A valued client, BugWorks Research, approached ApconiX to help them investigate the effect of intracellular pH on the inhibition of hERG potassium channel. At different pH, molecules might carry a different charge, depending on their structure. This may affect the molecule’s activity at hERG. Their enquiry followed some unexpected hERG inhibition by their compounds and the discovery of a paper published in 2016 by Wang et al. The paper showed that dofetilide, a known hERG blocker, had a quicker onset of effect at lower intracellular pH than under standard conditions. As shown in Figure 1.
Figure 1: Decreased time to effect of dofetilide at intracellular pH 6.2 versus pH 7.2 (from Wang et al., 2016)
Electrophysiology experiments were performed on the Patchliner automated patch-clamp system (Nanion Technologies). These experiments showed no significant difference in the onset of dofetilide inhibition at lower intracellular pH, as illustrated in figure 2.
Figure 2: No change in time to effect of dofetilide on hERG current at pH 6.3 versus pH 7.3.
There is limited literature in this area. ApconiX found a second paper by Du et al., 2011, which reported no effect of intracellular pH on hERG inhibition by dofetilide, contesting Wang’s original data.
Based on data from ApconiX and others, it is unlikely that intracellular pH is affecting the onset of hERG inhibition. Changes in intracellular pH that might affect the charge of a molecule does not, in this case, explain unexpected hERG inhibition.
Du et al (2011) Enhanced inhibitory effect of acidosis on hERG potassium channels that incorporate the hERG1b isoform. Biochem Biophys Res Comm 405, 222–7
Wang et al. (2016) Role of the pH in state-dependent blockade of hERG currents. Scientific Reports 6: 32536
“Your data turnaround time is incredibly good and it really helps us track the SAR and progress our compounds in a rapid and efficient manner. Thanks ApconiX for your wonderful support to Bugworks.”
V Balasubramanian, PhD, Bugworks Research India Pvt. Ltd.
“Working with ApconiX has been effortless! They have provided high quality target safety assessments with a focus on comprehensive interpretation of findings. The information provided has helped contribute to decisions on activities when moving early molecules forward. ApconiX constantly meets or exceeds timelines, while still providing flexibility to fit in last minute requests without impacting previously scheduled work. It has been a pleasure to work with Ruth and her team.”
The U.S. Food and Drug Administration’s National Center for Toxicological Research (NCTR) is a global resource for collaboration providing consultation, training, and innovative scientific solutions in support of FDA’s mission to improve public health. Within NCTR, The Division of Bioinformatics and Biostatistics is developing bioinformatics methodologies and standards to support FDA research and regulation for regulatory and translational sciences. The Division, led by Weida Tong, has tremendous expertise in computational biology, molecular modeling and quantitative structure-activity relationships (QSARs) and a wealth of new data and ideas to disseminate. ApconiX was set the challenge to help refine and deliver a publication and communication strategy as well as helping to define new areas of potential impact for the team’s expertise.
We worked closely with the team at NCTR in individual and in syndicate sessions to identify key messages and match them to publication opportunities. Based on the strength of the teams, we focused on two of their flagship projects: developing and applying new computational approaches to the challenge of drug-induced liver injury (DILI) and to in vitro to in vivo extrapolation (IVIVE). Using the expertise of individual scientists, we worked one-to-one to author papers through from first draft to submission and response to reviewers’ comments.
By performing a systematic analysis of the new and unpublished data the team had generated, we developed a clear publication and dissemination strategy to maximise the impact of the team’s current and ongoing work.
The collaboration has resulted in the submission of 5 papers in just 12 months. In DILI, the in vitro to in vivo extrapolation (IVIVE) methodology and liver knowledge toxicology base (LKTB) classification of human liver injury papers are in press and a third paper on gene signatures is submitted 1-3. In the area of drug repositioning, a TiPS paper on computational approaches to analyse two decades of experience of anti-cancer drugs was recently published 4 and a second paper looking for new opportunities in rare diseases 5 is in press.
Liu, Z, Delavan, B, Roberts, R and Tong, W (2018). Gene Signature Reveals Differences among Preclinical Testing Systems for Rat Liver. Frontiers in Genetics. Submitted.
