In the biomedical and pharmaceutical industries, speed to market of safe and effective new therapies is everything—both for patients who need them and for the life sciences companies that develop them. As companies look to accelerate R&D, there has been an increasing focus on clinical development, where the availability of efficiency-enabling technology is currently outpacing workforce enablement.

Biostatistics leaders, in particular, are aiming to modernize the skillset of their current statistical programming organizations. The prevailing approach has been to get established Statistical Analysis System (SAS) programmers proficient in R and eventually in Python, two open-source programming languages that are constantly evolving due to thriving communities of active contributors who are continually expanding the languages’ toolsets.

However, having all SAS programmers proficient in R or Python may not be necessary to take advantage of all the functionality that these languages offer. Novel, flexible statistical computing environments (SCEs) can solve the unique challenges that biostatistics leaders face in enabling diverse teams to effectively collaborate and accelerate study submissions.

A rift appears in the biostatistics workforce

Although FDA has long held to the principle of language independence, SAS has until recently been the predominant statistical computing language used for study submissions. This is because both the expertise and infrastructure within the industry have long been SAS-based.

However, SAS is a closed-source language, it is not extensible, and it requires licensing. Because of the availability and extensibility of open-source alternatives, such as R and Python, the speed at which these latter two languages have evolved to meet the statistical and data science needs of the user community has far outpaced SAS in recent years.

New talent entering the field of biometrics has a clear preference for using R and Python over SAS, leaving pharmaceutical organizations with an interoperability challenge. Consequently, a schism is widening between more experienced biostatisticians, who tend to prefer SAS, and those who are entering or have just recently entered the field, who are more likely to be proficient in R or Python.

This fluency gap has placed an added burden on the emerging workforce to develop SAS proficiency in addition to business domain expertise—an expensive and time-intensive operation for both workers and their employers. It also puts stress on experienced statistical programmers, forcing them to choose between relying on the SAS expertise they have spent years developing or moving to a new language they are not comfortable with, all while remaining productive and efficient in their jobs. For biostatistics organizations, the challenge is acute as the need for statistical programmers is greater than the number of jobseekers, contributing to resource shortages and delays.

All of this is unfolding at a pivotal moment in the broader evolution of technology. Recent advances such as rapidly expanding graphic processing unit compute power, the emergence of generative artificial intelligence, and increased efficiency of solid-state data storage are poised to radically transform all aspects of R&D.

A different approach to enabling the biostatistics workforce

Biostatistics leaders understand that opportunities exist to maximize the impact of available data. However, the challenge lies in enabling statistical programming teams to collaborate on studies as effectively as possible with minimal disruption, particularly when something as fundamental as the SAS and R/Python proficiency schism is so pronounced.

Biostatistics leaders have been thinking that the first step in this process is unifying the skillsets of their teams. However, this isn’t necessarily a prerequisite to be able to take advantage of today’s available open-source technologies. Instead, biostatistics organizations can adopt readily available SCE systems that enable all team members, regardless of their programming language expertise, to collaborate on studies and individually upskill with minimal disruption. Neither group needs to focus precious time and effort solely on learning a new language that can realistically require an entire career to master.

These new SCE systems allow tremendous flexibility in how individuals can contribute to team efforts:

Good Practice (GxP) and non-GxP work can be performed on the same platform without compromising on flexibility or compliance.

Each team member can use their language and integrated development environment software of choice to analyze data and create outputs within one organized project.

Each team member has the flexibility to choose the right tool for each individual deliverable.

The platform provides automatic versioning, traceability, and reproducibility of results.

Organized batches of SAS, R, and Python jobs can be executed from one command.

Organizations can leverage data for multiple purposes without having to make copies from one system to another.

In the author’s experience, the availability of these systems is most welcome news for biostatistics leaders struggling to build out and enable biostatistics teams that can accelerate R&D. There is a pool of candidates out there who have statistical programming expertise, but not in SAS: however, that is okay. When facilitated by the right technical infrastructure, these candidates can contribute meaningfully to the work at hand without needing as much additional training. Meanwhile, experienced SAS programmers don’t need to divert their effort and focus away from current deliverables to learn new languages. Biostatistics leaders finally have an easy solution to the challenge of the talent gap.

When the most important choice to make is the choice to empower team members to do their innovative work in the way they want to, biostatistics leaders will not only solve their workforce enablement challenges, but also enable their teams to move at the speed that their business and the life sciences industry require.

Caroline Phares is Global Head of Health and Life Sciences at Domino Data Lab.

Articles

Features

Interoperability difficulties resulting from discrepancies in preferred programming languages can be resolved via statistical computing environments.

