WO2020117360A1 - Formulation pour utilisation dans le traitement de l'arthrose - Google Patents

Formulation pour utilisation dans le traitement de l'arthrose Download PDF

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WO2020117360A1
WO2020117360A1 PCT/US2019/053657 US2019053657W WO2020117360A1 WO 2020117360 A1 WO2020117360 A1 WO 2020117360A1 US 2019053657 W US2019053657 W US 2019053657W WO 2020117360 A1 WO2020117360 A1 WO 2020117360A1
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bone
knee
peptide
formulation
seq
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PCT/US2019/053657
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English (en)
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Yoshinari Kumagai
Dawn Mcguire
Meghan MILLER
David Rosen
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Orthotrophix, Inc.
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Priority to CN201980079767.9A priority Critical patent/CN113164033A/zh
Priority to JP2021513299A priority patent/JP2022502356A/ja
Priority to AU2019391700A priority patent/AU2019391700A1/en
Priority to KR1020217017093A priority patent/KR20210098998A/ko
Priority to CA3120075A priority patent/CA3120075A1/fr
Priority to EP19893858.1A priority patent/EP3905942A4/fr
Priority to MX2021003584A priority patent/MX2021003584A/es
Publication of WO2020117360A1 publication Critical patent/WO2020117360A1/fr
Priority to JP2023014591A priority patent/JP2023058550A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B2017/564—Methods for bone or joint treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/45—For evaluating or diagnosing the musculoskeletal system or teeth
    • A61B5/4504—Bones

Definitions

  • the invention relates generally to methods of treating osteoarthritis by modifying joint bone shape change, which is a pathology underlying onset and progression of osteoarthritis.
  • Osteoarthritis is the most common disease of the joints, and one of the most widespread of all chronic diseases. In the US, osteoarthritis (OA) is second only to heart disease as a cause of work disability in men over 50 years of age. Globally, osteoarthritis is the 6th leading cause of years living with disability (Woolf 2003).
  • Pain is a common symptom in patients with knee OA. Pain typically is treated with acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). However, further to the initial Boxed Warning and Warnings and Precautions sections of the prescription labels of NSAIDs in 2005, FDA strengthened the existing label warning in 2015 that non-aspirin NSAIDs, including their over-the- counter products, increase the chance of a heart attack or stroke (hltps://www.fda gov/d gs/drug- safety-and-availabiiity/fda-drug-safety-communication-fda-strengdiens-warning-non ⁇ - aspirin- nonsteroidal-anti-inflammatory).
  • Corticosteroid injections have been implicated in further cartilage degeneration in the knees (McAlindon 2017) limiting the willingness of clinicians to use this treatment modality. Corticosteroid injections are not recommended by The American Academy of Orthopaedic Surgeons / American Association of Orthopaedic Surgeons for the treatment of knee OA.
  • Hyaluronic acid or“viscosupplementation” products are injected into the knee either in once -weekly doses (2 cc) for 3 weeks or in a single administration of a larger dose (6 cc; Chevalier 2010). Injected hyaluronic acid products stay within the joint space briefly, on the order of hours to days. While joint pain reduction may persist for weeks to months in some patients (Cohen 1998), multiple clinical trials have failed to demonstrate a clinically meaningful treatment effect.
  • osteoarthritis involves the progressive degeneration of articular (joint) cartilage.
  • Articular cartilage degeneration in the knee, hip and elbow typically advances slowly with age.
  • Joint degeneration can be accelerated after joint injury or in the setting of chronic or excessive stress on the joints from strenuous physical labor or athletic activities (Sandmark 2000, Felson 1991).
  • Articular cartilage enables smooth, almost frictionless movement of the joint. It cushions cyclic loads and offsets shear forces on the joint.
  • Articular cartilage is composed of chondrocytes embedded in an extracellular matrix of collagens, non-collagenous proteins, water, and proteoglycans such as aggrecan. Proteoglycans are hydrophilic molecules and enable hydration of the cartilage surface layer. This increases the ability of articular cartilage to buffer biomechanical stress.
  • Articular cartilage is biologically unique and unmatched by any artificially-engineered material or by the fibrocartilage (“scar” cartilage) that forms after injury or microfracture surgery.
  • fibrocartilage scar cartilage
  • Other invasive surgical procedures used for cartilage repair in the knee include drilling into subchondral bone and implanting plugs of cartilage cells (chondrocytes) or their progenitor cells taken from non- weight-bearing parts of the patient’s body or from a cadaver (osteochondral autograft/allograft transplantation, OATS procedure). Two surgeries are required, and the patient cannot return to full weight-bearing for approximately 6 weeks after the procedure. Treatment failures are common, as is the need for additional surgery to manage complications.
