ArQule receives orphan drug designation for ARQ 092 in Proteus syndrome

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ArQule and the National Human Genome Research Institute of the National Institutes of Health Announce Enrollment of First Patient in the Phase 1 Proteus Syndrome Trial With ARQ 092

BURLINGTON, Mass., Nov. 17, 2015 (GLOBE NEWSWIRE) — ArQule, Inc. (NASDAQ:ARQL) and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) today announced enrollment of the first patient in the phase 1 clinical trial for Proteus syndrome. This trial, with ARQ 092, an orally available, selective pan-AKT inhibitor, marks the first clinical trial in this rare disease. Proteus syndrome is characterized by overgrowth of the skeleton, skin, adipose tissue and central nervous system.

Additionally, ArQule received orphan drug designation from the Federal Drug Administration (FDA) for ARQ 092 in Proteus syndrome. This marks an important regulatory milestone and the first orphan drug designation for this population. Proteus syndrome impacts fewer than one in a million people worldwide.

In 2011, an NHGRI team led by Dr. Leslie G. Biesecker discovered that the somatic single (point) mutation in the AKT1 oncogene causes Proteus syndrome1. Subsequently the NHGRI team presented at the 2014 meeting of the American Society of Human Genetics (ASHG, Abstract # 2180M2) data that demonstrate that treatment with ARQ 092 caused a rapid shutdown of AKT signaling and a reduction in the viability of Proteus syndrome cells taken from patients compared to untreated diseased cells. These findings provided pre-clinical proof-of-concept for advancement of ARQ 092 into clinical testing for Proteus syndrome.

“The collaboration with ArQule has provided an opportunity to initiate a phase 1 trial to investigate the therapeutic impact of ARQ 092 in a rare, genetic disorder that has no approved therapy and for which the only current treatment is surgery,” said Dr. Leslie G. Biesecker, M.D., Chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute. “The goal of the trial is to identify a safe and effective dose to treat Proteus syndrome patients soon after diagnosis. It is hoped the drug, if shown to be safe and effective and approved by the FDA to treat Proteus syndrome in the future, could potentially be administered over many years in order to mitigate the abnormal cell signaling initiated by the point mutation.”

“We are excited to continue our collaboration with Dr. Biesecker and the NHGRI team on the first therapeutic drug clinical trial launched for Proteus syndrome,” said Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. “Proteus syndrome is the first rare disease indication to enter phase 1 for ARQ 092, and we are pleased to have received orphan drug designation from the FDA. We are also making progress with ARQ 092 in oncology where we have observed five partial responses in the phase 1b trial in patients harboring AKT1/PI3K mutations. We hope Proteus syndrome patients, with the same mutation, will achieve comparable clinical benefit once a therapeutic dose is established.”

The phase 1 trial for ARQ 092 in Proteus syndrome, being conducted by the NHGRI, is a biodynamic dose finding study. ArQule will be providing ARQ 092 for the trial.

About Proteus Syndrome

According to the patient advocacy and support group, the Proteus syndrome Foundation (, the condition was named for Proteus, the Greek god who could transform his shape. Patients experience changes in the shapes of certain body structures over time, including abnormal, often asymmetric, massive growth (overgrowth) of the skeleton, skin, adipose tissue and central nervous system out of proportion to the rest of the body, which may appear normal. Although patients may have minimal or no manifestations at birth, the disease develops and becomes apparent in early childhood (6-18 months) and rapidly progresses with intense growth in the first ten years of life. It is primarily a childhood-onset disease but there are very few living affected adults.

Proteus syndrome is a rare condition with an incidence of less than 1 in 1 million people worldwide. Only a few hundred individuals have been reported in the medical literature. At this time, there are more than 120 documented cases worldwide, but because not all cases are documented, it is not known how many individuals have this syndrome. The incidence of Proteus syndrome classifies it as a rare disorder, defined by the National Organization of Rare Diseases (NORD) as any disease affecting fewer than 200,000 Americans.

