PP353, the new ‘wonder drug’ for chronic low back pain? I DOUBT IT!

Recently, several papers reported about PP353 as a new ‘wonder drug’ for chronic low back pain (cLBP). The reason is that Persica Pharmaceuticals Limited (Persica) announced positive results of a randomised, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of PP353 as a treatment for patients with chronic low back pain (cLBP). PP353 is a specifically formulated combination of linezolid, iohexol and a thermosensitive gel that is injected into the degenerate lumbar disc, delivering prolonged exposure of a high concentration at the site of infection. A 2-dose regime (dosed 4 days apart) is said to eliminate the infection, thus addressing the underlying cause of cLBP which is claimed to be an infection.

Intradiscal administration of 3 mL of PP353 has been reported to be well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study.

The abovementioned efficacy trial enrolled 44 patients who had suffered from cLBP for more than 6 months (mean duration of 5.5 years) and had not been helped by existing non-surgical treatments. They were randomized to receive either PP353 or placebo injected into intervertebral discs. The results of the study demonstrated statistically significant and clinically meaningful results in patients with cLBP. Compared to placebo, the verum led to a 30% reduction of pain after 12 months. The placebo group did not achieve clinically meaningful change from baseline. The PP353 group also reported statistically significant and clinically meaningful reductions in disability with a within-group reduction of 9.4-points (63%) and a between-group reduction of 3.9-points (39%) from placebo in the Full Analysis Set of subjects at 12 months.

The manufacturer claims to provide an alternative, non-opioid, treatment for cLBP patients by replacing the 100-day high-dose oral antibiotics course to treat cLBP with an injectable antibiotic formulation that will achieve high local concentration and adequate duration of exposure in the spine to effect the sterilisation of the infected disc.

Local administration of antibiotic has the potential to elicit a faster response because an effective drug concentration in the infected tissue is immediately achieved. It also significantly reduces the amount of drug required, reducing the likelihood of systemic side effects, especially those associated with perturbation of the gut microbiome.

Intradiscal administration of therapeutics to treat cLBP is an established but mostly ineffective route. Persica believes that an effective treatment must address the underlying cause of disease – the infection. An effective antibacterial therapeutic should reduce the inflammatory stimuli in the intervertebral space and adjacent bone and allow repair over time, leading to a reduction in pain.

During the development of PP353, Persica tested several generic antibiotics in vitro and in vivo to find an antibiotic with the required properties: active against the bacteria identified in disc and herniated tissue samples, little to no resistance in clinical isolates, and the ability to be formulated to provide a depot to extend the duration of exposure.

To enable administration of the antibiotic, Persica developed a unique formulation which delivers the antibiotics to the site of infection and ensures that it remains within the infected area.

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Sounds good?

Yes, perhaps even a little too good to be true!

Here are some of my concerns:

1. The manufacturer has, as far as I can see, not published the findings in a peer-reviewed journal and thus wants us to believe the findings without scrutinizing the methodology.
2. Even if they eventually do publish the study in full, and even if it turns out to be rigorous, one would still want  independent preplications.
3. There is an undenialble and very substantial financial interest in the matter (anyone who comes out with an effective and safe pill against cLBP, will quickly make billions!), and one might therefore wonder how objective the manufacturer can be about the merits of PP353.
4. The assumption that many cases of cLBP are caused by a disc infection is a well-known theory, but it remains largely unproven.
5. As we dicuseed only recently, antibiotics have not been shown to be effective for cLBP.

Clearly, we have to wait and see – but my advice is to take PP353 with a healthy pinch of salt.