John McDermott, Quotient Sciences' Executive Drug Development Consultant, discusses Integrated Development Strategies Overcome Solubility Challenges, in Drug Development & Delivery's Special Feature in Drug Development & Delivery's Special Feature entitled: "Solubility & Bioavailability: Utilizing Enabling Technologies."

There is no one-size-fits-all solu­tion for improving bioavailability and solubility, and what is correct for one molecule could be over-engineering, or worse, limiting the potential of an­other drug. It is therefore crucial for development teams to understand the drivers of a given molecule’s solubility and its permeability properties to se­lect the correct technologies for as­sessment, and then back up that selection with data. “One of the biggest challenges we see is the expectation of an in vitro/in vivo cor­relation in developing these technolo­gies, which is not realized when clinical data is obtained,” says John McDermott, Executive Drug Develop­ment Consultant, Quotient Sciences. “Having access to human data to as­sess formulation technologies for poorly soluble drugs is therefore cru­cial in guiding formulation selection and optimization.”

Quotient Sciences has had the opportunity to work on several programs that have assessed the clinical performance of some of these novel and emerging technologies to enhance drug bioavailability. “We have seen some great successes for some drugs, and we have also had experiences where performance observed in preclinical and in vitro studies have not translated into humans,” he says.

Quotient Sciences delivers fully in­tegrated programs incorporating for­mulation development with clinical manufacturing, regulatory support, and clinical testing. This platform, termed Translational Pharmaceutics™, can be applied to accelerate the pro­gression of prototype formulations to clinical assessment and onward, to ef­ficiently and accurately assess candi­date formulations, and to improve the likelihood of clinical and commercial success, explains Mr. McDermott.

In one recent case study, a cus­tomer with a BCS II molecule had completed its first-in-human study, which demonstrated inadequate ex­posure and a significant food effect. These issues were stalling the project from advancing into proof-of-concept patient studies. To respond to this, the client needed to rapidly evaluate sol­ubility enhancement technologies and demonstrate its utility to enable effi­cacy assessments in order to proceed to the next project milestone.

In this program, Quotient Sci­ences developed three different solu­bility-enhancing formulations: a micronized form of API; a self-emulsi­fied lipid delivery system; and a spray-dried dispersion. A Translational Pharmaceutics study was performed to achieve a quick proof-of-concept as­sessment, removing the need to con­duct larger scale, cost-prohibitive process development and lengthy sta­bility programs for multiple technolo­gies. The human pharmacokinetic (PK) study used a 5 period cross-over de­sign in 16 healthy volunteers with the micronized formulation delivering the best outcome.

“By applying our Translational Pharmaceutics approach, the overall timeline – from initiating formulation lab work to having clinical PK data to select the optimal formulation – was just six months,” says Mr. McDermott. “While it’s exciting to be involved at the forefront of research in drug deliv­ery technologies, it’s important to re­main focused on the patient – and the best model for assessing humans is a human.”

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Accelerated formulation strategies can aid with cost and time-efficiencies in drug development. However, there are key challenges of which developers must be aware to ensure success.

Pharmaceutical Technology Europe recently spoke with a panel of experts including Vanessa Zann, Senior Drug Development Consultant, and Chris Roe, Senior Research Fellow, with Quotient Sciences to discuss the primary hurdles to accelerated formulation strategies and best practices for developers.

Q: Could you run through the primary challenges facing developers when employing accelerated formulation strategies in drug development?

A - Zann: The main challenge with accelerated formulation strategies is knowing which dosage form technology is the most appropriate to give optimum exposure in man. There is widespread acknowledgement of the lack of predictability of pre-clinical data for formulation assessments. Improvements in in-vitro and in-silico tools are emerging; however, there are still significant risks for innovator companies, particularly given continued drug delivery challenges presented by molecule chemistry. This uncertainty is magnified when batch sizes and stability packages are needed for new formulations, for testing in the clinic to even be considered.

A - Roe: Truly understanding the drivers of poor product performance is a key challenge to overcome. Using the correct techniques can provide meaningful improvements in in-vivo performance that can aid in rapidly progressing formulation efforts. At the same time, developers need to avoid the risk of trying to progress overly complex formulations, which may add unnecessary time or cost to the drug development process. While speed is critical, it shouldn’t come at the expense of sufficient product quality.

Q: Are the challenges more significant for large-molecule products versus small-molecule ones, in your opinion?

