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“Quotient Sciences’ integrated approach to drug development accelerates molecules to IND & beyond”
This week, SpeakPharma interviews Eleanor Row, Executive Director of Commercial at Quotient Sciences, a global drug development accelerator with state-of-the-art development, manufacturing and clinical testing facilities in the US and UK. Over the last 30 years, Quotient has worked on over 3,000 molecules across all stages of development. Row discusses the challenges and considerations that drug developers should be aware of when trying to quickly get their molecule from discovery to investigational new drug (IND) stage and onward into the clinic. While throwing light on the different development functions at an early stage of drug development, she also talks about how an integrated approach can help accelerate a molecule’s pathway to IND and beyond.What are the main challenges that drug developers face today in getting their molecules IND-ready?When transitioning from discovery to IND, there are many challenges that drug developers can face. The first challenge in any drug development program is to select the best molecule from various potential leads. During this stage, lead candidates are evaluated based on their early biopharmaceutical ‘developability’, in vitro activity, and their ability to demonstrate acceptable specificity and selectivity for the biological target of the desired therapeutic area.Once a solid lead candidate is selected, the next goal is to complete all necessary drug product development and safety studies that will support regulatory approval to begin a first-in-human (FIH) phase 1 clinical trial.In addition to exhibiting an acceptable pharmacokinetic (PK) profile and demonstrating in vivo efficacy, it is crucial to show that the drug has a good safety pharmacology margin with an acceptable drug-drug interaction (DDI) profile. Access to increasing quantities of drug substance becomes even more critical at this stage, and the focus shifts from synthesizing small quantities of material from medicinal chemistry routes to developing a scalable synthetic process (PR&D) and providing the first kilogram of Good Manufacturing Practice (GMP)-grade material suitable for early clinical development.What should drug substance decision-makers be considering at this stage?While developing a drug substance manufacturing process, it is crucial to optimize the synthetic route early on. Any changes to the route at a later stage can be time consuming, costly and may require additional bridging toxicology studies due to differences in the impurity profile.Designing a synthetic process that is robust and commercially scalable helps avoid common pitfalls that can add risk to material supply. During this stage, it is important to minimize the number of steps (either by telescoping or identifying commercially available starting materials with a robust supply chain), develop simple strategies for purification and isolation, and eliminate the use of any hazardous reagents or intermediates, particularly genotoxic impurities (GTIs).During the process of developing a drug substance, it is important to take into account the impurities that are produced along with the substance. Impurities can be easily identified and quantified by performing analytical method development alongside synthesis. This provides a good understanding of the fate of impurities and control points within the drug substance synthesis at an early stage and helps reduce development timelines. Non-GMP demonstration batches can be manufactured as soon as the synthetic methodology is available. Once material is available, stability studies can be initiated to support the clinical shelf life and pivotal data for the CMC dossier submission.It is also crucial to have a long-term regulatory strategy and to identify potential GMP starting materials appropriate to the development stage. Regulatory starting materials (RSMs) should be chosen to allow enough stages to be performed under GMP to demonstrate control over the drug substance’s quality. Changing the API at a later stage in clinical development to meet the increased regulatory requirements may cause additional costs, risks and delays, as additional clinical studies may be needed to prove that changes in the starting materials do not change the toxicology or impurity profiles of the final material.Finally, the selection of the right physical form is often overlooked during early development. Making the right decisions early on can lead to a more robust drug substance isolation strategy and formulation to take into the clinic, resulting in reduced drug product development timelines. Defining the desired salt form or free form of the molecule earlier in the project also brings with it the advantage of doing away with the need of bridging toxicology or stability studies further downstream. It can also lead to a