Exploring the Skills Gap in Statistical Programming Organizations

Drug development is a risky business. For a drug entering Phase I clinical trials, there is an estimated 10% probability of eventual FDA approval (1). At each milestone, the financial stakes increase for the next development phase: average costs are $30 million in Phase I, $70 million in Phase II, and $310 million in Phase III (2). These increasing stakes demand robust, strategic scientific and regulatory support for each transition.

Even big pharmaceutical companies (collectively, Big Pharma) have challenges in managing the end-to-end development process of new molecular entities (NMEs). For example, in 2016, Pfizer’s cumulative probability of success from start of Phase I (first-in-human [FIH] study) through approval was 4%, versus 8% for the entire industry (2). By 2020, Pfizer had revived their R&D pipeline (2) to achieve greater end-to-end success in the clinic, achieving a cumulative success of 21%, versus 11% for the industry (2). Pfizer has attributed their improvement in success rate to their increased early investments in understanding the biology of the target disease and the pharmacology of an NME, including exposure at the site of action, binding to the pharmacological target, and expression of pharmacological activity. Having a portfolio of NMEs enabled Pfizer to use this enhanced understanding to weed out failures early and take calculated risks to accelerate “winners” (2,3). Eli Lilly and Company (Lilly) (4,5) and AstraZeneca (6) have employed similar “truth-seeking” early development strategies that prune portfolios early of NMEs that are likely to fail during Phase II due to lack of efficacy. Lilly claims similar success for its autonomous Chorus early-stage drug development unit (4,5). AstraZeneca has published their framework of determinants for project success and for effective decision-making: right target, right patient, right tissue, right commercial potential, and right culture (6).

In contrast, the business model for most small pharma—include emerging, virtual, and small biotechnology companies—is different than those of Big Pharma and frequently anticipate investment tranches upon achievement of certain developmental milestones, such as opening an investigational new drug (IND) application, initiation of the FIH study, or the completion of a Phase II proof-of-concept (POC) study. Frequently, the achievement of the next value inflection point for development milestones results in activity for executing a strategic plan to attempt to sell and/or license the asset, make a public offering, or take on a partnership arrangement that can enable product commercialization. Reaching these milestones for the one (or few) small pharma-owned assets is sometimes at odds with the type of “truth-seeking” early development strategies that have allowed Big Pharma’s improved odds of success at the portfolio level.

This paper describes an intelligent drug development paradigm that enables small pharma to implement a truth-seeking early development approach such as those used by progressive Big Pharma companies, aimed at efficiently maximizing the value of information needed to inform key milestone decision points and optimize the probability of success.

All pharma developers face challenges in early clinical development (Phase I and Phase II) associated with drug substance manufacture, drug product formulation and manufacture, and anticipating the doses needed for clinical trials. These challenges arise from a lack of communication of and adherence to a common overall drug development strategy, generally as defined in the clinical development plan (CDP) to address the target product profile (TPP) across the siloed disciplines.

Historically, Big Pharma companies established standard operating procedures and ways of working within and across siloed disciplines, approaching drug development largely sequentially, handing an NME off from one siloed discipline to the next, with collaboration occurring at the end of each task. Big Pharma companies run programs in-house, and/or contract with contract development and manufacturing organizations (CDMOs) and clinical research organizations (CROs) for development services, and they have in-house teams with diverse expertise who build a robust early development strategy to accelerate entry into the clinic and keep the development program on track (4).

In contrast, today’s small pharma companies often have deep expertise in narrow areas, but they may lack internal expertise, infrastructure, and operating procedures to conduct many core drug development activities in-house, necessitating engagement of external vendors such as CDMOs, CROs, and consultants (7). This multi-vendor outsourcing approach often leads to fragmented operational challenges, loss of continuity, and failure to maximize information at each stage of development. In most cases in small pharma, the CDMO vendor is not responsible for creating the overall development strategy. Small pharma sponsors are often ill-equipped to define this strategy and yet are responsible for choosing the strengths/doses to manufacture, bearing the risk if development fails due to improper dose or formulation selection.

Further complicating this stage of development, the manufacturing of drug substance and drug product often occur in separate locations and on highly variable timelines. Drug substance and drug product manufacturing vendors have no incentive to align their schedules, leading to schedule adjustment at the Phase I clinic if drug product delivery is delayed.

With far fewer resources than Big Pharma, small pharma sponsors often feel pressure to minimize expenditures by limiting the scope of chemistry, manufacturing, and controls (CMC), nonclinical, and activities preparatory to start of an FIH or other Phase I study until the next investment tranche. Speed-to-clinic feels critical because a small pharma sponsor’s next round of funding may be tied to an upcoming development milestone, such as enrollment of the first subject in an FIH trial. The primary objectives of FIH clinical studies are to assess the safety, tolerability, and pharmacokinetic (PK) behavior of a compound, but due to financial and time pressures, sponsors may delay some critical tests until later POC studies. This rush through Phase I is often at the expense of gathering critical data that would lead to stronger Phase II trials with better chance of achieving POC and a higher probability of eventual marketing approval.

