Rare Disease Day: TTP and Caplacizumab

February 28th, 2023 by Potato

It’s rare disease day, so let’s look back on TTP, the rare disease that Wayfare had/has.

Thrombotic Thrombocytopenia Purpura

The tense is hard with TTP. It’s a sudden, short-term, life-threatening blood disorder. But even once the antibodies retreat as mysteriously as they appeared and the platelet count goes back to normal, it’s never really gone. There’s a good chance a survivor received organ damage from the clots or bleeding during a TTP attack, which may manifest as brain, kidney, liver, or heart damage — or just about anything else.

But beyond that, there’s the fear that it will come back. Roughly half of patients will at some point have another TTP attack, each of which carries with it a risk of dying during the episode, and accumulating more permanent organ damage and disabilities.

Wayfare essentially has PTSD from her rare disease. It took over a week and several visits to urgent care and the hospital before her TTP was finally diagnosed correctly and treatment started. By that point, she had so few platelets remaining that they had to call a vascular surgeon in to the ICU to do a cut-down on her leg to access a vein. They couldn’t run a central line because if it happened to bleed, she’d bleed out before they could stop it. In the leg at least they had the option of sacrificing the leg and tourniquetting it if the line went poorly.

We can’t afford to wait that long if she has a relapse, but the first signs of a potential relapse are fairly every-day occurrences. So any headache, any mysterious bruise (or one with a known cause that doesn’t look to be healing fast enough), any splotching on the skin, any time she feels maybe more tired than normal… these are all potential medical emergencies and we have to get her blood taken. Every few months we are off to the blood lab on short notice, or sometimes straight to the hospital to check.

Fortunately, there’s a new drug available that can help. She was part of the clinical trial, and was out of the hospital weeks sooner than they had predicted when she went in. Who knows how bad the strokes may have been if she hadn’t got it?

In Which Potato Learns How Drugs are Approved

Being in medical research, but not drug development itself, I thought I had an above-average idea of how drugs get to patients: Someone has an idea, it goes through pre-clinical testing, then clinical trials (Phases 1, 2, and 3) then reviewed by Health Canada, then ta-da, new drug on the market!

Caplacizumab went through all that. It’s safe and effective. Health Canada approved it. But TTP patients in Canada still can’t get it.

We can’t even choose to pay out of pocket for it.

There’s one more critical step: the drug has to make it onto a provincial formulary, the listing of drugs available for purchase somewhere in the province.

A big influence there is CADTH, which makes a cost-benefit analysis. In our case, they decided to recommend against caplacizumab, which as someone with expertise in a related field, who’s done a lot of reading into TTP for obvious reasons, I cannot understand why. Nearly every other nation that’s completed their equivalent review has approved it — if Wayfare gets sick again, we may be best served by putting her on a flight to the US or UK, ’cause their patients can get caplacizumab.

Reading their report, they seem to have mis-understood the feedback patients sent in, saying that we were concerned about the risk of a relapse but the clinical trial didn’t address that question. The subtext is that the company is welcome to fund another clinical trial to answer that question, after which CADTH may re-visit the decision. But that’s insane, no company is going to do that for a rare disease, especially for a tiny country like Canada if the big countries have already approved it!

And that isn’t the point we were making! The point is that caplacizumab works. It works to stop the early disease process where the platelets are forming tiny clots just fucking everywhere and ruining your very best brain tissue and nephrons. It gives you time for the conventional therapy (plasma exchange) to do its job and clear the bad antibodies that kicked the whole cascade off. It gets people out of hospital sooner and with fewer long-term disabilities.

And not just the first time. Half of TTP patients will have a relapse. Some of them have multiple relapses per year. Every time they relapse, they run that permanent organ damage and disability gauntlet: will it be a stroke this time? Will they lose a kidney? Will it affect their energy levels a little, or will everything get all scrambled so much they put the sugar in the coffee maker and the coffee in the cup in the mornings and just cry about how awful their coffee is, unable to make the connection about how to fix the problem?

We wanted them to consider that these risks don’t hit TTP patients just once, they’re a risk every relapse. Cutting those risks down by some significant percentage (the exact number would need more trials but the anecdotal evidence suggests it’s somewhere in the 50+% range) is huge if you have to face that risk over and over again — it compounds. A 10% risk of disability with each attack becomes a 40% chance after 5 relapses. Cutting just 5 percentage points off that risk doesn’t sound like a big deal when you only consider the initial attack in the cost-benefit analysis, but after a few years that’s half as many TTP survivors with a disability.

