Purple Canaries

Joyce Gould with Jill Gould


The earliest transcript of Alnylam’s givosiran (now Givlaari) Roundtables in the PC library is dated August, 21, 2014.(1) Dr. Karl Anderson, UTMB and chairman of APF’s scientific advisory board (SAB) was a participant of that session. I counted at least eleven times where Dr. Anderson provided ambiguous information during his presentation–an introduction to the disease (acute porphyria). These include: “we think it’s greater than 80%”; “what we think happens is”;  “but that’s very uncertain”; “we don’t really know how that works”; “we suspect there maybe[sic] other genetic factors”; “it’s been speculated they might be due to”; “some people think there is tachyphylaxis but that really hasn’t been proven”; “everybody agrees that it’s an effective drug [Panhematin]…but even that hasn’t been documented yet in high quality studies”; “I think the lack of evidence in…we don’t know”; “is certainly possible but there’s no data on that”. That the chief US porphyria expert didn’t provide specific, evidence-based information to support such an incredibly important undertaking as the beginning phase of development of an orphan drug to treat a “rare or ultra rare” metabolic disease throughout his presentation is disturbing.


For nearly forty years, American porphyria experts have tried to drum into the head of every one of its targeted audience’s members that the acute porphyrias are rare—or better yet, ultra rare. In 2014, Alnylam’s VP of Research & RNAi reported, “the total number of hepatic porphyria patients is around 37,000 of which about 12,500 patients are symptomatic acute porphyria patients. And that includes both the recurrent attack patients as well as the acute attack patients. There about 5,000 variegate porphyrias[sic] patients and about 1,500 hereditary coproporphyria patients.”(1)

Now remember, NPAW’s Day 5 commentary noted that in 2019, just five years later, Alnylam estimated there were 3,000 active disease patients of which 1,000 were considered recurrent attack patients and that “5,000 was the real number.” Now, I’m neither doctor nor math wiz, but something sure seems screwy here. How did the total number of hepatic porphyria patients (according to Alnylam and Invitae, defined as AIP, HCP, VP and ADP)(2)(3) drop from 12,500 in 2014 to 3,000 active (i.e. symptomatic) disease patients in 2019? And why is it there were 5,000 variegate porphyria patients in 2014 yet by 2019 “5,000 was the real number” of all active acute porphyria patients estimated to be identified?

It’s no wonder D. Lyon challenged a patient participant at the 3/1/2017 APF-sponsored FDA “Voice of the Patient” meeting with, “it’s rare [porphyria] because of the number of patients. It’s not rare because of the knowledge, it’s rare because the number of patients—the number of patients…”.(4)


A year or so ago, a debate between the mother/caregiver of an HCP patient and then APF director D. Lyon about heme deficiency appeared on a Facebook forum. The mother/caregiver posted something to the effect that heme deficiency was the cause of her daughter’s HCP symptoms. She was reporting what the experts who treat her daughter had told–and showed her. Not to mention that she’d observed her daughter recover from a deathly ill young woman who’d degenerated to the point of being wheelchair bound to, following innumerable infusions of heme over months, walking (albeit weakly at first) and returning slowly to life. Her daughter’s physicians and porphyria expert had produced heme-level measurements and used them to determine a treatment protocol. This amazed me no end when I first heard about the ability to measure heme levels; I’d watched my own daughter’s decline start sometimes just a week or so following a hematin treatment—especially early in on her ordeal and wondered why no one in the U.S. had figured out a way to “measure heme” to determine attack activity. Then I realized I’d already stumbled on a way: for months, I’d observed the steady decrease of my daughter’s PBGD synch up with her increasing symptoms/declining condition. Then I’d see her amazing response to Panhematin which to me, logically meant that her heme level had been depleted prior to the heme infusion—then repleted during the infusion. No brainer, right?

Nonetheless, the APF director continued to strongly refute the mother’s assertions that heme deficiency was the cause of her daughter’s HCP symptoms. Her refutation was nonsensical; she had even written in her book, “the rationale for administering heme therapy is to correct heme deficiency in the liver…”.(5) Further, the phrase “heme deficiency” or some version of it (i.e. heme deficit, heme deficient, depletion of heme pool, replete the heme pool, reconstitutes the heme pool, etc.) appears in a multitude of peer-reviewed medical articles and/or textbooks, including those researched and written by APF experts. One or another of these phrases was uttered by US porphyria experts Bonkovsky, Desnick, Anderson more than a dozen times during the 2017 APF-sponsored FDA “Voice of the Patient” meeting so they clearly understood the reality of heme deficiency. Or so I thought. Back to the 2014 Alnylan RNAi Roundtable. Alnylam executive Barry Green was on the ball in posing this question to Dr. Anderson: “Explain the potential of heme deficiency in targeting ALS-1. Do you see that in patients that might have heme deficiency treatment with ALN-AS1 might exacerbate that deficiency?” Dr. Anderson’s response was nothing short of priceless, “I think the evidence of heme deficiency and the acute porphyrias is pretty weak”.(6) Might as well said, “We’ve have no interest in conducting research into heme deficiency because we prefer to ‘wing it’”.

