Case Study: Phase I to commercial in 18 months

Druggability Technologies CEO, Gabor Heltovics, talks about using Quotient Sciences to progress and scale-up an improved pain relief drug formulation

Druggability Technologies (DRGT) is developing DRGT-46 as a novel therapy for pain. Gabor Heltovics, CEO of DRGT, explains how Quotient Sciences enabled the rapid development, clinical assessment and commercial readiness of its DRGT46 product using integrated services across Quotient’s network of harmonised development and manufacturing sites in the UK and US.

DRGT-46

DRGT is a speciality pharma company developing an array of drugs in diverse indications with the objective of achieving measurable and meaningful improvement in their clinical utility. The company uses its proprietary platform to screen and select Super-API compositions and its portfolio contains over 30 preclinical and clinical-stage compounds.

DRGT-46 is a novel composition of Celecoxib (Celebrex), a COX-2 inhibitor prescribed for pain. Celecoxib is the only COX-2 inhibitor on the market and, although the drug is off-patent, it still commands a large share of the market.

Gabor explains “Celebrex’s use is limited in acute pain management due to its relatively long “kickin” time of 50 mins to 1.5 hrs or, if taken with food, this can be as long as 3 hrs. This is particularly important with the current opiate crisis. There is a significant need for molecules which provide rapid pain relief to remove the need for opiates.”

Fast-track and de-risk programmes

Dog pharmacokinetics (PK) data showed that unlike Celecoxib, DRGT-46 reached the required blood concentration to give onset of pain relief in under 5 mins, providing preclinical proof of concept for the molecule.

DRGT wanted to rapidly develop a clinical formulation and, if successful, a commercial product. “This is where our collaboration with Quotient became very important for us. Our objective was to transition rapidly from a preclinical formulation to a commercial drug product. We needed to develop our product as fast as possible and reduce the complexity of drug development to de-risk the whole programme,” explained Heltovics.

Quotient has reduced our time-to-clinic and time-to-market taking us from early stage to commercial in the most efficient way

“We had worked with Quotient successfully on other programmes. Our first objective for this program was to demonstrate formulation proof of concept in a Phase I clinical PK study.” The Phase I drug product was manufactured and dosed in Quotient’s UK facility using their unique Translational Pharmaceutics platform which integrates formulation development, real-time adaptive manufacturing and clinical testing to rapidly select formulations to progress to scale up. As the molecule is poorly soluble, ‘a number of solubilisation technologies were applied with a spray-dried powder in a bottle format selected for the study. “Quotient has become an extension of our project team and have knowledge of our product. They are highly interactive and committed to helping us achieve our goals,” said Heltovics.

The healthy volunteer PK showed that DRGT-46 achieved the effective concentration claimed to be needed for pain relief within 12 minutes at 10O mg or 200 mg in comparison to 45 mins for 400 mg of Celebrex.

“Therefore, having demonstrated clinical proof of concept, we decided it was important to transition from a powder in bottle to a sachet format as that would be a more suitable commercial product for the patient group. To ensure patient acceptability, the sachet product would need the inclusion of taste-masking agents,” Heltovics explained.

We decided it was important to transition from a powder in bottle to a sachet format as that would be a more suitable commercial product

The successful drug product formulation was transferred to Quotient’s development and clinical manufacturing site in Philadelphia and optimised using flavour/sweetener combinations to provide the required taste enhanced sachet format for commercial manufacture.

The Translational Pharmaceutics platform was again used in the programme to rapidly manufacture these new formulations and to evaluate and optimise the taste properties and determine the PK profile at Quotient’s clinical pharmacology facility in Miami. Again, clinical data were used in real-time to drive the manufacture of the selected drug product formulation composition for this pivotal PK study.

Unique therapy for acute pain

“The optimised product developed by Quotient showed an even better PK profile in the pivotal study than in the Phase I study. The expected time to onset of action was reduced even further to 8 mins rather than 12 mins. This final drug formulation gives us a unique COX-2 therapeutic for the management of acute pain. This hasn’t been possible before now.”

Gabor Heltovics, CEO of DRGT

“The final stage of the programme was to scale the process to meet late-stage clinical and commercial needs, and develop process robustness and stability data to support product registration.”

Following the identification of the commercial formulation, the spray-drying process was scaled up alongside the establishment of suitable blending and granulation process trains. Manufacturing design spaces for the critical process steps were then identified to support the late-stage clinical and registration batch production.

In parallel, later-stage product development activities such as packaging development, longer-term stability studies and method validation were performed to efficiently transition the product to being commercial ready.

DRGT used the Translational Pharmaceutics platform twice; to clinically validate early formulations in the UK; and to optimise a commercial formulation in the US. “We are now moving rapidly to a Phase III multi-site clinical trial. While the Phase I pivotal study was ongoing, we continued to work with Quotient on the CMC and process scale up to get us ready for the late clinical stages and commercialization. As a result, Quotient will manufacture the drug product for the Phase III study.”

The optimised product developed by Quotient showed an even better PK profile in the pivotal study than in the Phase I study

Working with a development and manufacturing partner with integrated capabilities across countries and continents was so important for DRGT. Gabor explained: “Quotient has become an extension of our project team and has built up considerable knowledge of our product. Their internal capabilities and knowledge extend well beyond traditional CDMO services, with expertise that includes regulatory affairs, biopharmaceutics and medical research. This means we can access skills and resource as required, rather than investing in setting up those functions internally. For small companies like DRGT, Quotient’s project management team means we can rely on them to maintain timelines and work within an agreed budget.”

Through its partnership with Quotient Sciences, DRGT has clinically demonstrated that its novel drug product, DRGT-46, may have a significantly faster onset of action than Celebrex and at a lower dose. “In working with Quotient, we have been able to bridge from Phase I product to commercial ready in 18 months which really is remarkable!”

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