Thakkar, S, Chen, M, Fang, H, Liu, Z, Roberts, R, Tong, W (2018). The Liver Toxicity Knowledge Base (LKTB) and Drug-Induced Liver Injury (DILI) Classification for Assessment of Human Liver Injury. Expert review of Gastroenterology and Hepatology. 12, 31-38. https://doi.org/10.1080/17474124.2018.1383154
Liu, Z, Fang, H, Roberts, RA and Tong, W (2017). In vitro to in vivo extrapolation (IVIVE) for drug-induced liver injury: A genome wide analysis using a drug pair ranking (DPRank) method. ALTEX. https://doi.org/10.14573/altex.1610201
Delavan, B, Roberts, R, Goldsmith, J, Fang, H, Thakkar, S, Huang, R, Bao, W, Tong, W and Liu, Z (2017). Computational Drug Repositioning for Rare Diseases in the era of Precision Medicine. Drug Discovery Today. In press Dec 2017. DOI: http://dx.doi.org/10.1016/j.drudis.2017.10.009
‘It has been a tremendous pleasure to work with Ruth @ApconiX for the past year. Her in-depth knowledge in toxicology in general and drug discovery/development in specific has contributed significantly to my division’s research in the area of drug-induced liver injury and in vitro to in vivo extrapolation. I am expecting much great science will come out from the close collaboration with Ruth’.
Weida Tong, Director, Division of Bioinformatics and Biostatistics and NCTR/FDA
Our client had identified a clinical candidate aimed at a novel tumour target, with promising activity against a range of cancers. Upon completion of suitable GLP toxicity studies, the company intended to move into Phase I in patients, in combination with chemotherapy. There were a number of pressing issues, including choice of the appropriate nonclinical species, dosing schedule, achieving adequate exposure as well as the potential for greater target organ toxicity when dosed in combination.
ApconiX joined the client’s project team by providing a dedicated project toxicologist, supported by our other experts. With a clear understanding of the project goals and clinical objectives, we delivered a bespoke, focussed nonclinical safety package designed to ensure the right data were provided for regulatory success and rapid initiation of the Phase I patient studies.
A study that provided safety and DMPK data on the novel agent dosed with chemotherapy was also designed and conducted. Although not a regulatory requirement, this allowed a better understanding of the impact of the combination and supported a higher start dose in combination with chemotherapy.
ApconiX managed all aspects of the preclinical safety package, working closely with CROs to ensure appropriate study design, costs, dose level selection, data interpretation as well as timely delivery of quality study reports. Concurrently, we authored the nonclinical sections of the regulatory submission documents and represented the client at a regulatory agency meeting.
With ApconiX as part of the team, our client benefited from our many years of collective experience in preclinical safety, DMPK and drug development. The package was designed to ensure regulatory and clinical objectives were met, keeping to budget and agreed timelines.
The Clinical Trial Authorisation was approved, allowing the compound to move into clinical trials, in combination with chemotherapy. During this phase, we also assisted in the out-licencing of this asset to a third party. We continue to work with the new owners to ensure its further success.
“The support that we received from the ApconiX team has been excellent and they have helped us both in developing our nonclinical safety thinking and in providing direct support for the clinical trial application. We’re looking forward to continuing our collaboration as we progress our exciting new medicines into later-stage development and hopefully the clinic”
Dr. David Cook, Chief Scientific Officer, Blueberry Therapeutics
“ApconiX has provided hERG data to Redx Pharma from June 2016 to help support our discovery projects. Data turnaround times over this period have been rapid (under 1 week) and this has been critical in progressing projects quickly; outsourcing the assay with this turn-around has had no impact on our “design-make-test” cycle times.
Additionally, ApconiX’s approach is very collaborative providing expert advice on these data as part of their service. Another vital component to this screening is flexibility over compound numbers which enables us to maintain progress during the peaks and troughs of compound supply and prevents delays which can occur if you have to wait to reach a trigger point for submission of an assay.”
