Shimadzu, a laboratory instruments supplier, and University Medical Center Göttingen (UMG), announced a collaboration to develop new clinical laboratory methods. The focus of their research will be on using liquid chromatography-mass-spectrometry (LC-MS) for therapeutic drug monitoring (TDM) analysis. The collaboration is being performed under Shimadzu’s European Innovation Center program, which is designed to enable collaborations where outside experts can work with Shimadzu technologies.

According to a Oct. 27, 2022 press release, TDM tests, which measure the concentration of drugs currently in blood, have usually been done through an immunoassay, but LC-MS methods have recently grown in popularity due to advantages in strength and accuracy. However, complexity of sample preparation has prevented widespread adoption.

The collaboration will focus on developing Shimadzu's CLAM-2030, a fully automated sample preparation module for LC-MS. The device functions by placing blood collection tubes in position, wherein the module automatically performs sample pretreatment steps up to LC/MS/MS analysis. The collaboration aims to develop new methods for multiple target groups of drugs, as well as means of switching between these new methods easily and quickly.

Articles

News

The collaboration will see Shimadzu and UMG develop new clinical laboratory methods using LC-MS for TDM analysis.

Shimadzu and UMG Göttingen Enter Analytics Collaboration

Traditional drug development is costly and time-consuming, with many hours, days, and years spent researching and developing novel chemical entities that, for the most part, will likely fail to get to the commercial finishing line. Repurposing a drug can offer companies an approach to drug development that is much more time- and cost-efficient and offers a higher chance of success. According to research, 30% of repurposed drugs gain approval, which is three times higher than the rate for new drugs (1).

There are three main strategies to repurposing a drug product: determining a novel therapeutic indication for an already known drug (repositioning); developing a new formulation of a drug product (reformulation); and combining two or more drugs that were already being used as single drug products (combination) (2). Despite the various benefits of repurposing existing drug products can offer, each strategy also has certain challenges to overcome that can act as a deterrent to developers.

“Reformulation can be used very effectively to develop improved medicines and treatment options for patients,” confirms Jan Jezek, chief scientific officer of Arecor. “For example, creative formulation can be used to improve the pharmacodynamics and pharmacokinetics of a drug.” Highlighting a specific case of creative formulation, Jezek points to the development of a novel formulation of insulin that has is being developed by Arecor, which accelerates the drug’s absorption post-injection, leading to improved glycemic control.

“Another example benefit of reformulation is to convert a lyophilized powder medicine to stable liquid ready-to-use (RTU) product formats, which are becoming increasingly important to enable fast, safe, and effective treatment of patients,” Jezek continues. “Innovative formulation approaches can also lead to improvement in stability of small- and large-molecule products and enable their use outside the cold chain, which can significantly improve convenience of use.”

Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm, emphasizes that reformulation can be performed for several key reasons. “[Reformulation] can allow developers to improve the performance and patient centricity of an existing drug. For example, it may be done to create a version of an existing drug that is more convenient and easier to use for the patient, increasing quality of life or boosting adherence and, in turn, therapy success,” he says.

Additionally, Jagdish remarks that reformulation can be used to enhance solubility, to improve absorption, or to boost the stability of a drug product formulation. “In all cases, reformulation can save a considerable amount of time and financial resource compared with the discovery and development of an entirely new chemical entity,” he states.

Moreover, it is possible to use reformulation as a way of extending the line of an older drug product, Jagdish points out. “[Reformulation] offers an opportunity to change an excipient or evolve the manufacturing process to deliver marginal gains in performance or ensure compliance with new regulatory requirements,” he says. “Regardless of the reasons for the reformulation, assessment of the regulatory implications of reformulation is essential.”

First and foremost, Jagdish stresses that it is critical for companies to be aware of the regulatory requirements of the target geography of the reformulated drug product. “There is considerable variation in the regimes in each country, so pharmaceutical companies should evaluate their compliance needs on a case-by-case basis,” he says. “For example, the US Food and Drug Administration (FDA) has published its guidance for industry on Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, which can help companies understand the regulatory requirements in the [United States]” (3).

