, the development of this drug has been hampered somewhat due to bioavailability problems leading the reformulation.

“Even with the current formulation, there appears to be a limitation in the bioavailability of the drug,” said Dr Mel Spigelman of the TB Alliance. Also, there appears to be a drug interaction with one of the drugs in the first line regimen (either rifampicin or pyrazinamide) that reduces blood levels of OPC 67683 — which is yet another reason that Otsuka has decided to first study the drug in second line regimens.

So the company is launching a phase II randomised study comparing three dose regimens of OPC 67683 (200mg once a day, 100mg twice a day or 150mg twice a day) versus placebo in combination with background therapy. The study plans to enrol 200 people with MDR TB in Estonia, Latvia, the Philippines, Korea and Peru (which are all hotspots for MDR) and OPC 67683 treatment will last for eight weeks (background therapy will of course continue). The study’s major endpoint will be sputum conversion to negative at eight weeks, and the drug’s pharmacokinetic parametres will also be evaluated. Further plans are to do local studies of MDR-TB treatment in China and Japan next year.

The other new agents, PA-824, LL-3858, SQ109 are in much earlier phases of clinical development.

PA-824 is another nitroimidazole being developed by the TB Alliance which has gone through basic phase I studies, though with an additional toxicology analysis because of elevations in serum creatinine were noted in one study. Serum creatinine elevations can be a marker for kidney damage, but fortunately the results of this second study showed that this was more of a biochemical interaction in the kidney rather than causing any true side effect and so the programme has been continued.

Currently this drug’s early bactericidal activity is being evaluated in a 14-day study at several sites in South Africa and results should be available by early next year.

Lupin, a mid-sized company in India is working with another compound, LL-3858. The company has completed early pharmacokinetic studies and plans to launch early bactericidal activity studies early next year. However, the company plans to develop this drug for standard first line regimens as a replacement for ethambutol.

The most recent drug to enter the clinical pipeline is SQ109, being developed by a company called Sequella, a biotech company in Rockville, Maryland working closely with the NIH. Early phase I studies have demonstrated a long half-life (around 61 hours) and plans to move into multiple dose phase one studies next year if they can obtain adequate resources. It is not yet clear whether the company plans to go for first or second line.

“I give all the credit in the world to Tibotec and Otsuka a lot of credit for venturing into this space that really no one has ever ventured into before and therefore is a very difficult one,” said Dr Spigelman. But he listed some worries about developing drugs for MDR-TB.

It is not clear what will be clinical endpoints that will be acceptable to regulatory authorities. Will difference in culture conversion rates be seen as adequate when rates of relapse are so high? Or will cure be the endpoint?

Dr Spigelman also worries whether the drugs will be used in a safe and effective manner, that doesn’t lead to the development and spread of resistance to the new drugs. He believes their development will have to go hand in hand with improved drug sensitivity testing (DST) - not just to first line drugs, but to the second line drugs that these new compounds will be combined with — otherwise patients may wind up being given what is effectively monotherapy in combination with drugs that don’t work, and resistance will ultimately develop.

“We need more feedback from the field of the predictive value of DST, and I think there is a lot of information that could be made available based upon what is going on in the field today that we are not taking advantage of,” he said.

Another idea that FIND has been entertaining that would bypass DST altogether, would be to put three new drugs for MDR-TB into clinical trials all at once and increase the chances of a person getting a truly effective regimen.

But he believes activists should engage regulatory authorities to see whether this or other strategies would be acceptable and to work on defining optimised clinical development plans for resistant disease.

“We also need better data on the present treatment outcomes,” he said, “historical “controls” can be valuable and we have virtually none. Getting the data that we can get today already is feasible and can be done.

And of course, more resources and investment could speed development and access to new agents for MDR-TB. Finding ways to move more products into the pipeline for MDR-TB may be an uphill battle because posters presented later in the week at the 38th World Lung Health Conference suggested that the global market for second line treatment TB drugs is small (though clearly growing). Thus companies have less incentive to invest in the development of such drugs, unless their road to clinical development can be made a bit simpler.

References

Spigelman M. Current TB treatment research. Treatment Action Group and Stop TB Partnership Satellite Workshop on MDR- and XDR-TB in the context of HIV infection, Cape Town South Africa, 2007.

McNeeley D. Strategies to expedite DR TB R&D: Tibotec experience. Treatment Action Group and Stop TB Partnership Satellite Workshop on MDR- and XDR-TB in the context of HIV Infection, Cape Town South Africa, 2007.

Mitnick CD et al. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 4(11): e292. doi:10.1371/journal.pmed.0040292