More than a decade ago, CDMOs aimed to address these inefficiencies by creating end-to-end service networks, promising efficiency to deliver cost and time savings to sponsors (8). These networks delivered compressed timelines but brought on new challenges because sites within the network communicated and collaborated poorly. Today’s CDMO networks typically market the speed of their integrated offerings to deliver drug product to the clinic but fail to address the core challenge of choosing which doses or formulations the sponsor should manufacture.

A few CMDOs have also combined manufacturing to provide small-scale good manufacturing practice (GMP) batches of drug product (9) with clinical trial services to eliminate some time gaps between findings in the clinic and adjustment of dose at the manufacturing and drug product finishing sites. This “mini-GMP” setting enables iterative manufacture and clinical testing that is faster than the traditional GMP “make and ship-to-clinic” approach and may yield a more optimized formulation.

The intelligent drug development paradigm for small pharma

Small pharma sponsors frequently hire one or more independent consultants across a variety of disciplines to coordinate the early interactive phase between manufacturing and early clinical development. Such consultants play a vital role by providing nonclinical, manufacturing, regulatory, clinical, and technical support, often acting as liaisons between sponsors and vendors. However, when consultants operate from within their individual areas of expertise strategic value can be lost, mirroring the siloed model of Big Pharma approaches that increases development risk. In addition, the task of managing multiple independent consultants across disciplines is often challenging for a small pharma sponsor.

Instead of that fragmented approach, many of the challenges of typical small pharma development can be addressed by an intelligent drug development paradigm that is functionally integrated, dynamic, parallel, and iterative. Such a paradigm is like the paradigm followed by progressive Big Pharma companies such as Pfizer (2,3), Eli Lilly (4,5), and AstraZeneca (6).

A resource-constrained small pharma stands to derive great benefit through contracting with an integrated strategic team comprised of scientific experts across core disciplines, including clinical science, regulatory, CMC, biopharmaceutics, pharmacology, and toxicology, and operating under a unified goal with the sponsor to get an asset into the clinic, successfully through Phase I and beyond. This core team serves as thought partners with the sponsor’s internal experts on scientific and regulatory matters in an on-demand manner. The strategic team works with the sponsor to define the near- to long-term objectives, and then builds a strategic clinical plan to strengthen the information available to inform key milestone development decisions. In this intelligent drug development approach, the joint sponsor/vendor strategic team’s development plan covers scenarios and contingencies that make it possible to adjust strategies and tactics based on emerging data in CMC, non-clinical, and clinical spaces. With a comprehensive and adaptive clinical plan supported by evolving, phase-appropriate CMC resources, the development program runs more efficiently and on a more predictable timeline. The evolving CMC needs are supported in parallel by one or more vendors that are qualified and directed by the strategic team. This new service model is designed with small pharma companies in mind, getting faster and more intelligently into POC clinical trials with robust data support at each milestone transition. 

illustrates how the same level of expertise possessed by a Big Pharma entity could be deployed for resource-constrained sponsors, with examples shown for two consecutive phases of development: the first for progressing a compound from discovery into clinical development and the second for transitioning from Phase I into Phase II POC studies. 

In the intelligent drug development paradigm, the focus of Phases I and II is to achieve POC as efficiently as possible, completing all learning required to plan an efficient and complete Phase III program. Efficiency may mean parallel development of validated outcome and biomarker assessments while Phase I studies are in progress (or even before), so that they can be incorporated into Phase II studies. Efficiency may sometimes mean careful analysis of Phase I results to confirm a decision to advance the drug candidate to Phase II or Phase III.

The technical and financial failure risks of drug development add significant pressure to small, rapidly developing sponsors, making the POC a critical milestone in their business models. In many cases, partnering or selling the asset after POC is critical to carrying an asset toward commercialization. To realize these ends, small pharma sponsors need reliable and efficient execution of POC trials with deliberate speed to develop a robust data package that makes the asset attractive to potential buyers or partners. In this new intelligent clinical development paradigm, the strategic team also oversees the development of the due diligence data package, ensuring it includes all relevant efficacy, safety, and CMC data.

Around 2005, Lilly established Chorus, a small, operationally independent clinical development organization within the company that has specialized in drug development from candidate selection to POC (5). “The mission of Chorus is to achieve [POC] rapidly and at a low cost while positioning successful projects for ‘pharma-quality’ late-stage development. Chorus uses a small internal staff of experienced drug developers and a network of external vendors to design and implement CMC processes, preclinical toxicology and biology, and Phase I/II clinical trials” (5). “Since it was established, Chorus has demonstrated substantial productivity improvements in both time and cost compared to traditional pharmaceutical research and development” (5).

