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This compound was originally investigated as a potential new treatment for Parkinson’s disease.

In February 2015, the Company licensed exclusive world-wide rights in our adenosine receptor agonist programme, including the lead molecule CPI-444 (previously V81444), to Corvus for use in all therapeutic applications.

Corvus is looking to develop CPI-444 for immuno-oncology with clinical studies expected in 2016.

Description

This next generation antagonist was originally discovered by Vernalis. In June 2004, Vernalis and Biogen Idec entered into an agreement whereby Biogen Idec would develop molecules within the adenosine A2A receptor antagonist programme in exchange for milestone payments and subsequent royalties on future sales. Vernalis successfully regained the programme in April 2011.

  • Generated from in-house research programme
  • Programme successfully regained from Biogen Idec in April 2011
  • Partnered with Corvus in February 2015

Rationale for using A2A in immuno-oncology

A2A receptors have been identified on a range of immune and inflammatory cell types including macrophages, dendritic cells, myeloid-derived suppressor cells, T cells and NK cells. The binding of adenosine to A2A receptors suppresses the effector functions of these immune cells.  Antagonism of A2A signalling has been demonstrated to increase anti-tumour immunity predominantly through the enhancement of CD8+ T cell and NK cell depedent cytotoxicity.



Background

A2A receptors have been identified on a range of immune and inflammatory cell types including macrophages, dendritic cells, myeloid-derived suppressor cells, T cells and NK cells. The binding of adenosine to A2A receptors suppresses the effector functions of these immune cells.  Antagonism of A2A signalling has been demonstrated to increase anti-tumour immunity predominantly through the enhancement of CD8+ T cell and NK cell depedent cytotoxicity.


Pre-clinical studies

Pre-clinical studies were completed in readiness for Phase I.


Clinical studies

This programme was initially being investigated for the treatment of Parkinson's Disease.

Phase I SAD/MAD study was successfully completed in May 2012. A receptor occupancy study was initiated in August 2012, with positive results reported in December 2012.

Data from these studies was presented at the World Congress of Neurology meeting in August 2013.

In mid-2013, a Phase Ib/II POC combined safety/tolerability and pharmacokinetic study was initiated to explore the properties of the compound following twice daily dosing in adult patients with ADHD, including measuring the efficacy of V81444 using the ADHD Rating Scale (primary measure), PERMP-P measure and CGI assessment (secondary measures). The efficacy measures were conducted using the AWE Model.

Positive results of this study were announced in April 2014 showing V81444 achieved significant improvement in the number of correct scores in PERMP measure (P=0.9) compared to placebo. Although not statistically significant, V81444 also showed improvements in both ADHD Rating Scale and CGI. There were no drug related serious adverse events and no other new or significant safety findings.

In February 2015, the Company licensed the compound to Corvus.  The lead molecule, CPI-444, is a patented small molecule that has been evaluated in Phase I and II trials under an IND in the US.  Corvus is looking to develop the compound for immuno-oncology, with clinical studies expected in 2016.


Project Status

Originally discovered by Vernalis, pre-clinical studies were completed by Biogen Idec in a partnership established in June 2004. Vernalis successfully regained the rights to the programme in April 2011. With Phase I SAD/MAD and receptor occupancy studies successfully completed, Vernalis initiated a Phase Ib/II proof-of-concept study in 2013. Positive results of this study were announced in April 2014 showing V81444 achieved significant improvement in the number of correct scores in PERMP measure (P=0.9) compared to placebo. Although not statistically significant, V81444 also showed improvements in both ADHD Rating Scale and CGI. There were no drug related serious adverse events and no other new or significant safety findings.

In February 2015, the Company licensed exclusive, worldwide rights in its adenosine receptor antagonist (A2A) programme for use in all therapeutic applications to Corvus, a US-based biotechnolgoy company. At the time, the name of the company was not disclosed and nor was the initial therapeutic focus. Corvus was launched through a $33.5 million Series A fundraising in 2014 by the founder and former senior management at Pharmacyclics Inc. and it raised a further $75 million (Series B) in September 2015.

The lead molecule, CPI-444, is a patented small molecule that has been evaluated in Phase I and II trials under an IND in the US. Corvus brings a wealth of clinical and commercial expertise and experience and is looking to develop the CPI-444 for immuno-oncology, with clinical studies expected in 2016.


 

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The lead molecule arising from our Fatty Acid Amide Hydrolase research programme, V158866 completed a phase II study in spinal cord injury patients in August 2015.  It is now available for partnering.


Description

The FAAH enzyme metabolises the endocannabinoids (ECs) which are neurotransmitters acting on a range of different receptors. Inhibit FAAH, and elevated EC levels appear in the nervous system. Amongst the receptors which the ECs act upon are the CB1, CB2 and TRPV1 receptors, stimulation of which has been shown to relieve pain. ECs also act on the PPARα receptor which is known to reduce inflammation.

  • Generated from in-house research programme
  • Potentially profound analgesic response
  • Effective in pre-clinical pain models

FAAH inhibitors

May cause powerful analgesic response

Since endocannabinoids are only produced on demand, it may be that FAAH inhibitors, such as V158866, can selectively increase the local levels of neurotransmitter in tissues. This could deliver a powerful analgesic and anti-inflammatory response, without the side effects that more widespread cannabinoid receptor activation can generate.


Background

Vernalis identified Fatty Acid Amide Hydrolase as a target that might be particularly amenable to our research techniques back in 2007. V158866 was the lead molecule to emerge from this research programme, demonstrating our ability to generate promising candidates that go on to full pipeline development.

