Drug Discovery Task 1 R Collin 13221787 PDF

Preview

Summary

Download Drug Discovery Task 1 R Collin 13221787 PDF

Description

Rex Collin 13221787

ZEMDRI Introduction Over recent years, there has been a significant increase in the prevalence of multidrug-resistant gram-negative pathogens. Of these, multidrug-resistant Enterobacteriaceae is the most recent, and one of the most dangerous threats ( 5,7). Carbapenems are usually used as the last line of treatment for Enterobacteriaceae infections, however, the rise of carbapenem-resistant Enterobacteriaceae (CRE) has led to the need for alternatives (7). This is further complicated by the fact that they usually have extensive resistances to other potential drugs ( 3). CRE infections are a big issue because they have a higher mortality rate than their CSE (carbapenemsusceptible Enterobacteriaceae) counterparts, at somewhere between 2 and 3 times the mortality rate (8,9). Due to the extensive resistance, the usefulness of most common treatment methods is neutralised and the possible alternatives are generally restricted to tigecycline, colistin, gentamicin, and amikacin ( 9), which have a successful treatment rate of 69.3%, 70.6%, 75% and 75% respectively (7). Another multidrug-resistant pathogen, the rise of Enterobacteriaceae that produce extended-spectrum -lactamase (ESBL-) poses another big threat to the healthcare industry, particularly hospitals. They are resistant to -lactam antibiotics, including most aminoglycosides. Both of these groups of pathogens are a concern in urinary tract infections (UTIs), and are a big problem in the treatment of complicated urinary tract infections, being labelled as number one priority bacteria by the World Health Organisation (3). UTIs are one of the most common infections, in both the community and also in the hospital setting. Between 2010 and 2014, ESBL-producing pathogens presence in complicated UTIs increased from 7.8% to 18.3% in the US (10). Carbapenems are the most used treatment for ESBL-producing pathogen infections (12), but with the increased use of the drug, the faster resistance to it arises, thus leading to more CRE pathogens and other extensive drug-resistant pathogens.

Zemdri, licensed by Achaogen, is a semi-synthetic aminoglycoside that was approved by the Food and Drug Administration (FDA) in the US in 2018 for the treatment of complicated UTIs (4). The Therapeutic Goods Administration (TGA) in Australia has yet to approve it, as well as the European Medicines Agency. Zemdri is the brand name for the compound plazomicin. It is an effective treatment for CRE infections, ESBL-producing pathogens and other aerobic gram-negative bacteria ( 13) because it escapes all clinically significant aminoglycoside-modifying enzymes ( 14). Just like its aminoglycoside counterparts, Zemdri’s mechanism of action is inhibiting protein synthesis in the bacteria, and it demonstrates concentration-dependent bactericidal properties (3,14). The standard dosage is 15mg / kg administered intravenously once every 24 hours for 4-7 days (13). It has shown to be a suitable replacement for carbapenems in the treatment of complicated UTIs. One Stage III study showed that it was non-inferior to meropenem for the treatment of CRE infections, with 81.% of plazomicin-treated patients presenting as successfully treated versus 70.1% of

Rex Collin 13221787

meropenem-treated patients at a te patients treated with plazomicin had and 82.4% had a microbiological era of these values were significantly hig tested as an antibiotic for bloodstre FDA.

Challenges Zemdri did not come without its cha FDA for its serious and potentially lif patients who have limited/no other aminoglycosides, it has the potentia ototoxicity, diarrhoea, hypertension likely to produce adverse effects to t Though during clinical Trial 1 in heal with side effects at a similar rate to t counterpart, meropenem. Zemdri di impaired renal function at 3.6% of th There is limited clinical safety and effi the very small number of patients th ability to test the drug’s effectivenes infections caused by CRE and ESBL-p was stopped prematurely due to a la clinical safety data, it is not recomm (15), although a Phase 2 study found patients that were on a different me Before Zemdri was approved by the under Vabomere was approved on A treating complicated UTIs, and func the two is that Vabomere is affected Vabomere, the FDA had already app another drug that aimed to treat co -lactamase inhibitor and again fun predecessors to Zemdri had cornere inhibitors, pushing Achaogen to dev Timeline 19/10/43 First aminoglycoside discovered (streptomycin)