The intelligent drug development paradigm provides small pharma with access to an aligned and integrated multi-disciplinary team that builds and drives a strategic plan as seen in leading Big Pharma drug development. Aligned with a sponsor’s clinical and business objectives, the strategic team ensures maximum flexibility, coordination, and speed for efficiently executed Phase I and II studies, supported by robust preparatory nonclinical and CMC work. The team coordinates partners from the fragmented vendor space and directs activities to enhance the scientific knowledge by maximizing interaction and rapid iterative cycling across disciplines, more efficiently using resources. The resulting robust and more complete datasets across disciplines facilitate better go/no-go decisions at development milestones that are value inflection points.

1. Takebe, T.; Imai, R.; Ono. S. The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development. 

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2. Fernando, K.; Menon, S.; Jansen, K.; et al. Achieving End-to-End Success in the Clinic: Pfizer’s Learnings on R&D Productivity. 

 (3), 697–704. DOI: 10.1016/j.drudis.2021.12.0101/cts.12577
3. Wu, S. S.; Fernando, K.; Allerton, C.; et al. Reviving an R&D Pipeline: A Step Change in the Phase II Success Rate. 

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4. Bonabeau, E.; Bodick, N.; Armstrong, R. W. A More Rational Approach to New-Product Development. 

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8. DiMasi, J. A.; Smith, Z.; Getz, K. A. Assessing the Financial Benefits of Faster Development Times: The Case of Single-Source Versus Multi-Vendor Outsourced Biopharmaceutical Manufacturing. 

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9. DiMasi, J. A.; Wilkinson, M. The Financial Benefits of Faster Development Times: Integrated Formulation Development, Real-Time Manufacturing, and Clinical Testing. 

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Kevin M. Kane, PhD, is CMC strategy director; Eugene J. McNally, PhD, is vice-president, early engagement and regulatory strategy; Jeff L. Garwin, PhD, MD, is associate clinical science director; and Debra A. Schaumberg is vice-president and global head; all at Strategic Development Consulting, PPD, part of Thermo Fisher Scientific.

An intelligent drug development paradigm can enable small pharma to implement an effective early drug development approach.

Exploring an Intelligent Drug Development Paradigm

Manufacture of medicines is most often required to be performed in a sterile environment to ensure the quality and safety of these products. Microorganisms lurking in the air or on surfaces may degrade APIs and impact their effectiveness, according to Anne-Grit Klees, PhD, BioMonitoring Portfolio Manager for The Life Science business of Merck KGaA, Darmstadt, Germany. “Furthermore, pathogenic and even many non-pathogenic microorganisms can cause serious and life-threatening infections in patients, especially if immunodeficient. For this reason, particularly injectable drugs must be sterile. This can be achieved by final sterilization of the drug or, if not possible, by aseptic manufacturing.”

It is recommended by regulators that microbial monitoring of cleanrooms and isolators is performed by a combination of methods, says Klees. “Air monitoring is performed with a combination of volumetric microbial air samplers (active air monitoring) and settle plates (continuous passive air monitoring). Surfaces and personnel should be monitored with contact plates or swabs. Using alternative methods is also permissible if these have been validated and show comparable or superior efficacies.”

® spoke with Anne-Grit Klees to find out some environmental monitoring (EM) best practices manufacturers can follow to ensure the safety of their products.

What are the differences between environmental monitoring in aseptic versus non-aseptic manufacturing?

Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany):

 The environmental monitoring methods are usually the same for both. The higher the cleanroom grade, the higher the monitoring frequency and number of sample locations. The monitoring equipment and culture media should possess features to match the cleanroom-grade requirements. For air samplers, features such as cleanability, resistance towards disinfectants, emission of particles, and disturbance of the unidirectional air flow are important to consider and should match the cleanroom concept. For culture media, there is a choice between single bagged ones for lower risk areas and irradiated, double, or triple bagged ones for the different manufacturing lines.

 What are some best practices for air monitoring?

Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): 

When selecting an air sampler, important features to consider are sampling volume accuracy, a good efficiency of the method to collect small particles, and whether damage to microorganisms is avoided during the sampling process. The recovery efficiency should be validated by the supplier according to ISO [International Organization for Standardization] 14698. What also matters is ease-of-use to minimize the risk of human errors, low particle emissions to prevent contamination of the cleanroom, good cleanability, and minimal disturbances of the unidirectional air flow. If the air sampler can be integrated into external tracking software systems, all data can be handled. This helps to observe trends.

What are some best practices for surface monitoring?

