Intradiscal antibiotic for use it the treatment of low back pain

Abstract

Provided herein are methods of treating chronic low back pain in a patient, comprising administering a therapeutically effective amount of a first antibiotic to one or more targeted sites in the spine of the patient, wherein the method provides improvements as compared to oral administration of a second antibiotic. Also provided herein are methods of improving the treatment of chronic low back pain in a patient with a first antibiotic as compared to oral administration of a second antibiotic to the patient, comprising administering a therapeutically effective amount of the first antibiotic to one or more targeted sites in the spine of the patient.

Description

[0001] LOW BACK PAIN TREATMENT

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to treatment to alleviate pain and disability in patients with chronic low back pain (CLBP).

[0004] BACKGROUND OF THE DISCLOSURE

[0005] Chronic low back pain (CLBP) is common among the general population worldwide. A positive association between Modic changes and CLBP has been reported. Modic change Type I, and Modic change Types I + II are found in a higher proportion of patients with CLBP than in the general population. Although the pathogenesis of Modic changes, which are characterized by edema (or inflammation) in vertebrae, is unclear, one hypothesis is that Modic changes and low back pain are caused by low grade bacterial discitis (i.e., infection of the spinal discs) (Braten et al., (2019). BMJ, 15654. https: / / doi.org / 10.1136 / bmj.15654). Several pathogens including anaerobic bacteria, e.g., Cutibacterium acnes (C. acnes) (previously known as Propionibacterium acnes (P. acnes)), can infect intervertebral discs and may cause Modic changes and low back pain (id.).

[0006] Antibiotic therapy may be effective in the treatment of CLBP associated with Modic changes. For example, one study reported that patients with CLBP receiving 100 days of oral antibiotic (amoxicillin-clavulanate) obtained a “clinically important” and statistically significant (p< 0.001) improvement in all measured parameters (Albert et al., (2013). European Spine Journal, 22(4), 697-707. https: / / doi.org / 10.1007 / s00586-013-2675-y). However, there is no consensus regarding the effectiveness of oral antibiotic treatment on CLBP. For example, a follow-on study concluded that three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo (Braten et al., (2019). BMJ, 15654. http s : / / doi . org / 10.1136 / bmj .15654).

[0007] The present disclosure addresses these unmet issues by providing antibiotic compositions and formulations and spinal injection methods and dosing regimens for treatment of CLBP, which provides improvements as compared to oral administration of an antibiotic.

[0008] SUMMARY OF THE DISCLOSURE

[0009] In one aspect, the present disclosure provides a method of treating chronic low back pain in a patient, the method comprising administering a therapeutically effective amount of a first P1216.70006US00 1 / 72

[0010] #13667512vlantibiotic to one or more targeted sites in the spine of the patient, wherein the method provides improvements as compared to oral administration of a second antibiotic.

[0011] In another aspect, the present disclosure provides a method of improving the treatment of chronic low back pain in a patient with a first antibiotic as compared to oral administration of a second antibiotic to the patient, the method comprising administering a therapeutically effective amount of the first antibiotic to one or more targeted sites in the spine of the patient.

[0012] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Drawings, and Claims.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The accompanying drawings, which constitute a part of this application, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

[0015] Figure 1 shows the change in Low Back Pain Numerical Rating Scale mean scores from baseline at 1, 3, 6, 9 and 12 months, for both the intradiscal administration group and placebo group, using a MMRM statistical model for the full analysis set. * indicates a statistically significant difference (p<0.05).

[0016] Figure 2 shows the percentage change in Low Back Pain Numerical Rating Scale mean scores from baseline at 12 months with intradiscal administration according to the present disclosure as compared to oral administration (Braten et al., 2019).

[0017] Figure 3 shows the change in Low Back Pain Numerical Rating Scale mean scores from placebo at 12 months with intradiscal administration according to the present disclosure as compared to oral administration (Braten et al., 2019).

[0018] Figure 4 shows the percentage change in Low Back Pain Numerical Rating Scale median scores from baseline at 12 months with intradiscal administration according to the present disclosure as compared to oral administration (Albert et al., 2013).

[0019] P1216.70006US00 2 / 72

[0020] #13667512vlFigure 5 shows the change in Roland Morris Disability Questionnaire mean scores from baseline at 1, 3, 6, 9 and 12 months, for both the intradiscal administration treatment group and placebo group, using a MMRM statistical model for the full analysis set. * indicates a statistically significant difference (p<0.05).

[0021] Figure 6 shows a comparison in the change in Roland Morris Disability Questionnaire mean scores from baseline at 1, 3, 6, 9 and 12 months, for both the intradiscal administration treatment group and placebo group, using a MMRM statistical model for the full analysis set, for RMDQ-23 and RMDQ-24.

[0022] Figure 7 shows the percentage change in Roland Morris Disability Questionnaire mean scores from baseline at 12 months with intradiscal administration according to the present disclosure as compared to oral administration (Braten et al., 2019).

[0023] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0024] In one aspect, the present disclosure provides a method of treating chronic low back pain in a patient, the method comprising administering a therapeutically effective amount of a first antibiotic to one or more targeted sites in the spine of the patient, wherein the method provides improvements as compared to oral administration of a second antibiotic.

[0025] In another aspect, the present disclosure provides a method of improving the treatment of chronic low back pain in a patient with a first antibiotic as compared to oral administration of a second antibiotic to the patient, the method comprising administering a therapeutically effective amount of the first antibiotic to one or more targeted sites in the spine of the patient.

[0026] Chronic low back pain substantially affects people’s lifestyle, work and activities. The current management of low back pain offers low to moderate improvement in pain and disability. A variety of factors could cause low back pain, and pathogenesis is not well-understood. The present disclosure addresses this by providing antibiotic compositions and formulations and spinal injection methods and dosing regimens for treatment of CLBP, which unexpectedly provides improvements as compared to oral administration of an antibiotic.

[0027] In some embodiments, the improvements provided by the methods disclosed herein are by way of comparison to oral administration of a second antibiotic. In some embodiments, the P1216.70006US00 3 / 72

[0028] #13667512vlcomparison is to oral administration of a second antibiotic to the same patient receiving the first antibiotic. In some embodiments, the comparison is to oral administration of a second antibiotic to a different patient than the patient receiving the first antibiotic. In some embodiments, the comparison is to oral administration of a second antibiotic to an individual patient. In some embodiments, the comparison is to oral administration of a second antibiotic to a population of patients.

[0029] In some embodiments, the patient receiving the first antibiotic is an individual patient. In some embodiments, the patient receiving the first antibiotic is a population of patients. In some embodiments, the patient receiving the first antibiotic is an individual patient and the comparison is to oral administration of a second antibiotic to an individual patient.

[0030] In some embodiments, the patient receiving the first antibiotic is an individual patient and the comparison is to oral administration of a second antibiotic to a population of patients. In some embodiments, the patient receiving the first antibiotic is a population of patients and the comparison is to oral administration of a second antibiotic to an individual patient. In some embodiments, the patient receiving the first antibiotic is a population of patients and the comparison is to oral administration of a second antibiotic to a population of patients. In some embodiments, the patient receiving the first antibiotic is an individual patient and the comparison is to oral administration of a second antibiotic to a different patient than the patient receiving the first antibiotic. In some embodiments, the patient receiving the first antibiotic is an individual patient and the comparison is to oral administration of a second antibiotic to the same patient as the patient receiving the first antibiotic. In some embodiments, the patient receiving the first antibiotic is a population of patients and the comparison is to oral administration of a second antibiotic to a different population of patients than the patients receiving the first antibiotic. In some embodiments, the patient receiving the first antibiotic is a population of patients and the comparison is to oral administration of a second antibiotic to the same patient population receiving the first antibiotic.

[0031] In some embodiments, the method provides improvement in efficacy, safety, and / or a reduction in analgesic use by the patient. In some embodiments, the improvement is measured as a reduction in the therapeutically effective amount of the first antibiotic as compared to the amount of the second antibiotic. In some embodiments, the therapeutically effective amount of

[0032] P1216.70006US00 4 / 72

[0033] #13667512vlthe first antibiotic is about 10%, about 1%, or about 0.1% by mass of the amount of the second antibiotic.

[0034] In some embodiments, the improvement is measured as a reduction in frequency of administration of the first antibiotic as compared to the frequency of administration of the second antibiotic.

[0035] In some embodiments, the improvement comprises a reduction in pain and / or adverse events.

[0036] Reduction in disability

[0037] In some embodiments, the improvement is measured in a reduction in disability. In some embodiments, the improvement is measured as a faster and / or greater reduction in disability as compared to administration of the second antibiotic.

[0038] In some embodiments, the reduction in disability is about 20% or more, such as about 30 % or more, compared to baseline after about 3 months. In some embodiments, the reduction in disability is about 50% or more compared to baseline after about 3 months.

[0039] In some embodiments, the reduction in disability is about 17% or more compared to placebo after about 3 months. In some embodiments, the reduction in disability is about 20% or more compared to placebo after about 3 months.

[0040] In some embodiments, the reduction in disability is about 20% or more compared to placebo after about 12 months. In some embodiments, the reduction in disability is about 25% or more, such as about 30% or more, compared to placebo after about 12 months. In some embodiments, the reduction in disability is about 45% or more compared to placebo after about 12 months.

[0041] In some embodiments, the reduction in disability is about 36% or more compared to baseline after about 12 months. In some embodiments, the reduction in disability is about 50% or more compared to baseline after about 12 months. In some embodiments, the reduction in disability is about 60% or more compared to baseline after about 12 months.

[0042] In some embodiments, the reduction in disability is measured by the Roland Morris Disability Questionnaire (RMDQ). In some embodiments, the RMDQ is RMDQ-23 or RMDQ-24. P1216.70006US00 5 / 72

[0043] #13667512vlIn some embodiments the RMDQ mean baseline value is from about 12 to about 18, such as about 15, when calculated from a patient population. In some embodiments, the RMDQ baseline value is calculated from a patient population within a treatment group.

[0044] In some embodiments, the RMDQ baseline value is from about 9 to about 23 or about 24. In some embodiments, the RMDQ baseline value is taken from an individual patient.

[0045] In some embodiments, the RMDQ value is calculated from a patient population within a treatment group. In some embodiments, the RMDQ value is taken from an individual patient.

[0046] In some embodiments, the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value. In some embodiments, the decrease in the RMDQ value is a decrease from the RMDQ mean baseline value. In some embodiments, the decrease in the RMDQ value is a decrease from the RMDQ baseline value for an individual patient.

[0047] In some embodiments, the reduction in disability is measured by a percentage decrease compared to the RMDQ baseline value. In some embodiments, the reduction in disability is measured by a percentage decrease compared to the RMDQ mean baseline value. In some embodiments, the reduction in disability is measured by a percentage decrease compared to the RMDQ baseline value for an individual patient.

[0048] In some embodiments, the decrease in the RMDQ value from the RMDQ baseline value is from about 1 unit to about 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, such as about 5 units, when evaluated after about 1 month. In some embodiments, the decrease in the RMDQ value from the RMDQ baseline value is from about 1 unit to about 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, optionally about 5 units, when evaluated after about 3 months. In some embodiments, the decrease in the RMDQ value from the RMDQ baseline value is from about 3 units to about 12 units, optionally about 5 units to about 10 units, optionally about 6 unit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 6 months. In some embodiments, the decrease in the RMDQ value from the RMDQ baseline value is from about 3 units to about 12 units, optionally about 5 units to about 10 units, optionally about 6 unit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 9 P1216.70006US00 6 / 72

[0049] #13667512vlmonths. In some embodiments, the decrease in the RMDQ value from the RMDQ baseline value is from about 5 units to about 14 units, optionally about 7 units to about 12 units, optionally about 9 units or about 10 units, when evaluated after about 12 months.

[0050] In some embodiments, the percentage decrease compared to the RMDQ baseline value is from about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 1 month. In some embodiments, the percentage decrease compared to the RMDQ baseline value is from about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 3 months. In some embodiments, the percentage decrease compared to the RMDQ baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 6 months. In some embodiments, the percentage decrease compared to the RMDQ baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 9 months. In some embodiments, the percentage decrease compared to the RMDQ baseline value is from about 30% to about 90%, optionally about 40% to about 80%, optionally about 60% to about 70%, optionally about 65%, when evaluated after about 12 months.

[0051] In some embodiments, the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 15 to about 11.5 or lower when evaluated after about 3 months. In some embodiments, the reduction in disability is measured by a decrease from the RMDQ baseline value of about 14.9 to about 9.9 or lower when evaluated after about 3 months.

[0052] In some embodiments, the reduction in disability is measured by a decrease in RMDQ from the RMDQ baseline value of about 15 to about 7 or lower when evaluated after about 12 months. In some embodiments, the reduction in disability is measured by a decrease in RMDQ from the RMDQ baseline value of about 14.9 to about 5.5 or lower when evaluated after about 12 months. In some embodiments, the reduction in disability is measured by a decrease in RMDQ from the RMDQ baseline value of about 12.9 to about 8.2 or lower when evaluated after about 12 months.

[0053] In some embodiments, the reduction in disability is measured by a between group difference in RMDQ baseline value between treatment and placebo, when evaluated using a patient population. In some embodiments, the between group difference in RMDQ baseline value is P1216.70006US00 7 / 72

[0054] #13667512vlfrom about -1 to about -10, such as from about -2 to about -8, for example about -3 to about -6. In some embodiments, the between group difference in RMDQ baseline value is about -2.0 to about -4.0, when evaluated after about 9 months. In some embodiments, the between group difference in RMDQ baseline value is about -3.0 to about -4.0, when evaluated after about 12 months. In some embodiments, the between group difference in RMDQ baseline value is about -3.8 to about -4.0, when evaluated after about 12 months.