1943 2006 2008 2009 2012 2010 2013 2011 2014

2015 2016 2017

2018

2019 2028 2032

25/01/06 18/12/14 Achaogen licensing 02/01/18 Zemdri is enters grantedinto Qualified 15/05/12 17/10/18 agreement with Ionis Pharmaceuticals 15/04/19 Achaogen announces FDA Infectious Disease Product Phase 2 cUTI Study reports XX/11/28-XX/XX/32 11/01-22/09/16 02/09/14 27/06/17 Achaogen submits Zemdri application to Achaogen files for bankruptcy acceptance of Zemdri with priority Zemdri patents expire Designation by FDA positive results Phase 3 EPIC (CRE) study Second Zemdri patent issued Fourth Zemdri patent issued European Medicines Agency i

it. It also showed that 78.8% of gical eradication of CRE pathogens, BL-producing pathogens (5). Both meropenem group. Zemdri was also but has yet to be approved by the

been given a boxed warning by the side effects and is reserved for eatment ( 1). Like other ts including nephrotoxicity, es (1). Fortunately, Zemdri is less t older aminoglycosides do ( 5). emdri-treated patients presented eated with its carbapenem igher rate of patients affected by

Zemdri, and this is in part due to d in studies. This has limited the dstream infections and secondary hogens ( 13). A Phase 3 study, CARE ents ( 33,34). Also due to the limited Zemdri with any other medications ere no adverse effects from urrently to the test (5). enem/vaborbactam drug licensed 7 (16). Both drugs are aimed at arly. The main difference between em-resistance. Even before (ceftazidime and avibactam), s. Unlike the other two, Avycaz is a tly to the other two ( 17). These two on carbapenems and -lactamase glycoside to fill the niche.

XX/01/06 Achaogen initiates new drug discovery project XX/12/18 26/10/17 Achaogen submits Formal Dispute 19/12/08 18/08/15 25/06/18 Achaogen submits New 06/06/19 Request to FDA for theDrug indication 16/09/14 Initial IND submitted with CARE study ends Zemdri approved byZemdri FDA for 20/07/18 Application for plazomicin tocUTI FDA for Cipla USA buys for US$16 26/02/13 of Zemdri a treatment for Phase 3asCARE (bloodstream 23/02/16 prematurely due to low use in US Zemdri available in US only both bloodstream infection and cUTIs First patent issuedinfections for million Third Zemdri patent issued infection) study begins enrollment bloodstream enrollment Z di

Rex Collin 13221787

19/10/43 – (33)

19/12/08 – (3)

16/09/14 – (30) 18/12/14 – (3)

23/02/16 – (32) 27/06/17 – (32)

25/06/18 – (4) 20/07/18 – (34)

06/06/19 – (21)

The average wholesale price for Zemdri is around US$37.80 / mL. For a 68kg person a single dose of Zemdri would cost US$756.00 ( 18). Zemdri treatments are run over 4-7 days, so full treatment could cost US$5292.00. It was also g es for Medicare and Medicaid 19), reimbursing hospitals ha for the first 3 years of use. When Zemdri was first released, revenue forecasts were favourable. Clarivate Analytics Cortellis predicted a 2019 revenue of US$70 million and Leerink Partners analyst Ami Fadia predicted US$400 million by 2025 (20). The drug proved unprofitable as Achaogen filed bankruptcy in June 2019 and was bought by Cipla USA Inc. during a Chapter 11 bankruptcy auction for US$16 million ( 21,22). Research and Development expenses for Achaogen in 2018 were US$103 million, mainly due to the pre-launch costs in the first half of the year. In contrast, the total Zemdri revenue for 2018 after its July launch was only U$0.8 million (23). Achaogen was supported wholly by funding since its founding in 2006. In 2009, it was awarded a US$8 million

