A DMOAD Definition

ver the last year or so I've been asked on a number of occasions, Mozz, what is a DMOAD defined as, are we eligible? Do we have an FDA definition for DMOAD? What is required to get this on our label? What is required of our drug?

Just recently I was sent an article by my Western Correspondent...


PROLOGUE

Just before we get into the main thrust of this Mozz Post, a back story if I may, I got receipt of this super topical paper and got out my blue highlighter, I normally don't do that but thought as its so relevant to us at the moment, it might be nice to highlight some points from the said article that I can bring to your attention. I kid you not, I highlighted MOST of the article! Every paragraph seemed relevant to us!! I prob should've highlighted the bits that weren't relevant (not many!)


You know I love gleaning data from research papers and scientist's words. But Par Folk, if I did that, I would be a mere boring parrot. No no, I want to interpret it and MAKE it relevant to us...I want to APPLY it....watch out for Mozz Notes^© that do just that, that take the info being presented in theory and practically apply it to iPPS and our share holding potential (not advice).



Tonight, lets explore what a DMOAD is, what the experts define a DMOAD to be and perhaps where we might stand in this domain.

I've had to break this into two parts, there is just so much material and its easier for me to break it up so I can edit as required (I get all of three blessed minutes to do so once I hit submit and you and I both know the HC editor has a mind of its own sometimes!).




Please of course, enjoy.



PART 1 - A DMOAD Definition


INTRO

Currently, there are no Disease Modifying OA drugs. There have been some in the past that might have had a chance, but failed for various reasons. At the end of the day, you need a drug that has a DMOAD capacity but it must have a fairly safe profile for it to be adopted on a wider scale.

According to the article, a DMOAD should look at not only phenotypes but molecular endotypes of OA. What they mean is that you want an all rounder, not just someone that can bat, but they should also have some chance of being a bowler too.






Yes cricket analogy...but what I mean is that we, in a perfect world want a safe drug to positively effect both biochemical properties as well as structural. Yes, we kinda want a lot...the good news is, is that I think we will deliver a lot too!


Traditionally OA disease progression is assessed by changes in the Joint Space Width (JSW) measured by X-rays...its only in more recent times that scientists have realised its not just cartilage degradation at play here, its all encompassing. Yep, its all of the tissues being involved.

• Inflammation
• Articular cartilage degradation
• Subchondral bone changes
• Synovitis

Once we understand that there are many panoply's at work, we understand why past single targeting drugs don't seem to address the overall OA to any great or worthwhile extent.

Entre the Magic...

iPPS we know has many ways of acting. I'm getting the impression you just couldn't have a DMOAD in this area without MUTPLE actions happening all at once.


According to the article, OA progression is caused by two sets of factors, extrinsic and intrinsic.

Extrinsic factors are factors that occur outside the joint whereas intrinsic occur within the joint.

To have a successful drug you need action in multiple ways addressing underlying problems with biomechanics, low grade inflammation and metabolism.

Here is a sobering fact...


"In the United States, one-third of adults aged ⩾ 60 years currently show evidence of symptomatic OA, and the number of patients with OA is predicted to exceed 70 million by 2040".



We also know that the current so called remedy of arthroplasty only work for some, many still find themselves in pain with little symptomatic improvement.


WHAT IS NEEDED

What are the requirements of a DMOAD?

1) A therapeutic agent that can prevent further structural damage

2) A drug that can restore joint structure

3) A magic drug that can also improve symptoms

We really want all three facets. When the agencies learn that we may have this in iPPS, they are going to be fairly amazed. Yes that's true, but they will also want a good amount of proof and not just on a few patients. Yes this takes time...but will it be worth it?

I very much think so.


Why haven't there been any DMOADs so far?

1) Lack of safety (AE's, side effects)

2) Unfavourable risk to benefit ratios

3) Failure to demonstrate patient benefits including symptom modification and structural protection



The article goes on to explore key topics and the direction for future DMOAD development


DEFINITION

The article states it succinctly:


"To our knowledge, there is no updated definition for DMOADs. Furthermore, there are no regulatory guidelines for the assessment of clinical outcomes for DMOADs. Instead, with reference to the ‘guidelines for the development of OA drugs’, as described by the US Food and Drug Administration (FDA)".


However, the FDA has produced a guide, here is an excerpt:

"The ultimate goal of treatments related to inhibition of structural damage or targeting the underlying pathophysiology associated with OA is to avoid or significantly delay the complications of joint failure and the need for joint replacement, and also to reduce the deterioration of function and worsening of pain".


The article then interprets the guide by stating the following:

For a drug to be classified as a DMOAD...

1) It should delay or reverse the course of the disease

MOZZ note:
What evidence do we have of this? A few MRI's from Phase 2B OA (005)
We also have the wonderful statement from our RRV study. Want a reminder, here you go:




The word remission is the Mozz Clue.


2) Provide Patient with long term medical improvements

Mozz Note: We don't have a lot of longitudinal evidence...how about people like Paul R who have managed to stave off the requirement of surgery, not for a few years, for coming up on ten years! He isn't the only case, there is a famous case of a lady that forms part of our patent evidence, she managed to also avoid surgery.^1.5

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THE DRUG THAT CANCELLED KAYE’S KNEE REPLACEMENT

Kaye O’Loughlin has worked with race horses all her life and knew the drug Pentosan Polysulfate Sodium got them back on their feet when they were injured.

Now it’s changed her life.

The breakthrough treatment has cured the osteoarthritis pain in 71 year old’s knee and she no longer needs a knee replacement.

In February, 2016 Kaye injured her knee while helping out a friend with some race horses.

Her meniscus was torn, the knee swelled and she had an arthroscopy but the injury did not resolve and she was on a waiting list for knee surgery.