About ARQ 092 and the AKT Pathway

ARQ 092 is an orally available, selective small molecule inhibitor of the AKT kinase. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications.

ARQ 092, the lead compound in ArQule’s AKT program, has completed Phase 1a clinical testing and has advanced into Phase 1b expansion testing in cohorts of patients with endometrial cancer, lymphoma and tumors harboring either AKT or PI3K mutations. A number of next-generation compounds in the Company’s AKT program are in early to late stages of pre-clinical development.

About ArQule

ArQule is a biopharmaceutical company engaged in the research and development of targeted therapeutics to treat cancers and rare diseases. Our mission is to discover, develop and commercialize novel small molecule drugs in areas of high unmet need that will dramatically extend and improve the lives of our patients. Our prioritized clinical-stage pipeline consists of four drug candidates, all of which are in targeted, biomarker-defined patient populations, making ArQule an early leader in precision medicine. ArQule’s lead product, in Phase 2 and Phase 3 clinical development, is tivantinib (ARQ 197), an oral, selective inhibitor of the c-MET receptor tyrosine kinase. The Company’s pipeline includes: ARQ 092, designed to inhibit the AKT serine/threonine kinase; ARQ 087, a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family; and ARQ 761, a Beta lapachone analog being evaluated as a promoter of NQ01-mediated programmed cancer cell necrosis. ArQule’s current discovery efforts are focused on the identification of novel kinase inhibitors, leveraging the Company’s proprietary library of compounds.

This press release contains forward-looking statements regarding the Company’s clinical trials with ARQ 092. These statements are based on the Company’s current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about pre-clinical and early stage clinical trial results, including in Proteus syndrome, does not ensure that later stage or larger scale clinical trials will be successful. For example, ARQ 092 may not demonstrate promising therapeutic effect; in addition, it may not demonstrate appropriate safety profiles in current or later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards or to justify further development. Problems or delays may arise during clinical trials or in the course of developing, testing or manufacturing these compounds that could lead the Company or its partners, including the National Institutes of Health, to discontinue development. Even if later stage clinical trials are successful, unexpected concerns may arise from subsequent analysis of data or from additional data. Obstacles may arise or issues may be identified in connection with review of clinical data with regulatory authorities. Regulatory authorities may disagree with the Company’s view of the data or require additional data or information or additional studies. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product.

Positive pre-clinical data may not be supported in later stages of development. Furthermore, ArQule may not have the financial or human resources to successfully pursue drug discovery in the future. For more detailed information on the risks and uncertainties associated with the Company’s drug development and other activities, see the Company’s periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forwardlooking statements.

1 N Engl J Med 2011; 365:611-619, August 18, 2011

2 Sci Reports, In Press


Dawn Schottlandt

Sr. Director, Investor Relations/

Corp. Communications

(781) 994-0300

Primary Logo

Source: ArQule, Inc.

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Patron – Joe Drake

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Joe has been a huge benefit to the PSF UK since he joined us as a patron, supporting the Thames 1000 fundraising event. He attended the event and met the participants at the finish line.


Joe also invited to his appearance as Romeo in a Rose Theatre production of the classic Shakespeare play in March this year. Amanda and I went to see the show that was powerful, exhilarating and edgy with amazing choreography and music. The Collins family also went along to watch the show and thoroughly enjoyed it. Joe arranged a collection at the shows and this raised over £300 for the PSF UK.

Segmental overgrowth

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Segmental overgrowth – printed with the permission of Mandy Sellars from her website

Mandy writes – Back in 2012 I was a patient at Addenbrookes hospital in Cambridge where two amazing doctors, Dr Robert Semple and Dr Vicki Parker had been researching my condition using DNA sequencing. Their result was utterly amazing and something that I never thought would happen in my lifetime. They had found the faulty gene that causes the overgrowth in my legs and feet, which also indicated that my upper body is not affected by this gene mutation. This turned out to be a single letter mutation in the PIK3CA gene. I was the first person in the world to be discovered with this exact gene mutation, which is something that I am extremely proud to say.