[0055] Reduction in pain

[0056] In some embodiments, the improvement is measured in reduction in pain. In some embodiments, the improvement is measured as a greater reduction in pain as compared to administration of the second antibiotic.

[0057] In some embodiments, the reduction in pain is about 25% or more compared to baseline after about 3 months. In some embodiments, the reduction in pain is about 30% or more compared to baseline after about 3 months.

[0058] In some embodiments, the reduction in pain is about 30% or more compared to baseline after about 12 months. In some embodiments, the reduction in pain is about 45% or more compared to baseline after about 12 months. In some embodiments, the reduction in pain is about 50% or more compared to baseline after about 12 months. In some embodiments, the reduction in pain is about 60% or more, such as about 65% or more, compared to baseline after about 12 months.

[0059] In some embodiments, the reduction in pain is about 10% or more compared to placebo after about 3 months. In some embodiments, the reduction in pain is about 25% or more compared to placebo after about 3 months.

[0060] In some embodiments, the reduction in pain is about 15% or more compared to placebo after about 12 months. In some embodiments, the reduction in pain is about 25% or more compared to placebo after about 12 months. In some embodiments, the reduction in pain is about 35% or more compared to placebo after about 12 months. In some embodiments, the reduction in pain is about 45% or more compared to placebo after about 12 months.

[0061] In some embodiments, the reduction in pain comprises a reduction in low back pain. In some embodiments, the reduction in low back pain is measured by the Low Back Pain Numerical P1216.70006US00 8 / 72

[0062] #13667512vlRating Scale (LBP NRS). In some embodiments, the LBP NRS baseline value is calculated from a patient population. In some embodiments, the LBP NRS baseline value is calculated for a treatment population. In some embodiments, the LBP NRS baseline value is calculated for a placebo population.

[0063] In some embodiments, the LBP NRS baseline mean value is from about 4 to about 10, such as from about 5 to about 8, when calculated from a patient population. In some embodiments, the LBP NRS baseline value is taken from an individual patient.

[0064] In some embodiments, the LBP NRS value is calculated from a patient population. In some embodiments, the LBP NRS value is calculated for a treatment population. In some embodiments, the LBP NRS value is calculated for a placebo population. In some embodiments, the LBP NRS value is taken from an individual patient.

[0065] In some embodiments, the reduction in low back pain is measured by a decrease in the LBP NRS value from the LBP NRS baseline value. In some embodiments, the decrease in the LBP NRS value is a decrease from the LBP NRS mean baseline value. In some embodiments, the decrease in the LBP NRS value is a decrease from the LBP NRS baseline value for an individual patient.

[0066] In some embodiments, the reduction in low back pain is measured by a percentage decrease compared to the LBP NRS baseline value. In some embodiments, the reduction in low back pain is measured by a percentage decrease compared to the LBP NRS mean baseline value. In some embodiments, the reduction in disability is measured by a percentage decrease compared to the LBP NRS baseline value for an individual patient.

[0067] In some embodiments, the decrease in the LBP NRS value from the LBP NRS baseline value is from about 1 unit to about 6 units, such as about 1 unit to about 4 units, optionally about 1 unit to about 3 units, such as about 1 unit or about 2 units, when evaluated after about 1 month. In some embodiments, the decrease in the LBP NRS value from the LBP NRS baseline value is from about 1 unit to about 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, optionally about 5 units, when evaluated after about 3 months. In some embodiments, the decrease in the LBP NRS value from the LBP NRS baseline value is from about 3 units to about 10 units, optionally about 5 units to about 10 units, optionally about 6 P1216.70006US00 9 / 72

[0068] #13667512vlunit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 6 months. In some embodiments, the decrease in the LBP NRS value from the LBP NRS baseline value is from about 4 units to about 10 units, optionally about 5 units to about 9 units, optionally about 7 units, when evaluated after about 9 months. In some embodiments, the decrease in the LBP NRS value from the LBP NRS baseline value is about 5 units to about 10 units, optionally about 7 units to about 10 units, optionally about 9 units or about 10 units, when evaluated after about 12 months.

[0069] In some embodiments, the percentage decrease compared to the LBP NRS baseline value is from about 10% to about 40%, optionally about 15% to about 30%, optionally about 25%, when evaluated after about 1 month. In some embodiments, the percentage decrease compared to the LBP NRS baseline value is from about 10% to about 40%, optionally about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 3 months. In some embodiments, the percentage decrease compared to the LBP NRS baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 6 months. In some embodiments, the percentage decrease compared to the LBP NRS baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 50%, when evaluated after about 9 months. In some embodiments, the percentage decrease compared to the LBP NRS baseline value is from about 30% to about 90%, optionally about 40% to about 80%, optionally about 60% to about 70%, optionally about 65%, when evaluated after about 12 months.

[0070] In some embodiments, the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 5.0 or lower when evaluated after about 3 months. In some embodiments, the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 4.7 or lower when evaluated after about 3 months. In some embodiments, the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 3.7 or lower when evaluated after about 12 months. In some embodiments, the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 3.34 or lower when evaluated after about 12 months. In some embodiments, the reduction in low back pain is measured by a reduction in the LBP

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[0072] #13667512vlNRS value from the LBP NRS baseline value of about 6.5 to about 4.5 or lower when evaluated after about 12 months.

[0073] In some embodiments, the reduction in low back pain is measured by a between group difference from LBP NRS baseline value between treatment and placebo, when evaluated using a patient population. In some embodiments, the between group difference from LBP NRS baseline value is from about -1 to about -10, such as from about -2 to about -8, for example about -3 to about -6. In some embodiments, the between group difference from LBP NRS baseline value is about -1.3 or -1.4 when evaluated after about 12 months.

[0074] Reduction in occurrence of GI side effects

[0075] In some embodiments, the improvement is measured as a reduction in occurrence of gastrointestinal (GI) side effects as compared to occurrence of GI side effects after oral administration of the second antibiotic.

[0076] In some embodiments, the GI side effects are one or more of loose bowel movements, increased flatus, or increased burping. In some embodiments, GI side effects are loose bowl movements lasting more than 3 weeks.

[0077] In some embodiments, the improvement comprises the occurrence of substantially no GI side effects. In some embodiments, occurrence of GI side effects after administration of the second antibiotic is at least about 50%, such as at least about 56% or at least about 65%. In some embodiments, occurrence of GI side effects after administration of the second antibiotic is in the range of about 40% to about 80%, for example about 65% or about 56%.

[0078] Lower risk benefit

[0079] In some embodiments, the improvement is measured by a lower risk benefit as compared to the risk benefit obtained for oral administration of a second antibiotic.

[0080] In some embodiments, the risk benefit is calculated based on the number needed to treat (NNT) divided by the number needed to harm (NNH). In some embodiments, the risk benefit for all adverse events is no greater than about 1.0, such as no greater than about 0.8 or no greater than about 0.6, for example no greater than about 0.4. In some embodiments, the risk benefit for diarrhea is no greater than about 0.4 or about 0.3, for example no greater than about 0.2. P1216.70006US00 11 / 72

[0081] #13667512vlReduction in analgesic use

[0082] In some embodiments, the improvement is a reduction in analgesic use by the patient.

[0083] In some embodiments, the analgesic use is reduced by at least about 30%, such as at least about 35%. In some embodiments, the analgesic use is reduced from an initial value in the range of about 75% to about 85%, to a final value in the range of about 45% to about 55%, for example from about 80% to about 50%, when evaluated after about 12 months.

[0084] In some embodiments, the improvement is a reduction in non-steroidal anti-inflammatory drug (NSAID) use and / or opioid use by the patient. In some embodiments, the NSAID use is reduced by at least about 30%, such as at least about 35%. In some embodiments, the NSAID use is reduced from an initial value in the range of about 55% to about 65%, to a final value in the range of about 35% to about 45%, for example from about 60% to about 39%, when evaluated after about 12 months.

[0085] In some embodiments, the opioid use is reduced by at least about 60%, such as at least about 70%. In some embodiments, the opioid use is reduced from an initial value in the range of about 20% to about 30% to a final value in the range of about 5% to about 8%, for example from about 25% to about 6%, when evaluated after about 12 months.

[0086] Low back pain

[0087] In some embodiments, the patient is human. Accordingly, the present disclosure relates to methods of treating chronic low back pain in a human.

[0088] Chronic low back pain (CLBP) is persistent, z.e., chronic, which may last for three months or longer. Types of pain may include, but are not limited to, acute pain, sub-acute pain, chronic or constant pain, local pain, radicular pain, referred pain, somatic pain, radiating pain, neuropathic pain, inflammatory pain, and mixed pain.

[0089] It has been reported that patients with chronic low back pain are often diagnosed with vertebral body endplate bone edema (Modic changes, MCs), such as Modic change Type I, Modic change Type II, or Modic change Type I + Type II, at the painful disc level in the MRI. Bacterial infection can induce a local inflammatory process that leads to vertebral end plate P1216.70006US00 12 / 72

[0090] #13667512vlchanges. Because Modic changes are associated with LBP, the finding of the etiological correlation between Modic changes and bacterial infection provides a novel strategy for treating LBP, specifically CLBP.

[0091] In some embodiments, the patient has vertebral body endplate bone edema (Modic change). In some embodiments, the Modic change is Modic change Type I, Modic change Type II, or Modic change Type I+II.

[0092] First antibiotic

[0093] The selection of antibiotics for the first antibiotic may depend on the bacterial pathogens isolated from Modic discs. The bacterial pathogens most frequently isolated from Modic discs are Staphylococcus spp. and C. acnes. Antibiotic resistances vary in different populations and territories worldwide. To have a robust and widely effective therapy, coverage of common resistances would be preferred with C. acnes and Staphylococcus, or with C. acnes only as a minimum.

[0094] Preferably, antibiotics that are effective against current clinical isolates from any infection site may be selected as active agents of the present compositions and formulations, given the resistance profiles of pathogens isolated at the site of infection associated with Modic changes. In some embodiments, antibiotics that are effective against both C. acnes and Staphylococci may be selected as active agents of the present compositions and formulations. In some embodiments, a combination of the antibiotics that are effective against both C. acnes and Staphylococci may be selected. In some non-limiting examples, the antibiotic composition comprises at least one antibiotic for the treatment of the C. acnes infection that is associated with Modic change Type I.

[0095] In some embodiments, the first antibiotic is from the class of oxazolidinones. In some embodiments, the first antibiotic is selected from the group consisting of linezolid, tedizolid, sutezolid, eperezolid, radezolid contezolid, posizolid, delpazolid and TB 1-233.

[0096] In some embodiments, the antibiotic is linezolid (chemical name: ((S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide).

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[0098] #13667512vlDifferent polymorphic forms (z.e., crystal modifications) of linezolid can be selected as the active ingredient of the composition. For example, linezolid can be linezolid Form I (e.g., U.S. Pat. No. 6,444,813), or Form II (e.g., U.S. Pat. No. 6,559,305), or Form III (e.g., US. Pat. NO.

[0099] 7,718,799; U.S. Patent publication No. 2007 / 0104785), or Form IV (e.g., U.S. Patent Publication No. 2008 / 0319191), or other crystal forms as described in PCT Application Publication Nos. W02007 / 026369, W02006 / 110155 and WO2014 / 013498; and U.S. Patent Publication No. 2017 / 0008919; the contents of each of which are incorporated herein by reference in their entirety.

[0100] For example, linezolid Form II may be characterised by a powder X-ray diffraction (XPRD) pattern comprising peaks at 16.8, 14.2 and 22.4 degrees two theta. The XPRD pattern may further comprise peaks at 21.6 and 25.3 degrees two theta. When a crystalline form is identified using one or more XRPD peaks given as angles 29 (two theta), each of the 29 values is understood to mean the given value ± 0.2 degrees, unless otherwise expressed.

[0101] Linezolid Form II may be characterized by an XRPD spectrum substantially as follows:

[0102]

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[0104] #13667512vl

[0105]

[0106] Linezolid Form II may be characterised by an infrared (IR) spectrum as a mineral oil mull having the following peaks: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852, and 758 cm'1.

[0107] Linezolid Form II may be characterized by a differential scanning calorimetry transition temperature of about 155°C ± 5°C for the first transition and 179°C ± 5°C for the second transition.

[0108] As a non-limiting example, linezolid can be linezolid Form II, in milled powder form. Linezolid (Form II) can be milled into micronized powder and sterilized for preparing sterile injectable compositions of the present disclosure, using any suitable method. Preferably, the linezolid Form II is sterilized by gamma irradiation. The linezolid Form II may be prepared and packed separately.

[0109] Compositions comprising the first antibiotic

[0110] In some embodiments, the first antibiotic as the active pharmaceutical ingredient (the API) may be formulated in a delivery vehicle, z.e., as an antibiotic composition.

[0111] In accordance, the compositions as discussed herein are formulated to deliver a therapeutically effective amount of the first antibiotic to one or more target sites in a subject in need.

[0112] The effective amount of antibiotic is provided based, at least in part, on the target bacteria, means of administration, and other determinants. In general, an effective amount of antibiotic (e.g., linezolid) provides efficient killing or inhibition of target bacteria and reduces pain or the risk of developing pain in the subject in need.

[0113] In some embodiments, the antibiotic is prepared as an aqueous suspension at room temperature, while after in vivo injection, the suspension can transition into a gel at body temperature. Over several hours or days, the gels break down (z.e., biodegradable).