  • ACI autologous chondrocyte implantation
  • healthy cartilage is harvested from the knee arthroscopically and grown in culture.
  • the cultured chondrocytes then are implanted.
  • Open-knee surgery is required.
  • the patient’ s cartilage is cut (debrided) down to the bone and either a periosteal or bioengineered flap is stitched or glued into place.
  • the cultured cells then are injected into the flap.
  • Carticel® study of more than 150 patients with ACI 49% of patients required repeat surgery for complications (Zaslav 2009). Common complications include delamination, graft failure, and disturbed graft fusion (Niemeyer 2008).
  • DMOAD Osteoarthritis Drug
  • TGF Transforming Growth Factor b
  • BMP-7 Bone Morphogenetic Protein-7
  • FGF-18 Fibroblast Growth Factor-18
  • Sprifermin Fibroblast Growth Factor-18
  • DMOADs Disease Modifying Osteoarthritis Drugs
  • TPX-100 a peptide of SEQ ID No. 1
  • the peptide of SEQ ID No. 1 has been tested in a randomized, double-blind, placebo- controlled trial of subjects with bilateral knee OA.
  • TRC-100-treated knees demonstrated statistically significant and clinically meaningful improvements in knee function as well as in other clinical outcomes compared to placebo-treated knees (McGuire 2017).
  • Knee functional improvement in TRC-100-treated knees was robust and was sustained through the end of the year-long study. Knee’s functional improvement was associated with increase or stabilization of tibiofemoral cartilage thickness at 12 months, as measured by MRI (McGuire 2018).
  • Therapeutic agents used to treat osteoporosis such as strontium ranelate (Reginster 2013), calcitonin (Karsdal 2015), and zolendronate (Laslett 2012) have been clinically tested as potential treatments for OA. These agents promote new bone formation or inhibit bone resorption. Their efficacy in stabilizing or strengthening subchondral bone has not been demonstrated clinically, and significant adverse effects have dampened enthusiasm for these agents. For example, strontium ranelate was found to increase the risk of myocardial infarction and its use has been limited by the European Medicines Agency.
  • a recently proposed marker of OA progression is measurement of the three-dimensional (3D) change in periarticular bone shape.
  • 3D three-dimensional
  • OAI National Institutes of Health Osteoarthritis Initiative
  • 3D analyses of changes in periarticular bone shape among subjects from the OAI have revealed a consistent, uni-directional pattern associated with progression of OA.
  • Flattening of bone shape occurs in femur, tibia and patella even in the absence of marked cartilage loss.
  • the 3D shape change of periarticular bones can be measured using multiple anchor points (“principal components”) that are defined on the bone surface.
  • the shift in position of these anchor points over time is measured on MRI images and analyzed algorithmically using active appearance modelling (AAM).
  • AAM active appearance modelling
  • Bone shape change is normalized to a“B Score”, representing the extent of bone shape change in terms of standard deviations from the range of periarticular shape changes in knees unaffected by OA (Neogi, 2013; Hunter 2016).
  • bone mass increase or strengthening does not necessarily improve or reduce the risk of OA.
  • TPX-100 is a synthetic peptide consisting of 23 amino acids with amino acid sequence of
  • TDLQERGDNDISPFSGDGQPFKD (SEQ ID No. 1), derived from human Matrix Extracellular
  • Phosphoglycoprotein or MEPE.
  • the TPX-100 drug substance has been manufactured as acetate and sodium salts, respectively, and the final formulation in either case is lyophilized powder with the C-terminus ami dated.
  • the TPX-100 injection (drug product) used in the clinical study was formulated in water for injection.
  • TPX-100 has been shown to promote tissue-appropriate regeneration of dentin, bone, and cartilage without any soft tissue calcification or ossification.
  • TPX-100 can be administered by conventional methods such as subcutaneous or intra-articular injection.
  • TPX-100 was first tested for its bone formation activity. TPX-100 peptide was identified as a“bone formation active site” of human MEPE,
  • TPX-100 administered by subcutaneous injection demonstrated acceleration of bone fracture healing in a widely-used rat long bone fracture model (a.k.a., Einhorn model) (Lazarov 2004).
  • a.k.a., Einhorn model rat long bone fracture model
  • TPX-100 was well tolerated in these in vivo bone formation and dentin formation studies. Safety of the TPX-100 peptide was further confirmed in multiple GLP toxicology studies and a Phase 1 clinical study with healthy volunteers.
