IPL344 Molecular Therapy

[KevinM]

I know, I know. There are many, many caveats, limitations, and unanswered questions about today’s article in ALS News Today describing the results of the very small (six patients) initial Phase 1/2a results of the Israeli investigational molecule IPL344. But it caught my eye.

I also know too well that the articles in ALS News Today re: “promising” therapies occur constantly and tend to be rather, um, optimistic. That is, until you find out that a promising result occurred with zebra fish that swam a little straighter after a dose of “fill in the blank.”

But this one did get my attention, and I’m hoping our resident data and clinical trial experts (looking at you Laurie and Nikki) can add your thoughts.

Yes, it was a very small sample size with no placebo group, and save for an initial advanced stage patient given the treatment under Right to Try that apparently was not one of the six, we don’t really have info on their various stages, whether they were slow or fast progressors, why the treatment duration ranged from 4-13 months (did any drop out, pass away, etc), and so on. Not to mention that the date to complete just the full Phase 2 won’t be until December 2022 (Early Access, and PPA, anyone)?

And yet. These early results were on actual PALS, not zebrafish or mice. And they were positive for both muscle function and lung function, which I note because some therapies appear to help one more than the other, but not always both. It seems that a 57% slowing (61% after the first two months of treatment) of progression is worth an eyebrow raise or two. Yes, it’s a press release from the research company that is obviously hoping to engender further investments, but this is an IV injection that I presume would be far less costly and much easier to reproduce than the NurOwn treatment, as an example.

I hear a lot of PALS citing Dr. Appels 3-person TReg study from 2016 and trying to gain access to that treatment, but these early results with IPL344 might warrant similar interest, especially after the 28-day safety/dosing study is completed. Of course, this circles back to early access if safe. No PALS can wait 3-5 more years to confirm efficacy (or not, but I suspect most PALS would be ecstatic to try this treatment before top shelf data is obtained).

That’s all. Sorry for the long post, but as I said in the Roll Call, I have too much time on my hands. Love to hear further insights. Kevin

 

[lgelb]

You wrote everything I would write, Kevin, except that they've been working with this compound since at least 2012, and just released interim open-label single-center results for six patients out of a planned 15, that is still recruiting (Israelis, take note). All this suggests a lack of funding, expertise and accrual that is typical of small, one-agent portfolio biopharmas. This trial isn't even scheduled for completion till 2022, either, and it's behind schedule or it would have fully accrued.

Bottom line -- they need to outlicense it pronto (likely under heavy contingencies, given the scanty data) or sell out, and perhaps this PR is aimed at a deal -- but without one, I would be shocked to see it come to market.

And no, you're right, we can't judge efficacy or even safety from 4-13 treatment months and six patients. That would be a max of 78 patient months. I am discounting the compassionate use case entirely, as that kind of thing is less controlled than standard open label.

The protocol answers your questions about how advanced the six are supposed to be. They're looking for fast progressors essentially with limb onset, so as to show maximum treatment effect. Far more likely is that after a quick start to the disease, they regress to the mean for a while, and that is one of the reasons why small studies often do not pan out, because you don't have the power to discern a true treatment effect, esp. with the Ancient Mariner FRS. More data will tell.

Best,
Laurie

 

[KevinM]

Thanks for the always insightful input, Laurie. I’ve got a lot on my mind this morning about this discussion, so here goes.

The ALS community is painfully aware that studies like this, as with virtually every ALS trial, suffers from difficulties in recruiting enough subjects (the revolving door of death problem) and, without bio markers, the reliance on FRS as the measurement for progression. I’m not particularly surprised that investigation of this molecule has been around in some form since 2012, as it seems numerous therapies move at a glacial pace, especially those from the smaller companies.

I’m always torn between hope for access to something, anything, that might keep me functioning and on this planet for a while longer (evolutionary instincts are quite powerful) and the “screw it, carpe f—-king diem, the cavalry ain’t coming” mindset. I know it doesn’t have to be an either/or attitude, as I think all PALS wake up and try to make the best of each day given our prognosis. But hope, even the smallest scrap of positive news, is really important, at least for our mental health. That’s really important, we all know the ample evidence that mental health and physical health go hand in hand.

I truly believe that if one were to poll 100 PALS, most if not all would say they would rush—well, maybe roll— to the front of the line for something like this, regardless of whether efficacy has been demonstrated in a more exhaustive, larger scale, better funded—and very lengthy—process. So long as it is shown not to grow a second head or melt ones brain, the hope for some treatment that might have a positive effect is incredibly persuasive, especially when actual PALS have been studied.

And yes, they all might have regressed to the mean or hit a plateau that coincided with the study period and skewed the published data, but from my perspective that doesn’t matter. It wasn’t a result based on mice, zebrafish, or primeval slime. It was based on someone like me.

