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