Surface monitoring is usually performed either with contact plates or swabs, depending on the accessibility of the sample location. Culture medium selection should be based on the ability over the complete shelf-life to detect a broad range of microorganisms. Furthermore, the media formulation should ensure that any potential growth-inhibiting substances such as disinfectant residues or antibiotics are inactivated. To maintain the cleanliness of the sampled surface any culture media residues should be removed after sampling.

 What are some best practices for personnel monitoring?

Personnel monitoring is always performed on the gloves, but also on gowning. The growth promotion properties of the selected media must [often] allow in-house skin flora of the personnel to grow. It is important that contact plate samples are taken of the personnel’s gowning or gloves before leaving the cleanroom. If glove tests are performed after critical interventions, the outer gloves should be replaced before continuing manual work.

 What are the latest advancements in processes and workflows for environmental monitoring?

 These are stated in the current 2022 version of the EU [European Union] CGMP [current good manufacturing practice] Annex 1. While the well-established volumetric air samplers, settle plates, contact plates, and swabs are still recommended to be used frequently, a new focus is on the importance of a contamination control strategy of the pharmaceutical company. This should include a risk-based sample plan that states the frequency and sample locations for those methods. There are additions about using validated rapid or automated technologies, also for continuous volumetric air sampling. These need to be equal to or superior to the above-described methods.

What are some of the best tools for performing environmental monitoring of cleanrooms?

Some portable microbial air samplers (e.g., the MAS-100 NT) offer high accuracy and excellent sampling efficiency. It is small enough to sample close to critical sample locations, can take up to 30 samples in one cleanroom, is easy to disinfect and available with an exhaust filter. It minimizes disturbance of the unidirectional air flow and is compatible with several EM software systems. Triple-bagged and gamma-irradiated ICR or ICR+ culture media for grade A and B cleanrooms reduce the contamination risk because outer bags can be removed in the material lock. Plate versions with locks allow safe transportation for incubation after sampling.

 What are some of the best tools for performing environmental monitoring of a restricted-access barrier system (RABS)?

In a RABS the same environmental monitoring tools can be used as in a cleanroom. However, if a RABS system is decontaminated with vaporized hydrogen peroxide (VHP), it must be ensured that the culture media within the RABS during decontamination are protected by VHP-impermeable bags. These can be hung up during decontamination. To prevent false negative results, all ICR settle plates, contact plates and ICR swabs are formulated to neutralize VHP residues. The MAS-100 NT can also withstand VHP decontamination if in switched-off mode. Alternatively, MAS-100 air samplers specially designed for isolators can be used.

 What are some of the best tools for performing environmental monitoring of isolators?

 In isolators, space is limited, so the control unit of the dedicated air samplers (e.g., MAS-100 Iso line) for isolators are positioned on the outside, saving space inside. The distance can be up to 10 m. A double-valve system prevents cross-contamination and the air tubing can be decontaminated with VHP (e.g., with the MAS-100 Iso MH, one control unit can handle up to four sampling locations.)

Certain packaging designs (e.g., IsoBag rapid transfer bags) save space in isolators. They readily provide ICR settle or contact plates in a DPTE [differential pressure transmitter for air] beta bag. Plates can be safely transferred via rapid transfer alpha ports whenever needed.

How are data obtained from environmental monitoring? How are these data used in pharma manufacturing?

 The data are usually obtained as colony forming units from the culture media used in active and passive air sampling as well as surface and personnel sampling. The new EU GMP Annex 1 suggests using the data both for batch release decisions and for trending analyses. It is possible to detect adverse trends by increasing excursions from action limits or consecutive excursions from alert levels. Also, noticing changes in the microbial flora is important. This helps to maintain the level of cleanliness and address issues by corrective and preventive actions.

Are there specific analytical tools that work best for different types of environmental
monitoring?

As the amount of data generated by environmental monitoring is huge, the PDA [Parenteral Drug Association] Technical Report No. 13 outlines computer-based tracking tools as essential. Specific software systems designed for environmental monitoring help to find adverse trends, and the stored data may allow conclusions as to what the root cause is. One important feature of the sampling equipment is that it should allow data transfer into such software systems, so that all tracked data are handled in a single database. This helps to stay compliant with the standard rules for data integrity.

Environmental monitoring data can help keep sterile environments sterile.

Microbe Monitoring

On July 24, 2023, Teva Pharmaceuticals, Inc., a US-based affiliate of Teva Pharmaceutical Industries, and Alvotech, an Iceland-based biotech company specializing in biosimilars, announced that they are expanding an existing strategic partnership for the development and commercialization of several biosimilar candidates. Under the expanded agreement, Teva will also acquire subordinated convertible bonds—to be issued by Alvotech—for $40 million.

With the expanded agreement, Teva will have exclusive commercialization rights in the United States for two new biosimilar candidates and line extensions of two current biosimilar candidates. Alvotech will be responsible for the development and manufacturing of these four candidates. The agreement includes milestone payments, the majority of which will be paid upon approval of the products and upon achieving significant sales milestones. Teva and Alvotech will share the profit from the commercialization of the biosimilars.

