Susan Haigney

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The European Medicines Agency (EMA) announced on June 14, 2024 that the agency’s Pharmacovigilance Risk Assessment Committee (PRAC) is evaluating potential risks associated with the painkiller metamizole. PRAC is also researching the possible risk of secondary cancers developing in patients who are treated with chimeric antigen receptor (CAR) T-cell medicines.

According to EMA, concerns that measures put in place to minimize the risk of agranulocytosis in the painkiller metamizole might not be adequate. Drugs containing metamizole are authorized in the European Union, varying from country to country, for treating moderate to severe pain and fever. These medicines have a known side effect, agranulocytosis, where a sudden drop in white blood cells occurs. Agranulocytosis is a rare or very rare side effect that may lead to serious, and possibly fatal, infections. There are measures set by EU countries to minimize the risk; however, PRAC is looking into the effectiveness of these measures.

Regarding CAR T-cell medicines, PRAC states that patients receiving these treatments should be monitored for the rest of their lives for secondary cancers. New cancers, different from the original malignancy, may develop after treatment with CAR T-cell medicines.

PRAC came to this conclusion after reviewing data from 38 cases of secondary malignancies of T-cell origin in approximately 42,500 patients. “Tissue samples were tested in half of the cases, revealing the presence of the CAR construct in 7 cases. This suggests that the CAR T-cell medicine was involved in disease development. The secondary malignancies of T-cell origin have been reported within weeks and up to several years following administration of CAR T-cell medicines. Patients treated with these medicines should be monitored life-long for new malignancies,” EMA stated in a press release (1).

Product information, which has advisory information about secondary malignancies, will be updated to include new information about T-cells. PRAC is discussing direct healthcare professional communication about CAR T-cell medicines and will inform professionals about its new conclusion.

There are six approved CAR T-cell treatments in the EU: Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta. They treat a range of blood cancers.

In November 2023, FDA in the United States announced it was investigating the risk of T-cell malignancy following CAR T-cell immunotherapies (2). “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” FDA states on its website. “The initial approvals of these products included postmarketing requirements (PMRs) under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to conduct 15-year long term follow-up observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment.” The agency also said that patients of these treatments should be monitored for life for new malignancies.

EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 10-13 June 2024. Press Release. June 14, 2024.

FDA. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T Cell Immunotherapies. Nov. 28, 2024. 

https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

Articles

PRAC is reviewing the risk of secondary malignancies in patients treated with CAR T-cell medicines. 

EMA Reviews Risks of CAR T-Cell Medicines and Painkillers

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Ascidian Therapeutics, a biotechnology company developing treatments by rewriting RNA, announced on June 18, 2024 that it has signed a licensing agreement with Roche to collaborate on the discovery and development of RNA exon editing therapeutics to treat neurological diseases (1). The collaboration will combine RNA exon editors with Roche’s next-generation central nervous system (CNS) delivery capabilities. Ascidian enables precise post-transcriptional editing of genes by editing exons at the RNA level.

As part of the agreement, Ascidian will receive an initial payment of $42 million with up to $1.8 billion in research, clinical, and commercial milestone payments, including commercial royalties. The partnership will allow Ascidian to create internal and collaborative programs within the neurology area. Roche will receive exclusive, target-specific rights to Ascidian’s RNA exon editing technology and will perform certain preclinical activities. Roche will also be responsible for further clinical development, manufacturing, and commercialization.

“Roche is known and respected worldwide for their expertise in complex neurological diseases, and I am proud of the scientific rigor and quality of the work done at Ascidian that has led to this partnership,” Michael Ehlers, MD, PhD, president and chief executive officer of Ascidian Therapeutics, said in a press release. “The potential of treating disease by large-scale exon editing of RNA is vast. We look forward to working with the Roche team to develop first-in-class RNA exon editing medicines for multiple neurological diseases, with a mission and passion to relieve suffering and improve lives.”

“Our partnership with Ascidian is an opportunity to harness advanced RNA exon editing technology, which has the potential to deliver transformative one-time therapeutics by editing multiple whole exons at the RNA level with a single treatment,” James Sabry, MD, PhD, global head of Pharma Partnering at Roche, said in the release.

In May 2024, Ascidian presented preclinical data that enabled the clearance of an investigational new drug (IND) application through Phase I/II testing for its RNA exon editor, ACDN-01, at the American Society of Gene & Cell Therapy (ASGCT) annual meeting in Baltimore, Md. FDA granted ACDN-01 Rare Pediatric Disease Designation as well as Fast Track Designation.