And yet, if you are right as I suspect you are, this treatment will probably never make it to market. I suspect though, that wealthy PALS from outside Israel will eagerly sign up for the next trial phase. For normal folks like me, though, we will never get a shot at it.

This to me is at the heart of why so many PALS are advocating for immediate access to NurOwn, TRegs, CUATSM and now AMX0035. It is why numerous PALS, at least three whom I know are physicians with deep knowledge of physiology and a full understanding of their impending death, have travelled halfway around the world and spent tens of thousands of dollars to receive stem cell infusions despite very little compelling efficacy data. We’ve been raised to believe that science and medicine can save us, so we grasp at any straw that might be dangling out there.

On a smaller scale, it is why I, and most other PALS, spend a fair amount each month on supplements that deep down we probably know do very little if anything (other than occasionally upset my stomach)! Why do we do this despite serious doubts about whether they actually work? Because we feel a need to do Something beyond buying adaptive equipment.

Okay, enough rambling for today. I think I’ll drink a lunchtime beer and try to beat that damn IPad solitaire. Oh, and temper my excitement about the next ALS News Today “promising therapy” article. K

 

[Nikki J]

There is a lot of serious discussion about expanded access. MGH has a program to implement it where they can. It is expensive. they are pushing the drug companies to donate their drugs but even when that happens there are costs. Insurance might pay for the odd safety lab but other things cost money and sometimes hospital stays are needed.

open label extensions are becoming the norm but that doesn’t help those ineligible for trials hence expanded access.

for people like you if you are recently diagnosed pick a good trial and go for it.

Nurown has about one more week and then the trial is done. Amylyx is working as hard as they can with the fda. There will either be a phase 3 plus expanded access or early approval. Things are happening not fast enough maybe but more than we have ever had.

you have a lot more options than people like me. Take advantage of one of them

 

[KevinM]

Thanks Nikki. I always appreciate your suggestions and upbeat observations. I know you are right in saying I have more options right now than you, but I truly believe that therapies for FALS mutations will be the first real breakthrough, so keep hanging in there.

I continue to struggle to find a trial that meets my criteria. I would love to say that I am a pure altruist that is willing to participate in a trial mainly for the advancement of our ALS knowledge, but I don’t rise to that level of integrity. Of course there is a chance that one of the trials might be the one that helps me, assuming I don’t receive a placebo, but there are lots of factors that come into play.

Every trial I review involves an instant cost/benefit analysis (beyond just the placebo component) which I’m sure is true for every PALS considering one. How far away? How much time and costs? How often to travel somewhere to be poked and prodded more than I have already had done? What is the trial phase, and if it is to determine safety, do I want to potentially suffer adverse effects? What is the conceptual or research argument for that particular trial? How invasive? And so on.

I am always looking for a good fit, and I’ll let folks know if I become enrolled. Best, Kevin

 

[EricInLA]

When I was first diagnosed, I read up on all the advances going in Israel, and for a minute thought about just going there for a trial. (I have lots of family there that could put me up and support me) But realistically that doesn't work for my family situation.

I go through the same analysis as Kevin re clinical trials. Am I doing this for general research so others don't have to get hit with this sledgehammer of a diagnosis, or for me? If I'm being honest, it's more the latter, at least at this stage. Or, really more for my family. The confusing part is the interplay between different trials. In other words, I think we more or less have to choose one, because once you get in one, you're generally excluded from others. (Right?) I think I've decided to choose the platform trial, because of 1) strength of sponsorship; 2) smaller chance of placebo (25%); and 3) proximity to my house. Also, I see the multiple drug approach as moving the needle faster for our community than one-offs.

 

[Nikki J]

Kevin You aren’t a ridiculous distance from Gainesville which is going to be a platform trial site. lower chance of placebo. Open label extension Drugs that were picked as promising by an expert panel. No guarantees but are there ever?

 

[Nikki J]

Eric if you still qualify for a trial if it has been long enough for drug washout prior participation doesn’t exclude you from a second trial after finish the first. It tends to be symptoms length or diagnosis length that knocks people out of doing two

 

[KevinM]

You’re right about Gainesville, Nikki, and I am looking closely at the platform options.

 

[lgelb]

Kevin, I've worked in new products within big pharma and small biotech, as well as regulated medical devices, and I know how hard drug and device development is. I am not throwing shade on the company or on PALS who participate in trials, nor on anyone who carefully selects a few supplements and self-monitors safety and efficacy.

But there is a long way between being thoughtful about what you sign up for (and I agree that the platform trial has merits as a choice), put in your body, and advocate for, vs. jumping at all the shiny objects out there, many of which are dangled by players with something less than the best intentions, because you feel it's your right (not you personally, just making a point).

Everything powerful enough to help is powerful enough to hurt. Experimental therapies and buy-in-any-drug-store supplements have killed before, and will kill again. Just be careful out there.