In addition, Teva will be involved in overseeing manufacturing activities and quality control at Alvotech’s manufacturing facility in Iceland. Teva is on site in Iceland to actively support Alvotech and to help ensure that the facility is fully ready for an FDA inspection, according to a company press release.

Meanwhile, the partners will continue to work closely on the pending US approval of AVT02, an interchangeable high-concentration biosimilar candidate for Humira (adalimumab). Under the existing partnership, the companies are also collaborating on four other biosimilar candidates, including AVT04, a proposed biosimilar for Stelara (ustekinumab), which is currently pending FDA approval. Furthermore, Teva’s investment under the expanded agreement (i.e., the acquisition of subordinated convertible bonds) will be used by Alvotech to fund the continued development of its biosimilars pipeline in the near-term.

“We welcome Teva’s continued partnership, and this expansion of our partnership agreement,” said Robert Wessman, chairman and CEO of Alvotech, in the press release. “We remain focused on preparing for a successful pre-approval inspection and resolving any outstanding issues identified by [FDA] to be able to bring our biosimilar candidates to patients in the US with Teva as soon as possible.”

News

Teva Pharmaceuticals and Alvotech will expand their partnership for the development and commercialization of biosimilar candidates.

Teva Pharmaceuticals and Alvotech Expand Existing Biosimilars Partnership

Alnylam Pharmaceuticals, a pharmaceutical company specializing in RNA interference (RNAi) therapeutics, announced a strategic agreement with Roche on July 24, 2023. The focus of this agreement is to develop and commercialize zilebesiran, Alynlam’s investigational RNAi therapeutic intended for the treatment of hypertension. Under the agreement, Alnylam will receive $310 million in upfront payments for the rights to zilebesiran, with a total payment of approximately $2.8 billion contingent on satisfying various development, regulatory, and sales milestones.

According to a company press release, in a Phase I study, zilebesiran was associated with dose-dependent reductions in serum angiotensinogen relative to placebo. Patients achieved tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after single doses of ≥ 200 mg. The treatment is now in Phase II of clinical trial testing.

“We are thrilled to announce this collaboration, as it combines Alnylam’s proven track record in RNAi therapeutics with Roche’s global commercial reach, commitment to innovation, and desire to transform the landscape for patients with severe cardiovascular diseases,” said Yvonne Greenstreet, CEO, Alnylam, in the release. “With this collaboration, we now can develop zilebesiran in a more robust way, allowing us to have cardiovascular outcomes data in hand at launch to ensure results relevant not only for health authorities but also for access and clinical practice in order to ultimately reach as many patients as possible.”

“We are excited to work together with Alnylam and leverage our strong R&D capabilities, our leadership in cardiovascular diagnostics and our global commercial footprint to further develop and provide this promising therapy with best-in-disease potential to patients,” said Teresa Graham, CEO, Roche Pharma, in the release. “... Together with a strong partner like Alnylam, we are looking forward to making a significant impact for patients living with hypertension at high cardiovascular risk and potentially other cardiovascular indications.”

The agreement stipulates that Roche will receive exclusive rights to commercialize zilebeserian outside of the United States in exchange for low double-digit royalties on net sales of the treatment. The companies will co-commercialize the treatment in the US, splitting profits equally.

Roche will pay up to $2.8 billion for the rights to Alnylam’s RNA-based hypertension therapeutic.

Roche and Alnylam Strike $2.8 Billion RNAi Deal

Sanofi and Recludix Pharma, a pharma company specializing in inflammatory diseases and cancer, announced a strategic collaboration on July 20, 2023. The partnership focuses on developing and commercializing small-molecule signal transducer and activator of transcription 6 (STAT6) inhibitors for patients with immunological and inflammatory (I&I) diseases. Under the agreement, Sanofi will pay Recludix $125 million in near-term payments and $1.2 billion in additional payments contingent on various development, regulatory, and sales-based milestones.

According to a company press release, Recludix will advance various STAT6 inhibitors from preclinical research and development until the start of Phase II clinical trials, after which Sanofi will handle further development and commercialization of the candidate. Sanofi will retain global rights to any small-molecule STAT6 inhibitors produced from the partnership, although Recludixhas the opportunity to participate in profit/loss share and certain co-promotion opportunities in the United States. Recludix will also be eligible for double-digit royalties on future product sales.

