An Open-Labeled Randomized Prospective Multi-center Study to Evaluate the Efficacy and Safety of Intra-articular Injection of OSSINEXT™, an Autologous Growth Factor Concentrate (AGFC) Compared to Hyaluronic Acid (HA) in Knee Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is known as degenerative arthritis and is the second most common rheumatologic problem with a prevalence of 22%-39% in India. Knee OA (KOA) is a major cause of mobility impairment, particularly among females. Non-surgical treatment options for KOA include intra-articular injections of platelet-rich plasma (PRP) and hyaluronic acid (HA). Most commercially available PRP preparation kits do not remove RBCs and WBCs which are detrimental to the healing effects. Wockhardt Regenerative Pvt. Ltd., Mumbai, India has developed a kit known as Ossinext™ which has an advantage over traditional PRP in that it eliminates RBCs and WBCs. This study was conducted to evaluate the effectiveness and safety of intra-articular injection of Wockhardt's Ossinext™ an autologous growth factor concentrate (AGFC) versus HA in KOA. METHODS:  Male and female patients in the age group between 30 and 75 years with confirmed KOA on radiological assessment with Grades I-III on the Kellgren-Lawrence Grading Scale and with visual analog scale (VAS) pain score of 4 or more (on the numeric rating scale) in spite of taking non-steroidal anti-inflammatory drugs (NSAIDs) since past 2 weeks were considered for study participation. This was an open-labeled study and eligible patients were randomly allocated to AGFC or HA in a 1:1 fashion. Three intra-articular injections were given in the affected knee joint, i.e. at baseline, month 1, and month 2 visits. Patients were evaluated at regular intervals, i.e. at months 5, 8, and 11 for primary and secondary endpoints. The primary efficacy endpoint for this study was change from baseline in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores at month 11 whereas the secondary efficacy endpoints were change from baseline of VAS pain scale at months 1, 2, 5, 8, and 11 as well as change from baseline of WOMAC, KOOS (Knee and Osteoarthritis Outcome System), and IKDC (International Knee Documentation Committee) scale at month 5, 8, and 11. For analysis a mixed model for repeated measures was used. RESULTS:  Out of the 100 patients who were enrolled, 50 patients each were randomized to AGFC and HA arm. The results were analyzed from 99 patients (49 for AGFC and 50 for HA) who met the criteria for the modified intent to treat (mITT) population. At month 11 on the WOMAC scale, there was greater improvement seen with Ossinext™ compared to HA group which was also statistically significant with p-value of 0.0332. Within the group, there was statistically significant improvement before and after treatment in all scales, i.e. WOMAC, KOOS, IKDC, and VAS at all time points, i.e. months 5, 8, and 11 with a p-value as low as <0.0001. Within the group, the VAS score showed statistically significant improvement even at months 1 and 2 as well. A total of 24 patients reported 37 adverse events (AEs) during the study, most common being pain, pyrexia and swelling but none of the AEs reported during the study were considered as severe in intensity. There were no safety concerns reported. CONCLUSIONS: In conclusion, greater and statistically significant improvement was seen with Ossinext™ in WOMAC scores at month 11 compared to HA. Ossinext™ also showed marked statistically significant improvement from before treatment to after treatment in the WOMAC, KOOS, IKDC, and VAS scales used for the assessment of KOA with a p-value as low as <0.0001. Ossinext™ was also safe and well-tolerated.

A Prospective Multicenter Study to Evaluate the Safety and Efficacy of the Topical Application of MYOWNN™, an Autologous Growth Factor Concentrate (AGFC) Serum, in Anti-Aging.

Background Growth factors from platelets have been emerging as a revolutionary treatment with the ability to induce cell growth in the skin, which results in retarding and reversing the aging process. Platelet-rich plasma (PRP) allows for greater release of growth factors and biologically active proteins, which in turn activates the cascade of stimulation of neoangiogenesis and collagen production. PRP is used in anti-aging and facial skin rejuvenation in the form of dermal injections and topical application during micro-needling. This study was conducted to assess the safety and efficacy of a topically applied face serum, MYOWNN™ (Wockhardt Ltd., Mumbai, India). MYOWNN™ is an autologous growth factor concentrate that has been made into a topical face serum. Methods Male and female subjects in the age group between 30 and 55 years (both inclusive) with Fitzpatrick skin type III-V who had not taken any oral or topical treatments for at least four weeks before and any platelet-rich plasma (PRP) based facial treatment (injections) at least six months before the study entry were included. MYOWNN™ serum was applied on the face once daily at night, approximately 30 minutes before sleeping preferably, for a total duration of five months. Six parameters, i.e. spots, pores, wrinkles, texture, moisture, and pigmentation, were evaluated at regular intervals with Visage-LS (dermaindia®, Tamil Nadu, India), a face analysis system that gives the live status of these six parameters and is an advanced live status skin detection equipment together with shooting, analyzing, and displaying functions, as well as the subjective analysis, was performed by subjects and physicians using different globally accepted scales like physician's global aesthetic improvement scale (PGAIS), subject's global aesthetic improvement scale (SGAIS), subject satisfaction score (SSS), and wrinkle severity rating scale (WSRS). For analysis, a mixed model for repeated measures was used. The model had change from baseline as the dependent variable visit as a factor and baseline assessment result as a covariate. All primary and secondary efficacy endpoints were analyzed using Modified Intent-to-Treat (mITT) populations. Results Improvement in an average of six anti-aging parameters was observed as early as three months while statistically significant improvement was observed by the end of five months of application. A statistically significant improvement in wrinkles was observed by the end of three months of the application itself. There were no product-related adverse events reported. Conclusions Five months of application of MYOWNN™ serum showed a statistically significant improvement in an average of six parameters of anti-aging and face rejuvenation with a p-value of 0.0150 (<5% level of significance (i.e. 0.05) and was also well-tolerated.

Safety, tolerability and pharmacokinetics of oral nafithromycin (WCK4873) after single or multiple doses and effects of food on single-dose bioavailability in healthy adult subjects.

Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0-t ) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.

Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects.

WCK 5222 is a combination of cefepime and the novel ß-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug (Cmax) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC0-8 values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC0-8 values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.

Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects.

Alalevonadifloxacin (WCK 2349) is a novel l-alanine ester prodrug of levonadifloxacin that is being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM samples from 30 healthy subjects were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following oral dosing of alalevonadifloxacin (1,000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage (BAL) fluid sampling time, i.e., 2, 4, 6, 8, or 12 h after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-h interval following the first and ninth oral doses. Penetration ratios were calculated from the areas under the concentration-time curves from 0 to 12 h (AUC0-12) for plasma, ELF, and AM by using mean (and median) concentrations at each BAL sampling time. Unbound plasma concentrations (∼85% plasma protein binding) were used to determine site-to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg · h/liter, respectively. The penetration ratios for ELF and AM levonadifloxacin concentrations to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02253342.).

Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects.

The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (Cmax) of 1.02 ± 0.31 µg/ml and 1.39 ± 0.36 µg/ml, respectively; times to Cmax of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 µg · h/ml. For ELF, the respective AUC0-24 values based on the mean and median concentrations were 224.1 and 176.3 µg · h/ml, whereas for AM, the respective AUC0-24 values were 8,538 and 5,894 µg · h/ml. Penetration ratios based on ELF and total plasma AUC0-24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.).