For Jezek, considering the formulation excipients and whether those being used in the reformulated product are indeed approved for the intended use—administration route and desired dosage regimen—is critical. “[Whether or not the excipients are considered novel] impacts the complexity of development as it is necessary to justify the use of the excipients and to demonstrate the safety of the excipients required. Novel excipients will carry a higher regulatory and development burden,” he specifies.

When approaching a reformulation strategy for a drug product, developers should define the target product profile at the outset, Jezek continues. “In other words, the formulation scientist needs to understand the desired stability and other requirements that the products must meet, such as specific impurity levels, to be approved by the regulatory authorities,” he says.

After defining the target product profile, the developer needs to understand the degradation pathways that can potentially impact the stability of the drug product during storage, Jezek adds. Appropriate methods must be established so that any degradation pathways can be measured and understood. “Such methods are often referred to as stability‑indicating methods,” he notes.

“The last challenge, which is most critical for successful reformulation, is to be able to select the right combination of inactive ingredients that will collectively interact with the small- or large-molecule drug in a way that reduces the degradation rate and thus enables the desired product profile,” Jezek confirms.

According to Jagdish, the challenges that pharmaceutical companies need to overcome when approaching a reformulation project depend upon the type of reformulation they are undertaking. “For example, when developing a new formulation of a drug for the same indication, achieving bioequivalence for the new formulation with the existing one poses a significant challenge, because it is no longer a like-for-like comparison,” he asserts.

“Reformulation can also be considered to reduce the size of the dose of a medication, to improve safety profile and patient compliance,” Jagdish continues. “Again, in this case, there is a need to demonstrate that the efficacy of the lower dose is equivalent to that of the already clinically proven and approved higher dose.”

Providing another example, Jagdish points out that when developing a fixed-dose combination therapy from two independently approved drugs, demonstration of the bioequivalence can also be tricky. “Here, in addition to maintaining bioequivalence with the two existing single-dose products, companies have to ensure the compatibility of the two drugs when in the same formulation,” he says.

When reformulating large molecules, Jagdish emphasizes that additional challenges—when compared with those facing small-molecule formulators—need to be addressed. Challenges such as solubility, absorption, and stability, he specifies.

Because large molecules are commonly administered via intravenous injection, it can be desirable and more patient-friendly to reformulate a drug product to be administered in an alternative way. “Often the focus of a change in the route of administration for a biological medicine is to enable a change from a time-intensive intravenous administration to a single subcutaneous injection,” Jezek confirms. “This [change] requires developing a highly concentrated formulation of the product that can be delivered via a small volume in a single injection.”

However, by reducing the volume of injectable product, the viscosity can become problematic. “Challenges that need to be overcome in developing these high concentration formulations is high viscosity (which can make the product too difficult to inject) as well as the propensity of proteins to aggregate (resulting in the formation of particles, which are unacceptable in pharmaceutical compositions),” Jezek explains. “In addition, proteins are subject to chemical degradation such as hydrolytic cleavage or oxidation. Innovative approaches to formulation design are often required to overcome these challenges.”

Yet, there are relatively easier reformulation routes, such as updating the excipients or the manufacturing process to extend the product’s line, Jagdish states. “Reformulation in these cases often simply involve step changes in the production process or the preparation of ingredients to enhance product quality or to improve manufacturing efficiency,” he specifies. “New ingredients are not generally involved, reducing the number of challenges that need to be overcome.”

1. N. Sommerford, “Drug Repurposing Basics,” Blog, IQVIA, May 12, 2022.
2. S. Murteira, et al., 

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Felicity Thomas is the senior editor for 

Features

Companies need to consider and address formulation challenges to employ a successful reformulation strategy.