What follows is information from my doctors in to Segmental Overgrowth which includes the PIK3CA mutation:

What is segmental overgrowth?

Segmental overgrowth describes a condition where there is an excess of growth in different parts of the body, but normal growth elsewhere. Examples of this include:

·         PIK3CA related overgrowth spectrum (PROS)

·         Congenital lipomatous overgrowth, vascular malformations, epidermal naevi and skeletal abnormalities (CLOVES)

·         Macrodactyly

·         Macrocephaly-capillary malformation (M-CM)

·         Proteus syndrome

·         Klippel-Trenauney Syndrome (KTS)

What causes segmental overgrowth?

Segmental overgrowth disorders have recently been shown to be caused by changes in genes (genetic mutations) which cause key growth signals in cells to be switched on all of the time. The genes in which these mutations have been found include;

·         PIK3CA

·         PIK3R2

·         mTOR

·         AKT1

·         AKT3

Is this an inherited condition?

These conditions are not inherited in the usual way from parents, and are equally not passed onto children. A genetic mutation occurs early on in pregnancy in a single cell when the foetus is just a tiny ball of cells. As just one cell is affected at this time, only some parts of the body are affected, whilst other parts grow normally. The genetic mutation occurs because the cell makes a mistake in copying DNA when dividing to create a new cell; there are no known in utero triggers for this.

Will the overgrowth ever stop?

In some patients, overgrowth continues into early adulthood and then slows down or stops, but in others, growth continues into adult life. At present there is no way of predicting whether someone will keep growing or not, but research efforts are underway to answer this question.

Is there an increased risk of cancer?

Many of the genetic mutations found in segmental overgrowth conditions are also found in cancers. However, cancers have lots of different genetic mutations and current scientific evidence suggests that the gene changes found in segmental overgrowth do not trigger cancer. The current reported rate of cancers is low in patients with segmental overgrowth, however future research studies are needed to determine the true risk, and in the meantime, your doctors will monitor you or your child closely for this.

Are there any available treatments?

At present the main treatment for overgrowth is surgical removal of tissue, or operations to slow down growth. However, finding the genetic cause of these conditions has opened up the possibility of treatments with drugs that may be able to stop or slow down overgrowth. If you or your child is severely affected, your doctor may discuss with you a treatment called sirolimus (rapamycin) or everolimus. These drugs help to slow growth in cells, and there is a small amount of evidence to suggest these may help in some forms of segmental overgrowth.

We are currently setting up a trial in patients with PIK3CA related overgrowth (PROS) to see if sirolimus is better than sugar tablets (placebo) at reducing overgrowth. If you are interested in treatments or wish to know more about our trial please you can check our clinical trials page for more details.

How do I get myself or my child tested?

As part of our research study, we can test for the gene changes commonly found in segmental overgrowth conditions, and can be contacted directly to organise this via our email address: Alternatively, you can discuss testing with your GP or local doctor. In order to test, doctors will need to look at DNA taken from an affected area of overgrowth, and this may require taking a small sample of skin (skin biopsy).

You can also take a look at the Facebook and Twitter pages for more information:

Proposals for super specialised clinic for segmental overgrowth disorders

I was invited to attend a meeting with Dr Rob Semple and Dr Victoria Parker from Addenbrookes Cambridge.

Other attendees were Miss Rachel Knox, Ms Leena De Silva and Mr Graeme Clark from Cambridge, Professor Peter Mortimer, Dr Sahra Mansour and Dr Glenn Brice from St George’s Hospital, London, Dr Veronica Kinsler, Dr Anna Matinez, Dr Lindsay Shaw from GOSH and Professor Jill Clayton-Smith from Manchester.

Patient Support Groups represented were Mandy Sellars and Sue Harper for GoPI3Ks, Ms Lorraine Yeomans and Ms Julia Higgins from M  and Jean Harrison and Sarah Gardiner from the Proteus Family Network.

The meeting discussed proposals for setting up regional clinics for segmental (mosaic) overgrowth disorders including those mentioned in the information from Mandy Sellars.