[0114] P1216.70006US00 15 / 72

[0115] #13667512vlAny suitable delivery carriers may be used for delivering antibiotics (e.g., linezolid) to the spine. The delivery carrier may be suitable for injection, particularly for injection into the spine or areas near to the spine. For example, the delivery carrier may be an aqueous solution, a low viscous solution, a suspension, or a reversible thermogel. The carrier preferably is a biodegradable and biocompatible carrier. As used herein, the term “biocompatible” means the carriers are not toxic to the tissues and cells. As used herein, the terms “biodegradable” and “bioabsorbable” are used interchangeably. The biodegradation or bioabsorbance refers to the degradation, disassembly, digestion or disappearance of the delivery materials after releasing formulated therapeutically effective antibiotics e.g., linezolid), in the biological environment.

[0116] In some embodiments, the delivery carrier is a thermosensitive hydrogel. The injectable thermosensitive hydrogels may have a solution-gel transition temperature around or below physiological temperature. As a non-limiting example, the injectable thermosensitive hydrogel is composed of poloxamer. The antibiotic- thermosensitive hydrogel compositions provide local delivery of an effective amount of linezolid to a diseased site / sites, such as one or more spinal compartments.

[0117] Poloxamers are FDA-approved thermosensitive synthetic polymers, which are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Biocompatible poloxamers have been widely used for drug delivery and tissue engineering. Poloxamer-based hydrogels allow reversible gelation under certain physiological temperature and pH by adjusting the composition of PEO and PPO, and the overall molecular weight and concentration.

[0118] In some embodiments, the thermosensitive hydrogel is composed of poloxamer 407 (also known as Pluronic® F-127, Kolliphor 407, and SynperonicPE / F 127). Poloxamer 407 is a triblock copolymer consisting by weight of approximately 70% PEO (polyethylene glycol) and 30% PPO (polypropylene oxide) with an average molecular weight of 11500. Poloxamer 407 exhibits thermoreversible gelation behaviour.

[0119] In some embodiments, the poloxamer 407 based thermo sensitive hydrogel further comprises a radiocontrast agent such as iohexol to facilitate the application of the linezolid formulation to P1216.70006US00 16 / 72

[0120] #13667512vla target site / sites, for example, an intervertebral disc. The addition of a radiocontrast agent in the present antibiotic formulations will assist a clinical practitioner (like a physician) to see the product being administered, and monitor the administration using e.g., fluoroscopy or CT. This real-time information can help the practitioner to decide when to stop injection when the disc is full and is starting to leak.

[0121] In some embodiments, the first antibiotic is administered as a composition comprising:

[0122] the first antibiotic, and

[0123] a thermosensitive hydrogel delivery carrier comprising poloxamer 407 and iohexol.

[0124] The composition may further comprise a pharmaceutically acceptable excipient.

[0125] The ratio and concentrations of poloxamer 407 and iohexol in the delivery carrier may be optimized in the context of linezolid concentrations and gelling temperature and / or other parameters. The amounts of iohexol and poloxamer 407 in the delivery carrier are optimized to achieve the target temperature range for the solution-to-gel transition of the present thermosensitive hydrogel formulations.

[0126] In one preferred embodiment, the poloxamer 407 and iohexol containing delivery carrier is prepared as a separate solution. As discussed above, the concentrations of poloxamer and iohexol are optimized to certain concentrations so that the gelation temperature of the solution is optimized at or close to the body temperature. As a non-limiting example, the concentrations of iohexol and poloxamer 407 are optimized to achieve a gelling temperature ranging from 26°C to 38°C, or from 26°C to 32°C, or from 32°C to 36°C.

[0127] In one preferred embodiment, the delivery carrier comprises poloxamer 407 with about 10% to about 17% by weight of the delivery carrier, or at a concentration of about 121 mg / ml to about 207 mg / ml by volume of the carrier. Preferably it may comprise poloxamer 407 with about 11.5% to about 13.5% by weight of the carrier, or at a concentration of about 140 mg / ml to about 165 mg / ml in the carrier. In other embodiments, the carrier comprises iohexol with about 14.5% to about 62.5% by weight of the carrier, or at a concentration of about 174 mg / ml to about 755 mg / ml in the carrier. Preferably the delivery carrier may comprise iohexol with about 18% to about 35% by weight of the carrier, or at a concentration of about 206 mg / ml to

[0128] P1216.70006US00 17 / 72

[0129] #13667512vlabout 425 mg / ml in the carrier. The delivery carrier as described herein can be used to deliver any drug, for example an antibiotic, for delivering to a deep cavity of the body.

[0130] As a non-limiting example, the poloxamer hydrogel solution may be made following the steps of (1) preparing a cold iohexol solution by adding iohexol to a solution comprising tromethamine and calcium disodium EDTA (pH at about 8.0); and (2) adding poloxamer 407 powder slowly to the cold iohexol solution and stirring the solution until the poloxamer powder is completely dissolved, wherein the poloxamer powder is added as portions. The poloxamer-iohexol solution may be sterilized and packed into separate vials, or syringes (e.g., dual chamber syringes) ready for use.

[0131] The compositions described herein may further comprise one or more pharmaceutically-acceptable excipients, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.

[0132] The first antibiotic may be loaded to the delivery carrier at a concentration ranging from about 1% to about 20% by weight or by volume of the composition, or about 2.5% to about 20% or about 2.5% to about 10%, or about 3.0% to about 10% by weight or by volume of the composition. In one aspect, the formulation may comprise about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5% or 20% of the first antibiotic by weight of the final composition. The first antibiotic may be present at a concentration from about 10 mg / ml to about 200 mg / ml, or from about 20 mg / ml to about 200 mg / ml, or from about 50 mg / ml to about 200 mg / ml. Particularly the first antibiotic may be present in the formulation at a concentration of 10 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 100 mg / ml, 150 mg / ml, or 200 mg / ml.

[0133] P1216.70006US00 18 / 72

[0134] #13667512vlIn some embodiments, the first antibiotic is linezolid, for example linezolid Form II, administered as a composition comprising:

[0135] linezolid, such as linezolid Form II, and

[0136] a thermosensitive hydrogel delivery carrier comprising poloxamer 407 and iohexol.

[0137] Prior to use, a linezolid preparation such as a unit of pre-prepared sterilized powder of linezolid Form II is loaded to a delivery carrier (e.g., a thermosensitive hydrogel delivery carrier to form the linezolid composition (z.e., linezolid suspension). The linezolid composition may comprise a thermosensitive poloxamer hydrogel loaded with an effective amount of linezolid, a nonionic contrast agent iohexol at a concentration which is optimized for the poloxamer solution-to-gel transition, and optionally one or more pharmaceutically acceptable excipient. The linezolid Form II, which is milled to form micronized powder and sterilized by gamma irradiation, forms a suspension in the poloxamer-iohexol thermosensitive hydrogel carrier. The linezolid Form II micronized powder may have a D90 of about 50 pm or less, optionally about 20 pm or less, optionally about 10 pm or less, optionally from about 3 to about 10 pm. The linezolid Form II micronized powder may have a D10 of about 5 pm or less, optionally about 3 pm or less, optionally about 1 pm or less, optionally from about 0.1 to about 1 pm. As used herein, the terms D10 and D90 have their conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, static light scattering, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. Preferably, D10 and D90 are measured using laser diffraction.

[0138] Linezolid may be loaded to the delivery carrier at a concentration ranging from about 1% to about 20% by weight or by volume of the composition, or about 2.5% to about 20% or about 2.5% to about 10%, or about 3.0% to about 10% by weight or by volume of the composition. In one aspect, the linezolid formulation may comprise about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5% or 20% linezolid by weight of the final composition. Linezolid may be present at a concentration from about 10 mg / ml to about 200 mg / ml, or from about 20 mg / ml to about 200 mg / ml, or from about 50 mg / ml to about 200 mg / ml. Particularly linezolid may be present in the formulation at a concentration of 10 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 100 mg / ml, 150 mg / ml, or 200 mg / ml.

[0139] P1216.70006US00 19 / 72

[0140] #13667512vlIn one preferred embodiment, the linezolid composition comprises (i) about 1% to about 20% linezolid by weight of the formulation (w / w); (ii) about 9.5% to about 14.5 % poloxamer 407 by weight of the formulation (w / w) (z.e., at a concentration of about 115 mg / ml to about 173 mg / ml in the composition), or about 10.8% to about 12.8% poloxamer 407 by weight of the formulation (z.e., at a concentration of about 130 mg / ml to about 156 mg / ml in the composition); and (iii) about 14% to 59% iohexol by weight of the formulation (w / w) (z.e., at a concentration of about 165 mg / ml to about 718 mg / ml in the formulation) or about 17% to about 30% iohexol by weight of the formulation (z.e., at a concentration of about 206 mg / ml to 364 mg / ml in the formulation). As a non-limiting example, the linezolid formulation comprises about 5% w / w linezolid, about 11.8% w / w poloxamer 407 and about 27.2% w / w iohexol. In some embodiments, the aqueous linezolid composition may gel at about 26 °C, or about 27 °C, or about 28 °C, or about 30 °C, or about 31 °C, or about 32 °C, or about 33 °C, or about 34 °C, or about 35 °C, or about 36 °C, or about 37 °C, or about 38 °C. In one non-limiting example, the linezolid composition gels at about 28 °C. Linezolid can diffuse from the gel. Over several days, the gel breaks down.

[0141] In some embodiments, the linezolid composition for spinal administration comprises about 2.5% to 20% linezolid Form II, about 17% to 30% iohexol, and about 10.8% to 12.8% poloxamer 407 by weight of the composition.

[0142] The linezolid homogenous suspension mixed prior to the application may be taken up into an injection device (e.g., a dual chambered syringe) and prepared with the intended dose volume. In some embodiments, the linezolid composition is administered using a dual chambered syringe. The linezolid composition is sterilized using any suitable methods.

[0143] The linezolid composition is injectable. The injectable antibiotic composition is formulated for delivering an effective amount of the antibiotic to the spine of a subject, including but not limited to, an intervertebral disc, intervertebral space, intra-articular space , ligamentum flavum, ligament associated with the spine (e.g., interspinous ligament and anterior / posterior longitudinal ligament), epidural space, tendon associated with the spine, site adjacent to bone edema, bone junction, facet joint, and / or other spinal compartments.

[0144] P1216.70006US00 20 / 72

[0145] #13667512vlDosage and dosing regimens for the first antibiotic

[0146] Antibiotic compositions and methods for spinal administration as discussed in the present disclosure ensure delivery of an effective amount of antibiotic to the infected sites for treating, ameliorating, and / or mitigating low back pain and / or phenotypic presentation, e.g., disability, found to be coincident with diseases, conditions or disorders associated with Modic changes or bone edema caused by bacteria infection.

[0147] In some embodiments, a single dose or multiple doses of the antibiotic (which may be present as an antibiotic composition) may be administered to a patient for chronic low back pain treatment. Reference to a single dose or multiple doses may refer to a single dose or multiple doses in each of the one or more targeted sites in the spine, such as in each of the one or more intervertebral discs.

[0148] In some embodiments, a single dose of the composition is administered for treating CLBP. The single dosage brings an effective amount of linezolid to inhibit bacterial infection. In accordance, a dosage of linezolid provides an effective amount of linezolid above the minimum inhibitory concentration (MIC) of the target bacteria. The target bacteria are Gram-positive bacteria, such as C. acnes, Corynebacterium propinquum, or those of the genus Staphylococcus. The MIC may range from 0.1-16mg / L. In a non-limiting example, a single dose of the antibiotic composition may deliver about 10 mg to about 200 mg of the first anitbiotic, or 10 mg to 100 mg, or 10 mg to 150 mg, or 20 mg to 100 mg, or 20 mg to 150 mg, or 20 mg to 200 mg, or 30 mg to 150 mg, or 30 mg to 200 mg, or 50 mg to 100 mg, or 50 mg to 150 mg, or 50 mg to 200 mg, or 100 mg to 120 mg, or lOOmg to 150 mg, or 120 mg to 200 mg of the first antibiotic.

[0149] In one embodiment, the amount of the first antibiotic is 150 mg. In one preferred embodiment, the first antibiotic is linezolid and the amount of linezolid is 150 mg.

[0150] In some embodiments, more than one dose of the antibiotic composition is administered to a patient with low back pain. In some embodiments, a dosing interval e.g., time between doses during a dosing regimen) is about 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, or longer. In some embodiments, a dosing interval is from about 24 hours to about 168 hours, from about 48 hours to about 144 hours, or from about 72 hours to about 120 hours. In some embodiments, a dosing interval is from about 72 hours to about 168 hours, from about P1216.70006US00 2 H2

[0151] #13667512vl72 hours to about 144 hours, from about 72 hours to about 132 hours, or from about 72 hours to about 120 hours. In some embodiments, the patient is administered a defined number of doses of the antibiotic composition in a defined period of time. For example, the patient may receive 2 doses of the antibiotic composition over 72 hours, 96 hours, or 120 hours.

[0152] The dosing regimens including specific amount, administration number, and frequency of doses over a specific period of time, are determined following clinical observations, and are as described by the various embodiments above.

[0153] In some embodiments, the antibiotic composition comprising the first antibiotic is administered twice in a period of about 10 days, such that there is a first administration and a second administration of the first antibiotic. For example, the second administration of the first antibiotic may be from about 3 to 5 days following the first administration of the first antibiotic.

[0154] In one preferred embodiment, the amount of the first antibiotic is 150 mg linezolid, administered once or twice over a period of no more than 10 days, such as no more than 8 days. In one preferred embodiment, the first antibiotic is administered no more than once or twice in a one-year period.

[0155] In some embodiments, a single dosing interval is used over the course of pain treatment with the linezolid composition. In some embodiments, multiple dosing intervals are used over the course of pain treatment with the linezolid composition. In some embodiments, a dosing interval is fixed. In some embodiments, a dosing interval is an individualized interval that is determined for a given subject based on, e.g., pharmacokinetic / toxicokinetic (PK / TK) data or other information about that subject, such as age, weight, height, body mass index, disease severity, comorbidities, race, ethnicity, national origin, genotype, and / or prior response to the antibiotic treatment. An individualized dose and dosing interval combination may be the same as those for fixed interval regimens or may differ.