And more than the hard economics of the cost-benefit analysis: nobody out there knows if they might get TTP. It’s super-rare, you may not have heard about it before now. But once you’ve had your first attack, you live with that constant fear that you might be one of the unlucky ~50% who will have a relapse. You live with PTSD, the constant triggers that any little every day thing might be the first sign of a relapse. Knowing caplacizumab is there to improve your odds if you do relapse would be a huge mental benefit even if you never actually need the drug yourself.

The other side of the cost-benefit was also hard to understand: it’s a niche, antibody-based drug, so it’s somewhat expensive, yes. But it’s not like a take every day forever kind of drug, more like an epi-pen: an emergency rescue medication taken during an acute episode to help buy time for other treatments to work, saving lives and tissue in the process.

Political Action

Right now, the patient group Answering TTP is sending a letter to some of the provincial leaders. It’s still possible for these leaders to choose to make caplacizumab available in their province — CADTH’s report is a recommendation only, it is ultimately a province-by-province decision.

Rare disease day doesn’t just have to be about awareness, we can also help improve treatment with a small step of getting a Health Canada-approved drug for a rare disease into the hands of the Canadian patients who need it.

So please, fire off an email to your province’s health minister, and CC your MPP. Or tweet at them and tell them CADTH made a whoopsie, it happens, but maybe they can go ahead and add caplacizumab to their formulary this rare disease day.

Thanks in advance from me.


Screw it, I’m clearly never getting a job at CADTH, let’s burn some bridges and nitpick that CADTH report to show you why I just don’t get why this wasn’t instantly approved and lauded as a modern medical marvel!

“During the overall study period, a statistically significantly (P = 0.0004) lower percentage of patients in the caplacizumab group (nine patients; 12.7%) compared to the placebo group (28 patients; 38.4%) experienced recurrence of aTTP…”

Holy fucking shit, how is this not approved on that alone?!?! Yes, above I focused so much on the part they missed, about reducing the risk associated with each relapse, but it also pretty convincingly reduced the risk of relapses themselves in a statistically significant way!

“The submitted price of caplacizumab is $6,200 per 11 mg dose. Assuming 37.2 days of therapy (i.e., the mean exposure to caplacizumab for patients in the active treatment group of the HERCULES trial; the reported maximum was 65 days), the cost of caplacizumab for an aTTP episode is $236,840 per patient…”

That’s the worst-case cost. And like in many clinical trials, they didn’t really know what dosing regimen to use. I would place a sizeable bet that caplacizumab would give almost all of the benefits in a 10-day course costing just $62,000. The mechanism of action strongly suggests to me that it works best early on, and the anecdotes from other patients we’ve heard of include many dramatic turn-arounds in the first week or so. But if you’re running a clinical trial you’re not going to take a chance on that, you’re going to flood the study participants with the medication and be sure it works, and do some real-world evidence gathering to fine-tune the dosage later. More to the point, if Wayfare had a recurrence, she would instantly pay $62,000 out of pocket to get a 10-day course of caplacizumab… if it were available to Canadian patients to purchase in the first place. But CADTH only considered the all-or-nothing case of using the same dosing regimen as the clinical trial.

Indeed, the real-world experience in the UK is that they are tapering down the dosing regimen, stopping when levels are normalized, rather than continuing all the way through plasma exchange. A few years ago their average days of use was already down to ~30, and is likely lower now (as a non-expert pointing to the outfield, I tell ya, 10 days).

A Different Take on the FHSA

April 13th, 2022 by Potato

Budget 2022 proposes to introduce the Tax-Free First Home Savings Account that would give prospective first-time home buyers the ability to save up to $40,000. Like an RRSP, contributions would be tax-deductible, and withdrawals to purchase a first home—including investment income— would be non-taxable, like a TFSA. Tax-free in, tax-free out.

The new Tax-Free First Home Savings Account (FHSA) is pitched as a way to save up for your first home. It’s like a super-charged RRSP: you get to put pre-tax money in, and in one specific circumstance (buying a home), you can take it out tax-free. And if you don’t buy, you can roll it into an RRIF like a regular RRSP.