Leading players in the pharmaceutical industry are paying particular interest to FAAH inhibitor molecules, with a number of them currently in development by the major companies. Additional possible indications for the class include the treatment of anxiety and depression.


Pre-clinical studies

V158866 has been shown to be a potent and selective slowly reversible inhibitor of human FAAH1 (IC50 24nM). It has been evaluated in a series of pre-clinical pain models and has been shown to have efficacy in:

  • Carageenan-induced thermal hyperalgesia
  • Carageenan-induced inflammation
  • Mono-iodoacetate model of osteoarthritis
  • Chronic constriction injury model of neuropathic pain

V158866

It has no significant effect on locomotor function in pre-clinical models, even at high doses.

A range of pre-clinical safety and pharmacokinetic studies were conducted on V158866.


Clinical studies

Positive results were announced in September 2011 for V158866 in a Phase I SAD and MAD study. The double-blind, placebo controlled study investigating single and multiple ascending doses was conducted in healthy male volunteers. The objective of the study, to identify doses of V158866 that are both safe and well tolerated and to measure the compound's effect on FAAH activity and endocannabinoid levels, was achieved. The study has confirmed V158866 is a potent inhibitor of human FAAH and has identified once daily doses to be tested in future studies in pain or other indications.

In August 2015, the Company announced results from a Phase II POC study in which the programme was being investigated in patients with neurophathic pain as a result of spinal cord injury.  Although the dosing of V158866 resulted in elevated endocannabanoid levels, on an intent-to-treat basis, the study failed to meet its pain reduction primary endpoint. Treatment did show a trend towards efficacy on a per protocol basis and was generally well tolerated.

We do not plan to make any further investment in this programme and seek to realise its potential value through partnering.


Project Status

Pre-clinical sudies completed, clinical studies were initiated in March 2011 and the positive results of the Phase I SAD and MAD study announced in September 2011. We initiated a Phase II proof-of-concept study in 2013 and clinical study results were announced in August 2015.

We do not plan to make any further investment in this programme and seek to realise its potential value through partnering

A novel, recombinant human thrombolytic protein, V10153 is being developed for the potential treatment of acute ischaemic stroke.

  • A modified form of human plasminogen
  • Only activated to plasmin by the presence of thrombin on newly formed clots
  • Unique action, not seen in other thrombolytics
  • Long half life allowing persistence of effect and bolus administration

V10153 is a biological molecule, first developed by one of Vernalis’s predecessor companies. V10153 is human plasminogen that has been altered so that it is activated to plasmin by thrombin, rather than by the natural plasminogen activators. This makes V10153 potentially much more location-specific than the drugs currently available to tackle ischaemic stroke, and the blood clots that are its cause.

Activation by thrombin

To deliver localised effect

Most thrombolytics are tissue plasminogen activators, and so can activate plasminogen circulating in the body. Because V10153 is a thrombolytic that is only activated by the presence of thrombin (occurring on the surface of newly formed blood clots) its effect is potentially much more localised.

V10153 has a half-life of 3-4 hours so can persist in the blood as an inactive pro-drug that can be selectively activated at fresh/forming thrombi by the thrombin localised there. A key feature of thrombin-activatable plasminogen is that thrombin is only found at the sites of ongoing clotting. This novel activation mechanism results in localised plasmin generation to remove thrombi and prevent them forming/reforming. Persistence in the circulation may also reduce re-occlusion rates.

Stroke affects the blood vessels supplying the brain and occurs when an artery ruptures or becomes blocked by a blood clot. This deprives the brain of oxygen. Nerve cells in the affected area die within minutes. A severe stroke can be fatal or can leave the victim permanently disabled, as dead brain cells cannot be replaced.

There are two main types of stroke, ischaemic stroke, caused by blockage of a blood vessel, and hemorrhagic stroke, caused by bleeding. Ischaemic stroke accounts for over 80 percent of all strokes. People of all ages, including children, suffer from stroke, and it occurs slightly more commonly in men than women.

Current therapeutic options for ischaemic stroke sufferers are limited since the only current approved therapy, recombinant tissue plasminogen activator (rt-PA), must be administered within a few hours of a stroke occurring. Stroke is the third most common cause of death, behind heart disease and cancer. The market for effective and safe stroke therapeutics is considerable.

A range of studies confirm both the thrombolytic and also the anti-thrombotic effect of V10153. It has comparable thrombolytic activity to rt-PA in inducing reperfusion of occluded arteries. It is better than rt-PA at preventing reocclusion, and achieves thrombolysis with no accompanying increase in bleeding. Thrombolytic efficacy (a summation of the ability of the agent to induce reperfusion and prevent reocclusion) was clearly seen to be superior to rt-PA. V10153 has been shown to be markedly superior to heparin as an antithrombotic.

We’ve successfully completed a number of clinical studies with V10153. These included a Phase I study in healthy volunteers, and a dose escalation Phase IIA safety study in patients with acute ischaemic stroke. We also conducted a study of patients with acute myocardial infarction. With both proof of concept as a thrombolytic and the appropriate dose to study in acute ischaemic stroke established, V10153 is ready to move to the next stage of development.

V10153

Pre-clinical studies completed by Vernalis. We’ve also completed Phase I and a number of Phase II clinical studies, again with positive results. V10153 is now ready for partnering and Vernalis welcomes expressions of interest.

Latest News

FDA Issues a Complete Response Letter on CCP-08 NDA

Vernalis plc announced today that the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for CCP-08. 

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To report SUSPECTED ADVERSE REACTIONS, contact Vernalis Therapeutics, Inc. at 1-855-705-9546 and drugsafety@propharmagroup.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch