[Debi Brooks]

Paula shared a sentiment/worry last week that funders may think "we've got Sinemet so we are ok". I think this raises a really important point upon which I’d like to expand.

The presence of a reasonably effective symptomatic treatment for PD is both a curse and a benefit. I’m sure many of you have heard stories from families about grandparents who lived with PD before Sinemet was available. One of our board members (he is in his 70’s, has PD as did his mother) has shared with many people the anguish of watching his mother struggle and lose her battle. Decades later, when he was diagnosed, and walked out the doctor’s office with a script for Sinemet in his hand…he wept. He wept for his mother who never experienced the relief from Sinemet and he wept for himself and the life in front of him that he knew all too well. He is one of the most unsatisfied patients I know. Few work harder to raise money to fund research for new treatments.

I personally have never seen anyone behave as if PD patients should be satisfied nor witnessed anyone dismiss the unmet needs of PD patients in the inhumane way in which Paula suggests. Most of what doesn’t get done to help patients (at least from my point of view) is about lack of data, inefficient processes and misaligned incentives. All real, all frustrating and all things that cost lives. But, Paula is right, there can be a feeling, a value statement in a way that because Sinemet exists, efforts should be placed elsewhere. I want to say a little about that with the hopes that it will also address a question I received last week about what I mean by MJFF’s strategy to de-risk.

It takes a bit to set up so the context for this discussion, so please bear with me.

If you were to visualize the path of an “aha” idea by a brilliant basic science lab through all the necessary steps / expert hands before ultimately landing as an approved drug or procedure for patients, the journey can be expected to take 20 to 30 years (just phase I clinical trials to FDA approval for a symptomatic PD drugs can take over 15 years) and the estimates for total costs of all the experiments and drug developments approach $1 billion.
First, that sucks…and second, why is that? Well, to start, biology is hard. And many ideas take decades to tease apart and determine their relevance. Next, the process is not linear…ideas can take one step forward and then, after additional results, take three steps back. (Trophic factors are a good example…failed phase II trials mean that we likely need to test more hypotheses about everything from patient selection to dosing to delivery strategies before we are in a position to reexamine efficacy). Additionally, the path requires work from scores of highly specialized experts. I liken this part to letters of the alphabet…it is necessary for an idea to pass from A to B to C…all the way to Z and these handouts aren’t orchestrated…and they definitely don’t operate with the same incentives.

Sticking with the alphabet, it probably helps to know where the capital is targeted along this “alphabet” and how it behaves. US Government money ~ 28 B annually (chiefly through NIH) goes to academic researchers in labs at esteemed institutions to fund basic science across all diseases (~175 million for PD). These taxpayer dollars fund “discovery” and likely drive innovation. This funding is highly competitive and ultimately, the rewards come in the form of publications, tenure, and status in scientific circles. This money and approach dominates A to E of our alphabet and hypotheses can kick around here for many years (role of inflammation, genetic risks factors, process of protein folding)…Little of the money is actually disease specific (except for in the cases of our largest known killers such as cancers and heart disease).
At the other end of the alphabet is “industry” (biotech, life science venture capital, pharma) capital (~ 60 billion overall with maybe $600 million in PD) invested with an eye toward commercializing ideas…let’s say P to Z and motivated by return on investment to share holders or private equity holders. The investments required are staggering…these are rough numbers but a phase I trial for PD (open label safety in 10 patients) $2 to 5 million and 1 to 2 years. If successful (which by the way essentially all Phase I PD trials are!) you go to phase II ($15 to 40 million and another 2 years) – so, now cumulative investment (including your preclinical investments) is probably at least $50 million and you don’t yet know if you have a decent candidate for a phase III trial… Basically… this is a high risk game. Big bets. And, frankly, return-oriented capital views PD as a borderline case…Here’s where the existence of Sinemet makes things tough.

Trial sponsors look at Sinemet and know that it sets a pretty high bar. In numerous grant review sessions when novel compounds are being evaluated for potential investment, discussants frequently mention the robustness of effect…Can a new treatment option (if proven effective) provide a new, better option for patients – enough to command a sufficient market share to justify the investment (which included money, time, scientific resources, patient volunteers for trials—all critical to demonstrating efficacy). Unfortunately, for many of the hypotheses, based on the pre-clinical data available, the answer is no. Sorting out which targets will go into the clinic is data driven. But, there are leaps of faith…can success in an animal model predict success in humans? Can success in open label trials predict success in double-blind, placebo-controlled trials. How strong an effect can we expect to see from a proposed novel treatment…will it prove to be a better symptomatic treatment than Sinemet?

