Patritumab

Pictured: Blue and white pills on a metal conveyer belt/iStock, guteksk7 It was a tough week for biopharma companies that rely on contract manufacturing, which is pretty much all the major industry players these days. The FDA on Tuesday again issued a Complete Response Letter (CRL) to AbbVie rejecting ABBV-951, a proposed treatment for motor fluctuations in adults with advanced Parkinson’s disease. Then on Thursday, the agency declined to approve Merck and Daiichi Sankyo’s HER3-targeted antibody-drug conjugate patritumab deruxtecan for lung cancer. In both cases, the FDA cited issues with third-party manufacturers. While some might argue that the rise in outsourcing of manufacturing is helping biopharma companies to focus on their core capabilities, it’s also an Achilles’ heel. Out of a total of 238 CRLs issued between 2017 and 2023, 30% involved quality/manufacturing issues—particularly problems with manufacturing processes, facility inspections, or chemical, manufacturing and controls (CMC). AbbVie and Merck/Daiichi did not provide details about the problems identified by the regulator in their respective CRLs. In its letter, AbbVie said the FDA cited “observations” that were identified during inspection of a third-party manufacturer, but hastened to add that it did not involve ABBV-951. Merck and Daiichi only reported that their CRL “results from findings pertaining to an inspection of a third-party manufacturing facility.” I’m one of those industry observers who believes it is time for the FDA to publicly release CRLs, or at least some kind of summary. It’s critical because biopharma companies are not being transparent. One study concluded: “Press releases are incomplete substitutes for the detailed information contained in Complete Response Letters.” The details of the manufacturing issues aside, just the fact that these CRLs focused on them over any clinical issues is cause for concern. At the same time, the FDA itself has been struggling for years with its inspection program. A December 2023 study in Health Affairs revealed that FDA inspections of drug manufacturing facilities in the U.S. and especially abroad dropped well below pre-pandemic levels between 2020 and 2022 and have not yet bounced back. As the agency begins to pick up the pace of foreign inspections, the import of several drugs from these facilities has been halted, leading to a spike in drug shortages. India-based Intas Pharmaceuticals, for example, has received warning letters from the FDA and is on the agency’s import alert list due to failures to comply with Current Good Manufacturing Practice (CGMP) regulations and poor data integrity. India’s own regulator has also been cracking down on manufacturing problems in the country. Reuters on Thursday reported that more than 36% of the 400 drug manufacturing units inspected since last year in India were ordered to be shut by the country’s drug regulator, after deaths linked to substandard cough syrups prompted an increase in scrutiny. While India is responding on some level, a ProPublica investigation last year of FDA oversight following deaths from bacteria-tainted eyedrops made in an Indian plant showed “the agency’s inspections of overseas drug manufacturers, located mostly in India and China, has dropped precipitously even as the number of manufacturers has remained relatively steady.” Neither AbbVie or Merck/Daiichi gave any indication of whether their CRLs involved foreign third-party manufacturers, but it wouldn’t be a surprise. More than 50% of manufacturers supplying the U.S. market are located overseas—mainly in India and China. With biopharma companies relying on the outsourcing of manufacturing, especially overseas, the FDA must do more to ensure quality controls are being implemented by third-party manufacturers. I’m not alone in this belief. A letter last week to FDA Commissioner Robert Califf from the chairs of the House Energy and Commerce Committee and two subcommittees pressed the agency for more information regarding “large variations” in its foreign drug inspection program. And in February, Mary Denigan-Macauley, the director of healthcare at the Government Accountability Office, testified before a congressional subcommittee that the FDA continues to face “persistent challenges” overseeing foreign drug manufacturing. That same month, the FDA said it planned to increase inspections of Indian manufacturing facilities this year. Whether that is happening remains to be seen. Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

On June 26th, three major events in the pharmaceutical industry caused a profound impact both within and outside the sector. Firstly, the global biopharmaceutical giant Novo Nordisk announced the detailed results of its highly anticipated Phase III CLARION-CKD study for its blockbuster drug Ocedurenone in the treatment of high blood pressure with chronic kidney disease (CKD). Contrary to expectations, the drug failed to meet the primary endpoints in improving renal function and reducing cardiovascular risk. This result not only inflicted a heavy financial burden on Novo Nordisk, as it is expected to incur an impairment loss of approximately 5.7 billion Danish kroner (equivalent to around 5.5 billion CNY or $828 million) in 2024, but also left patients and the entire medical community deeply disappointed.   Ocedurenone, as an innovative drug, embodied the wisdom and efforts of many scientists throughout its development process. However, the path of scientific research is often fraught with twists and turns, and this failure was not an isolated incident. It underscores the complexity and uncertainty inherent in the pharmaceutical research and development (R&D) field. In the medical field, the successful introduction of any new drug or technology requires rigorous clinical trials and scientific validation, which is a testament to the responsibility toward patients and the scientific community.   Simultaneously, the leading mRNA vaccine company Moderna also encountered a significant setback. On June 26th, Moderna announced the latest clinical data for its RSV mRNA vaccine, mRNA-1345, which disappointingly showed a significant drop in efficacy to around 50%, far below previous expectations. This news quickly sparked market concerns, leading to an 11% plunge in Moderna's stock price.   mRNA vaccines have demonstrated immense potential and value during the COVID-19 pandemic as a new vaccine technology. However, the path to success for any technology is not straightforward. Moderna's failed clinical trial for the RSV mRNA vaccine has provided a clearer understanding of the arduous challenges and difficulties in pharmaceutical R&D. Vaccine efficacy is a crucial performance metric, and the decline in the efficacy of mRNA-1345 undoubtedly introduces a high degree of uncertainty regarding its future market promotion and application.   On the same day, the pharmaceutical giants Daiichi Sankyo and Merck also faced setbacks. They jointly announced that due to issues with a third-party manufacturing facility, the FDA was unable to approve the HER3-ADC drug patritumab deruxtecan for market authorization. HER3-ADC, as a novel targeted therapy, was originally expected to make breakthrough progress in cancer treatment. However, the inability to obtain market approval due to manufacturing facility problems has undoubtedly dealt a significant blow to these two pharmaceutical giants.   These three events not only reveal the complexity and uncertainty inherent in the pharmaceutical R&D field but also underscore the fact that the success of any new drug or technology requires rigorous scientific validation and market testing. From Novo Nordisk's Ocedurenone to Moderna's mRNA-1345 and Daiichi Sankyo and Merck's HER3-ADC, these cases illustrate that pharmaceutical R&D is a pursuit that demands patience, perseverance, and continuous experimentation. At the same time, we should cherish those drugs and technologies that have already been successfully launched and are benefiting patients, as they represent the tireless efforts and unwavering dedication of countless scientists and medical professionals.