  • TPX-100 was tested in two Phase 2 studies for alveolar bone and dentin formation activities, respectively. TPX-100 was well tolerated in both studies. One of the studies testing dental activities demonstrated reparative dentin formation by TPX-100 administered in the defects in human molar (Lazarov 2006). The other study testing alveolar bone formation did not show a difference between drug vs. placebo-exposed groups.
  • TPX-100 affects these hard tissues in terms of their shape or other morphological features.
  • TPX-100 demonstrated only repair of flat and thin bone or dentin by increase in these hard tissues, and, in a rodent model, healing of experimental fractures located in the central region of a long bone.
  • Cartilage regeneration properties of TPX-100 subsequently were demonstrated in the goat model using standardized large cartilage defects.
  • a regimen of four weekly intra-articular (IA) injections of TPX-100 (125 mg and 250 mg) was associated with statistically significant, histologically-confirmed hyaline cartilage regeneration at 6 months post-surgery compared to cartilage regeneration in the vehicle control group.
  • the drug was safe and well-tolerated in these freely weight-bearing, ambulatory animals (U.S. Patents 7,888,462 and 8,426,558).
  • TPX-100 A randomized, double-blind, placebo-controlled clinical study of TPX-100 was performed in patients with mild to severe bilateral knee osteoarthritis. It was anticipated that TPX-100 would improve critical knee functions affected by knee OA.
  • test articles were administered by once-a-week intra-articular (IA) injections four times over three consecutive weeks (Days 0, 7, 14, and 21).
  • IA intra-articular
  • TRC-100-treated (Index) knees demonstrated clinically meaningful and statistically significant improvement in knee function in daily living activities (“ADL”) and in sports and recreational activities (“Sports and Adventure”) as measured by the Knee injury and Osteoarthritis Outcome Score (KOOS), Clinically meaningful and statistically significant improvements also were demonstrated in knee-related quality of life (“Knee -related QOL”) and pain going up or down stairs.
  • significant improvements in favor of Index knees were demonstrated in“Function” and“Total” scores as measured by the Western Ontario and McMaster Universities Osteoarthritis Score (WOMAC).
  • the improvements in TRC-100-treated knees were observed at 6 or 12 months, or both.
  • TPX-100 was derived from human MEPE.
  • Several other orthologues of MEPE have been known, and thus, the orthologues of TPX-100 are also known.
  • the examples of the TPX-100 orthologues are as follows:
  • rat / mouse orthologue has the least homology to that of human orthologue (15/23 identical, 65% homology). Since the rat orthologue is known to promote tritium-thymidine incorporation by human osteoblastic mesenchymal stem cells (U.S. Patents 7,888,462 and 8,426,558), it should be reasonable to assume that these orthologues and their analogues have common biological functions to those of TPX-100. These peptides contain a common amino acid sequence of
  • DLXXRGDNDXXPFSGDGXXF (SEQ ID No. 6), where X can be any amino acid.
  • a novel method of treating osteoarthritis comprises any therapeutic intervention that can delay, arrest, or reverse pathological changes of three-dimensional (3D) periarticular bone shape associated with disease onset and progression. This marks the first time that therapeutic intervention of pathological periarticular bone shape change was demonstrated and shown to correlate significantly with striking improvements in numerous disabling symptoms of knee OA.
  • 3D three-dimensional
  • An aspect of the invention is a method of modifying the pathological change of three- dimensional (3D) periarticular bone shape by administration (which may be by local injection) to a patient (which may be a human diagnosed with osteoarthritis) a formulation of the peptide of SEQ ID No. 1 in a therapeutically effective amount.
  • Another aspect of the invention is treating OA by delaying, arresting or reversing periarticular bone shape changes
  • the method includes diagnosing the periarticular bone shape of the affected joint by MRI-based 3D shape analysis of the joint, administering to the patient a formulation comprised of therapeutically effective amount of peptide of SEQ ID No. 1 , and measuring the periarticular bone shape change after a period such as 6 months, 12 months, 24 months, etc. to determine whether or not the bone shape was significantly changed as compared to the one prior to the drug treatment.
  • Bone shape analysis by an alternative imaging technology may be used, e.g., using joint images obtained by computerized tomography, ultrasound or other imaging modalities.
  • MRI commonly is used to diagnose features of osteoarthritis such as articular cartilage thinning or meniscal pathology. Bone shape before and after treatment can be analyzed using image sequences acquired for evaluation of cartilage. Combining bone shape and cartilage analyses could increase the sensitivity of evaluation of treatment effects of a therapeutic intervention.
  • the peptide is formulated into an injectable formulation that can include water or saline and can be injected locally into the knee by intra-articular or subcutaneous routes.
  • injectable formulation can include water or saline and can be injected locally into the knee by intra-articular or subcutaneous routes.