So, appropriately, the bar should be high for more “me too” symptomatic drugs…why spend resources/time on compounds that likely will offer little additional benefit to Sinemet. Well, in recent years we’ve seen two meaningful improvements to symptomatic therapeutic options…adjunct therapies to enhance l-dopa’s effect and DBS…(these options were emerging for patients just as MJFF started).

The challenge for disease modifying therapies remains more daunting. The science is less known and we lack essential tools to predict which hypotheses are worthy to move through the mid part of the alphabet.

Back to my alphabet analogy…note the F to N part remains uncovered by the two big players, government and industry… who then are the experts in the middle and where do they get their capital? This area is commonly referred to as the translational “valley of death”…it represents a different kind of science. So, NIH work at one end is substantially basic and industry at the other is commercial. So, ideas don’t move naturally along the alphabet at all and there are significant and systemic challenges to linking the academic and industrial parts of this enterprise.

If your goal, like ours, is to find new treatments, you really have to have a sense of the entire alphabet. You need to be in a position to appreciate all the hypotheses that could make the journey and then you need to appreciate real barriers to their progress and craft strategies to overcome them.

Then, what about a disease modifying therapy? Anything that slows, halts or reverses the disease process would surely beat Sinemet. So companies should shoot for those therapies, right? For one, there may be more on the horizon here than most folks think…at least I think it’s pretty good news that many pharmaceutical companies are working on LRRK2-based therapies (with the underlying assumption that such therapies would benefit all PD patients, not just those with a LRRK2 mutation). We are actively working to fund some of these start-up efforts within companies (and notably, if the work looks promising you are really starting an idea well along the alphabet—ie, things can happen much faster if the work is already in industry hands. We are also funding some academic work to better understand the basic biology around LRRK2 since it’s a relatively new finding. Importantly, we are aggressively working on research tools for LRRK2 specifically (supporting patient cohorts and developing animal models) and on tools that can benefit all sponsors of disease modifying therapies—like biomarkers.

So, the pragmatist in me appreciates that it’s not that industry dismisses patients because Sinemet is satisfactory. And the realist in me fully accepts that because Sinemet we must do more to ease that burden or else the homerun disease modifying therapy will remain elusive. But, the optimist in me does believe that despite these challenges, more can be done. So at MJFF, we are betting that our efforts to both strategically place investments along the alphabet to chaperone the most promising targets through the valley of death (de-risking them by adding important data to the molecule’s program package) and then developing key tools that enhance data read out for companies, we can help shift the argument within companies more in favor of PD investment—which, is our goal.

Debi

[paula_w]

Then, what about a disease modifying therapy? Anything that slows, halts or reverses the disease process would surely beat Sinemet. So companies should shoot for those therapies, right? For one, there may be more on the horizon here than most folks think…at least I think it’s pretty good news that many pharmaceutical companies are working on LRRK2-based therapies (with the underlying assumption that such therapies would benefit all PD patients, not just those with a LRRK2 mutation). We are actively working to fund some of these start-up efforts within companies (and notably, if the work looks promising you are really starting an idea well along the alphabet—ie, things can happen much faster if the work is already in industry hands. We are also funding some academic work to better understand the basic biology around LRRK2 since it’s a relatively new finding. Importantly, we are aggressively working on research tools for LRRK2 specifically (supporting patient cohorts and developing animal models) and on tools that can benefit all sponsors of disease modifying therapies—like biomarkers.

Thank you just seeing it. This is new to me and the best part of your post from where I'm sitting. It reinforces what genetic testing is capable of and it promises a tangible treatment. I know that you are constantly striving for a strategy that produces. I do understand the magnitude of it, but only from what i read until now. We get suspicious and paranoid, would much rather communicate.

thank you ,
paula

[RLSmi]

Debi, your description of the real pipeline for new PD therapies is just what was needed to help us all to understand the complexites of the process. The gaps between the basic science results, which often make the popular press with headlines of "Breakthrough in Curing Parkinson's Disease" and the actual prduction and release of significant, effective treatments are filled with huge traps and barriers.

Paula, I appreciate your affirming response to Debbie's description.