Rex Collin 13221787

seeding drug discovery grant by the Wellcome Trust, and then in 2010 secured a US$56 million Series C grant, as well as over US$150 million in US public grants between 2006 and 2010 (24). Also they received US$124.4 million in funding from the Biomedical Advanced Research and Development Authority, ending in March 2014 (20). By the end though, Achaogen was functioning at a net loss of US$125.6 million in 2017 and US$186.5 million in 2018 (23). Ultimately, this combined with the failure of Zemdri sales lead to them declaring bankruptcy and Cipla picking up the drug. No data has come out since the Cipla acquisition. Current status Zemdri is seeing use as a last resort antibiotic for dealing with multidrug-resistant UTIs. The drug is the preferred option over colistin, another alternative that has a higher toxicity ( 25). Zemdri is an answer to a pressing healthcare issue, but is only relevant to a very small but significant percentage of patients. As the 2018 sales have shown, it wasn’t profitable enough as an antibiotic for only complicated UTIs. There has been a push to get the FDA to approve Zemdri and plazomicin for treatment of CRE in bloodstream infections. It has been predicted that doctors may treat bloodstream infections of CRE with Zemdri off-label, against the recommendations of the FDA (25,26). In December 2018, Achaogen filed a Formal Dispute Resolution Request with the FDA in regards to the use of Zemdri in the treatment of bloodborne infections, and as of February 2019, is still awaiting a response. The company has also started a C-scape revision of the drug, beginning Phase 1 clinical trials on a revised product. Achaogen did file Chapter 11 bankruptcy in July 2019, and as a result Zemdri was acquired by Cipla. This will almost definitely result in a delay in the rollout of Zemdri to Europe and other countries. Cipla’s acquisition was for worldwide rights, excluding Greater China, as well as its assets and limited liabilities ( 21). Cipla has a history of humanitarian and proactive leadership in international healthcare, most notably for increasing the availability of HIV medications in Africa in 2001 ( 21). They’re an international organisation that has multiple sources of income, rather than just relying on Zemdri like Achaogen was. Zemdri is a drug that will become more and more necessary as drug-resistant bacteria become more prevalent, and Cipla has the resources to distribute it properly.

Bibliography 1. 'Drug Trials Snapshot: ZEMDRI' 2018, 18/08/2018, viewed 07/12/2019, . 2. 'Achaogen’s UTI Antibiotic Gets FDA Nod With Black Box Warning' 2018, 29/06/2018, viewed 18/08/2019, .

Rex Collin 13221787 3. Achaogen 2018, Antimicrobial Drugs Advisory Committee Meeting Briefing Book, viewed 18/08/2019, . 4. Stewart, J. 2018, Zemdri Approval History, Drugs.com, viewed 18/08/2019, . 5. Wagenlehner, F.M.E., Cloutier, D. J.,Komirenko, A. S.,Cebrik, D. S.,Krause, K. M.,Keepers, T. R., Connolly, L. E., Miller, L. G., Friedland, I., & Dwyer, J. P. 2019, 'OnceDaily Plazomicin for Complicated Urinary Tract Infections', The New England Journal of Medicine, no. 380, pp. 729-40. 6. Jackson, J., Chen, C., & Buising, K. 2013, 'Aminoglycosides: how should we use them in the 21st century?', Current Opinion in Infectious Diseases, vol. 512, no. 25, pp. 516-25. 7. Lee, C.S., & Doi, Y. 2014, 'Therapy of Infections due to Carbapenem-Resistant GramNegative Pathogens', Infection and Chemotherapy, vol. 46, no. 3, pp. 149-64. 8. Eliopoulos, G.M., Cosgrove, S. E., & Carmeli, Y. 2003, 'The Impact of Antimicrobial Resistance on Health and Economic Outcomes ', Clinical Infectious Diseases, vol. 36, no. 11, pp. 1433-7. 9. Martin, A., Fahrbach, K., Zhao, Q., & Lodise, T. 2018, 'Association Between Carbapenem Resistance and Mortality Among Adult, Hospitalized Patients With Serious Infections Due to Enterobacteriaceae: Results of a Systematic Literature Review and Meta-analysis', Open Forum Infectious Diseases, vol. 5, no. 7. 10. Lob, S.H., Nicolle, L. E., Hoban, D. J., Kazmierczak, K. M., Badal, R. E., & Sahm, D. F 2016, 'Susceptibility patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and the United States, SMART 2010–2014', Diagnostic Microbiology and Infectious Disease, vol. 85, no. 4, pp. 459-65. 11. Delgado-Valverde, M., Sojo-Dorado, J., Pascual, A., & Rodriguez-Bano, J. 2013, 'Clinical management of infections caused by multidrug-resistant Enterobacteriaceae', Therapeutic Advances in Infectious Diseases, vol. 1, no. 2, pp. 49-69. 12. Shaeer, K.M., Zmarlicka M. T., Chahine E. B., Piccicacco, N., & Cho, J. C. 2019, 'Plazomicin: A Next-Generation Aminoglycoside.', Pharmacotherapy, vol. 39, no. 1, pp. 77-93. 13. Zhanel, G.G., Lawson, C. D., Zelenitsky, S., Findlay, B., Schweizer, F., Adam, H., Walkty, A., Rubinstein, E., Gin, A. S., Hoban, D. J., Lynch, J. P., & Karlowsky, J. A. 2012, 'Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin', Expert Review of Anti-infective Therapy, vol. 10, no. 4, pp. 459-73 14. ZEMDRI™ Prescribing Information 2018, pamphlet, Achaogen, viewed 18/08/2019, . 15. Eisenman, T. 2017, FDA approves new antibacterial drug, U.S. Food and Drug AssosciationPlace, Published, viewed 18/08/2019, . 16. Avycaz Approval History 2019, Drugs.com, viewed 18/08/2019, . 17. Hastain, N. 2018, 'A New Executioner: Plazomicin for complicated UTIs', Pennsylvania Society of Health-System Pharmacists. 18. PR Newswire, 'Cipla USA Furthers AMR Stewardship With Acquisition of Key Antiinfective ZEMDRI™ (IV Plazomicin)', 25/07/2019, viewed 18/08/2019,