  • orthologues and analogues of the peptide of SEQ ID No. 1 are known to show similar activities to that of the peptide of SEQ ID No. 1. Any one of those peptide can be used by formulating them into an injectable formulation including water for injection, saline, and the like.
  • the method is carried out with the injection being
  • the dosing may be delivered daily, every three days, once a week, every ten days, once a month, once every other month, once a quarter, semiannually, once a year, or in different combinations thereof.
  • the method includes follow up evaluation of the patient’s knee function and/or pain using instruments such as the KOOS and/or WOMAC scales.
  • the evaluation may also be carried out based on other appropriate patient reported outcomes (PROs) and by clinical evaluation.
  • the dosing may be in a range of from 50 mg to 500 mg, or 100 mg to 400 mg, or 200 mg, wherein all milligram doses are ⁇ 20%, ⁇ 10%, ⁇ 5%.
  • the patient is first evaluated based on inclusion and exclusion criteria as described herein.
  • joint aging is delayed, arrested, or reversed by modifying an inevitable age-associated periarticular bone shape change.
  • An aspect of the invention includes a method and/or use of a compound in order to impact the shape change of a bone underlining articular cartilage in a patient which may be any animal but includes humans and canines which method or use comprises locally injecting into a joint of a patient a therapeutically effective amount of a formulation in an injectable carrier which formulation includes a peptide sequence of any of the SEQ ID NOs.: 1, 2, 3, 4, 5, and 6.
  • the injecting may be intra-articular and the injecting may be repeated as needed (PRN) or repeated weekly over a period of two, three, four or more weeks with the injecting including the peptide in an amount in a range of 50-400 mg ⁇ 20% with the treatment continuing in order to impact the shape change of a bone underlining articular cartilage in the patient whereby shape change of the bone is impacted wherein the shape change may be in a patient diagnosed with osteoarthritis.
  • An aspect of the invention includes the method and/or use as described above wherein the dosing amounts are adjusted based on a number of factors including the size, weight, sex, and condition of the patient.
  • dosing amounts are based on the species of the patient such as human or canine, and the particular joint being treated. Larger patients and larger joints require larger doses and smaller patients and smaller joints require smaller doses.
  • the basic concept of the invention is not limited by a particular dosing range as those skilled in the art will understand that dosing amounts vary depending on factors as described above as well as other factors to be taken into consideration.
  • the specific dosing amounts described above are preferred dosing ranges for an average adult human knee. Those skilled in the art can extrapolate from the dosing amounts to provide other dosing ranges for other joints and/or animals.
  • An aspect of the invention includes the method and/or use as described above wherein the sequence is a sequence of SEQ ID NO.:l and the patient is a human or a dog.
  • the injection may be intra- articular and the bone shape change may be due to either osteoarthritis or aging.
  • Another aspect of the invention comprises the method and/or use as described above wherein dosing and/or further treatment is determined at least in part by obtaining images before and/or during treatment and comparing images to determine impact of bone shape due to the injecting, wherein the measuring and remeasuring may be carried out using active appearance model (AAM) software.
  • AAM active appearance model
  • Figure 1 is a graph showing the results of an actual clinical study in which changes in knee function from baseline through 12 months are indicated as measured using the Activities of Daily Living subscale of the Knee injury and Osteoarthritic Outcome Score (“KOOS ADL”).
  • Figure 2 is a graph showing the results of an actual clinical study in which changes in knee function from baseline through 12 months are indicated as measured using the Sports and Adventure activities subscale of KOOS (“KOOS Sports and Adventure”).
  • Figure 3 is a graph showing the results of an actual clinical study in which changes from baseline through 12 months are indicated as measured using the Knee-Related Quality of Life subscale of KOOS (“KOOS Knee-Related QOL”).
  • Figure 4 shows the questions and scoring systems for KOOS Pain subscale.
  • Figure 5 is a graph showing the results of an actual clinical study in which changes from baseline through 12 months are indicated as measured using the component of the KOOS Pain subscale that specifically addresses“Pain going up or down stairs”.
  • Figure 6 is a graph showing the results of an actual clinical study in which changes from baseline through 12 months are indicated as measured using the component of the KOOS Pain subscale that specifically addresses frequency of knee pain.
  • Figure 7 contains graphs showing the results of an actual clinical study in which differences in the rates of change of periarticular bone area in OA vs. non-OA knees in four regions of knee joint are exhibited.
  • Figure 8 is a graph showing the results of an actual clinical study in which changes in the periarticular bone area of the medial femur from baseline through 12 months are indicated.
  • Figure 9 contains graphs showing differences of rate of change of periarticular bone area in three regions in Index (TRC-100-treated) and Control (placebo-exposed) Knees.