Considerations for a Successful Reformulation Strategy

The importance of messenger RNA (mRNA)-based vaccines and therapies in global healthcare is growing, spurred on by the success of Moderna’s Spikevax and Pfizer–BioNTech’s Comirnaty COVID-19 vaccines. Such efforts towards precision medicine, however, come with the challenge of increasing complexity (e.g., compared to small-molecule drugs). This complexity demands drug developers and manufacturers use the right analytical tools to fully understand their products.

Nowhere is this complexity more evident than in the lipid nanoparticles (LNPs) used to encapsulate fragile mRNA cargo. Size, composition, aggregation, surface charge, and structure of LNPs can all have significant effects on a therapeutic molecule’s success; and optimizing one property may come at the detriment of another. These interdependent characteristics can impact stability during production, transport, and storage, or affect the delivery and release of the drug product in target tissues.

Unlike small-molecule drugs or protein therapeutics, which are chemically or biologically synthesized, LNPs self-assemble during the mixing of their component ingredients. These components can include cationic lipids, helper lipids such as distearoylphosphatidylcholine (DSPC), sterols such as cholesterol, and polyethylene glycol-containing (i.e., PEGylated) lipids (

). To ensure drug formulators achieve their final product, they must optimize the ratios of these ingredients and perfect the way in which these ingredients are mixed. 

Small batch-to-batch differences in mixing can result in products that have significantly different compositions. Similarly, changes in ingredient flow rates can alter the size of the final product. For example, faster flow rates produce smaller LNPs than slower ones. Throughout process development and optimization, drug manufacturers need to confirm they are producing LNPs consistently and to specification.

Particle size is critical because it has implications for drug function. Particles that are too small may be cleared from the bloodstream by the kidneys before they can take effect, whereas larger or aggregated particles may fail to penetrate cells or could induce unwanted immune responses. Thus, drug developers need to ensure that the LNPs they are producing are the optimal size and that the size distribution (polydispersity) falls within acceptable parameters. Unexpected changes in size or polydispersity could signal problems in manufacturing processes or product degradation.

Another factor crucial to the success of an LNP is stability. Solvents used during production may need to be removed before administering the product to patients. Drug developers, therefore, need to be sure that the product created remains stable in the solvent’s absence. They also need to know that the product holds its structure during transport and storage.

Drug developers must also ensure that LNPs maintain their structure and successfully protect their mRNA cargo until the therapeutic is delivered to the target site in the patient’s body. As such, scientists must analyze LNP performance under conditions that mimic the bloodstream or target tissues as well as inter- and intracellular environments.

The surface charge is another critical factor that dictates how well an LNP functions within the body. For example, while LNPs with a positive charge have been investigated, they can trigger inflammatory responses, inducing problems such as hepatotoxicity (1). Negatively-charged LNPs avoid these toxicity issues; however, this is not the only place where the charge is important. LNPs need to respond to changes in the endosomal pH, often by changing charge, which can influence the endosomal escape of their mRNA payload.

Expanding the use of LNPs from intramuscular injections for vaccines to other applications such as cancer vaccines or gene therapies, in which the LNPs need to enter other cell types, the surface charge can impact the uptake of the LNPs to different cell types (2). Thus, formulators need to monitor surface charge to identify LNPs that can access the target cells. It can also be informative to understand how this surface charge varies across relevant pH ranges.

With such a complex range of attributes to navigate, developers must use complementary analytical technologies to provide a full understanding of LNPs. Fortunately, they don’t need to develop these methods 

. Rather, LNP specialists can tap into the well-established field of lipid-based drug characterization, where proven analytical technologies have long helped ensure product quality and function.

To monitor LNP size and sample polydispersity, LNP specialists can rely on dynamic light scattering (DLS)—whether single-angle or multi-angle (MADLS)—and nanoparticle tracking analysis (NTA). Using these methods, LNPs in suspension scatter laser light as they diffuse through a sample. Changes in the scattering pattern are translated to particle size and size distribution, with larger particles diffusing more slowly than smaller particles.