Rex Collin 13221787 . 19. Fitzhugh, M. 2018, Achaogen's Zemdri gains cUTI approval, but draws CRL for bloodstream infection, BioWorld, viewed 18/08/2019, . 20. BioSpectrum 2019, Cipla buys prescription drug Zemdri, BioSpectrum, viewed 18/08/2019, . 21. Terry, M. 2019, Losing the War on Antibiotic-Resistant Infections Because of Market Forces, Biospace, viewed 18/09/2019, . 22. Achaogen 2019, Achaogen Reports Fourth Quarter and Full Year 2018 Financial Results and Provides Corporate Update, Globe Newswire, viewed 18/08/2019, . 23. Moran, N. 2019, A decade of incentives to promote antibiotic development and still no viable route to commercial success, Clarivate Analytics, BioWorld Perspectives, viewed 18/08/2019, . 24. Dall, C. 2019, Plazomicin for tough infections: a tale of 2 clinical trials, Centre for Infectious Disease Research and Policy, viewed 18/08/2019, . 25. McKenna, M. 2019, The Antibiotics Business is Broken - But There is a Fix, Wired, viewed 18/08/2019, . 26. Achaogen 2019, Achaogen Provides Update on Corporate Progress and Key Preliminary Fourth Quarter 2018 Results, Globe Newswire, viewed 18/08/2019, . 27. Schanker, G. 2018, Plazomicin: Its Prospects and its Challenges, Northeastern University College of Science, College of Science, viewed 18/08/2019, . 28. Connolly, L.E. 2018, A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP) (EPIC), U.S. National Library of Medicine, ClinicalTrials.gov, viewed 18/08/2019, . 29. Karaiskos, I., Lagou, S., Pontikis, K., Rapti, V., & Poulakou, G. 2019, 'The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How', Frontiers in Public Health, vol. 7, p. 151. 30. Connolly, L.E. 2018, A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE) (CARE), U.S.

Rex Collin 13221787 National Library of Medicine, ClinicalTrials.gov, viewed 18/08/2019, . 31. Newman, S. 2009, Achaogen Initiates Phase 1 Trial of ACHN-490 for Treatment of Multi-Drug Resistant Gram-Negative Bacterial Infections, AchaegonPlace, Published, viewed 18/08/2019, . 32. Achaogen 2019, FORM 10-K, United States Security and Exchange Commission, Washington, D.C. 20549, . 33. The Editors of Encyclopedia Britannica, 2019, Aminoglycoside, Encyclopedia Britannica, viewed 18/08/2019, . 34. Achaogen 2018, Achaogen Launches ZEMDRI™ (plazomicin), a Once-Daily Aminoglycoside for use in complicated Urinary Tract Infections (cUTI), Published, viewed 18/08/2019, . 35. Achaogen 2018, 'Achaogen Submits Marketing Authorization Application to the European Medicines Agency for Plazomicin'....