  • Figure 10 is a graph showing the results of an actual clinical study in which changes in the bone shape score of the femur from baseline through 12 months are indicated.
  • Figure 11 is a graph showing the results of an actual clinical study in which changes in pain frequency from baseline through 12 months are indicated comparing responders vs. non-responders to active treatment with the peptide of SEQ ID No. 1.
  • Figure 12 is a graph showing the results of an actual clinical study in which 3D bone shape changes in the patella from baseline to 12 months are correlated to pain frequency in responders vs. non responders to active treatment with the peptide of SEQ ID No. 1.
  • Figure 13 is a graph showing the results of an actual clinical study in which 3D bone shape of the femur from baseline through 12 months are indicated.
  • Figure 14 is a graph showing the results of an actual clinical study in which changes in pain frequency from baseline through 12 months are indicated comparing responders vs. non-responders to active treatment with the peptide of SEQ ID No. 1.
  • Figure 15 is a graph showing the results of an actual clinical study in which 3D bone shape changes in the patella from baseline to 12 months are correlated to pain frequency in responders vs. non responders to active treatment with the peptide of SEQ ID No. 1.
  • an injection includes a plurality of such injections and reference to “the measurement” includes reference to one or more measurements and equivalents thereof known to those skilled in the art, and so forth.
  • the peptide of SEQ ID No. 1 (a.k.a., TPX-100) has been known to promote new cartilage formation (See U.S. Patents 7,888,462 and 8,426,558).
  • Table 1 Correlation between Tibiofemoral Cartilage Thickening/Stabilization and Improvement of Knee Function at 6 and 12 Months after Treatment in Index Knees
  • periarticular bone surface area and three-dimensional (3D) bone shape of Index and Control Knees were measured and compared.
  • periarticular bone shape is altered in a predictable fashion in normal aging, with acceleration of bone shape changes in association with onset and progression of knee OA.
  • the pattern of periarticular bone shape change is common to all knees that develop OA.
  • Periarticular bone shape flattens and becomes irregular, while bone surface area increases. Such bone shape change begins years earlier than detectable radiographic changes among patients who go on to develop OA (Reichenbach 2008).
  • the 3D bone shape change can be quantified using active appearance modelling (AAM).
  • AAM enables encoding of the 3D shape and appearance of an object using multiple anchor points (“principal components”) on the surface of the object. These principal components describe
  • periarticular bone area and bone shape changes in OA and non-OA knees of subjects enrolled in the National Institute of Health Osteoarthritis Initiative were compared.
  • percentage changes in bone area and changes of bone shape scores for femur, tibia, patella, and trochlear femur (the anterior subregion of femur which articulates with the patella; this region is also called patellofemoral bone or PF) between OA vs. non-OA knees were compared over a period of four years. Bone area of all regions, regardless of OA status, showed an increase from baseline. Bone shape scores of all regions also increased from baseline. Changes were uni-directional and irreversible per natural history.
  • OA knees showed a significantly greater rate of bone area increase in all regions as compared to non-OA knees. See Figure 7. Periarticular bones of OA knees typically showed bone area increases from baseline that were statistically significantly larger compared to non-OA knees as measured over a one-year period (Bowes 2015). Periarticular bones of OA knees also show statistically significantly faster bone shape score increase as compared to non-OA knees.
  • Knees showed slower rate of changes when compared with those in Control Knees by AAM analysis by iMorphics (www.imorphics.com).
  • Bone shape scores in femur, trochlear femur, tibia, and patella were also measured using the same MRI images.
  • Figure 9 shows the bone area change of periarticular bones of Index vs. Control Knees in lateral femur, lateral patella, and medial patella, respectively. Although these comparisons did not show statistically significant differences between the treatment arms, it is notable that the bone area change in Index Knees in the first 6 months was nearly zero in all regions.
  • pathological 3D bone shape and bone area changes should be reduced or normalized over a longer period.
  • the femur is the largest periarticular bone. Structure change in the femur is believed to be highly influential in the pathophysiology and progression of knee OA.
  • the peptide of SEQ ID No. 1 significantly reduced pathological 3D bone shape changes in the femur within 6 months after administration ( Figure 10).
  • Both Pearson and Spearman analyses demonstrated a correlation between the reduction of pathological femur 3D bone shape change and tibiofemoral (TF) cartilage thickening/stabilization in knees treated with the peptide of SEQ ID No. 1 (Index Knees), with robust statistical significance at 12 months. See Table 2.
  • Cartilage thickening/stabilization in the entire TF cartilage, as well as lateral and medial TF and femoral condyle cartilage was significantly correlated with the reduction of 3D bone shape changes in the femur.