I am in a position similar to that of the man Debbie described on the MJFF board who watched his mother suffer and finally succumb to PD. My mother also died after more than 30 years of PD, in spite of my efforts to obtain l-dopa treatment for her in 1968, as it was being developed. My older brother was diagnosed some ten years later, but had access to sinemet for the twelve or so years it was effective for his symptoms. I recieved my own Dx in 2001, three years before his death from the disease in 2004. Although not presently in the advanced stages of PD, I have no illusions about what awaits me in a few years as my current attempts at slowing disease progression eventually fail. My real hope is that true disease-modifying or curative treatment breakthoughs will be forthcoming before my own children or grandchildren may have to face the same situation.

Robert

[TommyI]

Debi
I agree with all that you say. Industry has all the responsibility vested in it to supply treatments. The risks are high, funding is scarce and there are no cast iron outcome measures or biomarkers to mitigate the problem.
Your investment in these companies adds credibility to whatever science they are trying to turn into treatments allowing them to secure funding from other sources. This is seed funding and it works.
BUT I wonder whether this goes far enough? Couldn't we do more? There are some potentially disease modifying treatments out there and it strikes me that we need to be arguing for "the State" to get involved as well. The economic burden of Parkinson's is set to rise dramatically in the next few years. I think we should be researching this to show politicians and healthcare authorities that actually a relatively small investment now could reap huge dividends for the future.
OK so may be they won't play ball with this idea. But at the very least we should be encouraging a culture of teamwork rather than leave it all to Big Pharma. If there was some way of bringing the three principal stakeholders (patients, industry and government) together so that their required outputs were all met (better health, profits and value/votes) then risk COULD be mitigated perhaps.
There has to be a better way of working than the current system. What do you think? It should not be impossible to satisfy all stakeholder outputs satisfactorily. TEAMWORK has to be the way forward. It makes sense for everyone.
Not sure if I have explained all that adequately , but gotta go. Will revisit.

[reverett123]

The lack of urgency and the demands of the investor are the main problems. About 30 years ago, the US was sold on the idea that the State should not be spending tax dollars on research and that the private sector could do better. That turned out to be ideological slop and we are paying the price.

We need the equivalent of the Apollo program. The patient's need is obvious. That of the State is as well if one looks at the demographics. The research community would get funds. Big Pharma would try to screw things up.

The State needs to assume the lead on the no-profit end.

Originally Posted by TommyI

Debi
I agree with all that you say. Industry has all the responsibility vested in it to supply treatments. The risks are high, funding is scarce and there are no cast iron outcome measures or biomarkers to mitigate the problem.
Your investment in these companies adds credibility to whatever science they are trying to turn into treatments allowing them to secure funding from other sources. This is seed funding and it works.
BUT I wonder whether this goes far enough? Couldn't we do more? There are some potentially disease modifying treatments out there and it strikes me that we need to be arguing for "the State" to get involved as well. The economic burden of Parkinson's is set to rise dramatically in the next few years. I think we should be researching this to show politicians and healthcare authorities that actually a relatively small investment now could reap huge dividends for the future.
OK so may be they won't play ball with this idea. But at the very least we should be encouraging a culture of teamwork rather than leave it all to Big Pharma. If there was some way of bringing the three principal stakeholders (patients, industry and government) together so that their required outputs were all met (better health, profits and value/votes) then risk COULD be mitigated perhaps.
There has to be a better way of working than the current system. What do you think? It should not be impossible to satisfy all stakeholder outputs satisfactorily. TEAMWORK has to be the way forward. It makes sense for everyone.
Not sure if I have explained all that adequately , but gotta go. Will revisit.

[indigogo]

1. Wondering if comparing state funding of research in the UK and the US possible (apples to oranges or not?) because I don't know how the UK works.

2. Rick, you said, "About 30 years ago, the US was sold on the idea that the State should not be spending tax dollars on research and that the private sector could do better. That turned out to be ideological slop and we are paying the price."

Wondering how you can back this up. One of the reasons dropping stem cell research from the NIH agenda was such a big deal was the loss of money that couldn't possibly be made up by the private sector (government research dollars traditionally fund R&D projects before they are transferred to industry in the profit-making phase) . In fact, Bill Gates once said that the US government was the biggest venture capitalist in the world.

Now, whether all that government research money has been well spent is another question entirely. But I didn't think the amount of money was in question.

[reverett123]

The one time I rely on the common wisdom....
http://education.stateuniversity.com...-Research.html

Originally Posted by indigogo

1. Wondering if comparing state funding of research in the UK and the US possible (apples to oranges or not?) because I don't know how the UK works.

2. Rick, you said, "About 30 years ago, the US was sold on the idea that the State should not be spending tax dollars on research and that the private sector could do better. That turned out to be ideological slop and we are paying the price."

