Neuroderm BouNDless

Introduction

This Study is an example of the next generation of levodopa-based therapy for the treatment of Parkinson’s. The target audience for this Phase 3 trial is the community of PwPs who have spent some years under the yoke of Parkinson’s.

Is this you? You will have been reliably levodopa-responsive for several years, but are now keenly aware of the persistent, creeping reduction of On Time. The quality of On Time is deteriorating courtesy of fellow travellers bradykinesia and dyskinesia with possibly the occasional unpredictable dose response failure. The practicalities of oral medication are no longer coping with the “progress” of your Parkinson’s motor functions.

Imagine …

Let’s step away from the complexities of biology and biochemistry for a moment and consider the situation in a simple thought experiment. You are now inside your body and have been put in charge of finding and implementing a  substantially better way of moving levodopa from the mouth to the blood-brain barrier according to the demands of your customer, the brain. You discover that more than 80% of the levodopa package vanishes during in this journey, and shipments may not reach the blood-brain barrier at all.

The vanishing act begins as soon as the pill is popped because levodopa is a prodrug, a type of drug that is inactive until it is converted in the body into an active ingredient, in our case dopamine. The problem, to make it clear, is that conversion begins straightaway and  so time is of the essence from the perspectives of both the drug in the package and the brain. Furthermore, this thievery is happening despite guarding the shipments with carbidopa (e.g., in Sinemet) or benserazide (e.g., eg in Madopar). To add to the challenge your customer is now demanding more frequent and precise deliveries as the brain’s dopamine factory warehouse can no longer manage the stock of its own product.

On further investigation you establish that the two largest losses by proportion are to the intestines and the liver. Together they are responsible for more than half of each and every levodopa package being converted to dopamine before they get anywhere near the brain.

What Would You Do ?

What options are open to you to improve delivery of the goods? Constricting blood flow to the liver sounds like a bad plan, so what can be done with or in the intestines?

We know that most of the transfer of levodopa through the gut wall happens in the small intestine, not the stomach. The Duodopa intestinal levodopa gel pump (Duopa in the US) is derived from this clinical observation, although the science of the transfer is not so clear. It is a proven method, safe and well tolerated. It requires the permanent  installation of a tube through the abdomen and is therefore invasive and can only mitigate the main problem.

Can we cut out the middleman?

Yes we can. Cue the next generation of levodopa delivery techniques, subcutaneous infusion and  thereby absorbed into the bloodstream.

It is interesting to note that the first such trial (in the UK) was the Abbvie (ABV-951) therapy, because Abbvie owns the Duodopa/Duopa pump  method.  They either see the posssibility of both therapies co-existing because they will appeal to different PwP communities, or they are relaxed about the intestinal pump loosing its audience to the subcutaneous method. We shall see.

The science of subcutaneous infusion transfer to the bloodstream is relatively straightforward, and clinical implementation is already proven in many different circumstances such as diabetes and palliative care. These applications and others have created a large competitive marketplace for infusion pumps and the associated consumables such as cannulae. The Parkinson’s therapies take advantage of this, but the devil is in the detail, and the detail here is how the levodopa formulation, by its nature slightly acidic, can safely be infused day in day out in a domestic environment.

AbbVie and BouNDless employ notably different approaches to the delivery of the medication, but otherwise both studies have similar characteristics: a long study period, a complicated trial protocol (notably the conversion and calibration phase for the infusion itself), the double-blind double-dummy investigation phase, and considerable amounts of data collection. Both require, as in “obligatory”, the involvement of a partner who will be trained in the infusion process and clinical paraphenalia. Both studies have post-trial open label arrangements.

The study material provided to the BouNDless Site Investigation Team (locally, the Lind Centre at Derriford Hospital) is of a high standard, as is the material and face-to-face support provided to the participants to train them for the daily infusion process.

Participant Information Sheet

The Participant Information Sheet is a heavyweight 28 pages that is not a bed-time read. (By the way, 10/10 for “Participant”).

Participant Information Sheet, Neuroderm ND0612

 

Partner Information Sheet

The Partner Information Sheet makes it clear that this trial is a joint enterprise. The active support of a Partner is mandatory.

Partner Information Sheet

 

Genetic Extension Study

An option for Genetic Testing consolidates the impression of a serious attempt to identify relationships between response to the medication and different strands of the Parkinson’s syndrome.

Genetic Study

Footnote

The Sponsor is Neuroderm, a pharma company founded in Israel. The UK Contract Testing Organisation is Syneos, who has in turn subcontracted the Participant and Partner infusion support programme to IQVIA. Neuroderm was purchased outright in 2017 by Mitsubishi Tanabe, a Japanese Pharma company. The Study is not being conducted in Japan.