There’s lots to nit-pick with this idea: the $40k lifetime limit doesn’t make it much more effective for saving for a home than the old HBP option did. And while this is even better as you don’t have to pay it back and get to keep that tax savings, that’s a benefit you only see in later years vs the HBP — the $35k HBP was already letting you put that much pre-tax money to work for the purchase itself. On top of that, the $8k yearly limit means it will take 5 years to max out (and 4 to match what you could do in 90 days with the HBP and a regular RRSP). So at least it will push demand out if some people want to max it out before buying.

It’s a bit regressive, in that people in the highest tax brackets will see the biggest advantage from using the FHSA.

However, ignore all of the talk about using it for a downpayment. The fact that they took out the age limit and let you roll it into an RRIF mean that the FHSA serves another purpose: it helps renters shelter more investment income, functioning basically as more (and with an embedded option!) RRSP room. Someone who buys a place gets any increase in equity as a tax-free gain thanks to the principal residence exemption. That’s been a huge windfall in recent years, and can push people toward buying in an environment where prices are going up double-digits every year. That tax advantage also makes it even harder for those who don’t own to keep up. Someone can choose to rent instead and save the difference in monthly cashflows, but may soon run out of TFSA and RRSP room. An extra $8k/yr will help them shelter more of those gains.

And of course, provide that option to take the whole FHSA out at some point in the future to buy, tax-free.

Imagine a world where the cap and 15-year lifespan were removed and renters continued to get $8k/yr in room until they bought or turned 71 (and rolled it into a RRIF). Someone renting in a big, unaffordable city like Toronto could prioritize their FHSA, knowing that it would make it that much more possible to eventually buy when their indentured servitude in the city was over. $8k/yr at a 5% return would leave someone with nearly $400k after 25 years*. You could make a solid plan to do your time, renting happily along the way, and know that you could — tax-free — have nearly enough to buy a place in the boonies outright when your commuting days were done. Or, have more in your RRSP to support the costs of lifelong renting in retirement if you stayed in the city.

So while I don’t think this was a necessary thing to create (indeed it adds more complication to our tax and savings account system, and yet another financial literacy hurdle), and don’t think it’s going to do a damned thing for housing affordability… I welcome the FHSA. For many people, it will be the obvious first account to fill (even edging out a TFSA for those who plan to buy eventually). However, to be truly great and to help incentivize more people to rent and invest the difference and keep open the option to buy in the future, they’ll have to remove the fairly low lifetime contribution cap.

Indeed, I’m not sure many brokerages will bother to offer registered accounts that can only ever accept $40k, and are only available to the subset of renters who save money to invest — see how few bother to offer RDSPs.

* – remember that this is a hypothetical where they remove the cap and time limit. As it stands, the 2022 Federal Budget proposes a $40k lifetime cap and a 15 year maximum term to either buy a home or roll it into a RRSP/RRIF.

Housing Bubble Harms

August 27th, 2021 by Potato

Adam Vaughan made himself the face of government callousness and inaction earlier this year[0]. It started with an appearance on TVO’s the Agenda, where when talking about what the government should do about housing, he said “We’re in a safe market for foreign investment but we’re not in a great market for Canadians looking for choices around housing.” Which wasn’t news to a lot of people, but it was news that the government knew and was choosing to do nothing rather than just being incompetent and unaware.

He then continued to say (and followed it up and in various Twitter battles) that the government would not do anything if it meant risking even a 10% decline in house prices — which in the context of the time (over 20%/yr increases, and not just in the big cities) would have been rolling prices back just a few months. But even that was too much for them.

In other words, he said the quiet part loud. And now we all know that they know, and that they don’t care.

He’s tried to make the case that housing prices falling is bad, as have others throughout this decade+ run-up in house prices. People don’t like seeing their biggest asset fall in value, and recent buyers could be underwater and financially stressed. If it gets rolling, it might lead to a recession.

And sure, it’s pretty obvious that if we have a housing crash, it would have many negative effects. The problem is, high prices also have negative effects, and there’s a chance prices will fall anyway in the future, and inaction just delays and exacerbates that.

Why Housing Bubbles are Bad

A housing crash and its associated harms is hard to miss, but the harms of a bubble are more subtle and insidious, but just as bad for society.

Bad? The wealth effect? Our cities becoming “world-class”? These are bad things? Well, those aren’t the only side effects of a housing bubble.