A - Zann: The challenges for large molecules are still present but different. Large molecules will typically be administered parenterally via intravenous (IV) or subcutaneous (SC) routes, hence formulation options will be more limited compared to the likes of solubility enhancement or modified release development solutions for oral small molecules. There will be less dependency of the formulation composition on its clinical performance. The challenges still remain with regard to predictability from preclinical species and also manufacturing and stability for drug products.

A - Roe: Arguably the most significant challenges for large molecules would be to achieve adequate exposure from the oral route to exert a systemic therapeutic effect, given this is often seen as the gold standard for convenience and compliance. Issues for large molecule oral formulation strategies include poor permeability and potential instability in the gastrointestinal tract, both of which need to be addressed via compound selection and/or formulation technologies. Success is possible, as evident from the recent [US Food and Drug Administration] FDA approval of Rybelsus (Novo Nordisk), an oral glucagon-like peptide (GLP)-1 agonist (1).

Q: What sort of activities can developers pursue to ensure their accelerated formulation strategies are successful?

A - Zann: For large molecules where oral delivery is required, one optimizing strategy is to formulate with penetration enhancers to increase oral absorption either through modification of the tight junctions or membrane perturbation. There are in-vitro permeability assays that can be used to assess large-molecule permeability in the presence of various formulation components that are available to increase permeability, both early and relatively rapidly within the development programme. However, these models have limitations in terms of being able to test formulated drug products that do not damage the in-vitro cell-based system.

A - Roe: For oral small molecules, having a data driven formulation strategy based on the compounds’ biopharmaceutic properties is likely to result in a greater chance of success. Employing the developability classification system (DCS) to molecules will allow a targeted formulation strategy for poorly soluble compounds that is based on whether the absorption is either limited by dissolution rate (Class IIa) or solubility (Class IIb). Where there is uncertainty (border-line case) in the classification, Quotient Sciences would recommend assessing both a particle-size reduced formulation (a DSC IIa strategy) and a solubility-enhanced formulation (DCS Iib strategy) to cover both situations to maximize the potential for success.

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Source: F. Thomas, “Successfully Accelerating Formulation Strategies,” Pharmaceutical Technology Europe 34 (3) 2022.

NEW ORLEANS, LA, March 23, 2022 – South Rampart Pharma (“South Rampart” or the “Company”), a clinical-stage life science company focused on advancing innovative medications for the treatment of pain and fever, announced today patient enrollment and dosing in its Phase 1 study evaluating SRP-3D (DA) for pain is underway.

“We are committed to improving the lives of people suffering from acute, chronic, or neuropathic pain by developing a new class of small molecule, non-opioid pain medicines. To date, SRP-3D (DA) has shown promising efficacy in reducing both pain and fever while lacking the liver and kidney toxicity associated with current prescription and over-the-counter analgesics,” said Hernan Bazan, M.D., Chief Executive Officer and Co-Founder of South Rampart Pharma and Professor of Surgery at the Ochsner Clinic. “We are pleased with SRP-3D (DA)’s development and clinical progress, and we know the market needs this. With patient enrollment and dosing now well underway, we continue to advance toward reporting topline results, expected in the third quarter of this year.”

The Company’s lead program, SRP-3D (DA), is a novel acetaminophen analog with a unique mechanism of action that lacks the liver toxicity present in acetaminophen. It is in development to treat various forms of pain.

The ongoing Phase 1 study is a randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics (PK) of single ascending oral doses of SRP-3D (DA). Further, it will characterize the pharmacodynamics and food effect on SRP-3D (DA) in healthy male and female subjects. South Rampart Pharma is enrolling 60 subjects in the Phase 1 study in Quotient Sciences, Miami, FL. The primary endpoint for the study is to provide SRP-3D (DA)’s safety and tolerability by assessing: adverse events (AEs), vital signs, electrocardiograms (ECGs), physical examinations, and multiple laboratory safety tests. Secondary endpoints include oral PK of single ascending dose (SAD) of SRP-3D (DA) administered as an oral suspension, followed by multiple ascending doses.

“Acute and chronic pain continues to affect a growing section of the global population. While opioids, acetaminophen, ibuprofen, and similar NSAIDs are widely available, there remains a significant need for effective pain medications with fewer adverse effects and without the abuse liability of opioid analgesics. I believe SRP-3D (DA) may represent a cutting-edge opportunity to treat pain effectively, and importantly, without the hepatic, gastrointestinal, cardiovascular, or kidney toxicity commonly associated with acetaminophen or NSAIDs,” added William K. Schmidt, Ph.D., Chairperson for the Annual Arrowhead Pain Summit and expert on analgesic drug development.