  • trends toward significant correlations were observed in the entire TF region as well as in the medial TF region and in the femoral condyle.
  • patella 3D bone shape change of the patella has not been characterized as well as that of femur. Whereas the severity of knee pain has been associated most consistently with severity of patellar pathology (Joseph 2016), this invention is the first time that patella 3D bone shape change is specifically proposed as a pathophysiologic mechanism of knee pain in OA.
  • the patient can determine whether or not the pain is reduced shortly after the treatments.
  • this disease modifying therapy through delaying, arresting, or reversing the pathological 3D bone shape change, pain reduction occurs as a result of the structural effects on the bone, which seems to take a few months based on the present clinical data.
  • peptide of SEQ ID No. 1 in knee OA patients induces significant slowing or even reversion of pathological periarticular 3D bone shape changes in multiple knee joint compartments, resulting in desired clinical benefits including improved function and reduction in frequency of knee pain.
  • the peptide of SEQ ID No. 1 positively affects both periarticular bone and cartilage structure over the same time course; therefore, pathological changes in both components of the knee joint can be treated by a therapeutic composition comprising the peptide of SEQ ID No. 1 as a single pharmaceutical ingredient.
  • the therapeutic or prophylactic use of the peptide of SEQ ID No. 1 for OA is not limited to OA of the knee but may include hip, ankle, elbow, shoulder, neck, spine, wrist and finger joints. Also, this method can be used to repair, rebuild, or stabilize a joint affected by other arthritis such as rheumatoid arthritis after their disease specific causes such as autoimmunity and inflammation have been managed.
  • the method comprises any therapeutic intervention that can delay, arrest, or reverse pathological periarticular bone shape change thereby treating OA. While the pathological nature of periarticular bone shape change for onset and progression of knee OA are supported by data from the natural history studies of OA patients participating in the OAI, the clinical study results described herein have for the first time demonstrated that such naturally irreversible periarticular bone shape change associated with OA can be delayed, arrested, and even reversed. Most importantly, delay, arrest or reversal of periarticular bone shape change correlates with clinically meaningful patient benefits, including function and pain of the affected joint. The present invention confirms in a controlled human clinical trial that slowing pathological periarticular bone shape change is possible and correlates with improvement in critical symptoms of knee OA.
  • An important component of the method comprises injecting a patient afflicted with OA with a formulation of peptide of SEQ ID No. 1 in a therapeutically effective amount, thereby reducing the rate of bone area and bone shape change in affected joints.
  • a formulation of peptide of SEQ ID No. 1 in a therapeutically effective amount, thereby reducing the rate of bone area and bone shape change in affected joints.
  • Analogue peptides of the peptide of SEQ ID No. 1, its orthologues, which are believed to have similar biological activities to the peptide of SEQ ID No. 1 , including those sharing a common amino acid sequence shown as SEQ ID No. 6 are within the scope of this invention as well.
  • this method by reducing the rate of pathological periarticular bone area and shape changes, includes preventing, delaying or arresting an otherwise inevitable process that increases the risk of OA.
  • One of important components of this invention is a new method to reduce knee pain frequency in knee OA by delaying, arresting, or reversing 3D bone shape change in patella.
  • a pharmaceutical composition containing the peptide of SEQ ID No. 1 which treats OA by delaying, arresting, or reversing pathological structural change of periarticular bone is within the scope of this invention.
  • this invention is based on the data from clinical trials in knee OA patients, it is applicable to OA in other joints such as hip, ankle, elbow, shoulder, neck, spine, wrist, fingers, and so forth, because similar pathological change in periarticular bone structure should occur in such other joints as well.
  • this new method can be used to treat joint conditions other than OA, including, but not limited to, rheumatoid arthritis and trauma-induced arthritis.
  • Part A The study was divided into Part A and Part B.
  • the Part A was designed to evaluate safety of intra-articular (I. A.) administration of TPX-100 at different dosing levels (20, 50, 100, or 200mg per injection in sequential cohorts) in the subjects with osteoarthritis of the knees and to select a dose for Part B.
  • Part B was to evaluate safety and efficacy of the selected dose of TPX-100.
  • Subjects in Part A were enrolled in sequential cohorts and randomized to receive 20, 50, 100 or 200 mg of TPX-100 in one knee (Index Knee) and identical placebo in the contralateral (Control) knee. Subjects, sites and sponsor and central MRI readers were blinded as to treatment assignment.
  • a Safety Review Committee (SRC) evaluated safety in each dosing cohort. The SRC assessed safety and determined whether the next higher dosing regimen could be enrolled. All dosing cohorts in Part A were completed and analyzed with regard to safety prior to dose selection and initiation of Part B.