We discussed locations of these clinics and the most likely locations are London, Manchester and Cambridge.

The support groups that attended were asked to survey their members in order to influence and support the clinic proposals that were going to the NHS. We need to demonstrate that these clinics will not require additional funds and may actually save the NHS money. Some of you will have received surveys and thank you to those who returned these. The results have been passed on to Cambridge and we await the results.

How to get tested for the AKT1 mutation /get your Proteus diagnosis confirmed

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Dr Robert Semple has explained:

Any who are interested in genetic testing, especially those who do not have easy access to this through their existing doctors (for example in Manchester or at Great Ormond Street) are welcome to contact the Cambridge team (details below) to discuss how this can be arranged most easily.

Sometimes testing can be organised by arrangement with local hospitals, or using stored tissue samples where relevant, but often a trip to Cambridge is be required for consultation and skin biopsy. Travel costs are reimbursed for research visits, and every effort is made to work around patients work and school schedules and other commitments.

Dr Robert Semple FRCP PhD

Reader in Endocrinology and Metabolism,

University of Cambridge

Wellcome Trust-MRC Institute of Metabolic Science,

Level 4, Addenbrookes Treatment Centre

Cambridge CB2 OQQ UK

Tel: +44 (0)1223 769035

Fax: +44 (0)1223 330 598


Or contact:

Dr Victoria ER Parker MBBS MRCP

Box 289 Level 4 WT-MRC IMS

ATC Addenbrooke’s Hospital

Cambridge CB2 0QQ

01223 768455

Trials for PIK3CA and other overgrowth conditions are already underway.

Research and drugs trial update

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I attended the Proteus conference in Bethesda, USA from 17 to 19 September 2015. Dr Les Biesecker and his team have been successful in getting agreement to run a drugs trial.  You will recall that his team discovered the gene that causes Proteus (AKT1), back in 2011. This followed around 19 years of research involving patients from around the world who gave tissue samples from biopsies and surgeries. The research looked for the gene mutation in around 3 billion possible changes, so a mammoth task.  Funding provided by PSF in America and our UK group helped with the research, allowing use of new technologies, such as next generation sequencing. AKT1 is a protein involved in signalling, these processes are essential to cell growth, telling cells to grow, to not grow or to die or divide. You can still read about finding the cause at:

The pharmaceutical company ArQule are on board with the drugs trial and have been using ARQ 092 for some time, treating some forms of cancer. The drug targets the AKT1 mutation that causes Proteus. The drug treatment is intended to deactivate or “calm down” the AKT1 effect. ARQ 092 achieves this in the laboratory but also in cancers so Dr Les Biesecker and ArQule are confident that it can work on Proteus.

The objective of the drug treatment is to inhibit the effects of AKT1 and allow normal growth signals. It does not kill the cells with the gene change. Remember that Proteus is a mosaic condition and not all cells have the AKT1 mutation.

Very low side effects are expected and the treatment would be long term. AKT1 is known to regulate insulin so one expected side effect would be an increase in blood sugar. This is manageable.

The FDA have now given approval for the trial. The design of the study (to test the drug) involves giving a dose of the drug and measuring the effect in the tissues.  The dosage can then be adjusted up or down.  Tissue samples would be collected before the drug was administered and patients in the drug trial will receive a low dose to start with. Tissue would be collected again and the activity of AKT1 would be measured again.  They are aiming for a 50% reduction in activity and the drug can be adjusted to achieve this.  There are rigid protocols for the study which are not individually tailored.  To begin with this will involve a 4 week stay at National Institutes of Health, Bethesda, USA.  This will involve blood test, urine tests, genetics examinations, ECG, MRI etc. The first week would involve being an inpatient at NIH, the next 3 weeks as an outpatient (although people living a distance from NIH could apply to live on the site).  Thereafter visits every other month.  The study would continue over a period of one year. Anyone on the drugs trial, where success is identified can receive the drug cost free.