Pain is one of the most prevalent and costly public health issues worldwide1. In the U.S. alone, an estimated 20% (50 million) of adults experience chronic pain2, and more than 76 million have suffered from pain that lasts longer than 24 hours3. Currently available medications are either highly addictive or cause harm to the liver and kidney. For example, acetaminophen hepatotoxicity remains the most common cause of acute liver failure in the U.S., and opioids were associated with over 100,000 drug overdose deaths in 20214, a nearly 30% increase from the 78,056 deaths during the same period the year before.

South Rampart Pharma’s proprietary compounds have consistently reduced pain and fever in preclinical studies without liver and kidney toxicity associated with current common over-the-counter analgesics. In all of the Company’s FDA Investigational New Drug (IND)-enabling toxicology studies, SRP-3D (DA) was shown to have a favorable safety profile. Additionally, as a non-opioid SRP-3D (DA) lacks abuse potential.

About South Rampart Pharma
South Rampart Pharma is a clinical-stage life science company that aims to advance the safe treatment of pain by developing new small-molecule solutions that can overcome many risks associated with current pain medicines. The Company’s lead compounds have effectively reduced both pain and fever in preclinical studies without the liver and kidney toxicity of current non-opioid analgesics. As a new small molecule treatment option that is not a biologic therapy, South Rampart Pharma’s compounds have great potential as a value product that will be low cost and accessible to many patients. Please visit the Company’s website at southrampart.com and connect on Twitter, LinkedIn, and Facebook for more information.

About Quotient Sciences
Quotient Sciences is a drug development and manufacturing accelerator providing integrated programs and tailored services across the entire development pathway. Cutting through silosacross a range of drug development capabilities, we save precious time and money in getting drugs to patients. Everything we do for our customers is driven by an unswerving belief that ideas need to become solutions, and molecules need to become cures, fast. Because humanity needs solutions, fast. For more information visit quotientsciences.com

References:

Relieving Pain in America. (2011). National Academy of Sciences. doi: 10.17226/13172
Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults – United States, 2016. (2019, September 16). Retrieved from https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.htm?s_cid=mm6736a2_w.
Partners for Understanding Pain. (n.d.). TOOL KIT – The ACPA Health Care Professionals September 2019. Retrieved from Tool-Kit-2019-Final-8-27-19.pdf.
https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm

Quotient Sciences contributes to Pharma Manufacturing "2022 Pharma Predictions" Article

Matthew Paterson, Vice President of Corporate Strategy, comments on growing demand for integrated drug substance and drug product services.

We're seeing a greater desire to move deeper in development toward proof-of-concept. Biotechs want to have confidence in drug substance and drug product suitability for development, mitigating risks for commercialization and in turn driving up their valuations. This means we’re observing strong demand for integrated drug substance and drug product services — to help biotech’s accelerate development programs, anticipate downstream challenges, and improve the likelihood of clinical success.

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Featured Author

NOTTINGHAM, U.K.; July 1, 2021 – Quotient Sciences, the drug development and manufacturing accelerator, announces that it has completed the rebrand of Arcinova, the Alnwick U.K.-based contract development and manufacturing organization (CDMO). Now called Quotient Sciences - Alnwick, the site has significant expertise in drug substance manufacture, isotope labelling, bioanalysis and drug product development, playing a key role in strengthening Quotient’s services portfolio from candidate selection to commercial manufacturing.

Quotient Sciences acquired Arcinova in February 2021 with the strategic goal of providing an "end-to-end" offering for customers and creating further differentiation for Quotient in the marketplace. The combined business uniquely supports customers with drug substance, drug product and clinical testing capabilities all under one organization. "By cutting through silos and integrating these capabilities, Quotient simplifies outsourcing for customers and creates substantial timeline acceleration," said Mark Egerton, CEO of Quotient Sciences. This differentiation extends the 12-month drug development time savings already delivered by Quotient’s flagship platform Translational Pharmaceutics^®.

Quotient strives to help customers save time and money in the pharmaceutical development process and the combined business has already identified several new integrated service packages that will be offered to customers in the coming months. These integrated programs include a holistic candidate selection offering and a streamlined program that fully integrates drug substance and drug product manufacturing.