much stronger intellectual property (IP) position.What considerations should formulation and clinical manufacturing teams be aware of at this stage of dosage form development?Understanding the physical form and behavior of a molecule is crucial for designing a suitable formulation for the clinic. Technology selection is determined by the solubility and permeability of a molecule, utilizing the Developability Classification System (DCS) or the Bioavailability Classification System (BCS). Providing the data sooner to the formulators can significantly reduce the lead time to a clinic-ready formulation. The use of a simple, fit-for-purpose formulation during an early clinical evaluation program is a tried and tested solution that offers significant time and cost benefits compared to alternative strategies. This approach also provides flexibility for dosing administration during early clinical studies since dosing regimens are not fully defined at this stage.Why is it beneficial for chemistry, CMC and clinical groups to be engaged with one another in early development?Typically, drug substance, drug product, and clinical testing activities are conducted by different organizations. This is a classic approach, but it is time consuming and costly, leading to poor knowledge and material transfer between organizations and increasing the risk of program delays.At Quotient Sciences, we offer a unique approach to drug development through our proprietary Translational Pharmaceutics platform. We have the unique ability to integrate drug substance, drug product, and clinical testing activities under a single organization and program manager. This enables process development, analytical, and formulation chemists to interact and work together from the beginning till the end of the project, ensuring data and drug substance information is shared between teams. As a result, activities that would typically begin after the completion of the drug substance program can begin several months earlier.Using this integrated approach, we can reduce drug development timelines in the candidate development stage by an average of three to six months, which translates into significant R&D cost savings. Our collective experience of over 15 years and 500 Translational Pharmaceutics programs ensures a smooth review by regulators, accelerating clinical trial approval. Our integrated approach significantly reduces drug development timelines from candidate selection to clinical development, reducing the overall program risk and enhancing the likelihood of downstream clinical and commercial success.What should clinical operations teams be aware of during early-stage development?As a molecule approaches IND transition, there are several unknowns that can affect its future success in downstream development and clinical trials. Success in the clinic is often linked to the early establishment of efficacy and the current trend of including patient investigations in the first clinical protocol. However, this approach has several factors that can impact the program’s timeline, such as patient population size for recruitment and resource constraints. Implementing such a study design can often result in a significant delay in the first dose in human milestone, which is critical to confirming real drug exposures that will ultimately drive the efficacy question.Leveraging a healthy volunteer study can help clinical operations teams focus their attention on answering immediate questions about their molecule’s development. This approach allows clinical teams to keep an eye on future pivotal efficacy investigations without delaying the collection of decision-making data.How can an integrated program help accelerate the pathway to IND?When drug developers move from drug discovery to pre-clinical and clinical development, one of the challenges they face is splitting their program across multiple service providers. This places the burden of project management on them and creates gaps in the development timeline, leading to limited knowledge and material sharing as well as adding time and cost to the program. Quotient Sciences’ Translational Pharmaceutics platform lets customers benefit from holistic scientific advice. Our projects are data-driven and scientific, and are led by multi-disciplinary project teams with expertise in CMC, clinical and biopharmaceutics.Through tight integration of early development activities under a single organization, Quotient Sciences breaks down traditional industry silos, accelerating timelines and reducing risks. Customers not only benefit from the time and cost savings that Quotient Sciences and our Translational Pharmaceutics platform provide for their programs, but they also meet the end-goal of getting new medicines to patients faster. 

Impressions: 1116


#SpeakPharma With Quotient Sciences
15 May 2023
“For orphan drugs, we identify a patient-ready formulation in less than half the time.”