DLS offers the lowest resolution of particle size determination but gives a good indication of the size of LNPs in a sample. Using back, side, and forward detection angles, MADLS offers a higher resolution than DLS, allowing it to identify additional populations of LNPs that DLS might miss. NTA offers even higher resolution but often requires sample dilution, which can perturb LNP stability. The choice between these complementary techniques depends on factors, such as LNP size and polydispersity, sample heterogeneity, and the questions being asked.

When Pfizer–BioNTech contracted PolymunScientific to scale up the process of producing LNPs for the Comirnaty program, Polymun needed to develop

robust manufacturing processes to support large-scale production (3). Key to this development were analytical methods, including those described in this article, to guide process development and control manufacturing processes. Such efforts allowed the company to confirm batch-to-batch consistency and long-term stability of its liposomal and LNP formulations (

MADLS and NTA also offer the opportunity to determine particle concentration, which provides quick information on process yield and any potential losses from process steps. Recently, researchers applied these methods to liposome samples and showed that the accessible concentration range for MADLS (108 to 1012 particles/mL) overlapped with and extended that for NTA (107 to 109) (

). MADLS offered a similar range when the method was applied to LNPs.

As pH can differ significantly between production and storage conditions as well as physiological environments, it is vital to monitor surface charge throughout the product’s life cycle. Electrophoretic light scattering (ELS) is a powerful tool that can determine the apparent charge of a particle in different conditions; for example, mimicking a pH range from slightly alkaline blood to the acidic endosome. The obtained surface charge measurements allow developers to balance the needs of product development and long-term storage with the requirements for clinical efficacy, optimizing cellular delivery while minimizing toxicity risks.

Production, storage, and application add temperature stresses to LNPs, which can be investigated using DLS thermal ramp experiments or differential scanning calorimetry (DSC). Thermal ramps use DLS to monitor particle stability over a temperature range, while DSC measures heat uptake or release linked to structural transitions or changes in molecular interactions.

Drug developers can use these methods to examine the thermal stability of both the LNP delivery vehicle and its mRNA cargo. Such information is critical during LNP formulation as developers optimize ingredient combinations to improve stability without negatively impacting efficacy. Furthermore, as the DSC thermogram is also a fingerprint of mRNA and LNP’s higher-order structure, companies can use it to inform the selection of mRNA sequence variants during design stages and to compare different formulations and batches of the LNP product. This detailed characterization helps support intellectual property protection.

A method commonly used to monitor particle size and polydispersity is size-exclusion chromatography (SEC) coupled to static light scattering (SLS) or another detection system. But beyond questions of particle size, developers continue to evolve the applications of SEC–SLS to help answer questions about LNP composition, monitoring not only the lipid complexes but also the mRNA cargo. For example, researchers used SEC–SLS to perform compositional analysis of two mRNA–LNPs (4). Monitoring the concentrations of the mRNA and LNPs across the entire particle distribution, the researchers could determine the relative weight fractions of the components—a measure of therapeutic payload. In both mRNA–LNPs tested, the scientists observed variation in mRNA loading across the population.

SEC–SLS offers analytical insights in minutes, accelerating throughput across development and manufacturing. The analysis also eliminates the need for multiple analytical steps and fluorescent reagents and reduces operator impact on measurement consistency. Although still relatively new to LNP manufacture, compositional analysis has proven vital to other medical applications, such as studies of viral vectors in gene therapy, antibody-drug conjugates, and antibody aggregation.

In the complex world of mRNA-based vaccines and therapies, tried and tested analytical technologies, such as DLS/MADLS, NTA, and ELS, are shining a light on the LNPs that help those medicines survive the journey from lab to factory to cellular site-of-action. Researchers are further augmenting those insights by evolving and expanding the applications of DSC and SEC–SLS to build further a more reliable picture of LNP attributes, improving the chances for project success.

Although individual biophysical characterization techniques provide valuable insights into the nature of LNPs, no single technology can provide a complete picture. Instead, orthogonal and complementary approaches are needed to provide a more comprehensive understanding of the critical quality attributes that define product quality, consistency, and, ultimately, efficacy (

This prospect may be daunting if a company is unfamiliar with some of these techniques. The broad expertise of an analytical partner can, therefore, help in the development of the applications needed to achieve a deeper understanding of LNPs.