“This collaboration for the advancement of a preclinical oral STAT6 inhibitor speaks to our ability to successfully solve the challenge of drugging this attractive, yet elusive, therapeutic target,” said Nancy Whiting, CEO, Recludix, in the press release. “We are proud of the breakthroughs we have made in drugging SH2 [Src homology 2] domains as demonstrated by the STAT6 program, and we are excited to partner with Sanofi … who shares our vision for advancing an oral STAT6 inhibitor forward quickly for the benefit of patients. This strategic collaboration empowers the program while ensuring meaningful development participation and economic value for Recludix.”

“Recludix’s approach to targeting STAT6 has significant potential for a number of I&I diseases, especially where a precisely tailored oral therapy could best fit within the patient’s needs at various stages of disease,” said Frank Nestle, global head, Research, and chief science officer, Sanofi, in the release. “We are excited to partner with the Recludix team to continue to advance innovative strategies for targeting this previously considered undruggable target, aligned with our mission to best serve patients with inflammatory disease.”

Sanofi and Recludix Pharma’s deal centers on developing treatments for various immunological and inflammatory diseases.

Sanofi and Recludix Enter STAT6 Inhibitor Partnership Worth More Than $1.3 Billion 

Bristol Myers Squibb has exercised its option to enter into an exclusive global license agreement with Germany-based Evotec, a drug discovery company, for selected late-stage discovery programs that were developed and progressed from a collaboration between the companies.

According to a July 11, 2023 press release, the companies originally formed a neurodegeneration partnership in 2016, which proved to be highly productive. Under the collaboration, Evotec and Bristol Myers Squibb generated a pipeline of discovery-to-clinical-stage programs. The current licensing agreement expands on that original collaboration, extending the partnership to another eight years.

Under the license agreement, Bristol Myers Squibb has selected a number of programs (not disclosed) that were developed and progressed in a short time frame using Evotec’s precision medicine platforms. Based on this achievement, Evotec get a $40 million payment and is eligible to earn performance-based milestone payments. The company is also eligible to receive tiered royalties up to low double-digit percentages based on product sales, according to the press release.

“This license agreement will further bolster our joint pipeline of programs targeting several neurodegenerative conditions. We are confident that the strong collaboration of the experienced teams at Evotec and Bristol Myers Squibb will make novel innovative treatment options available to patients living with a broad range of neurodegenerative conditions,” said Cord Dohrmann, chief scientific officer, Evotec, in the release.

Under a global license agreement, Bristol Myers Squibb and Evotec will advance the development of neurodegeneration pipeline assets.

Bristol Myers Squibb and Evotec Extend Neuroscience Pact

Pfizer and Flagship Pioneering, a venture capital firm that creates bioplatform companies, announced a partnership on July 18, 2023 that is centered on creating a new pipeline of innovative medicines. The deal mentions that both companies will invest $50 million upfront to explore opportunities to develop 10 single-asset programs.

According to a Flagship press release, Pfizer will fund and have the option to acquire each selected development program, whereas Flagship and its bioplatform companies will be eligible to receive up to $700 million in milestones and royalties for each successfully commercialized program. In addition, Pioneering Medicines, a Flagship initiative, will work with Pfizer to lead the rapid portfolio creation process.

"Flagship and Pfizer enter into this strategic alliance driven by a shared sense of urgency to develop novel medicines that make a difference for patients," said Paul Biondi, president, Pioneering Medicines, and executive partner, Flagship Pioneering, in the release. "This new partnership brings together the best of our organizations to maximize discovery and development potential from inception to impact through a unique innovation supply chain that sets us on a path to potentially realize transformational medicines more quickly and effectively."

"At Pfizer, we are expanding our efforts to pursue potential breakthrough science with unique approaches and funding mechanisms designed to leverage the dynamic scientific ecosystem," said Mikael Dolsten, chief scientific officer and president, Worldwide Research, Development and Medical, Pfizer, in the release. "This collaboration is an exciting opportunity for Pfizer to bring deep scientific expertise and apply our development and regulatory strength to Flagship's diverse portfolio of technology platforms, translating early-stage innovation to potential medicines."

The partnership will see Flagship and Pfizer work to create a new pipeline of innovative medicines.

Pfizer and Flagship Pioneering Enter Innovation Partnership

Scribe Therapeutics, a genetic medicines company, and Sanofi announced an expanded collaboration on July 17, 2023. The agreement will see Sanofi receive an exclusive license to use Scribe’s CRISPR X-Editing (XE) genome editing technologies for the development of in vivo therapies, including sickle cell disease.

According to a company press release, Scribe will receive $40 million in upfront payment and is eligible to potentially receive more than $1.2 billion based on the successful completion of certain development and sales milestones, as well as tiered royalties. This agreement builds on the companies’ existing collaboration, which is focused on ex vivo editing of natural killer (NK) cell therapies for cancer treatment.