“ACDN-01 is the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease, and we look forward to sharing the preclinical data that led to its IND clearance, along with the plans for the first-in-human trial,” said Ehlers in a press release (2). “ACDN-01 is designed to overcome challenges that have long kept Stargardt disease out of reach and to provide persistent therapeutic benefit with one dose. Our progress with ACDN-01 speaks to its therapeutic potential in Stargardt disease and the broader promise of our RNA exon editing platform to significantly expand the possibilities of RNA medicines.”

Ascidian Therapeutics. Ascidian Therapeutics Enters Collaboration with Roche for Discovery and Development of RNA Exon Editing Therapeutics Targeting Neurological Diseases. Press Release. June 18, 2024. 

https://ascidian-tx.com/wp-content/uploads/2024/06/Ascidian-Roche-Partnership-Press-Release_06.18.24.pdf

Ascidian Therapeutics. Ascidian Therapeutics to Present Preclinical Data for RNA Exon Editor, ACDN-01, Supporting an Open IND for Phase 1/2 Clinical Testing at ASGCT 2024 Annual Meeting. Press Release. April 25, 2024. 

https://ascidian-tx.com/wp-content/uploads/2024/04/FINAL-ACDN-01-ASGCT-2024-Curtain-Raiser_4.25.24.pdf

The research collaboration and licensing agreement will focus on the discovery and development of RNA exon editing therapeutics.

Roche and Ascidian Therapeutics Collaborate on Treatments for Neurological Diseases

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan

Flexibility in Outsourcing Models

Outsourcing pharmaceutical manufacturing and development processes can provide pharmaceutical companies with financial flexibility, according to Jessica Madigan, director of Business Development, Nucleic Acid Modalities, at BIOVECTRA. The PharmTech Group spoke with Madigan after the BIO International 2024 Convention to learn more about the flexibility outsourcing models can provide.

“At BIOVECTRA, we offer flexible pricing models that can help companies manage cash flow and financial risks,” said Madigan. “[Pharmaceutical companies can reduce] capital investments by leveraging the infrastructure and specialized equipment that is already onboarded at CDMOs [contract development and manufacturing organizations]. This can be especially important for startups and small biotechs. … it allows them to direct the resources to their other business areas, rather than building up infrastructure and investing in specialized equipment.”

Madigan details the five different models her company provides, including a dedicated facility model what includes an entire building or facility reserved for the customer. Fractional ownership of a facilities with other customers is also available. “That way, we can [leverage] essentially a platform manufacturing process or a similar platform manufacturing process across several clients, that offers flexibility of capacity between those different partners, and allows a lower entry into a larger capacity.”

Click on the video above to watch the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

Videos

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan, about the concept of flexibility in outsourcing and the 2024 BIO Convention.

 Flexibility in Outsourcing Models (BIO 2024)

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Syntegon, a processing and packaging company, announced on June 7, 2024 that it is acquiring Telstar, an equipment manufacturer located in Barcelona, Spain. The acquisition will add liquid pharmaceutical processing to Syntegon’s portfolio, including freeze-dryers and loading and unloading systems that will enhance the company’s vial filling and isolator solutions. The expanded portfolio will allow Syntegon to provide seamless line solutions from a single source and offer additional engineers, geographic coverage, proximity, and application expertise.

“Syntegon is world market leader in liquid vial filling. With the acquisition of Telstar, we will enhance our portfolio of innovative technologies and many successful references in the market. Our customers will benefit from even more comprehensive solutions, seamless processes, and lifecycle services,” said Torsten Türling, CEO of the Syntegon Group, in a press release. “At the same time, we can jointly capture growth opportunities and expand our market presence.”

Telstar was founded in 1963 and has been part of the Azbil Corporation since 2013. The company has four production plants located in Spain, China, and the United Kingdom; six technology centers; 10 consultancy and engineering centers; and commercial offices worldwide. Syntegon, headquartered in Germany, has 39 sites in 20 countries with 6300 employees.

“Azbil has been strengthening its product capabilities, particularly in loading systems, and enhancing the overall competitiveness of Telstar since the acquisition in 2013. Now Azbil has decided to transfer Telstar to the company we consider best to further drive Telstar’s business. We are convinced that Syntegon will make the best use of the accumulated technological capabilities and products and will achieve sustainable growth,” said Kiyohiro Yamamoto, president and Group CEO of Azbil, in the release.