 31 (26) 6867–6875 (2010).
2. R. Pattipeiluhu, et al., 

 34, 2201095 (2022).
3. Malvern Panalytical, 

Developing an Analytical Workflow for Nanomedicine and 3rd Generation Vaccine Production at Scale

, Whitepaper (2022).
4. N. Markova, et al., 

Hanna Jankevics Jones, PhD, and Natalia Markova, PhD, are pharmaceutical segment marketing managers at Malvern Panalytical.

An orthogonal approach to lipid nanoparticle analysis is recommended to optimize drug development success.

Taking a Closer Look at Lipid Nanoparticle Characterization

Gerresheimer, a provider of drug delivery systems, and Nelson Labs, a provider of microbiological and analytical chemistry testing, announced a strategic partnership on Oct. 31, 2022. Under the partnership, which is designed to reduce risk and time-to-market for primary packaging solutions for injectables, Nelson Labs will conduct extractables and leachables testing, toxicological risk assessments, impurity identifications, and biocompatibility testing of injectable primary container closure systems or components for Gerresheimer.

“With this agreement, [we] will be able to offer an extended service package to our pharmaceutical and biotechnological customers for their new drug development and product life cycle management,” said Jen-Edouard Rabier, director, Business Development, Gx Biological Solutions, Gerresheimer, in a company press release. We are now able to provide our customers the best selection of primary packaging systems (vials, syringes, and cartridges) made of glass or cyclic olefin polymer (COP) without any concerns about compatibility, stability, or safety of the drug product.”

“I am extremely pleased that Gerresheimer and Nelson Labs have taken this very important step forward in joining our forces to provide customers with stellar testing and expert advice in container/closure qualification,” said Piet Christiaens, scientific director, Nelson Labs, in the release. “This partnership is designed to help the pharmaceutical industry take full advantage of our scientific leadership, unique Compounds Screener Database, personalized support, and other resources that will be offered through this alliance.”

Gerresheimer and Nelson Labs will work together to conduct extractables and leachables testing on upcoming primary packaging solutions.

Gerresheimer and Nelson Labs NV Announce E&L Partnership

Lonza and Singzyme, a biotechnology company specializing in developing enzymes for protein ligation, announced a strategic collaboration on Oct. 31, 2022. The goal of this partnership is for the companies to use Singzyme’s enzymatic conjugation platform to develop novel bioconjugates.

The partnership will grant Lonza access to Singzyme’s enzymatic conjugation platform, which is designed to enable the site-specific binding of payloads with peptidic linkers to proteins of interest. In return, Singzyme will gain access to Lonza’s network and expertise in the development and manufacture of bioconjugates.

“Singzyme’s highly-specific conjugation platform represents an attractive addition to Lonza’s Bioconjugation toolbox that includes protein expression, linker and payload manufacturing, manufacturability assessments, de-risking, and bioconjugation,” said Stefan Egli, vice-president and head of Bioconjugates, Lonza, in the release. “Its implementation into our offering will further increase our bioconjugation repertoire and provide reliable and selective conjugation solutions for our customers aiming to develop novel bioconjugates.”

“The collaboration between Lonza and Singzyme will provide Lonza’s customers with access to a one-stop technology platform allowing for rapid site-specific bioconjugation including dual payloads, with fully controllable drug-to-antibody ratio, while preserving antibody activity,” said Abbas El Sahili, chief technology officer, Singzyme, in the release. “We foresee that this collaboration will significantly shorten the [antibody drug conjugate] development timeline and bring a wealth of novel drugs faster to the clinic for the benefit of cancer patients.”

Lonza and Singzyme will use Singzyme’s enzymatic conjugation platform to develop novel bioconjugates.