[0156] In some embodiments, a dosing regimen e.g., the first dosing regimen and / or the second dosing regimen) including dose frequency, dose and duration time, may be personalized according to the subject’s reaction, side effects, and treatment efficacy.

[0157] P1216.70006US00 22 / 72

[0158] #13667512vlSpinal administration

[0159] The present disclosure relates to spinal injection to produce an effective level of the first antibiotic (above MIC of target bacteria) to bring beneficial outcomes (e.g., pain relief and reduced disability). In one embodiment, the present disclosure relates to spinal injection to produce an effective level of linezolid.

[0160] In accordance with the present disclosure, the antibiotic composition may be administered to vertebrae, intervertebral disc, intervertebral space, intra-articular space, ligamentum flavum, ligament associated with the spine (e.g., interspinous ligament, and anterior / posterior longitudinal ligament), epidural space, tendon associated with the spine, site adjacent to bone edema, bone junction, facet joint, and / or other spinal compartments.

[0161] In some embodiments, the antibiotic composition is administered to one or more vertebrae, intervertebral discs, intervertebral spaces, intra-articular spaces, ligamentum flavum, ligament associated with the spine, epidural space, tendon associated with the spine, site adjacent to bone oedema, bone junction, facet joint, and / or other spinal compartments.

[0162] Methods and devices known in the art for spinal administration are contemplated for use in conjunction with the methods and compositions disclosed herein. These include, for example, those methods and devices having multiple needles, hybrid devices employing for example lumens or catheters as well as devices utilizing heat, electric current or radiation driven mechanisms.

[0163] In some embodiments, the antibiotic composition is injected to one or more intervertebral discs. In some embodiments, the first antibiotic is delivered to the one or more intervertebral discs using an administration needle. In some embodiments, the administration needle is connected to a Luer-lock syringe. In some embodiments, the administration needle and the Luer-lock syringe are connected via a flexible connector.

[0164] A double needle system including an introducer needle and an administration needle may be used for intervertebral disc administration. An introducer needle may be used for safely achieving access to the intervertebral space, which may have a beveled side opening at its distal tip which provides a tissue piercing point at the distal tip. The introducer needle may be positioned against the outer annulus fibrosis of the disc, or as close to the edge of outer annulus

[0165] P1216.70006US00 23 / 72

[0166] #13667512vlas possible. An administration needle is then used to inject an effective amount of the antibiotic composition directly in the center of the nucleus pulposus. In addition to aiding in the targeting of the disc, use of the introducer needle can avoid contact between the administration needle and the skin, thereby keeping the antibiotic composition as cool as possible during administration and minimize risk of infection. The position of the introducer needle at the entry point is close to the foramen and at such an angle as to allow the tip of the administration needle to cross the disc to the center without penetrating the endplate. Under image guidance, the administration needle is advanced to the center of the nucleus pulposus across the line of diameter but does not penetrate the far side of the annulus fibrosus. This guided injection can fill the disc pulposus with the antibiotic composition, including as many of the degenerate splits in the annulus as may have occurred. This injection method brings a comprehensive fill but not one associated with material extravasation into adjacent spaces beyond the intervertebral space itself. A dose of antibiotic to be administered to the intervertebral disc may be injected slowly over minutes, e.g., 1-10 minutes, or 1-5 minutes, or 2-10 minutes, or 2-8 minutes, or 3-10 minutes.

[0167] The present injection procedure provides several advantages over other methods for delivering antibiotics to the deep spine compartments. A major advantage is that the deep spinal compartments, such as intervertebral disc, intervertebral space, intra- articular space, ligamentum flavum, ligament (such as interspinous ligament and anterior / posterior longitudinal ligament), epidural space, tendon associated with the spine, site adjacent to bone edema, bone junction, facet joint, and / or other spinal compartments, are specifically targeted, allowing the effective amount of antibiotic to be locally delivered to the targeted area.

[0168] Second antibiotic

[0169] In some embodiments, the first antibiotic and the second antibiotic are different. In some embodiments, the first antibiotic and the second antibiotic are the same.

[0170] In some embodiments, the second antibiotic is a beta-lactam antibiotic. In some embodiments, the beta-lactam antibiotic is amoxicillin. In some embodiments, the second antibiotic is coadministered with a beta-lactamase inhibitor, optionally wherein the beta-lactamase inhibitor is clavulanate, sulbactam, tazobactam, avibactam, durlobactam, relebactam, vaborbactam or enmetazobactam, optionally wherein the beta-lactamase inhibitor is clavulanate.

[0171] P1216.70006US00 24 / 72

[0172] #13667512vlIn some embodiments, the amount of the second antibiotic is from about 0.5 g to about 2 g, administered 2, 3, or 4 times per day. In some embodiments, the amount of the second antibiotic is about 1.5 g to about 6.0 g amoxicillin, for example about 1.5 g to about 4.0 g, such as about 1.5 g to 3.0 g, administered daily. In some embodiments, the second antibiotic is amoxicillin and the amount of amoxicillin is about 1.5 g, about 2.25 g, or about 3.0 g, administered daily.

[0173] In some embodiments, the second antibiotic is administered daily for about 3 months.

[0174] Also disclosed herein is a method for treating low back pain, the method comprising administering a therapeutically effective amount of linezolid Form II to a patient; wherein the linezolid Form II is provided in a composition comprising about 2.5% to 20% of linezolid Form II, about 17% to 30% iohexol and about 10.8% to 12.8% poloxamer 407 by weight of the composition;

[0175] the composition is administered to one or more intervertebral discs;

[0176] the patient receives two doses of the composition in each of the one or more intervertebral discs;

[0177] the first and second doses contain about 150 mg linezolid Form II for each dose; and the composition is administered twice in a period of about 10 days.

[0178] Methods of the present disclosure may provide one or more improvements described herein, which may be measured in one or more manners described herein. As such, an improvement described herein may be combined with any other improvement described herein, and may be measured in any manner described herein. As a non-limiting example, a method of the present disclosure may provide one or more of: an improvement in efficacy, safety, and / or a reduction in analgesic use by the patient; an improvement being substantially no GI side effects; an improvement being a reduction in analgesic use by the patient; an improvement being a reduction in non-steroidal anti-inflammatory drug (NSAID) use and / or opioid use by the patient; and / or an improvement comprising a reduction in pain and / or adverse events; wherein the improvements are measured as one or more of: a reduction in the therapeutically effective amount of the first antibiotic as compared to the amount of the second antibiotic, and / or a reduction in frequency of administration of the first antibiotic as compared to the frequency of administration of the second antibiotic; a reduction in disability; a faster and / or greater reduction in disability as compared to administration of the second antibiotic; a reduction in pain; a greater reduction in pain as compared to administration of the second antibiotic; a P1216.70006US00 25 / 72

[0179] #13667512vlreduction in occurrence of gastrointestinal (GI) side effects after intrasical administration with the first antibiotic as compared to occurrence of GI side effects after oral administration of the second antibiotic; and / or a lower risk benefit as compared to the risk benefit obtained for oral administration of a second antibiotic.

[0180] The low back pain, composition, linezolid Form II, iohexol, poloxamer 407, interverterbral discs, dosages, dosing interval and dosage regimens may be as described as for any of the foregoing embodiments.

[0181] DEFINITIONS

[0182] Administer. As used herein, the term “administer” or “administering” are used interchangeably herein to mean the delivery of a composition such as, for example, an antibiotic to a subject. Administration to a subject can include all suitable modes known to those of ordinary skill in the art. For example, administration as used in the present methods can include systemic or targeted modes of administration, such as injection, oral administration, topical administration, spinal injection, or intrathecal administration.

[0183] Active pharmaceutical ingredient (API): As used herein, the term “active pharmaceutical ingredient (API)” refers to a pharmaceutical agent that is biologically active. For example, a substance that, when it is administered to an organism, has a biological effect on that organism, is considered to be biologically active. In accordance with the present invention, the API is the first antibiotic.

[0184] Chronic low back pain: Chronic low back pain (CLBP) is defined as low back pain lasting for longer than 3 months. In some instances, the low back pain may last for longer than 6 months.

[0185] Delivery carrier: As used herein, the term “delivery carrier” refers to any agent, compound, or any combination thereof that can be used to carry an active ingredient (e.g., the API of the present invention) and deliver the same to a designated site. A delivery carrier can be, but is not limited to, a solution, a suspension, a hydrogel, and a nanoparticle.

[0186] Dosing interval'. As used herein, the term “dosing interval” refers to the amount of time that elapses between multiple doses being administered to a subject.

[0187] P1216.70006US00 26 / 72

[0188] #13667512vlFormulation'. As used herein, a “formulation” includes at least an active ingredient and a delivery agent.

[0189] Hydrogel'. As used herein, the term “hydrogels” are viewed as water insoluble, crosslinked, three-dimensional networks of polymer chains plus water that fills the voids between polymer chains. Crosslinking facilitates insolubility in water and provides required mechanical strength and physical integrity. Hydrogel is mostly water (the mass fraction of water is much greater than that of polymer). The ability of a hydrogel to hold significant amount of water implies that the polymer chains must have at least moderate hydrophilic character.

[0190] MIC (minimum inhibitory concentration): As used herein, the term “MIC” refers to the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. A lower MIC value indicates that less drug is required for inhibiting growth of the organism; therefore, drugs with lower MIC scores are more effective antimicrobial agents.

[0191] Patient'. As used herein, the term “patient” or “subject” refers to any organism who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition. The organism is a mammal such as mice, rats, rabbits, non-human primates, and humans. Preferably, a patient or subject is a human.

[0192] Patient population'. A patient population refers to a collection of individuals grouped together. In the present disclosure, the term may be applied to, for example, the treatment group of subjects, who are receiving the first antibiotic as defined herein.

[0193] Pharmaceutically acceptable'. As used herein, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0194] Pharmaceutical composition: As used herein, the phrase “pharmaceutical composition” refers to a composition that alters the etiology of a disease, disorder and / or condition.

[0195] P1216.70006US00 27 / 72

[0196] #13667512vlPlacebo'. Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate group receives a sham “placebo” treatment which does not contain the active ingredient of the treatment. The term “placebo” is used herein to define a group of subjects that have not received the first antibiotic or the second antibiotic as defined in the present disclosure.

[0197] Number of months: As used herein, the phrase “[X] months”, wherein [X] represents a number of months, is used in its usual sense. For example “about 3 months” refers to a time period of from about 90 days to about 100 days.

[0198] Therapeutically effective amount'. As used herein, the term “therapeutically effective amount” means an amount of an agent to be delivered (e.g. , antibiotic, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition.

[0199] Treating'. As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0200] Some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value. As used herein, the term “about” means a quantity within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0201] P1216.70006US00 28 / 72

[0202] #13667512vlIn the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process.

[0203] It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of’ is thus also encompassed and disclosed.

[0204] Unless otherwise indicated, the term “substantially”, as applied to characteristics, generally encompasses slight deviations in that characteristic which the skilled person would nonetheless consider equivalent (e.g., having substantially the same function or result and / or achieving the function / result and / or substantially in the same way).

[0205] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0206] EQUIVALENTS AND SCOPE

[0207] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

[0208] In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be P1216.70006US00 29 / 72

[0209] #13667512vlexcluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[0210] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the invention in its broader aspects.

[0211] While the present invention has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the invention.

[0212] EXAMPLES

[0213] Example 1: Injection of intradiscal linezolid

[0214] Preparation of intradiscal linezolid formulation

[0215] An intradiscal linezolid formulation of the present disclosure is made up using a vial of 253 mg micronized gamma-irradiated linezolid Form II powder and a delivery solution for suspension of linezolid powder which contains iohexol, poloxamer 407, other excipients and water for injection. Both the vial and delivery solution are kept cool i.e., at 2-8°C prior to use. The method of preparation is set out in Example 9 of WO 2019 / 097242 (hereby incorporated by reference in its entirety).

[0216] As set out therein, specifications for the micronized linezolid Form II were set at DIO 0.2 to 1.0pm, D90 3 to 10pm, and the components of the delivery vehicle were as follows in Table 1:

[0217] Table 1: Components of delivery solution.

[0218]

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[0220] #13667512vl

[0221]

[0222] The components, including linezolid Form II, were obtained commercially.

[0223] The preparation process includes the following steps:

[0224] (i) Invert the vial of linezolid Form II powder and gently tap on a hard surface 2-4 times to loosen any compacted powder from the base of the vial.

[0225] (ii) Remove the tear off portion of the aluminium seal and swab the top of the bung of the vial with an alcohol impregnated lint free wipe.

[0226] (iii) Assemble a vent filter unit (MinisartTM PLUS 0.2pm pre- sterilized filter or equivalent and 19G 38mm (1.5” hypodermic needle (quincke point)); and insert the vent filter unit into the vial, positioning the needle tip below the vial shoulder and pointing towards the vial wall, without touching the powder base or the wall of the vial.

[0227] (iv) Select the container of the delivery vehicle and invert gently 5 times to mix, holding the vial by the aluminium seal and bottom edge of the vial ensuring minimal contact. Remove the plastic flip lid, and swab the bung of the vehicle diluent for suspension with an alcohol impregnated lint free wipe.

[0228] (v) Using a 5 ml luer-lock syringe and 19 G 38 mm (1.5”) quincke point needle (a sharp needle to minimize the risk of stopper coring) and good clinical injection practice, draw up approximately 5.3 ml delivery vehicle.

[0229] (vi) Replace the 19 G needle with a clean 19 G 38 mm (1.5”) quincke point needle, expel any bubbles and prime the needle leaving a volume of 4.8 ml; Inject the 4.8 ml delivery vehicle into the linezolid Form II powder, by inserting the needle vertically in the center of the bung. The vial body can be held to ensure stability during this step.

[0230] (vii) Remove the needle and empty syringe and dispose safely, and remove the vent and venting needle and dispose safely.

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[0232] #13667512vl(viii) Gently shake the vial (now referred to as the intradiscal linezolid formulation) holding the aluminium seal and bottom edge of the vial between forefinger and thumb, ensuring minimal skin contact, for approximately 1-2 minutes to mix well until a visibly homogenous suspension is obtained; Inspect the base of the vial for solid powder.

[0233] (ix) Once the intradiscal linezolid formulation has reached a smooth milky consistency, with no obvious clumps of powder present, the preparation is complete. Keep at 2-8°C prior to use.

[0234] The formulation may be used within 3 hours of preparation.

[0235] Administration of the intradiscal linezolid formulation

[0236] The intradiscal linezolid formulation is administered using a double needle technique. An introducer needle with an internal bore wide enough to insert the administration needle is positioned adjacent to the spinal disc to be injected after aseptic preparation and infiltration of skin with a suitable local anaesthetic agent. Preferably patients are conscious and alert during needle positioning so that they can report pain should the needle touch a nerve root.

[0237] Intradiscal injection of discs affected by Modic 1 endplate oedema may be painful. Appropriate anaesthesia may be used. Once paravertebral block / local anaesthesia is established, the administration needle is inserted into the introducer needle and advanced to the edge of the disc and then inserted to the center of the disc using image guidance. It is recommended that an 18G Quincke-point luer-lock spinal needle of at least 90 mm in length is used as an introducer (outer) needle and a 22G Quincke-point luer-lock spinal needle of up to 178 mm in length, is used as the administration (inner) needle.

[0238] Dose preparation

[0239] Dose preparation involves swabbing the bung of the intradiscal linezolid formulation vial (as discussed herein) with an alcohol impregnated lint free wipe. Using a 19G 38 mm (1.5”) hypodermic needle (quincke-point), fill three sterile 1 ml luer-lock syringes with the intradiscal linezolid formulation ensuring the absence of air bubbles and an accurate fill to the 1 ml marker. Place in the sterile area at 2-8°C. If air is noticed in the syringe subsequent to this preparation, the administrator, after excluding the air, can use their judgement to ensure that the subject is dosed correctly. Using a further 1 ml sterile syringe, prime the 10 cm luer-lock extension tubing with the intradiscal linezolid formulation again ensuring all air bubbles are excluded and the fill is complete and replace the cap on the tubing. Connect the filled extension tube to one of P1216.70006US00 32 / 72

[0240] #13667512vlthe filled 1 ml syringes. The injection is performed as soon as possible to minimize warming of the intradiscal linezolid formulation which would make it more viscous and therefore more difficult to inject. The administration needle should not be primed to avoid the intradiscal linezolid formulation warming and becoming too viscous in the needle tract whilst the needle is being positioned.

[0241] Needle positioning

[0242] The introducer needle is positioned against the outer annulus of the disc, or as close to the edge of the outer annulus as possible if not long enough. The purpose of the introducer needle is primarily to avoid contact between the intradiscal 22G needle and the skin to minimize risk of infection, to keep intradiscal linezolid formulation as cool as possible during administration, and to aid in the targeting of the disc. The entry point into the disc should be close to the foramen and at such an angle as to allow the tip of the intradiscal administration 22G needle to cross the disc to the center without penetrating the endplate. The introducer needle needs to be close to the ipsilateral foramen but not to impinge on the exiting nerve root which lies in the cranial part of the foramen.

[0243] A confirmatory AP and lateral screening / imaging is performed. If necessary, the needle is repositioned until the appropriate positioning is achieved. Once positioned, the stylet is removed from the 18G needle.

[0244] Then, the 22G administration needle is advanced to the center of the nucleus pulposus across the line of diameter under image guidance. The 22G needle needs not to penetrate the far side of the annulus fibrosus. The aim is to fill the disc pulposus with the intradiscal linezolid formulation and for this “fill” to include as many of the degenerate splits in the annulus as may have occurred. This practice brings a comprehensive fill but not one associated with material extravasation into adjacent spaces beyond the intervertebral space itself.

[0245] Dosing / inj ection

[0246] After the needle is correctly positioned, the following steps are performed to finish the administration.

[0247] (i) Remove the stylet from the administration needle; and connect the primed connecting tubing and 1 ml syringe to the administration needle ensuring the luer-lock is secure and the introducer needle position is not altered;

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[0249] #13667512vl(ii) Perform imaging at 90° to the trajectory of the needle to check the placement of the needle; and inject 1 ml (one syringe full) of intradiscal linezolid formulation and perform imaging at 90° to the trajectory of the needle to check for extravasation;

[0250] (iii) Replace the empty 1 ml syringe with a second primed 1 ml syringe and inject a second 1 ml of intradiscal linezolid formulation; and perform imaging at 90° to the trajectory of the needle to check for extravasation;

[0251] (iv) Replace the empty 1 ml syringe with the third and final full syringe and inject a third 1 ml of study medication; and perform imaging at 90° to the trajectory of the needle to check for extravasation; and

[0252] (v) Remove both the administration needle and the introducer needle together, and clean the puncture site and apply an occlusive sterile dressing.

[0253] Example 2: Phase lb 12-month study

[0254] This study was conducted to assess, amongst other criteria, the safety and efficacy of two-doses of intradiscal linezolid, in subjects with CLBP and MCI with a 12-month follow-up. Subjects were randomised to receive either intradiscal linezolid or a sham-procedure placebo (1:1).

[0255] The safety assessments included Treatment Emergent Adverse Events (TEAEs), concomitant medications, vital signs, physical examinations and clinical laboratory tests.

[0256] Subject selection

[0257] For inclusion, subjects were aged between 18 and 70 years, with a body weight between 50 kg and 120 kg, and were able to understand the study and to provide written informed consent, and considered reliable, capable of completing the 12-month study with multiple questionnaires at multiple timepoints and had failed standard of care treatment.

[0258] Subjects had a documented diagnosis of CLBP in the area of LI to S 1 , associated with vertebral body endplate bone oedema (MCI) or vertebral body endplate bone oedema and fat (MCI and MC2) at a single lumbar level, with the current CLBP episode lasting for 6-months duration at the time of randomisation. Additional MCI or mixed MCI / 2 were allowed at non-lumbar levels. MC2-only was allowed at levels more than 2 vertebrae away from the painful level. MC3 (subchondral bone sclerosis) was permitted at any level. At screening and prerandomisation LBP NRS was recorded. Eligible patients were required to have a LBP NRS of >4 if taking chronic pain medication and >6 if not, and LBP being greater than their leg pain. P1216.70006US00 34 / 72

[0259] #13667512vlChronic pain medication was defined as taking analgesia on at least 4 days out of 7 in the week prior to screening and the week prior to randomisation. Disability was assessed with a modification of the Roland-Morris Disability Questionnaire, RMDQ-23 (0-23) which records the impact of the low back or leg pain on the patient, and eligible subjects scored >9.

[0260] Laboratory and clinical data that showed evidence of generally good health were required. Subjects were excluded if the target lumbar disc for injection had lost more than half of its original height based on comparison with adjacent discs, there was a clear alternative cause of back pain, an interventional back procedure had taken place within 6 months prior to screening, or antimicrobial therapy had been previously used to treat the CLBP.

[0261] Magnetic resonance imaging (MRI) using qualified 1.5T scanners with Tl, T2 and STIR sequences across the T8-S3 Sagittal plane with a field of view of >40 cm and Dixon Sagittal and Coronal cover across Tl 1-S3 with field of view >30 cm, in craniocaudal direction (4 mm) slice thickness and 10% gap, was used to assess radiological findings. A prior MRI scan confirmed the presence of MCI. Baseline MRI was performed before the first treatment procedure. In addition to the site radiologist, a central reader confirmed subject eligibility for enrolment and confirmed that there were no other significant spinal pathologies e.g. gross facet joint degeneration or inflammatory joint disorders, that could otherwise account for the pain symptoms.

[0262] Additional exclusions were: subjects unable to stop anticoagulant or antiplatelet treatment around the time of the injection (the use of low dose aspirin (up to and including 100 mg per day) was permitted), poorly controlled diabetes mellitus type 1 or type 2, hypertension, pregnancy or plans to become pregnant, breastfeeding, receipt of any investigational drug or experimental procedure to treat CLBP within 180-days of screening, current active bacterial infection, extensive (>14-days) antibiotic therapy within the last 6-months, major surgery within 12- weeks prior to screening, hypersensitivity to linezolid, poloxamer 407 or iohexol, intolerance of local anaesthetics, significant acute illness within 30-days of randomisation and contraindications for MRI.

[0263] Randomisation and blinding

[0264] Subjects were consented and randomly assigned in a 1:1 ratio to receive intradiscal linezolid treatment or a sham-procedure placebo control. On enrolment, sites requested treatment P1216.70006US00 35 / 72

[0265] #13667512vlallocation from an independent CRO and were provided with a sequential assignment based on a block size of 4. Treatment assignment was not revealed to blinded members of the study team until after the last 12-month visit and database lock. The study was a sham-procedure placebo-controlled, investigator and subject-blinded, third-party (injector and pharmacy) unblinded because of the impracticality of blinding intradiscal linezolid for injection due to differences between the active and placebo injections.

[0266] Intradiscal linezolid

[0267] A suspension of micronized crystal linezolid Form II powder (50 mg / ml) was prepared by combining 4.8 ml of a delivery carrier containing poloxamer 407 and iohexol, with 253 mg of linezolid form II powder, as set out in Example 1.

[0268] The suspension was shaken briefly by hand, and the resulting preparation was used within 3 hours. Both the micronized linezolid powder and suspension vehicle were manufactured to Good Manufacturing Practice conditions.

[0269] Intervertebral disc injection procedure

[0270] Intradiscal linezolid was injected into the nucleus pulposus of the target lumbar vertebral disc associated with adjacent endplate MCI, as set out in Example 1.

[0271] Subjects received treatment on day 1 and day 5+1 of 3 ml of intradiscal linezolid. The total dose of linezolid administered on day 1 and day 5+1 was 300 mg linezolid. The procedure was an out-patient visit but subjects’ physical activity was limited for 8 hours after each injection in order to maximise the opportunity for the study medication to remain within the intervertebral disc space e.g. bed rest for the first 4 hours and then limited activity for the subsequent 4 hours after each injection. For subjects allocated placebo, the whole procedure was acted out by the administration team but only the guide needle was placed into the deep facia towards the disc. The annulus fibrosis was not entered. All subjects were permitted to receive prophylactic antibiotic coverage for the intradiscal procedure as per standard institutional policy with the exception that linezolid could not be used.

[0272] Statistical analyses and populations

[0273] Statistical analyses were performed with SAS° Version 9.4. All correctly randomised subjects (Full Analysis Set; FAS) were included in the safety assessments and were analysed based on P1216.70006US00 36 / 72

[0274] #13667512vlallocated treatment. Efficacy assessments were performed on the FAS population and on the subjects who received both allocated procedures and adhered to the protocol, (Per Protocol Set, PPS). Means, mean changes from baseline and significance of LBP NRS, RMDQ-23, and ODI scores were calculated using mixed model repeated measures (MMRM) with baseline, treatment group, visit and treat-by- visit interactions or using logistic regression for clinically relevant improvement. Comparison of the difference between intradiscal linezolid and placebo treatments, with expectation that intradiscal linezolid improvement would be greater than the placebo group and hence a one-sided test was appropriate, were reported as 95% CI with p-values 0.05 considered significant. The MMRM analysis assumed random missing data. For logistic regression, last observation carried forward was used for missing datapoints.

[0275] Results

[0276] Study population

[0277] Through hospital CEBP clinics and social media campaigns, 136 subjects were assessed for eligibility by sites and 41 subjects were correctly randomised: 21 into intradiscal linezolid treatment and 20 to placebo. Two subjects did not receive both allocated procedures. One subject was considered potentially unblinded. The Full Analysis Set (FAS) comprises 20 subjects allocated to intradiscal linezolid and 20 subjects allocated placebo. The Per Protocol Set (PPS) comprised 18 subjects allocated to intradiscal linezolid and 19 subjects allocated placebo.

[0278] Baseline characteristics were not tested for statistical significance (Tables 2-4). 72.5% percent (n=29 / 40) of FAS subjects were female. There was a higher proportion of males in the intradiscal linezolid group than placebo (8 / 20 vs 3 / 20). Groups were well matched for the primary outcome EBP NRS and for RMDQ-23 at baseline.

[0279] In Table 4, the Nordic Modic Score (NMS) (also known as the Nordic Model Protocol) is a standardized MRI-based classification system for assessing the severity and extent of Modic changes in vertebral endplates. See, e.g., Jensen TS, Sorensen JS, Kjaer P (2007) Intra- and interobserver reproducibility of vertebral endplate signal (modic) changes in the lumbar spine: the Nordic Modic Consensus Group classification. Acta Radiol 48:748-754.

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[0281] #13667512vlTable 2: Baseline demographic and disease characteristics

[0282]

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[0285]

[0286] Table 3: Baseline MR Imaging characteristics

[0287]

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[0290]

[0291] Table 4: Nordic Modic Score at Baseline

[0292]

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[0294] #13667512vlLow Back Pain Numerical Rating Scale (EBP NRS )

[0295] Low Back Pain Numerical Rating Scale (LBP NRS) is an index scale which includes measurements of pain intensity. The scale was designed to monitor the outcome of clinical trials of low back pain treatment. It has been shown to be valid and reliable in the assessment of low back pain.

[0296] The LBP NRS score was defined as the average score of the below three questions:

[0297] 1. Low back pain intensity now;

[0298] 2. Worst low back pain intensity in the last 14 days; and

[0299] 3. Average low back pain intensity over the last 14 days.

[0300] Each question was assessed by the subject on an 11-point scale with 0 = “no pain” and 10 = “the worst possible pain you can imagine”.

[0301] The average of the three scores was used to summarise the subject’s LBP NRS score.

[0302] The LBP NRS scores were analysed using a mixed model for repeated measures (MMRM) and adjusted for baseline to test the difference in the treatment and placebo groups for LBP. For between group difference in change from baseline for LBP NRS at 12 months, a 1- sided hypothesis test was performed to test the primary hypothesis of superiority of intradiscal treatment versus placebo at 12 months, i.e. that the reduction of LBP NRS score at month 12 relative to baseline for intradiscal treatment is greater than the reduction of LBP NRS score at month 12 relative to baseline for placebo. The null hypothesis is that intradiscal treatment is not superior to placebo at 12 months, i.e. that the reduction of LBP NRS score at month 12 relative to baseline for intradiscal treatment is not greater than the reduction of LBP NRS score at month 12 relative to baseline for placebo.

[0303] Table 5: Change in Low Back Pain NRS score at Months 1, 3, 6, and 12 (FAS)

[0304]

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[0307]

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[0310]

[0311] The change in LBP NRS mean score was measured from baseline at 1, 3, 6, 9, and 12 months, for both the treatment group and placebo group, using a MMRM statistical model for the FAS, as seen in Figure 1 and shown in Table 5.

[0312] A clinically meaningful within group change from baseline (>30% reduction) in the intradiscal treatment group from 3 months onwards was observed.

[0313] At 12 months, the intradiscal treatment within group reduction from baseline was -3.36 points, representing a 50% reduction in pain. At 12 months, the placebo within group reduction from baseline was -2.00 points, representing a 29% reduction in pain.

[0314] At 12 months, the between group difference (intradiscal treatment to placebo) was -1.37 points with 95% CI (-2.77 to 0.04). The study was powered for a 1-sided test of statistical significance at 12 months and achieved a p=0.0284, meeting the study primary endpoint.

[0315] Conclusion

[0316] The intradiscal treatment group mean change from baseline was clinically meaningful from 3 months onwards. The placebo group did not reach clinically meaningful change even at 12 months. The between group change was statistically significant at 12 months. Note that the improvement in the intradiscal treatment had not plateaued at 12 months and may continue thereafter. The intradiscal treatment group reported an average of 4.1 years of CLBP at baseline. Intradiscal treatment led to meaningful within group change at 3 months which continues to improve and appears durable. This demonstrates the potential for intradiscal treatment to be transformative for patients with CLBP with Modic changes type 1.

[0317] Comparison with Braten et al. (2019)

[0318] The efficacy of oral antibiotic treatment in patients with chronic low back pain and Modic changes was investigated in Braten et al. (2019). In the Braten et al. study, patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily.

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[0320] #13667512vlTable 6: LBP NRS mean scores for Braten et al. (2019)

[0321]

[0322] As shown in Table 6, Braten et al. (2019) provided their estimate of within group change from baseline at 12 months for antibiotic treatment (Modic type 1 changes in supplemental online data) which was from 6.5 to 4.5 points, a -2.0 point change or -30.8% compared with a -3.36 point change (-50% reduction) with intradiscal antibiotics according to the present disclosure.

[0323] This comparison of the percentage change in LBP NRS mean scores measured from baseline at 12 months between intradiscal administration according to the present disclosure and oral administration (Braten et al., 2019) is seen in Figure 2.

[0324] Braten et al. (2019) provided their estimate of between group change at 12 months, focusing on subjects with Modic changes type 1, in online supplemental data. Their estimate was a -0.8 point change with 95% CI (-1.6 to 0.0). The placebo LBP NRS score at 12 months was 5.2 and so a -0.8 point change from placebo which is a -15% reduction. This is compared to a -29% reduction observed in the intradiscal antibiotic study according to the present disclosure.

[0325] This comparison of the change in LBP NRS mean scores measured from placebo at 12 months between intradiscal administration according to the present disclosure and oral administration (Braten et al., 2019) is seen in Figure 3.

[0326] Comparison with Albert et al. ( 2013 )

[0327] The efficacy of oral antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes) was also investigated in Albert et al. (2013). In the Albert et al. study, patients were randomized to either 100 days of antibiotic treatment (Bioclavid) or placebo. Bioclavid contains amoxicillin and clavulanic acid.

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[0329] #13667512vlTable 7: LBP NRS median scores in oral antibiotic treatment for Albert et al. (2013)

[0330]

[0331] As shown in Table 7, at 100 days, the end of Albert et al. (2013)’s oral antibiotic administration, they observed a -1.7 point change from baseline in the antibiotic treatment group (-25.4%) and, at 12 months, a -3.0 point change (-44.8%). This compares with intradiscal antibiotic observations according to the present disclosure of a -1.7 point change (-25.4%) at 3 months (the same as Albert et al., 2013) and a -3.36 point change (-50% reduction) at 12 months. Intradiscal antibiotics according to the present disclosure had a 5.2% advantage at 12 months.

[0332] The assessment above compares intradiscal antibiotic treatment’s mean change with Albert et al. (2013)’s median change. To improve the comparison, observed median estimates for intradiscal antibiotic according to the present disclosure have been used, as shown in Table 8.

[0333] Table 8: LBP NRS medians in intradiscal antibiotic treatment.

[0334]

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[0336] #13667512vl

[0337]

[0338] This comparison of the percentage change in LBP NRS median scores measured from baseline at 12 months between intradiscal administration according to the present disclosure and oral administration (Albert et al., (2013) is seen in Figure 4.

[0339] Using medians, intradiscal antibiotic treatment led to a similar reduction in median pain from baseline at 100d / 3 months but a greater reduction (-60% vs -45% (Albert et al., (2013)) at 12 months. Compared to Albert et al. (2013), intradiscal antibiotic treatment according to the present disclosure was superior at 12 months and, combined with the improved safety profile, led to a better risk benefit ratio.

[0340] Roland Morris Disability Questionnaire

[0341] The Roland Morris Disability Questionnaire (RMDQ) is a self-administered disability measure comprising questions related to behaviours as a consequence of back pain. Subjects respond by reporting whether a functional statement describes their behaviour on the day of assessment. The RMDQ-23 scale is 0-23. The RMDQ-24 scale is 0-24. The RMDQ-23 and RMDQ-24 questionnaires are shown in Annex 1.

[0342] Table 9A: Change from Baseline in RMDQ-23 Scores at Months 1, 3, 6, and 12 (FAS).

[0343]

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[0345] #13667512vl

[0346]

[0347] The change in RMDQ-23 mean scores was measured from baseline at 1, 3, 6, 9 and 12 months, for both the treatment group and placebo group, using a MMRM statistical model for the FAS, as seen in Figure 5 and in Table 9A.

[0348] P1216.70006US00 47 / 72

[0349] #13667512vlA clinically meaningful change within the intradiscal treatment group from baseline (>30% reduction) was observed from 1 month onwards.

[0350] At 3 months, the intradiscal treatment within group reduction from baseline was -5.04 points, representing a 34% reduction in disability. At 3 months, the placebo within group reduction from baseline was -4.86 points, representing a 30% reduction in disability. At 3 months, the between group difference (intradiscal treatment to placebo) was -0.19 points.

[0351] At 12 months, the intradiscal treatment within group reduction from baseline was -9.43 points, representing a 63% reduction in disability. At 12 months, the placebo within group reduction from baseline was -5.54 points, representing a 34% reduction in disability.

[0352] At 12 months, the between group difference (intradiscal treatment to placebo) was -3.88 points with 95% CI (-7.69 to -0.07, p=0.0462). At 12 months, the placebo mean was 9.9 and a -3.88 point reduction, representing a -39% reduction in disability. This is considered a clinically meaningful change from placebo.

[0353] Conclusion

[0354] The intradiscal treatment group had an average duration of CLBP of 4.1 years. Intradiscal treatment according to the present disclosure led to a clinically meaningful reduction in disability as measured by the RMDQ-23 score at 1 month onwards, demonstrating an early onset of benefit of intradiscal treatment. Disability continued to reduce and did not reach a plateau at 12 months. Reduction in disability, appeared durable, and the results indicate that improvement may continue beyond 12 months. At 12 months, the intradiscal treatment group reported a mean reduction of 63% in disability vs a reduction of 34% in the placebo group -twice the improvement. At 12 months there was a clinically meaningful and statistically significant reduction of 39% in disability compared with placebo.

[0355] Comparison of RMDQ-23 and. RMDQ-24 scores

[0356] Both the RMDQ-23 and RMDQ-24 scales were used as a measure of disability. The comparison of the change from baseline for each of the scales is shown in Figure 6 and partly summarised in Table 9B.

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[0358] #13667512vlTable 9B: Change from Baseline in RMDQ-24 Scores

[0359]

[0360] As shown in Figure 5 and Table 9B, the scores for RMDQ-23 and RMDQ-24 are very similar and for the purposes of the comparison with oral antibitioc performance below are considered to be substantially interchangeable.

[0361] Comparison with Braten et al. (2019)

[0362] As shown in Table 10, Braten et al. (2019) provided their estimate of within group change from baseline at 12 months for antibiotic treatment (in supplemental online data) which was from 12.9 to 8.2 points, a -4.7 point change or -36% compared with -9.43 points, representing a 63% reduction in disability with intradiscal antibiotics according to the present disclosure. The between group change at 12m was -2.7 points which is a -26% change from placebo vs the intradiscal antibiotic trial point reduction of -3.88 which is -39%.

[0363] Table 10: RMDQ Means for Braten et al. (2019)

[0364]

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[0366] #13667512vl

[0367]

[0368] The percentage change in RMDQ mean scores was measured from baseline at 12 months with intradiscal administration and oral administration (Braten et al., 2019), as seen in Figure 7.

[0369] Comparison with Albert et al. ( 2013 )

[0370] As shown in Table 11, at 100 days, the end of Albert et al. (2013)’s oral antibiotic administration, a -3.5 point change from baseline was observed in the antibiotic treatment group disability (-23.3%) and at 12 months an -8.0 point change (-53.3%). This compares with intradiscal antibiotic observations of a -5.04 point change (-25.4%) in disability at 3 months and -9.43 point change (-63% reduction) at 12 months. Intradiscal antibiotics according to the present disclosure provided a 9.7% advantage at 12 months.

[0371] Table 11: RMDQ Medians for Albert et al. (2013)

[0372]

[0373] At 12 months, Albert et al. (2013) observed a change from placebo of -7.0 points which was -50%. In the intradiscal antibiotic study, the 12m change from placebo was -39%.

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[0375] #13667512vlConclusion

[0376] In terms of disability, intradiscal antibiotic treatment according to the present disclosure provides an improved outcome versus Braten et al. (2019), and a similar outcome to Albert et al. (2013). Given the reduced side effects, simplified administration and patient compliance (two outpatient procedures as compared to 100 days of oral antibiotics), the risk benefit of intradiscal antibiotics according to the present disclosure over oral antibiotics is a significant improvement over oral antibiotics.

[0377] The above comparison uses intradiscal antibiotic treatment means and oral antibiotic treatment medians (Albert et al., (2013). To improve the comparison, the intradiscal antibiotic treatment observed medians are provided below in Table 12.

[0378] Table 12: Intradiscal antibiotic treatment RMDQ medians.

[0379]

[0380] This direct comparison reveals that at 3 months, intradiscal antibiotic treatment achieved a 43% reduction in median disability vs Albert et al. (2013)’s 23% reduction, indicating a faster and greater early response with intradiscal dosing vs oral dosing. At 12 months, the improvements in median disability were similar for both groups.

[0381] Dosing

[0382] Frequency

[0383] Antibiotic efficacy is critically dependent on patients following recommended dosing regimens to ensure that adequate antibiotic exposure is achieved and that there is a high degree of

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[0385] #13667512vlcompliance with optimal dose frequency and dose intervals. In the present disclosure, the linezolid formulation is administered only twice on days 1 and day 5+1 via intradiscal administration. The procedure is performed in an out-patient setting. The procedural nature of the intervention leads to a high degree of patient compliance and physician assurance that the dose was administered.

[0386] In contrast, oral antibiotic administration three times a day for 100 days as used in the oral studies provides patient compliance challenges associated with the number and timing of the doses. Ideally, the three doses are as equally spaced as possible, meaning that the patients would take doses at 6 am, 2 pm and 10 pm (or other similar intervals) for 100 days. Amoxicillin is not very soluble and ideal drug exposure requires drinking a large glass of water with the tablets or capsules at each dose. Patients do not always follow this advice. Gastro-intestinal side effects, particularly loose bowels or diarrhoea, can lead to patients taking treatment breaks for several days or discontinuing antibiotic use altogether.

[0387] The two doses of intradiscal antibiotic as compared to literally hundreds of doses of oral antibiotic provides clear advantage with improved compliance and less onerous prolonged administration for the patient.

[0388] Dose of antibiotic

[0389] The intradiscal antibiotic dose according to the present disclosure is 150 mg and a two-dose course of treatment amounts to a total 300 mg of antibiotic. The oral antibiotic studies used doses of 0.5 g, 0.75 g or 1 g of antibiotic amoxicillin three times a day for 100 days. The oral antibiotic trial doses totalled 150 g, 225 g and 300 g. The intradiscal antibiotic total dose is 0.1% to 0.2% of the mass of the oral antibiotic treatment courses. This has a significant implication for systemic side effects and also for antibiotic stewardship to minimise the development of resistance to antibiotics.