The icing on the cake of the APF director/mother caregiver debate came in the form of a recent Porphyria News article. This online publication happens to garner approval from APF as it also features one of APF’s members as a regular contributor. I was astonished to read in the December 2020 issue, “Mutations in the genes that provide instructions for making the enzymes that convert heme precursors—called porphryins—into heme result in low amounts of heme along with the buildup of porphyrins.”(7) My goodness, IF I could do a jig I would have done so right there and then! At long last, there it was—in black and white and in a publication that APF couldn’t slough off. I tried to get in touch with the article’s author and fact checker but they must be shy. I’ll keep trying because I’d like to see for myself the source of “result in low amounts of heme”. I intend to frame it. The issue of porphyrin build up is another piece of the diagnostic “gold standard” that has been built into an impenetrable wall. That will be addressed next.

DIAGNOSTICS: We’re about see the whole U-PBG measurement thing debunked

Porphyria experts in several countries champion the “urinary biochemical proof is required in order to confirm a diagnosis of acute porphyria” issue. Yet it appears this belief was built purely on anecdotal observation from as far back as Hippocrates’ time. This subject has been brought up several times but hey, it’s causing anguish to too many people in this world so here we go again.  Swedish doctor/scientist Jan Waldenstrom is credited for having researched and named Acute Intermittent Porpyhyria in 1937. In 1939, his article “Neurological Symptoms Caused by Socalled Acute Porphyria” described how [he was] “able to observe a case where porphyrins could be detected neither in urine nor bile during an attack.” However, “two brothers of the patient suffer from typical a.p.” He concluded, “The diagnosis: porphyria without porphyrins and chromogen [porphobilinogen]…has now been proved.”(8) Four years later he collaborated with Vahlquist on another article, “Studies in the excretion of porphobilinogen in patients with socalled acute porphyria.” This time there was more to unpack. Most relevant to this discussion is that Waldenstrom/Vahlquist team concluded: 1) “the amount of porphyrin formed from porphobilinogen is largely dependent on accidental factors,” 2) “there exist cases with only transitory excretion of porphobilinogen,” 3) “we have observed a complete disappearance of the porphobilinogen from the urine in altogether four cases”, 4) “The possibility that excretion of these substances may be intermittent and has to be taken into account.” A most important fifth point was made by the team—one that threatens the urinary PBG measurement theory of diagnosing acute porphyria. And that was “the occurrence of porphobilinogen even in minute amounts is a sure sign of porphyuria.”(9) It is concerning that in the seventy-eight years since that paper was published, not one US, UK, Canadian or Australian porphyria expert has ever fully investigated and followed through on the  Waldenstrom/Vahlquist 1943 findings. It appears that the term diagnostic “gold standard” was coined by U.S. porphyria “experts”—most probably because ALA/PBG (particularly PBG) was used to “test” the efficacy first of Panhematin then givosiran (Givlaari). But reality is that not every acute porphyria patient excretes urinary PBG—even during potentially life-threatening attacks. The experts who participated in Alnylam’s clinical trials for Givlaari know this as it was proven by Alnylam’s 2017 EXPLORE study. Studies from different countries indicate similar results.

In the event urinary biomarkers (ALA/PBG) do “accidentally” appear, they can indeed provide the first indicator that acute porphyria may be afoot—but they are not the only biomarkers that are indicative of acute porphyria presence. And according to a geneticist I turned to years ago for help, “Every gene in any body can mutate” so, yes, more than one type of porphyria can occur in one person. As discussed above, whole blood, plasma, urine, stool, recurrent (and often severe) neurologically-based symptoms—the whole gamut of testing should be done in order to diagnose an acute porphyria. EPNET has an impressive and very comprehensive testing protocol. US—not so much. Yet an extremely important diagnostic point seems to not appear with consistency in medical articles about diagnosing the porphryias. And that is bio-family history. It’s the first question any medical professional should ask and patients should volunteer when recurrent, atypical symptoms are the complaint–and especially if colored urine is involved.

(1)https://www.alnylam.com/our-approach/summer-rnai-roundtable-series-2014  NOTE page not found (2)https://www.invitae.com/en/physician/tests/06226/#:~:text=Acute%20hepatic%20porphyrias%20are%20a%20group%20of%20diverse,and%20excess%20excretion%20of%20pathway%20intermediates%20and%20products

(3) https://www.givlaari.com/about-ahp

(4) https://www.youtube.com/watch?v=urHxVYVAals Timestamp ~27:50

(5)Lyon, Desiree; Porphyria, A Lyon’s Share of Trouble; 2004; Digital Dataworks; pg. 33

(6) https://www.alnylam.com/our-approach/summer-rnai-roundtable-series-2014  NOTE page not found

(7)Murphy, Brian; “Porphyria and Seizures”; Porphyria News; BioNews Services, LLC; 12/15/2020

(8)Waldenstrom, Jan; “Neurological Symptoms Caused By Socalled Acute Porphyria; Acta Psychiatrica Scandinavica; June 1939.

(9)Waldenstrom, Vahlquist; Studies in the excretion of porphobilinogen in patients with socalled acute porphyria; Acta Medica Scandinavica; November 1943.

BONUS 2021 NAPW WRAP-UP COMMENTARY—coming Sunday, April 18th.

Leave a Reply

Your email address will not be published.