Lonza and Singzyme Enter Bioconjugates Partnership

CSafe, a US-based provider of active and passive temperature-controlled shipping solutions, and BioLife Solutions, a US-based supplier of bioproduction tools and services for the cell and gene therapy (CGT) and broader biopharma markets, have formed a new partnership to provide a combined global service network to support CGT products. The partnership will focus on enhanced reliability, security, and quality, according to an Oct. 11, 2022 company press release.

BioLife expects to support 10,000–12,000 shipments of CGT starting materials and manufactured doses over the next 12 months using its evo cold chain management platform. The new partnership with CSafe will provide BioLife with expanded supply chain options for any CGT product at any stage of development, from early clinical-phase trials to global commercial scale. CSafe operates more than 50 service centers worldwide.

“CSafe is honored to partner with the team at BioLife Solutions, whose range of CGT bioproduction tools and services is peerless in the market. We are excited to merge these exceptional tools and services with our expertise in global, reliable scaled delivery,” said CSafe CEO Patrick Schafer in the press release. “CGT is hitting its stride and needs global support. We know how important these therapies are to patients everywhere, and it’s our mission at CSafe to protect every shipment.”

“We’re excited to work with a global partner with a strong history of reliability and performance and a deep dedication to innovative therapies,” said BioLife Solutions CEO Mike Rice in the release. “We have the best LN2 [liquid nitrogen] technology and [C]GMP [current good manufacturing practice] storage facilities in the market, in addition to our other world-class CGT solutions, and we are confident our collaboration with CSafe will extend our reach and result in even more reliability and real-time service for CGT partners.”

The newly formed partnership between CSafe and BioLife will expand cold chain supply chain solutions for the cell and gene therapy market.

CSafe and BioLife Solutions Partnership Will Expand Supply Chain for Cell and Gene Therapies

Gilead Sciences and MarcoGenics, a biopharmaceutical company focused on monoclonal antibody therapies, announced an exclusive option and collaboration agreement on Oct. 17, 2022. Gilead will pay $60 million upfront for the option to license MGD023, an investigational bispecific antibody, as well as two additional bispecific research programs. MacroGenics will be eligible for up to $1.7 billion in target nomination and option fees as well as development, regulatory and commercial milestones; should it reach commercialization, the company will also be entitled to various tiered royalties.

According to Gilead’s press release, MGD024 is currently being investigated as a potential treatment for certain blood cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The antibody was formed using MacroGenics DART platform to bind interleukin 3 receptor α and cluster of differentiation 2 (CD2). It also incorporates a cluster of differentiation 3 (CD3) components that are designed to minimize cytokine-release syndrome (CRS), a potentially life-threatening toxicity, while also increasing the magnitude of antitumor activity with a longer half-life to enable intermittent dosing.

Per the terms of the agreement, MacroGenics is responsible for the ongoing Phase I study for the MGD023. The study includes a dose escalation segment and an expansion segment intended to evaluate it as a monotherapy and in combination with various other therapies. Gilead may elect to exercise its licensing option at predefined decision points.

“MacroGenics’ bispecific expertise naturally complements Gilead’s portfolio strengths in immuno-oncology and our growing hematology franchise,” said Bill Grossman, senior VP, oncology clinical development, Gilead Sciences, in the release. “We believe MGD024, with its potential to reduce CRS and permit intermittent dosing through a longer half-life, could translate to more patient-friendly dosing and enhanced clinical outcomes for people living with AML and MDS. This partnership is the latest in our efforts to develop and advance transformative new cancer therapies as we deepen our portfolio across oncology indications.”

“Rapid advances over the last decade have made CD123 a very promising target in oncology research,” said Scott Koenig, president and CEO of MacroGenics, in the release. “Advancing our bispecific DART molecule, MGD024, through a strategic collaboration with the team at Gilead will accelerate our ability to drive further development of MGD024 to the potential benefit of people living with blood cancers.”

Gilead and MacroGenics will work together on bispecific antibodies for the treatment of blood cancers.