Helen Baker, Director of Pharmaceutical Sci­ences, has been featured in Drug Development & Delivery's special feature article, "Outsourcing Formulation Development & Manufacturing: Understanding Critical Attributes Earlier in Development Leads to a More Robust Drug Product."

Formulation development and manufacturing outsourcing compress timelines and mitigate risk, enticing many pharmaceutical and biotech companies worldwide to partner with outsourcing service providers in the early phases of the drug development process. This has resulted in an economic impact on the global formulation development out­sourcing market, which is expected to reach a value of $31.8 billion by 2027, up from $21.1 billion in 2021

“Clients need to ensure they part­ner with a CDMO that has a good awareness of both material supplier lead times, availability of alternate merchants, and who have the expert­ise to offer up viable alternatives that would not impact the performance of the end product,” says Helen Baker, Director, Pharmaceutical Sciences, Quotient Sciences. “A CDMO capable of both preempting and adapting to supply chain issues, while maintaining the integrity of a comprehensive and thorough development plan will be most attractive to pharmaceutical clients.”

The pandemic also forced the in­dustry to pivot toward new therapeu­tics, particularly mRNA-based drugs. As a result, many CDMOs have in­vested in new facilities and state-of-the-art equipment focused on biologics manufacturing.

This annual, exclusive Drug Devel­opment & Delivery report describes how drug sponsors and CDMOs are collaborating earlier, highlights how third-party contractors are navigating material shortages, and discusses how the industry is shifting to address dif­ferent therapeutic targets and mole­cules, such as mRNA.

Quotient Sciences: Clinical Testing & Development Under One Roof

A recent formulation development challenge that Quotient Sciences faced in­volved a BCS class IV candidate des­tined for solid oral delivery. The molecule exhibited poor solubility and permeability, with erratic absorption as an inevitable consequence. Al­though numerous solubility enhance­ment techniques exist, a critical factor in development was to ensure that the dosage form selected must be consis­tent and scalable to a sufficient size to support a commercial campaign. 

Hot melt extrusion offered not only a vehi­cle for manipulating the absorption properties by allowing for the incorpo­ration of enhancement aids but was easily controlled and scaled-up, with the additional benefit of optional con­tinuous manufacturing. 

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What technologies do you commonly use to generate fast, reliable data for drug development?

All the bioanalytical work is mass spectrometry-based, including liquid chromatography−mass spectrometry (LC−MS), gas chromatography−mass spectrometry (GC−MS) and inductively coupled plasma mass spectrometry (ICP−MS), which is one of our specialty areas. ICP−MS capability allows the team to measure elements that are very specific to a drug and there are very few companies who can offer a service as robust as ours.

Recently Arcinova was acquired by Quotient Sciences, how does this change things?

The coming together of Quotient Sciences and Arcinova is a perfect fit. Quotient Sciences is a leading drug development organization with clinical pharmacology units in the UK and US – performing a range of First-in-Human (FIH) and Phase I clinical trials. The company has a large Data Sciences group which provides pharmacokinetics, statistical analysis and data management services – but a key gap in Quotient’s service portfolio was bioanalysis – and now this gap can now be addressed.

Forging ahead, the combined business looks to expand on several fronts. The immediate opportunity is to integrate bioanalytical services with clinical pharmacology, pharmacokinetics and data sciences services – this integrated offering will provide clients the ability to move seamlessly from clinic to lab to rapid analysis and interpretation – speeding up clinical development times. Secondly, there will also be investment in new bioanalytical technologies and instrumentation to remain cutting edge and supporting customer needs.

On a practical level, how does integrating clinical pharmacology, bioanalysis and pharmacokinetics actually speed up clinical development times?

Time savings come in the form of efficiencies which are formed from the integration. Transfers of information and data move from being external to internal, allowing a set of agreed standard specifications/timelines (e.g. data transfer), being able to jointly track of samples, which will allow close coordination of delivery days to minimize white space/delays. All of which will be managed under a single quotient project manager for all services managing and driving the whole project timeline.

It also facilitates a much easier relationship with clients, with continuity of contacts, methods and templates, the same bioanalytical, pharmacokinetic, project manager, sample shipment/management contacts for clients throughout development.

Where do you see the future of the bioanalytical services industry and how is Arcinova/Quotient Sciences preparing to address needs of the future?

