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Novartis Acquires Marketing Rights For Novel Broad-spectrum Antibiotic

Novartis has signed an agreement with Paratek Pharmaceuticals that entitles Novartis to the worldwide rights to market PTK0796 — a novel broad-spectrum antibiotic capable of fighting multidrug-resistant bacterial infections. The agreement involves an upfront payment of an undisclosed amount from Novartis, with Paratek eligible to receive a total of US$485 million, including milestone payments. The companies will share the responsibility and costs for the development of PTK0796.

The increasing prevalence of multidrug-resistant bacterial strains, together with the decline in the discovery and development of new antibiotic classes, has made the effective treatment of many bacterial infections increasingly difficult. "Such multidrug-resistant organisms pose particular challenges in hospital environments," explains Professor Richard Wenzel, Virginia Commonwealth University, USA. "Efficacy, an oral regimen, and single daily dosing are desirable characteristics for novel antibiotics, but the ability of these organisms to acquire resistance genes readily, the high level of environmental contamination, inadequate infection control and the limited pipeline of antibiotics severely hamper these goals," he adds. "There is an urgent need for the identification of new antimicrobial targets and the development of new antibiotics with few side effects," says Professor Robert Daum, University of Chicago Medical Centre, USA.

In this context, studies of PTK0796 — the first in a new aminomethylcycline class of antibiotics, the activity of which is linked to inhibition of bacterial protein synthesis — are so far encouraging. PTK0796 exhibits potent, broad-spectrum activity against a wide range of bacteria and, most importantly, "...Appears to be active against many antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) infections, that have been occurring in epidemic numbers in the United States" notes Daum. Indeed, in a Phase II study involving 200 patients with complicated skin and skin structure infections (cSSSI), in which approximately 50% of the infecting bacteria were MRSA, once-daily oral or intravenous PTK0796 treatment for 14 days achieved a clinical success rate of 98%, with the drug meeting primary safety and tolerability end points. "The availability of PTK0796 in both oral and parenteral forms suggests that transition from parenteral treatment to an oral treatment phase may be performed easily," says Daum. This may offer a convenient way for patients to continue antibiotic treatment after leaving the hospital.

However, there are some potential limitations to the application of PTK0796. "In the case where the pathogen is known, health-care providers will prefer to narrow the antimicrobial treatment spectrum to accurately target the causative bacterium. Additionally, previous tetracycline derivatives have not been suitable for children younger than 9 years of age, as they tend to accumulate in teeth and bones, raising concern about unsightly cosmetic defects," notes Daum.

"Although PTK0796 would not solve all the problems due to burgeoning antibiotic-resistant infections, it could be an interesting addition to the anti-infective armamentarium. Further developmental activities should be conducted to identify its niche," concludes Daum. PTK0796 is currently in Phase III clinical trials for cSSSI, and clinical trials for a number of other potential indications are under way.

Venatorx Plans New Antibiotic Filing After Phase 3 Readout

Venatorx Pharma has moved a step closer to what has unfortunately become a rare event in pharma – the filing of a new antibiotic designed to tackle the increasing pressing problem of antimicrobial resistance.

Armed with positive phase 3 results, Venatorx has said it will file for approval its cefepime-taniborbactam combination with the FDA later this year for complicated urinary tract infections (cUTI), including severe kidney infections (acute pyelonephritis).

The new drug combines a well-established beta-lactam antibiotic – cefepime – with a new beta-lactamase inhibitor designed to overcome a key resistance mechanism that allows pathogens to protect themselves from the antimicrobial.

Years of neglect by a pharma industry unable to see a way to secure a commercial return on antibiotics R&D has created a situation where the world is running out of effective anti-infectives, with the WHO warning that AMR could be causing 10 million deaths a year by 2050 unless new drugs are developed.

Cefepime is a broad-spectrum antibiotic that first introduced in the 1990s, but has become increasingly ineffective against key resistant pathogens and was removed from the World Health Organization (WHO) list of essential medicines in 2019.

Combining it with taniborbactam restored its activity against some organisms are particularly troubling, including Enterobacterales species and Pseudomonas aeruginosa resistant to carbapenems – currently last-resort therapies for multidrug resistant (MDR) infections.

A similar approach has been taken by Merck & Co with Recarbrio (imipenem/cilastatin-relebactam), which was approved by the FDA for cUTIs and complicated intra-abdominal infections (cIAI) in 2019.

The company and regulator have both cautioned it should only be prescribed for when there are limited or no alternative antibacterial drugs for treating a patient's infection, revealing the disincentive behind antibiotics R&D.

That has results in efforts to find a new way to reimburse companies bringing new anti-infectives to market. In 2019, for example, the UK said it was looking into a system where companies would be paid upfront for access to new antibiotics based on their value to the NHS, rather than the volume of medicines sold.

In the 661-subject CERTAIN-1 trial, cefepime-taniborbactam was at least as effective as comparator beta-lactam meropenem in clearing cUTIs, achieving combined clinical and microbiologic responses in 70% of patients, versus 58% of those treated with the comparator drug.

A prespecified assessment found that cefepime-taniborbactam performed significantly better statistically than meropenem, an outcome that was sustained through the 35-day follow-up period.

Treatment-emergent adverse events (TEAEs) were seen in 35.5% of the cefepime- taniborbactam group and 29% of those taking meropenem, with a higher rate of discontinuations with Venatorx' drug (3% versus 0.9%).

There was one death in the cefepime-taniborbactam cohort, but it was considered to be unrelated to the antibiotic treatment.

Development of the new combination has been backed by the Global Antibiotic Research and Development Partnership (GARDP), a Swiss non-profit set up in 2016 to help tackle the problem of antimicrobial resistance.

Venatorx has granted GARDP exclusive rights to distribute and sub-distribute cefepime-taniborbactam, once it is approved for clinical use, in certain low- and lower middle-income countries, as well as in the public markets in India and South Africa.

Drug Regulator Asks States To Withdraw Sale Of Unapproved Antibiotic

The Central Drugs Standard Control Organisation (CDSCO) has mandated an immediate stop to sales of broad-spectrum antibiotic combination of meropenem and disodium EDTA injections. The directive comes as the drug is yet to receive approval from the regulatory authority.

A letter from the Drugs Controller General of India, Rajeev Raghuvanshi, dated 8 March, said that several manufacturers have been found producing and distributing this drug combination. Classified as a 'New Drug,' it has not secured the necessary regulatory approval.

"No new drug shall be manufactured for sale unless it is approved by the licensing authority as defined in Rule 3 of New Drugs and Clinical Trials Rules, 2019…a person who intends to manufacture new drug in the form of API or pharmaceutical formulation as the case may be for sale or distribution shall make an application for grant of permission to the Central Licence Approving Authority in Form CT-21 along with a fee as specified," according to the letter, a copy of which was seen by Mint.

"In view of the above, you are hereby directed to convey the matter to all the manufacturer under your jurisdiction and cancel the product permission granted by you of subject drug," it added.

In India, the combination of meropenem and disodium EDTA is marketed as a broad-spectrum antibacterial agent for the treatment of a variety of infections, including meningitis, pneumonia, urinary tract infections, intra-abdominal infections, gynaecological infections, skin infections, and sepsis.

Produced by numerous local pharmaceutical companies, the drug is offered at a price of around ₹2,000 per dose. It is marketed with claims of inhibiting the formation of bacterial cell walls, essential for bacterial survival, thus effectively treating bacterial infections.

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Published: 12 Mar 2024, 09:36 PM IST

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