Gilead and MacroGenics Enter $1.7 Billion Oncology Collaboration

Moderna announced on Oct. 12, 2022 that Merck, known as MSD outside the United States and Canada, had exercised its $250 million option to jointly develop and commercialize a personalized cancer vaccine (PCV), mRNA-4157/V940. The vaccine is currently being evaluated in a Phase II clinical trial in combination with pembrolizumab, Merck’s anti-programmed cell death protein 1 (PD-1), as an adjuvant treatment for patients with high-risk melanoma.

Under the agreement, originally established in 2016 and amended in 2018, the companies will collaborate on development and commercialization of Moderna’s PCVs, including mRNA-4157/V940. According to a company press release, costs and profits will be shared equally between the two companies.

"We have been collaborating with Merck on PCVs since 2016, and together we have made significant progress in advancing mRNA-4157 as an investigational personalized cancer treatment used in combination with [pembrolizumab]," said Stephen Hoge, President, Moderna, in the release. "With data expected this quarter on PCV, we continue to be excited about the future and the impact mRNA [messenger RNA] can have as a new treatment paradigm in the management of cancer. Continuing our strategic alliance with Merck is an important milestone as we continue to grow our mRNA platform with promising clinical programs in multiple therapeutic areas."

"This long-term collaboration combining Merck's expertise in immuno-oncology with Moderna's pioneering mRNA technology has yielded a novel tailored vaccine approach," said Eliav Barr, senior vice-president and head of global clinical development, chief medical officer, Merck Research Laboratories, in the release. "We look forward to working with our colleagues at Moderna to advance mRNA-4157/V940 in combination with [pembrolizumab] as it aligns with our strategy to impact early stage disease."

Merck has exercised a $250 million option with Moderna to jointly develop and commercialize cancer vaccine mRNA-4157/V940.

Merck and Moderna Enter $250 Million Cancer Vaccine Partnership

Alexion, a group within AstraZeneca focused on rare diseases, recently announced a definitive agreement to acquire LogicBio Therapeutics, a genomic medicines company. The deal, which is expected to close in November 2022, will see Alexion purchase all outstanding shares of LogicBio for $2.07 per share; a total sum was not disclosed.

According to a press release from Oct. 3, 2022, the intent of the acquisition is to grow Alexion’s genomic medicines through LogicBio’s technology as well as that company’s experienced rare disease R&D team and expertise in preclinical development. LogicBio has developed various technology platforms for the delivery and insertion of genes to address genetic diseases. The company has also designed a platform to improve the viral vector manufacturing process.

"The proposed acquisition of LogicBio is a significant development for our growing research in genomic medicine,” said Marc Dunoyer, CEO, Alexion, in the release. “LogicBio’s people, experience, and platforms provide new scientific capabilities by adding best-in-class technology and expertise to our genomic medicine strategy. The scientific collaboration between Alexion and AstraZeneca has been a substantial area of focus since last year’s acquisition and the addition of LogicBio will expand this foundational work.”

“We are excited about the opportunity to bring our science and expertise in genetic medicine to Alexion, which shares our commitment to discovering treatments for rare conditions and improving the lives of patients,” said Fred Chereau, president and CEO, LogicBio, in the release. Through this acquisition, we strive to accelerate our research in gene editing and AAV capsid development and together move the field of genomic medicine forward.”

Alexion’s acquisition of LogicBio is designed to accelerate the company’s growth in genomic medicines.

Alexion, AstraZeneca Acquire Genomic Medicines Company

FDA’s Center for Biologics Evaluation and Research (CBER) is updating how it manages a growing volume of cellular and gene therapy development programs, seeking added resources and revisions in its oversight of these cutting-edge therapies. Most visible in the elevation of CBER’s Office of Tissues and Advanced Therapies (OTAT) into a new “super” Office of Therapeutic Products (OTP). The change aims to improve functional alignment, increase review capabilities, and add expertise on new cell and gene therapies by establishing multiple branches and divisions in the expanded regulatory unit, as announced in the 

Stated goals are to help CBER address the “substantial growth in innovative, novel products” that present new “scientific, medical and regulatory challenges that require changes to its structure,” including strategies to advance the Regenerative Medicine Advanced Therapy (RMAT) program. The added resources are needed to oversee more than 2000 development programs involving cellular and gene therapies, many involving innovative testing and manufacturing processes. This soaring workload has over-taxed CBER staffers, resulting in serious difficulties in retaining and hiring capable scientists.