PSF UK have a new Patron

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I have some amazing news to share with you all – we have a new patron to sit along side John Hurt. We are very honoured to welcome Joseph Drake to our charity. This is what he had to say:

JosephDrake“I recently played Joseph Merrick in a television drama set in Victorian London. It was a moving experience, also an inspiring one.

He was a young man who suffered great pain at the hands of Proteus Syndrome, and yet without his strength of spirit and the help of numerous professionals and loved ones, his short life would’ve been an even harsher ordeal.

I am therefore incredibly proud to become a patron of the Proteus Syndrome Foundation, a vital charity that provides much needed support and care for sufferers of this debilitating condition.

The PSF is doing superb work in the attempt to find a cure for Proteus, and though there has been great progress, with the cause gene having been discovered, the urgent search for the cure continues. Due to the relative rareness of the condition, it is proving difficult to spur the pharmaceutical companies into action, so we need all the help we can get. 

I care passionately about this cause and I’m really keen to help in any way possible”.

Joseph Drake

Progress report from the Biesecker Lab at NIH

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It  was  great  to  see  so  many  of  you  involved  in  the  PSFs  at  the  US  and  UK  meetings this fall!   Congratulations to Kim, Tracey, and all the hard-­‐working  and dedicated PSF Board Members for putting on two great events!

As those of you who attended the meetings or watched the talks on-­line (see link below) may know, all of us in the NIH Proteus group are very excited about new avenues of research that have opened to us since we identified the genetic cause of Proteus syndrome.  We are very hopeful that this discovery will improve our understanding of why patients with Proteus syndrome have overgrowth and that this knowledge may lead to better treatments for the condition.

Dr. Biesecker and Julie Sapp recently met with a drug company to start talking about a possible drug treatment for Proteus syndrome.   Because of confidentiality agreements, we cannot share lots of concrete details at this time, but we left the meeting  quite  encouraged  about  the  potential  to  start  a  trial  of  a  new  drug  in patients with Proteus syndrome and we are optimistic that this trial could have promising results.

One  thing  that  we  talked  about  at  the  PSF  meetings  was  how  the  research  here  at NIH could evolve as we orient ourselves around the goal of trying new treatments for Proteus syndrome.  There are still many experiments we need to do and many procedures we need to put in place before we can start seeing patients as part of a drug trial, but we are working very hard on these problems and hope that we can provide more information soon.  In the meantime, it is a great idea to be sure that Kim and/or Tracey have up-­‐to-­‐date contact information for your family so that they can keep in touch with you about our progress.  As well, an important goal for the foundations is to help identify as many patients as possible who might be eligible for the next phase of the research.  It is often said that there is emotional power in numbers,  but  in  this  case  it  is  emotional  and  scientific  power  that  we  need  to generate!

Thank  you  again  to  the  PSF  Board  and  Membership  for  a  great  set  of  meetings  and for all you do to partner with us in our research!


Video coverage of PSF conference in USA

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Dear all

Jordan and I attended the Proteus conference in USA last weekend (8th Oct). We were very lucky to have volunteers to both record and edit the footage.

This means you can listen to all the speakers in the comfort of your own home!

There are talks by Les Biesecker, Dr Michael Cohen, Laura Tosi (orthopaedic surgeon), Barbara Biesecker (genetic counsellor), Tom Darling (dermatology) and also by individuals affected by Proteus. You can hear first hand about the research and the way forward.

I hope you enjoy watching and listening. Our videographer offers her apologies that there may be some places in the video that are not perfect but hopes it is a wonderful experience for all.



When you open the site below, look on the right of the home page and select each topic individually when you are ready to listen and watch.

To view and download, go to:


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Dr. Biesecker is now in communication with pharmaceutical research companies to develop and test drugs that may be useful for patients with Proteus Syndrome.

UK medical and family conference 24/25 September 2011

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UK medical and family conference 24/25 September 2011 – attended by Dr Leslie Biesecker and Julie Sapp from NIH

Contact Tracey whitewood-Neal for more information –

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