  • Part A included four (4) intra-articular (I. A.) injections, one per week, in sequential dosing cohorts of 20, 50, 100 and 200 mg TPX-100 versus placebo.
  • Six (6) subjects were enrolled in 20, 50, and lOOmg cohorts, respectively, and nine (9) subjects were enrolled in the 200mg cohort.
  • the 200mg dose was selected for Part B based on safety review and the approval of the SRC. There were no dose-limiting toxicities for this dose or the 3 lower doses investigated in Part A.
  • Eighty-seven (87) subjects were registered in Part B (200mg dose). Per the Statistical Analysis Plan, these subjects were combined with the nine subjects in the 200mg cohort of Part A for the efficacy analysis. In total, data from 93 subjects was analyzed for drug efficacy, each of whom received 4 once-weekly injections of TPX-100, 200mg/dose, in the Index knee and identical placebo in the contralateral knee, as randomly assigned.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • Contraindication to MRI including: metallic fragments, clips or devices in the brain, eye, or spinal canal; implanted devices that are magnetically programmed; weight > 300 lbs.;
  • Last viscosupplementation e.g. Synvisc ® or similar hyaluronic acid product
  • Last viscosupplementation e.g. Synvisc ® or similar hyaluronic acid product
  • MRIs of both knees were obtained and evaluated by a central reader to determine the ICRS grade (glCRS) of each knee as the final screening criterion. If the cartilage of pateho-femoral compartment in both knees fell within ICRS grades 1-3, or 4 with only small focal defects no greater than 1cm, the subject was registered. The randomization center randomized each subject to either“Right knee active” or“Left knee active”. The active knee was to receive TPX-100 and the contralateral knee was to receive identical placebo.
  • ICRS grade glCRS
  • KOOS Knee injury and Osteoarthritis Outcome Score
  • WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
  • the KOOS questionnaire assesses knee-specific activities of daily living, sports and recreation, knee-related quality of life, other symptoms such as stiffness, and knee pain.
  • the KOOS has been used extensively in longitudinal studies of knee osteoarthritis. After assessments were completed, subjects received one intra-articular injection in each knee, with each injection prepared from the vial(s) marked for that knee. One knee received TPX-100, and the contralateral knee received placebo with subject, site, and sponsor blinded to treatment assignment. Subjects were monitored for adverse events during the injections and for a few hours after the injections. Vital signs were also monitored after the injections.
  • KOOS subscale scores All KOOS subscale scores, WOMAC Total score and subscale scores, MRI-based patello- femoral and tibiofemoral cartilage thickness, and MRI-based periarticular bone area and 3D bone shape were analyzed.
  • MRI images were provided to central readers cartilage and periarticular bone measures. Central readers were blind as to treatment assignment.
  • Bone area and 3D shape of periarticular bone were analyzed using AAM software developed by iMorphics (www.imorphics.com) specifically for assessing these parameters in the osteoarthritic knee.
  • Statistical analyses were carried out using a two-sided paired t-test at the 5% level of significance. The outcome variables were the differences of the change of the score of each subscale of KOOS, change of cartilage thickness, periarticular bone area, and 3D bone shape score (“B Score”) change from baseline to 6 and 12 months in the treated knee (“Index Knee”) compared with the placebo- exposed knee (“Control Knee”).
  • TPX-100 treatments were safe and well tolerated. There were no severe adverse events that were related to TPX-100 treatment. Treatment-related adverse events were mild or moderate, transient, and common in many subjects at baseline.
  • the KOOS ADL (Function in Activities of Daily Living) subscale consists of 17 questions pertaining to various daily activities critical to everyday knee function. Results of the KOOS ADL domain demonstrated clinically meaningful and statistically significant (p ⁇ 0.05) improvements over baseline in Index Knees as compared to Control Knees at both 6 and 12-month time points. See Figure 1.
  • the WOMAC Function subscale which consists of the same questions as KOOS ADL, unsurprisingly also showed the same robust improvement in Index Knees as compared to Control Knees.
  • the KOOS Sports and Adventure subscale consists of five questions pertaining to sporting activities such as jumping, running, and squatting. The KOOS Sports and Adventure showed clinically meaningful and statistically significant improvement in Index Knees as compared to Control Knees at 6 months. See Figure 2.
  • the KOOS Knee -related Quality of Life (QOL) subscale consists of four questions including the subjects’ general difficulty with their knee and awareness of problems with confidence regarding each of their knees.
  • the KOOS Knee-related QOL exhibited clinically meaningful and statistically significant improvement in Index Knees as compared to Control Knees at 12 months. See
  • the KOOS Pain subscale consists of 9 questions regarding 1) frequency of pain and 2) amount of pain in performing different activities. See Figure 4.