The structural changes at CBER reflect agreed-on plans to hire new staffers with funding from recently reauthorized user fee programs. The PDUFA VII commitment letter calls for an additional 132 new hires for CBER in this coming year and another 48 employees the following year, most to support cell and gene therapy reviews at OTP. The reorganization plan calls for OTP to have seven offices—for therapeutic products, clinical evaluation, review management, pharmacology/toxicology, and two for CMC—for gene therapy and for cellular therapy and human tissues. There will be 14 divisions and 32 branches within those offices, providing attractive supervisory opportunities for both new and experienced staffers.

These changes come in the wake of FDA approval of two new gene therapies that have drawn wide attention for both their therapeutic potential and for million-dollar price tags. Bluebird bio’s Zynteglo was approved by FDA in August for patients with beta thalassemia, an inherited blood disorder causing serious anemia. That was followed a few weeks later with approval of Bluebird’s Skysona to treat a rare neurological disorder afflicting young boys. Zynteglo carries a $2.8 million price tag, Skysona’s list price is $4 million, but both therapies are expected to target fewer than 1500 patients, limiting the overall cost impact for the US healthcare system. A greater spending effect would come from FDA approval of a new treatment for sickle cell disease from Vertex Pharmaceuticals and CRISPR Therapeutics, which plan to begin a rolling review by FDA in the coming months. The important potential benefits of these treatments, along with concerns about their impact on healthcare spending and access, speaks to the need for a highly capable and sufficiently resourced FDA oversight program.

These developments also highlight the importance of sound testing and production methods for therapies made from living organisms, which are inherently variable and difficult to control and measure to assure product safety, identify, quality, purity, and strength. The surge in applications from a broad range of firms, moreover, has made it difficult for CBER staffers to schedule formal meetings with each sponsor seeking advice on how best to perform manufacturing and testing processes. And publishing new guidance on these changing and emerging issues also takes time and resources.

In response, FDA looks to engage a broad range of sponsors on topics related to product development through a series of virtual town hall meetings. The first was 

 and addressed how manufacturers should describe and inform FDA about chemistry, manufacturing, and controls (CMC) in applications for gene therapies. Wilson Bryan, OTAT (now OTP) director, opened the session by describing plans for establishing OTP as a super office to increase review capabilities and enhance expertise on gene and cellular therapies and set the stage for OTP branch chiefs to field a broad range of queries, ranging from basic CMC policies for various stages of development, to the scope of potency assays and impact of delivery devices on dose potency and quality [a recording of the town hall meeting is available at the FDA events link]. 

Main topics were comparability testing, assays for product characterization, and process controls. OTP staffers emphasized the importance of determining process requirements early in development to avoid late changes and analytical method variability that could raise uncertainties likely to delay clinical trials. Products with complex mechanisms of action, they advised, stand to benefit from early product characterization and potency assay development. And developers of gene therapies should use multiple production lots during a clinical study to ensure product consistency and quality, even for treatments for very small patient populations.

Manufacturers raised questions about differing CMC issues between early Phase I and late-stage clinical trials and voiced concerns about product characterization related to autologous cell-based gene therapies. A main theme from FDA was the importance of sponsors establishing a well-controlled manufacturing process and qualified analytical testing well before administering any new gene product. While CBER plans to issue guidance on manufacturing changes and comparability for cellular and gene therapy products, the information provided at this session provides unofficial guidance for implementing changes in product manufacturing and the scope of comparability assessments and development studies expected to support such changes.

CBER maps modernization plan to handle surge in research and applications. 

BioPharm International's BP Elements, November 2022