There are much more serious effects on people’s lives. There’s rising inequality, though that’s just part of it.

Housing is the biggest cost in most family’s budgets, and for young people that can be by a huge amount[1]. When housing gets more expensive, they feel the squeeze: literally, if they have to settle for being under-housed to make ends meet. That has real-world consequences.

I can write about the rent-vs-buy decision and raising a kid in a rental all I want, many people out there still want to put off starting families until they can buy sufficient housing for a family. The frenzied speculation makes rentals less secure even if rents themselves have lagged price appreciation. With higher prices (and rapidly rising prices), buying is harder — much harder — and young families have to settle for less space, and delay their purchases to save up. That means they put off having kids longer, and having fewer when they do. Toronto’s fertility rate dropped 16% in the last decade[2]. If anything else had caused our fertility rate to drop that much in just a decade (in the face of millennial demographics that we might have expected an increased fertility rate from) we would be rioting in the streets for the government to do something, holding up signs about the missing 10,000 babies. We’d be banning chemicals, exterminating mosquito vectors, or adding fertility treatments to OHIP coverage. But when it’s economic: crickets. Housing insecurity and microcondos are just the way of life here in a world-class city, and a few thousand unconceived babies are acceptable collateral damage for muh price growth.

Mike Moffat has also pointed out Toronto’s troublesome population movement patterns: the largest cohort of people leaving the city are newborns (followed by other young children and those in the parents of young children age bracket) — so even when a kid is born here, there’s a good chance its family promptly leaves.

Lower interest rates (that somehow keep going lower) have helped support housing prices: mortgage payments have not increased as much as prices. But they have gone up quite a bit, and even if more and more of that payment goes toward principal, the principal still has to be paid back. 10 years ago, a $775k average detached house required that, at some point, you paid back $775k. Spread evenly over 25 years, that’s $31k/yr. A big chunk of a couple’s after-tax income, but doable if you were pulling in $100-120k combined (and a monthly payment including interest of $3.1k). At $1.7M, that’s $68k/yr to pay it off in 25 years, which doesn’t leave much else for having kids or supporting the economy (and the monthly is up to $5.4k at lower interest rates).

This is a big black hole for the velocity of money: more and more of our salaries are going to paying for our houses. That’s money that isn’t circulating back through the economy, or investing in something productive. Wouldn’t we be better off with lower house prices, and more of our disposable income going to services, innovation, transitioning to a low-carbon economy, charities, etc., instead of having housing sucking up all the cash flow?

In conclusion, while a crash can be harmful, high (and rapidly rising) house prices also have harms. So far the government has made it clear which set of harms they see and care about.

Election Time

A federal election has been called, and more and more people are saying that housing is a big issue for them. Each party has come out with an ineffectual do-nothing housing plan, and not one has acknowledged the elephant in the room: that a solution must allow at least the risk that house prices will drop. The cure to affordability is not to create more loan programs and tax breaks to help people pay higher and higher prices for housing[3] — it’s to get prices lower.

The first step is admitting that there is a problem[4]. I’m a left-leaning voter — often ABC — and while there are a lot of issues I care about (science funding, the environment, electoral reform, etc.), man, at this point I would vote PC if they actually came out with a housing plan that was willing to actually address prices and affordability.

[0] And stealing that crown from DoFo in a pandemic was quite the achievement.

[1] Though for the wealthy who haven’t read my book, investment fees may edge out housing.

[2] And that’s before the effect of the pandemic and lockdowns, which looks to have created its own “baby bust”. Also, other cities did have birth rate declines over the last decade too, though they were lagging Toronto’s — Calgary and Halifax had held steady through to 2016 (which would be about 9 months after Alberta’s oil bust started) and then a step down; London had a small decline in 2016, which was then exacerbated in 2018, while Toronto just heads down and down the whole decade.

[3] which in a tight market just gives people more money to bid which drives prices up further — many of the proposed programs are counter-productive that way.

[4] Update: Rob Carrick had a similar take here (and he got around to hitting publish first while I was dicking around in MS Paint). “Only a major price reversal can restore mass affordability and the federal parties won’t touch policies that would make this happen.”

Ontario Covid Update – Jan 12

January 12th, 2021 by Potato

Ontario provided its updated figures and modelling for covid today. The slides are available here if you want to look at the data without squinting at the video.