[0390] Side-effects

[0391] Albert et al. (2013) reported 27% of patients had loose bowel movements for over 3 weeks and more considerable side effects in 21% of patients. Braten et al. (2019) reported 19% of patients reported diarrhoea in the antibiotic group. 100 days of high-dose oral antibiotics leads to significant GI side effects in at least 19% of patients.

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[0393] #13667512vlThe intradiscal antibiotic treatment had zero reports of GI side effects associated with loose bowel movements.

[0394] The intradiscal administration procedure was well tolerated with no evidence that injection of 300 mg of linezolid, poloxamer and iohexol to the disc causes irritation. Intradiscal antibiotic treatment according to the present disclosure accordingly represents significant advantages in side effects as compared to oral antibioitics.

[0395] Reduction in analgesic use

[0396] Intradiscal antibiotic treatment according to the present disclosure resulted in a substantial reduction is analgesic use from 80% to 50% of patients, in NSAID use from 60% to 39% of patients and in opioid use from 25% to 6% of patients, as shown in Table 13. The >70% reduction of opioid use is particularly remarkable. Conversely, the intradiscal antibiotic treatment placebo group showed an increase in NSAID and opioid use at 12 months compared to baseline. In the oral antibiotic arm, Braten et al. (2019) saw no change in NSAID or opioid use from baseline to 12 months. Albert et al. (2013) did not report analgesic use.

[0397] Table 13: Analgesic use of intradiscal antibiotic treatment.

[0398]

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[0400] #13667512vlSafety and exploratory semi-quantitative risk benefit analysis

[0401] The Number Needed to Treat to see one patient benefit from antibiotic therapy for each of the studies was estimated. All three studies estimated NTT based on >30% improvement in RMDQ at 12m and so were compared. The Number Needed to Harm based on the side effects reported was also estimated. All adverse events were reported by all three studies, with the results for intradiscal administration according to the present disclosure shown in Table 14 below.

[0402] As shown in Table 14, no Treatment Emergent Adverse Events (TEAEs) resulted in death or study discontinuation. One serious TEAE, a suspected viral encephalitis, was reported but was not considered related to treatment or procedure. TEAEs considered potentially related to treatment or procedure were at similar frequency or lower in the intradiscal linezolid group than placebo.

[0403] Table 14: Summary of treatment-emergent and treatment or procedure -related adverse events

[0404]

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[0406] #13667512vl

[0407]

[0408] Several of the ratios do not enable direct comparison. There were more GI side-effects in the placebo group than the treatment group, and therefore NNH is negative. There were no episodes of diarrhoea in the intradiscal antibiotic treatment study, and so NNH cannot be calculated but must be below the numbers stated.

[0409] Table 15: Number Needed to Treat (NNT) for intradiscal antibiotic treatment

[0410]

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[0412] #13667512vl

[0413]

[0414] * (rounded to whole patients)

[0415] Based on RMDQ responder analysis, intradiscal treatment according to the present disclosure has an equivalent NNT to the Albert et al. (2013) study and half that of the Braten et al. (2019) study. Based on AEs, the intradiscal antibiotic treatment NNH is much higher than the oral antibiotic studies and therefore the ratio of NNT / NNH as an indicator of risk benefit is much lower and therefore superior to oral antibiotics. The absence of diarrhoea in the intradiscal antibiotic treatment study provides clear differentiation and lower risk than oral antibiotic studies.

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[0417] #13667512vlAnnex 1: Roland Morris Disability Questionnaires

[0418] As described in:

[0419] Brinjikji, W., Luetmer, P., Comstock, B., Bresnahan, B., Chen, L., Deyo, R., Halabi, S., Turner, J., Avins, A., James, K., Wald, J., Kallmes, D., & Jarvik, J. (2014). Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. American Journal of Neuroradiology, 56(4), 811-816. https: / / doi.org / 10.3174 / ajnr.a4173

[0420] Longo, U. G., Loppini, M., Denaro, L., Maffulli, N., & Denaro, V. (2010). Rating scales for low back pain. British Medical Bulletin, 94(Y), 81-144. https: / / doi.org / 10.1093 / bmb / ldp052.

[0421] Roland Morris Disability Questionnaire-23 (RMDQ-23)

[0422] May be filled out on paper or using an e-diary. When your back or leg hurts, you may find it difficult to do some of the things you normally do.

[0423] This list contains some sentences people have used to describe themselves when they have back pain or leg pain (sciatica). When you read them, you may find that some stand out because they describe you today.

[0424] As you read the list, think of yourself today. When you read a sentence that describes you today, tick the “yes” box. If the sentence does not describe you today, then tick the “no” box.

[0425]

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[0427] #13667512vl

[0428]

[0429] P1216.70006US00 58 / 72

[0430] #13667512vl

[0431]

[0432] The number of “yes” responses provides the RMDQ-23 score.

[0433] Roland Morris Disability Questionnaire-24 (RMDQ-24)

[0434] The RMDQ-24 is related to the RMDQ-23 with four of the RMDQ-23 questions omitted (Questions 4, 20, 21 and 23 in the table above) and replaced with the five questions shown below. Although the standard RMDQ-24 questions focus on back pain and do not include leg pain (sciatica), in the present application statements about leg pain (sciatica) were added.

[0435] The 5 additional questions used in the present application are:

[0436] 1. Because of my back problem or leg pain (sciatica), I lie down to rest more often. 2. Because of my back problem or leg pain (sciatica), I try to get other people to do things for me.

[0437] 3. My appetite is not very good because of my back pain or leg pain (sciatica).

[0438] 4. Because of my back pain or leg pain (sciatica) I get dressed with help from someone else.

[0439] 5. I sit down for most of the day because of my back problem or leg pain (sciatica)

[0440] The RMDQ-24 score was derived by summing responses to RMDQ-23 questions 1-3, 5-19 and 22 and adding the responses from the additional five questions above to provide a score from 0 to 24.

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[0442] #13667512vl

Claims

CLAIMS1. A method of treating chronic low back pain in a patient, the method comprising administering a therapeutically effective amount of a first antibiotic to one or more targeted sites in the spine of the patient, wherein the method provides improvements as compared to oral administration of a second antibiotic.

2. A method of improving the treatment of chronic low back pain in a patient with a first antibiotic as compared to oral administration of a second antibiotic to the patient, the method comprising administering a therapeutically effective amount of the first antibiotic to one or more targeted sites in the spine of the patient.

3. The method of claim 1 or 2, wherein the improvement is in efficacy, safety, and / or a reduction in analgesic use by the patient.

4. The method of any one of claims 1-3, wherein the improvement is measured as a reduction in the therapeutically effective amount of the first antibiotic as compared to the amount of the second antibiotic; and / or a reduction in frequency of administration of the first antibiotic as compared to the frequency of administration of the second antibiotic.

5. The method of claim 4, wherein the therapeutically effective amount of the first antibiotic is about 10%, about 1%, or about 0.1% by mass of the amount of the second antibiotic.

6. The method of any one of claims 1-5, wherein the improvement is measured in reduction in disability.

7. The method of any one of claims 1-6, wherein the improvement is measured as a faster and / or greater reduction in disability as compared to administration of the second antibiotic.

8. The method of claim 6 or 7, wherein the reduction in disability is about 20% or more, such as about 30 % or more compared to baseline after about 3 months.

9. The method of any one of claims 6-8, wherein the reduction in disability is about 50% or more compared to baseline after about 3 months.

10. The method of any one of claims 6-9, wherein the reduction in disability is about 17% or more compared to placebo after about 3 months.

11. The method of any one of claims 6-10, wherein the reduction in disability is about 20% or more compared to placebo after about 3 months.P1216.70006US00 60 / 72#13667512vl12. The method of any one of claims 6-11, wherein the reduction in disability is about 25% or more, such as about 30% or more, compared to placebo after about 12 months.

13. The method of any one of claims 6-12, wherein the reduction in disability is about 45% or more compared to placebo after about 12 months.

14. The method of any one of claims 6-13, wherein the reduction in disability is about 50% or more compared to baseline after about 12 months.

15. The method of any one of claims 6-14, wherein the reduction in disability is about 36% or more compared to baseline after about 12 months.

16. The method of any one of claims 6-15, wherein the reduction in disability is about 60% or more compared to baseline after about 12 months.

17. The method of any one of claims 6-16, wherein the reduction in disability is about 20% or more compared to placebo after about 12 months.

18. The method of any one of claims 6-17, wherein the reduction in disability is measured by the Roland Morris Disability Questionnaire (RMDQ).

19. The method of claim 18, wherein the RMDQ is RMDQ-23 or RMDQ-24.

20. The method of claim 18 or 19, wherein the RMDQ baseline mean value is from about 12 to about 18, such as about 15 and / or wherein the RMDQ baseline individual value is from about 9 to about 23 or about 24.

21. The method of any one of claims 18-20, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value and / or a percentage decrease compared to the RMDQ baseline value.

22. The method of claim 21, wherein the decrease in the RMDQ value from the RMDQ baseline value is from about 1 unit to about 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, such as about 5 units, when evaluated after about 1 month.

23. The method of claim 21 or 22, wherein the percentage decrease compared to the RMDQ baseline value is from about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 1 month.

24. The method of any one of claims 21-23, wherein the decrease in the RMDQ value from the RMDQ baseline value is from about 1 unit to about 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, optionally about 5 units, when evaluated after about 3 months.P1216.70006US00 61 / 72#13667512vl25. The method of any one of claims 21-24, wherein the percentage decrease compared to the RMDQ baseline value is from about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 3 months.

26. The method of any one of claims 21-25, wherein the decrease in the RMDQ value from the RMDQ baseline value is from about 3 units to about 12 units, optionally about 5 units to about 10 units, optionally about 6 unit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 6 months.

27. The method of any one of claims 21-26, wherein the percentage decrease compared to the RMDQ baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 6 months.

28. The method of any one of claims 21-27, wherein the decrease in the RMDQ value from the RMDQ baseline value is from about 3 units to about 12 units, optionally about 5 units to about 10 units, optionally about 6 unit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 9 months.

29. The method of any one of claims 21-28, wherein the percentage decrease compared to the RMDQ baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 9 months.

30. The method of any one of claims 21-29, wherein the decrease in the RMDQ value from the RMDQ baseline value is from about 5 units to 14 units, optionally about 7 units to about 12 units, optionally about 9 units or about 10 units, when evaluated after about 12 months.

31. The method of any one of claims 21-30, wherein the percentage decrease compared to the RMDQ baseline value is from about 30% to about 90%, optionally about 40% to about 80%, optionally about 60% to about 70%, optionally about 65%, when evaluated after about 12 months.

32. The method of any one of claims 21-31, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 15 to about 11.5 or lower when evaluated after about 3 months.

33. The method of any one of claims 21-32, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 15 to about 7 or lower when evaluated after about 12 months.P1216.70006US00 62 / 72#13667512vl34. The method of any one of claims 21-33, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 14.9 to about 9.9 or lower when evaluated after three months.

35. The method of any one of claims 21-34, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 14.9 to about 5.5 or lower when evaluated after about 12 months.

36. The method of any one of claims 21-35, wherein the reduction in disability is measured by a decrease in the RMDQ value from the RMDQ baseline value of about 12.9 to about 8.2 or lower when evaluated after about 12 months.

37. The method of any one of claims 18-36, wherein the reduction in disability is measured by a between group difference from the RMDQ baseline value between treatment and placebo, when evaluated using a patient population.

38. The method of claim 37, wherein the between group difference from the RMDQ baseline value is from about -1 to about -10, such as from about -2 to about -8, for example about -3 to about -6.

39. The method of claim 38, wherein the between group difference from the RMDQ baseline value is about -2.0 to about -4.0, when evaluated after about 9 months.

40. The method of claim 38, wherein the between group difference from the RMDQ baseline value is about -3.0 to about -4.0, when evaluated after about 12 months.

41. The method of claim 38, wherein the between group difference from the RMDQ baseline value is about -3.8 to about -4.0, when evaluated after about 12 months.

42. The method of any one of claims 1-41, wherein the improvement is measured in reduction in pain.

43. The method of any one of claims 1-42, wherein the improvement is measured as a greater reduction in pain as compared to administration of the second antibiotic.

44. The method of claim 42 or 43, wherein the reduction in pain is about 25% or more compared to baseline after about 3 months.

45. The method of any one of claims 42-44, wherein the reduction in pain is about 45% or more compared to baseline after about 12 months.

46. The method of any one of claims 42-45, wherein the reduction in pain is about 60% or more compared to baseline after about 12 months.

47. The method of any one of claims 42-46, wherein the reduction in pain is about 25% or more compared to placebo after about 3 months.P1216.70006US00 63 / 72#13667512vl48. The method of any one of claims 42-47, wherein the reduction in pain is about 10% or more compared to placebo after about 3 months.

49. The method of any one of claims 42-48, wherein the reduction in pain is about 45% or more compared to placebo after about 12 months.

50. The method of any one of claims 42-49, wherein the reduction in pain is about 35% or more compared to placebo after about 12 months.

51. The method of any one of claims 42-50, wherein the reduction in pain is about 30% or more compared to baseline after about 3 months.

52. The method of any one of claims 42-51, wherein the reduction in pain is about 30% or more compared to baseline after about 12 months.

53. The method of any one of claims 42-52, wherein the reduction in pain is about 50% or more compared to baseline after about 12 months.

54. The method of any one of claims 42-53, wherein the reduction in pain is about 25% or more compared to placebo after about 3 months.

55. The method of any one of claims 42-54, wherein the reduction in pain is about 15% or more compared to placebo after about 12 months.

56. The method of any one of claims 42-55, wherein the reduction in pain is about 25% or more compared to placebo after about 12 months.