  • the KOOS Pain subscale demonstrated clinically meaningful improvement in Index Knees as compared to Control Knees at 12 months, with a trend towards statistical significance (p ⁇ 0.09).
  • the WOMAC Pain domain which consists of questions 6 - 9 in Figure 4, demonstrated a clinically meaningful improvement in Index Knees at 12 months compared with Control knees, although the difference did not reach statistical significance.
  • Pain during this common activity is one of the most common complaints made by patients with knee OA and was significantly improved (p ⁇ 0.05) in Index Knees as compared to Control Knees at 12 months. See Figure 5.
  • MRI was the primary efficacy outcome measure. There was no measurable difference between Index and Control Knees at either 6 or 12-months. The vast majority (84%) of knees had less than minimum detectable change in cartilage thickness change in the patello-femoral compartment over the 12-month study period. With only 16% of knees demonstrating measurable change in cartilage, whether increased or decreased, the effective sample size was markedly limited, and the power to detect a treatment difference was correspondingly low.
  • Three-dimensional (3D) periarticular bone shape change of femur as quantified by the bone shape (B) score showed a statistically significant (p ⁇ 0.05) difference in favor of Index Knees as compared to Control Knees at both 6 and 12 months. See Figure 10.
  • responders to TPX-100 demonstrated robust improvements in pain frequency, which were, on average, decreased from daily pain at baseline to semi-monthly pain at 12 months. See Figure 11.
  • the robust improvement of pain frequency was also associated with eventually no change in the 3D bone shape in patella.
  • overall analgesic use was reduced by 62.5% over the 12-month study period.
  • TRC-100-treated knees demonstrated clinically meaningful and statistically significant (p ⁇ 0.05) improvements as compared to Control (placebo-exposed) knees at 6 or 12 month, or both time points: KOOS ADL (Function in Activities of Daily Living), WOMAC Function, and KOOS Knee -related QOL.
  • responders to TPX-100 demonstrated robust improvements in pain frequency, which were, on average, decreased from daily pain at baseline to semi-monthly pain at 12 months. See Figure 14. The robust improvement of pain frequency was also associated with eventually no change in the 3D bone shape in patella. See Figure 15.
  • Neogi T Bowes M, Niu J, De Souza K, Vincent G, Goggins J, Zhang Y, Felson DT.
  • MRI-based three- dimensional bone shape of the knee predicts onset of knee osteoarthritis: Data from the Osteoarthritis Initiative. Arthritis Rheum. 2013;65(8):2048-2058
  • Zaslav K, et al. A prospective study of autologous chondrocyte implantation in subjects with failed prior treatment for articular cartilage defect of the knee: Results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med. 2009;37:42-55.

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Abstract

La présente invention concerne une formulation pour une utilisation dans le traitement de l'arthrose par modification du changement de forme de cartilage articulaire sous-jacent à un ou plusieurs os. L'utilisation comprend l'évaluation de la forme osseuse de l'articulation du patient, l'injection au patient d'un peptide de SEQ ID N° 1 ou l'application d'autres interventions thérapeutiques qui peuvent réduire le changement de forme du cartilage articulaire sous-jacent à un ou plusieurs os, puis l'évaluation de la forme osseuse de l'articulation du patient.
PCT/US2019/053657 2018-12-04 2019-09-27 Formulation pour utilisation dans le traitement de l'arthrose WO2020117360A1 (fr)

Priority Applications (8)

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CN201980079767.9A CN113164033A (zh) 2018-12-04 2019-09-27 用于治疗骨关节炎的制剂
JP2021513299A JP2022502356A (ja) 2018-12-04 2019-09-27 変形性関節症の治療に使用するための製剤
AU2019391700A AU2019391700A1 (en) 2018-12-04 2019-09-27 Formulation for use in treating osteoarthritis
KR1020217017093A KR20210098998A (ko) 2018-12-04 2019-09-27 골관절염 치료시 사용하기 위한 제형
CA3120075A CA3120075A1 (fr) 2018-12-04 2019-09-27 Formulation pour utilisation dans le traitement de l'arthrose
EP19893858.1A EP3905942A4 (fr) 2018-12-04 2019-09-27 Formulation pour utilisation dans le traitement de l'arthrose
MX2021003584A MX2021003584A (es) 2018-12-04 2019-09-27 Formulacion para su uso en el tratamiento de la osteoartritis.
JP2023014591A JP2023058550A (ja) 2018-12-04 2023-02-02 変形性関節症の治療に使用するための製剤

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