“It has been a tremendous pleasure to work with Ruth @ApconiX for the past year. Her in-depth knowledge in toxicology in general and drug discovery/development in specific has contributed significantly to my division’s research in the area of drug-induced liver injury and in vitro to in vivo extrapolation. I am expecting much great science will come out from the close collaboration with Ruth”
Weida Tong, Director, Division of Bioinformatics and Biostatistics and NCTR/FDA
“We would not be here without your excellent input and help. You and ApconiX have been absolutely fantastic. Great planning and execution…..strong, straightforward communication…..pragmatic and a strong sense of team”
“Toxicology and functional electrophysiology assessments are essential aspects of the drug discovery and development process to ensure the safety of a potential drug prior to administration in humans. The specialists at ApconiX are world renowned scientists in non-clinical safety strategies and their skills will be of great benefit to our clients. The alliance between Sygnature Discovery and ApconiX will be mutually beneficial and together we can offer a more comprehensive integrated approach to any clients’ drug discovery programme.
We are very much looking forward to working with ApconiX and introducing them to our clients.”
“We are delighted to have found a flexible way to access specialist technical expertise and operational support to complement our existing internal capabilities to support the ongoing development of our lead product, SFX-01. We selected this excellent group of providers as our partners as they have a proven track record of working well together and they are all co-located at Alderley Park where we too have a presence.”
Dr Stephen Franklin, Founder and CEO, Evgen Pharma
Redx Pharma is a drug discovery and development company focused on creating new drugs for areas of unmet medical need such as cancer and immunology. As their portfolio rapidly matured, Redx recognised a need for expert safety input as well as ion channel screening data, to develop high quality clinical candidates.
ApconiX was engaged by Redx in 2016 as a strategic partner to providenonclinical safetysupport to the portfolio. In this role, we provided ion channel screening services and project toxicology expertise to the Redx oncology, infection and inflammation business units.
Through this relationship, Redx had flexible access to the entire team of nonclinical safety experts, without needing to build this capability internally. Our experts worked closely with Redx scientists, to provide guidance on nonclinical safety and DMPK strategy, as well as gap analysis, data interpretation and advice on next steps. For the lead programs entering GLP toxicity studies, we worked with Redx to influence study design and decision-making, as well as data interpretation. We co-authored the submission documents and participated in regulatory agency interactions.
In this extremely successful partnership, we have developed a model relationship with Redx Pharma. For the two most advanced projects, one was successfully divested to a US biotech, and the other achieved a successful CTA, with the first cancer patients dosed in February 2018 (https://goo.gl/kfMv9p).
We continue to work closely with Redx to deliver the next wave of novel medicines to patients.
Blueberry Therapeutics is a dermatology biotech company developing innovative topical drugs for a range of diseases, using a novel ‘nano-delivery’ platform. This technique significantly enhances the penetration of drugs into cells and tissues. ApconiX was set the challenge to provide guidance on the most appropriate nonclinical safety studies needed to support the clinical development of Blueberry’s new treatments for fungal infection.
We worked closely with Blueberry scientists to develop an innovative strategy to support the initiation of clinical studies on their lead compound. We started by identifying the specific scientific questions that needed to be addressed and focusing on the data needed to answer them. By utilising existing information from numerous sources, we were able to build a case to present to regulatory agencies that sufficient evidence was already available to support the safe use in clinical studies.
By performing a systematic analysis of published data, we developed a clear scientific rationale to support the proposed clinical trial design, without the need for further nonclinical studies to support ‘First time in Man’ testing.
This work was discussed at a successful face-to-face meeting with European regulators resulting in approval for Blueberry to begin clinical testing of this novel therapeutic agent.
“The support that we received from the Apconix team has been excellent and they have helped us both in developing our nonclinical safety thinking and in providing direct support for the clinical trial application. We’re looking forward to continuing our collaboration as we progress our exciting new medicines into later-stage development and hopefully the clinic”
Dr. David Cook. Chief Scientific Officer, Blueberry Therapeutics
“I’ve worked with Guy Healing for the last year on CTA/IND enabling toxicology studies for 2 compounds. Guy did a fabulous job as a study monitor and toxicology consultant for the 15 studies in total placed at CROs in UK and Germany. As I am based in the US, Guy was pivotal in bridging both the time-zone difference and cultural differences with the CROs. He traveled to both CROs to conduct thorough audits of the studies and facilities providing timely and superb audit reports. Guy was also very helpful in pulling in needed expertise in other areas either via his colleagues at ApconiX or an external pathologist. Guy has great communication skills and is a real pleasure to work with!! He is very knowledgeable and a great resource for toxicology advice.”