Before the injury she used to love gardening and would walk for four hours every morning helping hose down and feed race horses.

Her knee problems meant she moved into a granny flat and she had to give up her work with horses.

“I didn’t do much because it hurt,” she said.

In August last year an MRI showed she had bone marrow lesions and she was offered a chance to trial a new medicine for osteoarthritis Pentosan Polysulfate Sodium.

She had two injections each week for three weeks.

“After the third injection I thought this feels good when I got out of bed,” she said.

“The discomfort went completely and I could walk for hours again, I didn’t feel anything,” she said.

Now she’s back working with race horses.

“I’m on my feet four hours a day, I start at 6am,” she said.

“This morning I took the horses for a swim in the river,” she said.

Kay’s doctor Jegan Krishnan says he has been trialling the medication on 30 other patients who have arthritis.

“We’ve seen improvement in 70 per cent of patients, of the remaining 30 per cent half had an initial response but they weren’t given another dose because of restrictions by the Therapeutic Goods Administration,” he said.

“At this stage it is not clear how it elicits a response, we think it may have an anti-inflammatory action,” he said.

“By controlling the bone marrow lesions we are reducing the symptoms,” he said.

“I don’t know if this is a cure but it possibly may change the arthritis, the joint destruction,” he said.

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3) Provide patients with clinical benefit and an improvement in how a patient feels and functions

Mozz Note: The FDA also values this info, not just clinical endpoints being satisfied which is err...well, you know, quite clinical, what about day to day life....also known as PGIC...The patients' real world perspective and perception, this is also being recorded.


In fact the article goes on to state that there are two distinct groups in terms of developing candidate OA drugs:

A) Those that impact on structure

B) Those that improve symptoms.

MOZZ Note: Wouldn't it be wonderful to address both critical groups. In fact this is where the definition of DMOAD is heading. Not just symptomatic relief, we don't JUST want some pain to go away...we also want Function to improve....we want the longer term fix too. No point in getting pain relief and some function improvement if the durability is measured on mere hours.

For a candidate, a global sensation, we not only want both groups, we want it meaningful, we want it statically significant , we want it safe BUT we want it to last and preferably to regress the disease.

Give me that and I'm yours



THE NEW DIAGNOSTIC

Gone are the days where just a radiological snapshot is used. MRI's are now the std.

MRI's indeed have lead to new insights, here are some examples:

1) Assists in the assessment of peri-articular soft tissues

MOZZ note: This is what we want, we want evidence of what's going on with the surrounding tissues as well.

2) Identifying BML's

Here is the extract from our own clinical trial protocols ²:

3) Identifying synovial inflammation


MOZZ note: Think also 008...a key study, a key puzzle piece in what's happening in the synovium!


4) Intravenous contrast agents can be detected by MRI to explore the differentiation of effusion and synovitis.

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In fact, there are quite a number of other observations noted down for our trial as exploratory observations such as Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index response rates, Quality of Life (QoL) measurements, Work Productivity and Activity Impairment (WPAI) questionnaire scores and Rescue Medication observations to mention just a few of them! You think a large amount of effort goes into a study like 008, 002 is a big project in itself.




Mozz Note: While typing this paragraph I had a vague recollection that I had seen some data on Quality of Life observations already, yep, another early clue for us early birds to this worm fest!


Ready?



Do ANY of you remember this from the RRV study? ³



Lovely.

We will cover placebo in Part 2...





LET'S TRUMPET?



As I keep saying, Paradigm are smart, they have built all of this in with the sheer foresight that the authorities will be exceedingly interested in knowing the outcome of such observations and just how supportive these exploratory endpoints might turn out to be (my views). You could argue that PAR could do an even better job of professing what they have already, but there may be reasons why they aren't trumpeting their wares just quite yet. The authorities, particularly the FDA simply do not like sponsors getting ahead of themselves when in the midst of a clinical trial.

Our day for mass media will indeed come (my thoughts).



THE CLUE

The researchers of the DMOAD paper had this to say:


"Although the correlation between structural changes and symptoms is important in OA, assessment of joint structure by itself is not sufficient for evaluating the efficacy of new DMOADs".


This is the very clue as to why Paul, Donna and team have gone to such effort and trouble, such delay and expense to set this up. But it is not just one component that the authorities want to see, ideally they want a SPREAD across phenotypes, across symptomatic relief BUT ALSO hard core objective data...structural AND BIO Chemical markers.

Its not the short term trader that will profit from our observations, in my own view, it will be the long term holder that will really delight. (Not advice).


It actually just goes beyond these observations, like OA is all encompassing of the joint and surrounding tissues, the authorities also want all encompassing observations and results...yes I'm talking Quality of Life for the patients and from the patient's perspectives...


"When evaluating an OA patient’s quality of life, outcomes related to functional improvement are far more relevant than just structural improvement".


So what other clues can we garner, what do we need from a clinical trial that we are undertaking, the researchers suggested:


A) RELIABILTY

B) VALIDITY

C) RELEVANCE

...of the mode of action of the drug.

Mozz Note:

Now we ask the above of us...

Are we reliable? Well yes, look at 2B, look at SAS...what are the numbers? Are we reducing pain in a clinical meaningful way? ARE WE CONSISTENT? This is the one theme that we have observed time after time, study after study...be it 005, EAP, SAS, RRV/MPS I & VI (other indications)...etc


Are we Valid? Does the thing work? Is it safe....

Are we relevant? Well are we addressing the demand? Is this a need we are satisfying? Are potential customers voting with their feet?

These indeed are the questions to ask...


Here concludes PART 1.


It's in PART 2 that we will go on to explore more DMOAD related requirements, what is the world searching for? What are the negatives we need to tackle and what is the proof so far? We also will cover some exciting news and how your company is tackling the DMOAD realm in a practical sense...