NEW DRUG DISCOVERY
WCK 771 (EMROK)
WCK 771 & WCK 2349 are the first two NCEs from Wockhardt’s antibiotic discovery program approved in India in 2019 as first ever India discovered novel antibiotics. Based on extensive preclinical and clinical development efforts spread over 12 years, WCK 771 (INN: levonadifloxacin, 800 mg, IV twice-daily) was introduced under the brand name EMROK. EMROK is derived from unique benzoquinolizine structural sub-class which was designed to offer excellent safety in patients with multiple-morbidities, assuring clinical efficacy based on favourable pharmacokinetic/pharmacodynamic features, broad spectrum bactericidal action and multi-indication utility. The differentiated structural features of EMROK and EMROK O has bestowed them with coverage of MDR/XDR Gram positive pathogens including MRSA, quinolone-resistant S. aureus, vancomycin/teicoplanin non-susceptible S. aureus, anaerobes, MDR streptococci. In addition, EMROK is enriched with several other patient-centric features such as freedom from on-therapy safety parameter monitoring and need for dose adjustments in patients with renal and hepatic function impairments as well as minimal drug-drug interaction facilitating co-medication with other drugs without safety or efficacy risk. EMROK is formally approved for acute bacterial skin and skin structure infections including diabetic-foot-infections and concurrent bacteraemia caused by Gram positive pathogens including MRSA. EMROK is designated as qualified infectious disease product (QIDP) by US FDA due to its ability to meet unmet need in the management of serious bacterial infections.
WCK 2349 (EMROK O)
Realizing pressing unmet need of a safer, oral MDR Gram positive MRSA antibiotic, in early 2000, Wockhardt discovery team embarked on identifying an appropriate oral dosage form of WCK 771. This was scientifically a challenge as the goal was to evolve an oral drug with a pharmacokinetic profile mimicking the injectable WCK 771 and safety commensurate to prolonged treatment required for certain recalcitrant MRSA infections and use in out-patient settings. With efforts spread over 3 years, the team designed >70 prodrug based NCEs and finally selected L-Alanine prodrug of WCK 771 (levonadifloxacin) code named as WCK 2349 (INN: Alalevonadifloxacin, 1000mg tablets, twice-daily). Subsequent extensive clinical evaluations including phase 3 study led to approval of WCK 2349 under the brand name EMROK O. Clinical studies conducted in US demonstrated that EMROK O shows 90% oral bioavailability and the human pharmacokinetic profile of oral EMROK O at 1000 mg BID mimics that of 800 mg BID of EMROK administered intravenously. Clinical pharmacology studies proved that, no dose adjustments are required for EMROK O for patients with renal (<5% renal elimination) or hepatic impairment (based on study conducted in US) and EMROK could be taken regardless of fed status as food has no impact on its bioavailability. Safety assessments based on clinical studies (approx. 1000 patients/subjects) and real-word use (>50,000 patients), have established a remarkable gastro-intestinal, CNS, CVS, hepatic and renal safety as well as enabling features of minimal drug-drug interaction and freedom from monitoring lab safety parameters on therapy. EMROK is also designated as qualified infectious disease product (QIDP) by US FDA.
Due to their uniquely attractive clinical profile, till date, >50,000 patients have been treated with EMROK and EMROK O involving a range of difficult-to-treat infections such as bone and joint infections, catheter-associated blood stream infection, pneumonia, diabetic-foot infection, COVID linked bacterial infection etc. Under partnership, EMROK and EMROK O are also being developed in Russia and registration of these drugs is on-going in several emerging markets.
Globally as well as in India, in terms of disease burden, community-acquired bacterial pneumonia (CABP) is one of the top-ranking infections. Its management is particularly challenging due to growing resistance to current 1st line antibiotics, their safety limitations and compliance-challenging longer dosing regimen. The treatment of respiratory infections in the out-patient settings is further complicated in older age patients and children; the most vulnerable segment of patients. Realizing this challenge, Wockhardt discovery team embarked on identifying a novel oral respiratory antibiotic with coverage of multi-drug resistant pathogens, assuring safety profile and easy to comply dosing regimen. After five years of discovery efforts, the team identified a well differentiated respiratory antibiotic WCK 4873 (INN: Nafithromycin). Phase 1 and Phase 2 studies conducted in US and globally helped evolve 1st time ever an ultra-short-course oral dosing regimen (800 mg once-daily for 3 days) for the treatment of CABP. Such ultra-short course oral dosing regimen was clinically successful due to high and sustained lung concentrations of nafithromycin. Importantly, nafithromycin is highly potent against entire range of respiratory pathogens such as S. pneumoniae, H. influenzae, M. catarrhallis, staphylococci and atypical pathogens regardless of underlying azithromycin, penicillin or quinolone resistance. Nafithromycin is currently nearing the completion of Phase 3 study with expected launch in 2024. Nafithromycin has also been designated as qualified infectious disease product (QIDP) by US FDA.