Wondering how you can back this up. One of the reasons dropping stem cell research from the NIH agenda was such a big deal was the loss of money that couldn't possibly be made up by the private sector (government research dollars traditionally fund R&D projects before they are transferred to industry in the profit-making phase) . In fact, Bill Gates once said that the US government was the biggest venture capitalist in the world.

Now, whether all that government research money has been well spent is another question entirely. But I didn't think the amount of money was in question.

[girija]

Carey and Debi,
Your post with NY times article (Paula's paradigms thread) and Debi's detailed analysis of bench to bedside process bring out a lot of issues that need attention. As far as I know NIH budgets in terms of absolute amount of money and research dollors spent per capita are the highest in the world. Even at the rate of 20-30 years from the time of first NIH grant to a pill for the patient, US is still at the top of discovering new cures. It was true atleast a few years ago, dont think it would have changed dramatically now. Thats the good news!
What I find troubling in this process of "Aha" moment as Debi described (I like that expression, thanks!) to industry is the time it takes. In many labs, there is no urgency to pursue aha to product stage what so ever and no accountability. Reseach for the sake of research. Why is that? 10-15 years ago, it was more prestigeous to be in academics and do basic research than go to industry. There was a general feeling among the grad students that those that could not get NIH grants go to industry. Drug development was not a choice for the "thinking types". I feel this is one of the road blocks to drug development. This has been my experience. Diagnosis with PD brought me down to reality. If any one from science back ground is reading this, please correct me if I am wrong.
Some of these attitudes have changed with biotech boom, small to mid size companies have translated discoveries to clinical trials. I think thats where the future of new therapies is. These mid size companies started by people who care about solid science and patients are the key to new developments.
NIH is also funding such entities with SBIR grants and MJFF does too. As always I am optimistic and hope one of these biotech would hand me "the cure"
So this is my two cents worth on this topic. Time to head home... may be more later.


Girija
Now, whether all that government research money has been well spent is another question entirely. But I didn't think the amount of money was in question.[/QUOTE]

[indigogo]

That's ok Rick! I have inside information; I worked 18 years in the Schools of Medicine and Social Work at the University of Washington. At the time of my 'retirement' in 2002, the UW topped the list of public universities receiving the most federal grants for medical research (only the private Johns Hopkins ranked higher).

I was always on "soft" (NIH grant) money; never "hard" (State of Washington funds). The living was easy; I never feared losing my job due to loss of funding (only PD could kick that chair out from under me). I was not a researcher, just a lowly staffer - but somebody had to run the office - and make sure the grants were filed correctly and on time! Our research dollars pay for that too (administrative overhead).

I hear the pickings are much more slim now, throughout the country (the UW is currently ranked 5th); but the feds, in this case the NIH, still run the gravy train.

[Debi Brooks]

Well, the federal government is involved to Carey and Girija’s point….taxpayer dollars ($28 billion each year just at NIH but additional dollars from Department of Defense and the Veterans Administration contribute as well)…and their “mission” is to improve human health by supporting basic research. Some would argue that government should and can do more…and while I would rather see more money allocated to research than less, I happen to believe we could actually improve how the government dollars are spent. I believe that one of the reason’s MJFF has had such an impact on PD research (despite the fact that it has significantly less money than government or industry) is because we can use our money differently and do. Innovation of process (being more strategic and urgent and results oriented) is part of our success.

Just to reiterate, in Sunday's New York Times, Gina Kolata wrote a very instructive piece about the government grant system and zero’s in on one of its great shortcomings…it discourages risk. The article is about cancer but we see the same issues / behaviors across many diseases. http://www.nytimes.com/2009/06/28/he...ncer.html?_r=1

Collaboration is an important concept but it may make the solution sound too simple…pharma lives for the innovative ideas that come out of academia---they regularly admit that if we will see innovation, it will come from the government-fed, discovery engine…as I tried to explain, one of the more difficult challenges is the lack of natural handoffs between experts let alone through the hands of the many and varied experts required to move an idea from A to Z in my alphabet analogy.

While we gain something by having all the cell biologists in the room at the same time, the real value is having experts from all the relevant stages of science needed to develop a therapy connected to each other…we have found that our convening power is unique and exceptionally valuable…much of our strength (both in understanding the full scale and context of our work and in executing our strategies) comes from getting these disparate groups to work together. More and more, academics and industry players are relying on MJFF to develop innovative strategy to bridge these key gaps (with targeted dollars and focused problem-solving)…a completely different kind of innovation but one that continues to get much traction.

Debi