It’s not all that unexpected — I was sketching vaguely similar curves and worried about what an even more contagious version might do. But hearing it made real was just crushing. Covid’s on track to challenge heart disease and cancer for the top cause of death in Ontario this year (and will make the top 10 easy). And the strain on the hospital system is delaying treatments (esp. surgeries) which will make those other conditions worse.

But the big, not entirely surprising bad news is the hospital system and ICU beds: we’re just about out of empty ones, and the curve is still rapidly going up and to the right. Surgeries are being cancelled (again), and we’re not far off from very painful decisions about what happens if there’s a car accident.

One thing that’s crushing is that we were so close to getting to zero in the summer, and just opened back up a few weeks too early, without the testing and tracing capabilities ready. Still, the cases were low, everyone had stocked up on masks, and I genuinely thought we could get back to normal-ish with masks, handwashing, and social distancing*. I signed up for curling, expecting we would get a season, esp. with the modified rules of play (everyone wears masks, and things like using one sweeper to maintain 2 m between players at all times) — I had my mask rotation all planned out, and even got contact lenses so my glasses wouldn’t fog up. Schools reopened, and we kind of talked about how important that was for parents to be able to go back to work.

Then the cases started rising in the fall, and we did nothing about it until we’re now finding the hospital capacity getting crushed again. More people are going to lose their dads and other loved ones to cancer because surgeries had to get postponed, again.

I’m depressed and angry and just crushed at the whole thing.

I’m also a touch confused. They showed some data about how many people were moving around — people going to work has stayed steady since the summer, even as Toronto, Peel, and York went into lockdown (code red or grey or whatever). How there was a big spike in people visiting other residences at Christmas (to the surprise of no one). But I haven’t heard much on contact tracing and explaining what’s behind all the transmission. Are masks and handwashing and social distancing working, but some people aren’t compliant, and it’s that movement that’s the problem? Is it schools or workplaces or superspreader weddings? A little bit of everything adding up?

For most of those questions there isn’t much I can do on a personal level. I’ve tried to cut out contact with the outside world as much as possible, stretching out the time between grocery trips to two weeks or so, and our social circle is a completely closed bubble of 5 people. Wayfare has been making homemade masks since the beginning, and she did a lot of research on the best patterns and designs. They’re 3 layers, with two layers of regular (cotton?) fabric sandwiched around a layer of non-woven interface material. They have metal strips to conform to the nose (important to minimize glasses fogging and get the air moving through the material for filtering and not around the material), and straps to tie tightly around the head, which keeps it pretty well sealed all the way around the face. Though she made a few models with noses or cone shapes or whatever, I wear the basic pleated rectangle ones, so there’s no tiny holes from stitching a seam right in front of your nose. I’m sure they’re a step up from disposable surgical masks, even after a few washes. And I’m very good about wearing it whenever I’m indoors (or with another person outside — though I don’t wear one on solo walks).

However, are cloth masks enough, especially with the new B117 variant? Should we all (but especially should I) be wearing a N95-equivalent to go grocery shopping?

* – Circling back around to add: I thought the masks, distancing, etc. precautions would be good enough to get r < 1 so life could return to more-or-less normal. It doesn’t look like those were sufficient in practice (whether it’s non-compliance or whatever is a bit of a moot point as we will have non-compliance, esp. as covid fatigue sets in). We are a long, long way from Covid-zero (and we were really close in the summer!), but that may be the only strategy that lets us avoid the hammer and the dance through the fall based on the current vaccine roll-out projections.

On Lags and Exponential Growth

January 7th, 2021 by Potato

Ontario hit 89 daily Covid deaths today. We could lockdown tonight, go full Wuhan and weld peoples’ doors shut, and it wouldn’t stop us from hitting 100/day by next week — those people already have the virus, it’s just taking time for them to get sick and die. [Though I’d be happy for the universe’s constant need to prove me wrong to kick in here and save a bunch of lives as this turns out to have been the peak]

Lags make it hard to manage things, especially when that management also involves really hard decisions. It’s hard to call for a lockdown when cases are barely into triple digits. But that’s when it has to happen when you only have a few hundred spare ICU beds in the province. Ah well, back to home schooling for at least a few weeks now, though I still don’t actually know what the plan is. Is it Covid-zero?

And of course this is also why we wanted to start curbing the growth in greenhouse gas emissions in the 90s… or now, I suppose.