Globally and in India, a significant surge in ESBL producing Gram negative pathogens has led to severe compromise in the efficacy of older work-horse antibiotics such as 3rd and 4th generation cephalosporins, quinolones, piperacillin/tazobactam and cefoperazone/sulbactam. For instance ESBL mediated resistance to piperacillin/tazobactam and cefoperazone/sulbactam in Enterobacterales is ~55% in India. WCK 4282 is designed to fill this critical therapeutic void by offering a significantly superior ESBL coverage as compared to piperacillin/tazobactam and cefoperazone/sulbactam along with excellent safety profile. It is a globally patented and pharmacodynamically optimised high dose combination of clinically well-established, cefepime and tazobactam, currently in Phase 3 stage of development. The safety of WCK 4282 has been established through several Phase 1 studies conducted in US and EU including in subjects with various degree of renal impairment. Upon approval, WCK 4282 would provide a superior replacement for piperacillin/tazobactam and cefoperazone/sulbactam and drastically minimize the dependence on carbapenems such as meropenem and imipenem, enable clinicians in reinstating antibiotic stewardship practice, and provide a much safer work horse therapy for hospitalized patients. WCK 4282 has also been designated as qualified infectious disease product (QIDP) by US FDA.
WCK 5222 is Wockhardt’s flagship project discovered to offer a lasting and assuring solution for life-threatening multi-drug/extensively drug-resistant Gram negative infections encountered in ICUs such as sepsis and hospital/ventilator associated pneumonia. WCK 5222 is a combination of cefepime and zidebactam, the latter being Wockhardt’s proprietary 1st ever β-lactam enhancer antibiotic discovered in past >50 years. Due to novel mechanism of action, WCK 5222 has been shown to possess broadest-ever spectrum of pathogen and resistance mechanism coverage encompassing highly drug resistant E. coli, K. pneumoniae, P. aeruginosa and A. baumannii. More than 50 international publications from top-notch independent US, EU, China and Indian investigators have established its potential to offer a life-saving, destination therapy for critically ill patients not responsive to existing therapeutic options. WCK 5222 would also eliminate the dependence of clinicians on toxic/poorly tolerated drug with suboptimal efficacy such as colistin, polymyxin and tigecycline. Several Phase 1 studies conducted in US have demonstrated its remarkable safety profile. WCK 5222 is currently undergoing global Phase 3 study with expected launch in 2025. As WCK 5222 caters several unmet needs in ICU settings, it has been designated as qualified infectious disease product (QIDP) by US FDA, also paving way for faster approval process.
Several countries in the world are experiencing high rates of multi-drug resistant pathogens, particularly in hospitals leading to serious hospital-associated infections often requiring long hospital stay and increased treatment. The scenario is further complicated by reports of rise in community-onset multi-drug resistant infections and in the absence of an effective out-patient therapy; currently such patients too require hospitalization, thus further burdening the already overloaded hospital infrastructure. This situation highlights the need for MDR-active effective outpatient parenteral antimicrobial therapies (OPAT). OPAT has the potential to be the ‘standard-of-care’ to enable community management of resistant infections currently requiring hospitalizations. WCK 6777, a combination of ertapenem and zidebactam is being developed to address this unmet need of an OPAT drug with potential to treat the toughest resistant pathogens. Preclinical translational studies have shown that once-daily IV treatment with WCK 6777 is bactericidal to nearly all variants of carbapenem-resistant Enterobacterales (E. coli, Klebsiella, Enterobacter etc) which are often the cause of community as well as hospital infections such as urinary tract and gastro-intestinal infections (UTIs). Taking note of envisaged OPAT clinical role, National Institutes of Health, USA have selected WCK 6777 to conduct its first-in-human Phase 1 studies at their phase I clinical trial units in the USA. Once-a-day therapeutic profile of WCK 6777 is expected to cut hospital admissions, facilitate early patient discharge and thus introduce patient-centric care for MDR infections. The Food and Drug Administration (USA) has granted a qualified infectious disease product (QIDP) designation to WCK 6777, which signifies its ability to meet unmet medical need and facilitates faster approval process.