57. The method of any one of claims 42-56, wherein the reduction in pain comprises a reduction in low back pain.

58. The method of claim 57, wherein the reduction in low back pain is measured by the Low Back Pain Numerical Rating Scale (LBP NRS).

59. The method of claim 58, wherein the LBP NRS baseline mean value is from about 4 to about 10, such as from about 5 to about 8 and / or wherein the LBP NRS baseline individual value is from about 4 to about 10.

60. The method of claim 58 or 59, wherein the reduction in low back pain is measured by a decrease in the LBP NRS value from the LBP NRS baseline value and / or a percentage decrease compared to the LBP NRS baseline value.

61. The method of claim 60, wherein the decrease in the LBP NRS value from the LBP NRS baseline value is from about 1 unit to 6 units, such as about 1 unit to about 4 units, optionally about 1 unit to about 3 units, such as about 1 unit or about 2 units, when evaluated after about 1 month.P1216.70006US00 64 / 72#13667512vl62. The method of claim 60 or 61, wherein the percentage decrease compared to the LBP NRS baseline value is from about 10% to about 40%, optionally about 15% to about 30%, optionally about 25%, when evaluated after about 1 month.

63. The method of any one of claims 60-62, wherein the decrease in the LBP NRS value from the LBP NRS baseline value is from about 1 unit to 10 units, optionally about 2 units to about 8 units, optionally about 3 units to about 7 units, optionally about 5 units, when evaluated after about 3 months.

64. The method of any one of claims 60-63, wherein the percentage decrease compared to the LBP NRS baseline value is from about 10% to about 40%, optionally about 10% to about 50%, optionally about 20% to about 40%, optionally about 30%, when evaluated after about 3 months.

65. The method of any one of claims 60-64, wherein the decrease in the LBP NRS value from the LBP NRS baseline value is from about 3 units to 12 units, optionally about 5 units to about 10 units, optionally about 6 unit to about 9 units, optionally about 7 units or about 8 units, when evaluated after about 6 months.

66. The method of any one of claims 60-65, wherein the percentage decrease compared to the LBP NRS baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 45% to about 55%, optionally about 50%, when evaluated after about 6 months.

67. The method of any one of claims 60-66, wherein the decrease in the LBP NRS value from the LBP NRS baseline value is from about 4 units to 10 units, optionally about 5 units to about 9 units, optionally about 7 units, when evaluated after about 9 months.

68. The method of any one of claims 60-67, wherein the percentage decrease compared to the LBP NRS baseline value is from about 20% to about 80%, optionally about 30% to about 70%, optionally about 50%, when evaluated after about 9 months.

69. The method of any one of claims 60-68, wherein the decrease in the LBP NRS value from the LBP NRS baseline value is about 5 units to 14 units, optionally about 7 units to about 12 units, optionally about 9 units or about 10 units, when evaluated after about 12 months.

70. The method of any one of claims 60-69, wherein the percentage decrease compared to the LBP NRS baseline value is from about 30% to about 90%, optionally about 40% to about 80%, optionally about 60% to about 70%, optionally about 65%, when evaluated after about 12 months.P1216.70006US00 65 / 72#13667512vl71. The method of any one of claims 58 to 70, wherein the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 5.0 or lower when evaluated after about 3 months.

72. The method of any one of claims 58-71, wherein the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 3.7 or lower when evaluated after about 12 months.

73. The method of any one of claims 58-72, wherein the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 4.7 or lower when evaluated after about 3 months.

74. The method of any one of claims 58-73, wherein the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.7 to about 3.34 or lower when evaluated after about 12 months.

75. The method of any one of claims 58-74, wherein the reduction in low back pain is measured by a reduction in the LBP NRS value from the LBP NRS baseline value of about 6.5 to about 4.5 or lower when evaluated after about 12 months.

76. The method of any one of claims 57-75, wherein the reduction in low back pain is measured by a between group difference in change from LBP NRS baseline values between treatment and placebo, when evaluated using a patient population.

77. The method of claim 76, wherein the between group difference in change from LBP NRS baseline values is from about -1 to about -10, such as from about -2 to about -8, for example about -3 to about -6.

78. The method of claim 77, wherein the between group difference in change from RMDQ baseline values is about -1.3 or -1.4 when evaluated after about 12 months.

79. The method of any one of claims 1-78, wherein the improvement is measured as a reduction in occurrence of gastrointestinal (GI) side effects after intrasical administration with the first antibiotic as compared to occurrence of GI side effects after oral administration of the second antibiotic.

80. The method of claim 79, wherein the improvement comprises substantially no GI side effects.

81. The method of claim 79 or 80, wherein the occurrence of GI side effects after administration of the second antibiotic is about 65% or about 56%.

82. The method of any one of claims 79-81, wherein the GI side effects are one or more of loose bowel movements, increased flatus, or increased burping.P1216.70006US00 66 / 72#13667512vl83. The method of any one of claims 79-82, wherein the GI side effects are loose bowl movements lasting more than 3 weeks.

84. The method of any one of claims 1-83, wherein the improvement is measured by a lower risk benefit as compared to the risk benefit obtained for oral administration of a second antibiotic.

85. The method of claim 84, wherein the risk benefit is calculated based on the number needed to treat (NNT) divided by the number needed to harm (NNH).

86. The method of claim 84 or 85, wherein the risk benefit for all adverse events is no greater than about 1.0, such as no greater than about 0.8 or no greater than about 0.6, for example no greater than about 0.4 and / or wherein the risk benefit for diarrhea is no greater than about 0.4 or about 0.3, for example no greater than about 0.2.

87. The method of any one of claims 1-86, wherein the improvement is a reduction in analgesic use by the patient.

88. The method of claim 87, wherein the analgesic use is reduced by at least about 30%, such as at least about 35%.

89. The method of claim 87 or 88, wherein the analgesic use is reduced from an initial value in the range of about 75% to about 85% to a final value in the range of about 45% to about 55%, for example from about 80% to about 50%, when evaluated after about 12 months.

90. The method of any one of claims 1-89, wherein the improvement is a reduction in nonsteroidal anti-inflammatory drug (NSAID) use and / or opioid use by the patient.

91. The method of claim 90, wherein the NSAID use is reduced by at least about 30%, such as at least about 35%.

92. The method of claim 90 or 91, wherein the NSAID use is reduced from an initial value in the range of about 55% to about 65% to a final value in the range of about 35% to about 45%, for example from about 60% to about 39%, when evaluated after about 12 months.

93. The method of any one of claims 90-92, wherein the opioid use is reduced by at least about 60%, such as at least about 70%.

94. The method of any one of claims 90-93, wherein the opioid use is reduced from an initial value in the range of about 20% to about 30% to a final value in the range of about 5% to about 8%, for example from about 25% to about 6%, when evaluated after about 12 months.

95. The method of any one of claims 1-94, wherein the improvement comprises a reduction in pain and / or adverse events.

96. The method of any one of claims 1-95, wherein the patient is human.P1216.70006US00 &ini#13667512vl97. The method of any one of claims 1-96, wherein the patient has vertebral body endplate bone edema (Modic change).

98. The method of claim 97, wherein the Modic change is Modic change Type I, Modic change Type II, or Modic change Type I+II.

99. The method of any one of claims 1-98, wherein the first antibiotic and the second antibiotic are different.

100. The method of any one of claims 1-98, wherein the first antibiotic and the second antibiotic are the same.

101. The method of any one of claims 1-100, wherein the first antibiotic is administered no more than once or twice in a one year period.

102. The method of any one of claims 1-101, wherein the first antibiotic is administered as a composition comprising:the first antibiotic, anda thermosensitive hydrogel delivery carrier comprising poloxamer 407 and iohexol.

103. The method of any one of claims 1-102, wherein the first antibiotic is an antibiotic from the class of oxazolidinones.

104. The method of any one of claims 1-103, wherein the first antibiotic is selected from the group consisting of linezolid, tedizolid, sutezolid, eperezolid, radezolid contezolid, posizolid, delpazolid and TBI-233.

105. The method of claim 103 or 104, wherein the first antibiotic is linezolid.

106. The method of claim 105, wherein the amount of the first antibiotic is 150 mg linezolid, administered once or twice over a period of no more than 8 days.

107. The method of claim 105 or 106, wherein the linezolid is linezolid Form II.

108. The method of claim 107, wherein linezolid Form II produces an X-ray powder diffraction pattern comprising peaks at 14.2, 16.8, 21.6, 22.4 and 25.3 degrees two theta ± 0.2 degrees two theta.

109. The method of claim 107 or 108, wherein the linezolid Form II has a differential scanning calorimetry transition temperature of about 155°C ± 5°C for the first transition and about 179 ± 5 °C for the second transition.

110. The method of any one of claims 1-109, wherein the first antibiotic is linezolid Form II administered as a composition comprising:linezolid Form II, anda thermosensitive hydrogel delivery carrier comprising poloxamer 407 and iohexol.P1216.70006US00 68 / 72#13667512vl111. The method of claim 110, wherein the linezolid Form II is pre-prepared as sterilized micronized powder in a dose unit and loaded to the thermosensitive hydrogel delivery carrier prior to the administration, and wherein the thermosensitive hydrogel delivery carrier is preprepared as a sterilized solution.

112. The method of claim 110 or 111, wherein the linezolid Form II forms a suspension in the thermosensitive hydrogel delivery carrier and has particle size distribution of D90<10pm.

113. The method of any one of claims 110-112, wherein the linezolid Form II is present from about 1% to about 20%, such as from about 2.5% to about 20%, by weight of the composition.

114. The method of any one of claims 102-113, wherein the poloxamer 407 is present from about 9.5% to about 17% by weight of the composition.

115. The method of any one of claims 102-114, wherein the poloxamer 407 is present from about 10.8% to about 12.8% by weight of the composition.

116. The method of any one of claims 102-115, wherein the iohexol is present from about 14% to about 59% by weight of the composition.

117. The method of any one of claims 102-116, wherein the iohexol is present from about 17% to about 30% by weight of the composition.

118. The method of any one of claims 112-117, wherein the suspension gels at a temperature from about 26°C to about 38 °C, from about 32°C to about 36°C, or from about 26°C to about 32°C.

119. The method of any one of claims 1-118, wherein the second antibiotic is an antibiotic from the class of beta-lactams; optionally wherein the second antibiotic is amoxicillin.

120. The method of claim 119, wherein the second antibiotic is co-administered with a betalactamase inhibitor, optionally wherein the beta-lactamase inhibitor is clavulanate, sulbactam, tazobactam, avibactam, durlobactam, relebactam, vaborbactam or enmetazobactam.

121. The method of any one of claims 1-120, wherein the amount of the second antibiotic is from about 0.5 g to about 2 g, administered 2, 3 or 4 times per day.

122. The method of claim 121, wherein the amount of the second antibiotic is about 1.5 g to about 6.0 g amoxicillin, for example about 1.5 g to about 4.0 g, such as about 1.5 g to 3.0 g, administered daily.

123. The method of any one of claims 119-122, wherein the second antibiotic is amoxicillin and wherein the amount of amoxicillin is about 1.5 g, about 2.25 g or about 3.0 g, administered daily.

124. The method of any one of claims 1-123, wherein the second antibiotic is administered daily for about 3 months.P1216.70006US00 69 / 72#13667512vl125. The method of any one of claims 1-124, wherein the first antibiotic is administered to at least one intervertebral disc, intervertebral space, intra- articular space, ligamentum flavum, ligament associated with the spine, epidural space, tendon associated with the spine, site adjacent to bone oedema, bone junction, facet joint, and / or other spinal compartments.

126. The method of any one of claims 1-125, wherein the first antibiotic is administered to one or more intervertebral discs.

127. The method of claim 126, wherein the first antibiotic is administered to the one or more intervertebral discs at about 150 mg per intervertebral disc.

128. The method of claim 126 or 127, wherein the first antibiotic is delivered to the one or more intervertebral discs using an administration needle.

129. The method of claim 128, wherein the administration needle is connected to a Luer-lock syringe.

130. The method of claim 129, wherein the administration needle and the Luer-lock syringe are connected via a flexible connector.

131. The method of any one of claims 126-130, wherein the first antibiotic is delivered to the one or more intervertebral discs using an introducer needle and an administration needle.

132. The method of any one of claims 1-131, wherein the patient receives a single dose of the first antibiotic.

133. The method of claim 132, wherein the patient receives the single dose of the first antibiotic in each of the one or more targeted sites in the spine.

134. The method of claim 132 or 133, wherein the patient receives the single dose of the first antibiotic in each of the one or more intervertebral discs.

135. The method of any one of claims 1-131, wherein the patient receives two doses of the first antibiotic.

136. The method of claim 135, wherein the patient receives the two doses of the first antibiotic in each of the one or more targeted sites in the spine.

137. The method of claim 135 or 136, wherein the patient receives the two doses of the first antibiotic in each of the one or more intervertebral discs.

138. The method of any one of claims 135-137, wherein a dosing interval between the first dose and second dose is from about 72 hours to about 132 hours.

139. The method of claim 138, wherein the dosing interval between the first dose and second dose is from about 72 hours to about 120 hours.

140. The method of claim 138 or 139, wherein the dosing interval between the first dose and second dose is about 72 hours, about 96 hours or about 120 hours.P1216.70006US00 70 / 72#13667512vl141. The method of any one of claims 138-140, wherein the first and second doses contain the same amount of the first antibiotic.

142. The method of any one of claims 138-141, wherein the first dose of the first antibiotic and the second dose of the first antibiotic each contain about 150 mg linezolid.

143. The method of any one of claims 6-142, wherein there is an early onset of the reduction in disability after about 1 month.P1216.70006US00 71 / 72#13667512vl

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