“We are continually impressed by the expertise, rigor, and urgency that Sanofi has brought to our existing ex vivo collaboration, as well as their rapid advancements and innovation in non-viral delivery technologies. Now, we are thrilled to expand our work together into new areas of high unmet need,” said Benjamin Oakes, co-founder and CEO, Scribe Therapeutics, in the release. “This in vivo collaboration further demonstrates the versatility of Scribe’s design-based approaches to CRISPR, which enable greater activity, specificity, and deliverability, ultimately accelerating the development of life-changing therapeutics.”

“We are pleased to expand our work with Scribe, an illustration of our shared commitment to advance best-in-class genome editing therapies for patients in need,” said Christian Mueller, global head, Genomic Medicine Unit, Sanofi, in the release. “We’re encouraged by what we’ve accomplished to date with Scribe in creating ex vivo NK cell therapies and now look forward to accelerating our ability to effectively leverage genome editing in vivo through Sanofi’s innovative research work in targeted lipid nanoparticles, for in vivo therapies with the potential to dramatically improve treatment outcomes and ultimately to change patients’ lives.”

“Scribe’s platform holds tremendous potential to address an unprecedented number of therapeutically relevant targets across the human genome for many serious diseases,” said Svetlana Lucas, chief business officer, Scribe Therapeutics, in the release. “We are excited to partner with companies like Sanofi that offer not only disease and drug development expertise but also the resources and technologies enabling the delivery of our molecules in vivo to specific disease tissues, allowing us to develop better therapies. We look forward to our continued collaboration with Sanofi to expand the application of Scribe’s best-in-class genome editing tools and fully realize the promise of CRISPR for patients as broadly and rapidly as possible.”

The expanded deal, now potentially worth more than $1.2 billion, will work to develop in vivo therapies, including sickle cell disease.

Sanofi and Scribe Therapeutics Expands Genomics Collaboration 

Thermo Fisher Scientific announced the launch of the Gibco OncePro Tumoroid Culture Medium Kit on June 28, 2023. According to a company press release, the kit is the first commercially available culture medium specifically developed for the expansion of patient-derived tumoroids, or cancer organoids, from multiple cancer indications. In an effort to improve ease of use, the kit includes a scalable, automation-compatible suspension culture method.

According to the release, patient-derived tumoroids hold promise in helping improve clinical trial success rates for cancer researchers seeking to better model disease and predict patient response to therapeutics 

; however, their use has been limited due to challenging cell culture requirements and a lack of commercially available media systems, according to the company in the release. The off-the-shelf modular tumoroid culture medium kit is designed to fill this perceived gap in the market.

“Cancer’s unpredictable nature presents a significant scientific and clinical challenge for future discoveries and in delivering life-saving treatments to patients,” said Brian Douglass, vice-president and general manager, Cell Biology, Thermo Fisher Scientific, in the release. “Globally, millions of patients and their families still await a cure for cancer despite the decades of advances in research, diagnostics, and treatments aimed at helping lower cancer mortality. We developed the new OncoPro Tumoroid Culture Medium Kit so the scientific community can take greater advantage of tumoroid models to help bring drug candidates to market faster and more cost-effectively.”

“It is well known that tumor organoids are more predictive of clinical outcomes, adverse events and resistance mechanisms than established 2D cell line counterparts,” said Erik Goka, vice-president, Biology, Revere Pharmaceuticals, in the release. “The OncoPro Tumoroid Culture Medium Kit allows us to seamlessly integrate tumoroids into our research and drug discovery processes. With the tumoroid media system, we can propagate all our organoid models in the same culture medium system irrespective of the tissue of origin. This media system has been instrumental in allowing us to bring tumor organoids into our lab for everyday use.”

In addition to the kit, Thermo Fisher Scientific offers services in tumoroid assay development to support outsourced screening and characterization. Customers may also access seven unique OncoProtumoroid cell lines, representing four different cancer indications including colorectal, lung, endometrial, and breast.

New Technology

Thermo Fisher Scientific’s new tumoroid culture medium kit is designed to help cancer researchers better model the disease.

Thermo Fisher Scientific Releases Tumoroid Culture Medium Kit 

Eurofins Genomics Blue Heron, a biotechnology company specializing in advanced gene synthesis, announced the launch of its in-vitro transcription (IVT) messenger RNA (mRNA) synthesis service on June 29, 2023. According to a company press release, the new synthesis service is designed to offer a comprehensive solution for researchers seeking high-quality, customizable mRNA synthesis with fast turnaround times.

According to the release, the new synthesis service is equipped to handle various applications and includes customizable mRNA synthesis capabilities to meet specific research needs. It is designed for use in molecular biology, drug discovery, vaccine development, and gene therapy, among other fields.

Eurofins Genomics Blue Heron’s novel mRNA synthesis service is designed for customizable applications.

Pharmaceutical Technology's In the Lab eNewsletter, August 2023