“For Telstar, the incorporation into the Syntegon Group represents a great opportunity to ensure stable business development and future growth. We look forward to bringing our knowledge, expertise, and high-value technologies for aseptic manufacturing to the joint portfolio and to becoming part of the Syntegon team, backed by a shared business culture,” said Jordi Puig, CEO of Telstar.

The transaction is subject to approval by regulators. “After leading the Life Science Engineering business division of Azbil during more than 11 years, Telstar also expresses its gratitude to the Japanese Corporation for their support throughout this time, during which Telstar has reached a more solid and stable structure, in addition of reinforcing innovation activity arised from solid synergies experienced in the R&D field,” Telstar stated in a press release (2).

Syntegon also announced on June 10, 2024 that its subsidiary, Pharmatech, is launching a new Modular Bioprocessing Platform (MBP) at the Achema 2024 conference. The MBP is a flexible, fully integrated automated solution that can be configured for a full range of microbial and mammalian cell culture applications.

“Its innovative, modular design allows our customers to profit from shorter lead times and lower costs, without compromising on functionality or the accustomed ‘made in Germany’ quality,” said Christian Lavarreda, global product manager at Pharmatec, in a press release (3). “Biopharmaceutical manufacturers can now turn to Syntegon for seamless, complete solutions along the entire production chain.”

1. Syntegon. Set for Future Growth: Syntegon Announces Acquisition of Testar. Press Release. June 7, 2024.


https://www.syntegon.com/press/set-for-further-growth-syntegon-announces-acquisition-of-telstar


2. Telstar. Telstar Starts a New Stage. Press Release. June 7, 2024.


https://www.telstar.com/en/about-telstar/news-events/news/telstar-starts-a-new-stage/


3. Syntegon. Syntegon Launches Modular Bioprocessing Platform at Achema. Press Release. June 10, 2024. 

https://www.syntegon.com/press/syntegon-launches-modular-bioprocessing-platform-at-achema/

Syntegon will expand its processing and packaging by acquiring the Spanish equipment supplier.

Syntegon Acquires Telstar

On June 10, 2024, FDA’s Center for Drug Evaluation and Research (CDER) announced that it is publishing a notice in the 

 on June 11, 2024 (1) introducing the Emerging Drug Safety Technology Meeting (EDSTM) program. The meetings, which will be administered through CDER’s Emerging Drug Safety Technology Program (EDSTP), will provide those involved in pharmacovigilance activities (e.g., manufacturers, academia, contract research organizations, vendors, software developers) the ability to interact with CDER staff regarding the use of artificial intelligence (AI) in the advancement of pharmacovigilance.

The EDSTM program will facilitate learning and discussion regarding the application of emerging pharmacovigilance technologies and the verification and validation of these models. The EDSTP is a central point of contact for these discussions between industry and FDA that will enable knowledge management and transfer within the agency. EDSTP will also work to understand the scope of the use of AI and other technologies in pharmacovigilance and look for regulatory policies.

“FDA expects increased communication with industry and/or other relevant parties during EDSTMs will accelerate our understanding of how AI-enabled tools are being used for PV, their associated risks and benefits, and barriers to implementation. We encourage interested parties to visit the 

 for more information about the program, including information on eligibility and selection criteria and how to request a meeting,” the agency stated in a press release.

“FDA plans to leverage these learnings to help inform potential regulatory and policy approaches, within the use of emerging technology in PV. The EDSTM program is not an avenue to seek regulatory advice on compliance with pharmacovigilance regulations. Rather, we expect that the information gained during this program will help CDER consider providing regulatory advice on specific technologies to facilitate their adoption when appropriate,” the agency states in the unpublished document (2).

Applicants may request EDSTMs on a rolling basis if they have at least one approved application with CDER, such as a new drug application, abbreviated new drug application, or biologics license application. Other individuals supporting industry pharmacovigilance activities may also request an EDSTM. These EDSTMS will be reviewed quarterly, and CDER will select up to nine participants that meet submission eligibility criteria.

“FDA has a longstanding commitment to ensure medicines marketed in the United States are safe through continued surveillance and research following approval. In the postmarket setting, regulated industry is obligated to review all adverse drug experience information received or otherwise obtained and submit timely reports to FDA,” the agency states in the document (2). “Both industry and regulatory authorities face challenges with timely and efficient collection, processing, and evaluation of single and aggregate patient safety data compounded by ever-increasing case volumes. Advances in emerging technology have the potential to address some of these challenges by creating more efficiencies within a PV system. For example, early adopters of AI are leveraging these emerging technologies to automate fundamental tasks (e.g., adverse event intake, data entry, and processing) with the intention to drive down associated administrative burden and costs. These technologies can also make safety surveillance more efficient and effective by capturing, aggregating, and analyzing larger and more diverse data sets.”