Contract bioanalytical services will continue to grow to meet the market demands. Whilst historically, most large pharmaceutical companies traditionally performed their bioanalysis in house, that model has dramatically changed over the last 10 years, with the majority now performed by CRO’s. Consequently, the intrinsic knowledge and new generation of bioanalytical scientists now reside with the CRO’s, who can now leverage that to support both traditional pharma and emerging biotech companies, who’s knowledge in this field may be limited. As our knowledge spans both pharma and CRO, we are in an ideal environment to support and guide our clients and this demand will continue to grow. We continue to invest in both technology and people, so the future is assured.

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Low-volume drugs, such as orphan drugs, present challenges in achieving favorable production economics and in managing the projects themselves. A roundtable of CDMOs provides perspectives on those challenges and best practices to resolve them. 

Quotient Sciences experts contributed insight to this recent article with DCAT Value Chain Insights. Read what Dr. Paul Quigley, Principal Research Fellow, Drug Substance, and John McDermott, Executive Drug Development Consultant, had to share about developments in rare diseases.

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Q: What particular challenges arise from a supply planning/management perspective when working with low-volume drugs?

Paul: Most CDMOs are dependent on large-volume processes to achieve economies of scale. We take a material-sparing mindset when developing scalable manufacturing processes, which is particularly important for low-volume drugs.

Q: Any particular challenges when scaling up from clinical to commercial scale when working with a low-volume drug? 

John: If the process of scale-up is well understood and there are appropriate processes in place to manage the scale-up from clinical to commercial scale, this shouldn’t present a technical problem as by definition low-volume drugs sit somewhere along the scale spectrum. However, low-volume drugs require expertise in controlling processes at the intended scale, sometimes with equipment that can be difficult to find in late-stage and commercial production.

Nand Singh, Medical Director at Quotient Sciences, contributions to a bial study paper in the British Journal of Clinical Pharmacology, published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This paper documents the study, absorption, metabolism and excretion of opicapone (2,5-dichloro-3-(5-[3,4-dihydroxy-5-nitrophenyl]-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide), a selective catechol-O-methyltransferase inhibitor.

Aims: The absorption, metabolism and excretion of opicapone (2,5-dichloro3-(5-[3,4-dihydroxy-5-nitrophenyl]-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide), a selective catechol-O-methyltransferase inhibitor, were investigated.

Methods: Plasma, urine and faeces were collected from healthy male subjects following a single oral dose of 100 mg [14C]-opicapone. The mass balance of [ 14C]-opicapone and metabolic profile were evaluated.

Results: The recovery of total administered radioactivity averaged >90% after 144 hours. Faeces were the major route of elimination, representing 70% of the administered dose; 5% and 20% were excreted in urine and expired air, respectively. The Cmax of total radioactivity matched that of unchanged opicapone, whereas the total radioactivity remained quantifiable for a longer period, attributed to the contribution of opicapone metabolites, involving primarily 3-O-sulfate conjugation (58.6% of total circulating radioactivity) at the nitrocatechol ring. Other circulating metabolites, accounting for <10% of the radioactivity exposure, were formed by glucuronidation, methylation, N-oxide reduction and gluthatione conjugation. Additionally, various other metabolites resulting from combinations with the opicapone N-oxide reduced form at the 2,5-dichloro-4,6-dimethylpyridine 1-oxide moiety, including nitro reduction and N-acetylation, reductive opening and cleavage of the 1,2,4-oxadiazole ring and the subsequent hydrolysis products were identified, but only in faeces, suggesting the involvement of gut bacteria.

Conclusion: [14C]-opicapone was fully excreted through multiple metabolic pathways. The main route of excretion was in faeces, where opicapone may be further metabolized via reductive metabolism involving the 1,2,4-oxadiazole ring-opening and subsequent hydrolysis

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Champion Award Winning Categories:

• Expertise (Overall)
• Reliability (Overall)

Leadership Award Winning Categories:

• Capabilities (Overall)
• Compatibility (Overall)
• Expertise (Overall)
• Reliability (Overall)
• Quality (Overall) 

For the 2022 CRO Leadership Awards, we once again teamed up with ISR Reports to determine the award recipients. 50 contract research organizations were assessed on 20+ performance metrics in ISR’s annual CRO Quality Benchmarking survey.  Respondents only evaluate companies with which they have worked on an outsourced project within the past 18 months. This level of qualification ensures that survey responses are based on actual involvement with CROs and clear experiential data.

See the report & full list of winners