This week, SpeakPharma interviews Dr. Peter Scholes, Chief Scientific Officer, Quotient Sciences, who talks about orphan drugs and some of the challenges drug developers face while developing them. In particular, Dr. Scholes tells us how Quotient Sciences has demonstrated the benefits of embedding formulation flexibility within first-in-human trials to enable rapid identification of a “patient ready” formulation. This way, Quotient helps customers get ready for proof-of-concept studies in an average of 12 months, which is less than half the time when compared with the industry standard. Excerpts:  What exactly are orphan drugs? An orphan drug is a drug for a rare disease or condition, affecting a small percentage of the population — in the US, it is less than 200,000 people, while in the EU, it is not more than one in 5,000 people. Worldwide, there are over 300 million people living with one or more identified rare diseases, representing 3.5 to 5.9 percent of the global population.  Some rare disease treatments have been “orphaned” or discontinued because there was not enough financial incentive to continue development or production. To encourage industry R&D, the US Food and Drug Administration’s Orphan Drug Act (which Europe reciprocated in 1999 via the Orphan Drug Regulation) incentivizes drug development for rare diseases. These regulatory frameworks recognize the importance of developing new treatments to address unmet clinical needs. Why is orphan drug development for rare diseases so important? Global regulatory agencies have sought to provide an impetus to pharma and biotech organizations for the development of new therapeutics for orphan diseases by offering enhanced regulatory support, expedited review times, reduced submission fees and market exclusivity periods. We have seen the benefits of these incentives most prominently in the US, with over 50 percent of NDA approvals in the last two years being for rare diseases. In Europe, of the 66 new medicines authorized by the EMA in 2019, seven (~10 percent) were orphan drugs. From a global perspective, it is estimated that approximately 30 percent of new drugs in development today are focused in these therapeutic areas. This is a great success story, but much more needs to be done to address global patient needs. Tell us about some of the challenges drug developers face while developing orphan drugs? Of late, we have seen four major chemistry, manufacturing, and control (CMC) challenges in the orphan drug space, which are arguably exacerbated by regulators providing pathways for expedited development. The overarching challenge is the effective development of patient-centric dosage forms based upon molecule properties and patient needs, particularly given the fact that many rare diseases will be in pediatric populations. The second major challenge is quickly identifying optimized drug products, whose performance is preferably demonstrated in humans prior to initiating protracted, difficult-to-recruit patient trials. Moreover, implementing a tailored manufacturing and supply plan for drug products into these patient trials also requires careful consideration. Finally, finding a long-term partner for scale-up and commercial manufacturing of what will inevitably be a low-volume product also poses as a challenge. What are the key factors to consider while selecting a CDMO partner for orphan drugs? While there is no shortage of CMC vendors in the marketplace, you need to select a partner who will provide maximum flexibility and agility to accommodate the inevitable CMC scope changes in a program, and can also bring expertise in clinical and regulatory elements. Always ask yourself the question: “Can my preferred vendor accommodate change and respond quickly to the needs of my program?” Other key attributes as always will include cost, timing and quality; however speed will always be a key driver in the rare disease CMC space.  How can Quotient Sciences help address these challenges? In the orphan drug space, Quotient is keenly aware of the need to “start with the end in mind.” Our approach has been to prioritize the key API characterization data required, which allows our scientific experts to recommend selection of the appropriate API form as well as informing a data-driven strategy for preclinical and clinical pharmaceutical development. At Quotient, we have demonstrated the benefits of embedding formulation flexibility within FIH (first-in-human) trials to enable a “patient ready” formulation to be identified and be ready for POC (proof of concept) studies in an average of 12 months, less than half the time of the industry standard. We then have unique flexibility in personalizing the manufacture and supply of patient products on a global basis. How does your company accomplish this? We accomplish this by integrating real-time manufacturing and clinical testing. Studies can start quickly with a simple FIH formulation, allowing parallel development of a solid oral format, which is introduced into a later part of the FIH protocol without the need for a separate clinical pharmacokinetic (PK) bridging study. At the end of dosing healthy volunteers in the FIH trial, the lead formulation is manufactured and supplied into the patient POC study. No further pharmaceutical development or clinical bridging work is required. This is ideally suited to rare disease therapeutics, as patient trials can be initiated with confidence in the clinical performance of the drug product. We have also developed significant expertise in providing manufacturing and supply chain solutions for challenging patient trials for over a decade. We are aware of the difficulties presented where recruitment rates are sporadic across multiple study sites in multiple countries. There may also be a need to customize the drug product based on specific patient attributes. To that end, we tailor the product manufacturing and supply based on program needs, whether with “traditional” large batch manufacturing, all the way through to the personalized “per patient” product manufacture. Our focus is on helping the customer get the right product to the right patient at the right time. Looking ahead, for orphan drug products, lean and flexible programs will be imperative to progress molecules effectively and efficiently from candidate selection through to the stage of commercialization. A flexible manufacturing and supply platform will be key and finding the right commercial manufacturing partner will be crucial, given the relatively low production volumes required and the variety of product formats. To find out more about Quotient Sciences and their capabilities, visit www.quotientsciences.com.  

Impressions: 4229


#SpeakPharma With Quotient Sciences
08 Feb 2021
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