1. FDA. Hearings, Meetings, Proceedings, etc.: Emerging Drug Safety Technology Meetings, Program Announcement. 

https://www.federalregister.gov/public-inspection/2024-12770/hearings-meetings-proceedings-etc-emerging-drug-safety-technology-meetings-program-announcement


2. FDA. Emerging Drug Safety Technology Meetings; Program Announcement. [Docket No. FDA-2024-N-2332]. June 10, 2024. 

https://public-inspection.federalregister.gov/2024-12770.pdf

The new meeting program will create a dialogue around AI and be administered through CDER’s Emerging Drug Safety Technology Program.

CDER Announces Emerging Drug Safety Technology Meeting Program

In early June 2024, FDA and the US Pharmacopeial Convention (USP) both published reports on drug shortages as of the end of 2023. The Center for Drug Evaluation and Research at FDA published its 11th annual report to Congress on drug shortages on June 6, 2024, in which the agency stated it had worked with manufacturers to prevent 236 drug shortages in 2023 (1). According to FDA, drug shortages decreased from 251 in 2011 to 55 in 2023.

“Although the number of new drug shortages has declined since 2011, shortages continue to pose a real challenge to public health, particularly when the shortage involves a critical drug, such as those used to treat cancer, to provide parenteral nutrition, or to address other serious medical conditions,” the agency stated in the Executive Summary of the report.” In the past calendar year, FDA has seen manufacturers in the United States and abroad continue to experience quality issues as well as struggle with capacity constraints. Additionally, as demand increased for numerous drugs over the last several years as a result of the COVID-19 pandemic, the flu season, and the respiratory virus season, FDA has seen further strain on drug availability and the pharmaceutical supply chain.”

The USP report released on June 4, 2024, 

USP Annual Drug Shortages Report: Economic Factors Underpin 2023 Shortages, 

includes drug shortage trends up to the end of 2023 in the US (2). These trends were based on use of USP’s Medicine Supply Man tool, which uses artificial intelligence and predictive analytics to predict supply chain risks. One such trend found by USP is that shortages are lasting more than three years compared to two years in 2020. Shortages are also impacting a variety of therapeutic classes with 53% being new generic sterile injectable drugs. 

According to the USP report, the supply of a medicine is at risk when one or more of the following factors are in play: low prices, complexity of manufacture, geographic concentration, and quality problems. Drugs with lower prices had an increased discontinuation rate of 40% in 2023 for one year. Sterile injectable drugs that were in shortage were almost 8.5 times lower in price than those not in shortage.

Sterile injectables also have a higher manufacturing complexity, making them even more vulnerable to shortages. Antibiotics, which sometimes require separate dedicated facilities, and APIs that require complex chemical synthesis are also at risk.

Limited locations for API and finished dosage production also contribute to shortages according to USP, but it is quality concerns that can plague manufacturers the most. When regulators discover quality problems at facility inspections or a recall must be made, manufacturers must inform regulators of the possibility of a shortage that may result from these quality control actions. “Quality comes at a price,” said Vimala Raghavendran, vice president for Informatics Product Development at USP, in a press release (3). “The economics of generic drugs often leave manufacturers with razor-thin margins, making it challenging to prioritize investment in modern machinery or to elevate standards of quality. Without sufficient profitability, the cycle of innovation and improvement becomes difficult to sustain.”

“As we navigate the complex landscape of drug shortages, it is paramount to shift the market into a stable state,” said Anthony Lakavage, senior vice-president for Global External Affairs at USP. “Economic pressures, especially the very low prices that generics manufacturers recover for many medicines, along with contracts that are frequently broken, have left our generic medicine supply chain fragile. Unexpected shocks can break the system and disrupt the supply of quality medicines. This worrisome trajectory leads to more frequent drug shortages, prolonged scarcity, and more people at risk of not getting the medicines they need, when they need them.”

Report to Congress. Drug Shortages CY 2023

https://www.fda.gov/media/179156/download

 USP Annual Drug Shortages Report: Economic Factors Underpin 2023 Shortages. USP.org

. June 2024.
3. USP. U.S. Drug Shortages Reach Decade-high and Last Longer. Press Release, June 4, 2024. https://www.usp.org/news/us-drug-shortages-reach-decade-high-and-last-longer

USP and FDA publish reports detailing drug shortage numbers and challenges through 2023.