Purple Canaries

Joyce Gould with Jill Gould

SNUBBED BY APF, BOOK CHALLENGES LONG-HELD ACUTE PORPHYRIA NARRATIVES

https://www.amazon.com/s?k=PURPLE+CANARY+by+Joyce+Gould&i=stripbooks&crid=1YKIDFRKJAY80&sprefix=purple+canary+by+joyce+gould%2Cstripbooks%2C87&ref=nb_sb_noss

In 2011, the front page of the American Porphyria Foundation’s (APF) 1st Quarter newsletter was dedicated to the upcoming Porphyria Awareness Week. It featured a list of activities submitted by APF members who planned to do their share during that week to “help the public and medical professionals in [their] community more readily recognize the need for better diagnosis and treatment of porphyria.” My submission, “Jill Gould and her mother are writing a book about Jill’s experiences with porphyria” made that list. It was the first and last time the book was publicly acknowledged by the non-profit foundation established in 1982 to provide “quality, understandable information.” [Porphyria, A Lyon’s Share of Trouble, 55]  Unbeknownst to me at the time, we were two and half years away from being unceremoniously dumped–without warning–into what can only be described as a porphyria twilight zone of APF-making that would take us years to emerge from. It was during that time that I came to understand that APF’s promised “quality, understandable information” had long ago morphed into an inconsistent communication style that served to keep porphyria illusorily rare—right under the noses of virtually every one of its audiences—including US federal rare disease oversight agencies.


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BONUS 2021 NAPW COMMENTARY: ***IMPORTANT PURPLE CANARY ALERT***

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TO PATIENTS WHO ARE DESPERATELY AWAITING AN ACUTE PORPHYRIA DIAGNOSIS but haven’t “met the metrics” that is, haven’t excreted “required” urinary porphyrins/precursors, please, for your own safety and sanity, DON’T divulge your doctor(s) name and/or location to ANYONE in this or any other FB forum. Unscrupulous people have been floating among these forums for years. They are known to cozy up to desperate patients–usually undiagnosed and/or allegedly “misdiagnosed” patients (that is, those who’ve been diagnosed by physician(s) other than so-called porphyria experts). Be especially wary of forum participants who take an interest in your personal story—particularly if that story includes present use, or planned (hoped for) use of Panhematin or Givlaari treatment(s).These people can be very attentive and may suggest that you or your doctor contact APF directly—might even give you direct phone numbers of Desiree, Kristin or Edwin or ask them to call you on the premise one or the other will “help” you. Undoubtedly, there will be offers to send your doctor a “kit” with their information about porphyria. They may cast aspersions against me and/or others I collaborate with and if that happens, it’s a good clue that it’s time to walk (or run) away.

Friends, this post is not a ploy nor is it a “bashing” party. It is intended to give you a heads up to potentially save you unneeded heartache. My naiveté in providing information to APF in order to get help for my daughter cost her and our family dearly. That’s when I ended up following another mother/caregiver’s lead and joined closed FB porphyria forums. In those forums I learned we were far from alone; the number of people who were casualties of the Foundation seemed unfathomable and was hard to take in. My daughter’s AIP diagnosis had just been revoked by Dr. Robert Desnick, an APF Scientific Advisory Board Member and the Foundation’s preferred provider of genetic testing. He was also the same “expert” that had first diagnosed her in 2008. I soon met patients whose diagnoses had either been revoked like my daughters’ or had been withheld altogether—because their bodies hadn’t produced the putative “gold standard.” But even if it had, that didn’t help some patients, some of whom had bio-family members with a bona fide diagnosis of acute porphyria; they were/are still denied the diagnosis. By the way, years after Desnick revoked my daughter’s diagnosis, he finally disclosed the paper he’d relied on to do that. It had been published in 2000—eight freaking years before her blood had been sent to Mount Sinai for diagnosing. We ended up ordering a 23andMe DNA test for her. It revealed that not only does she have the particular AIP mutation Desnick identified, but she has other AIP mutations with at least one identified as pathogenic—as well as  HCP, PCT and other porphyria genes. Funny how none of those mutations appeared on the report of supporting data for her DNA results that Desnick prepared at my HIPAA compliance request. At about the same time, a porphyria team from South America took an interest in my daughter’s case.  Based on her medical records and lab results that indicated consistently low PBGD levels, they confirmed her AIP diagnosis. These experts concluded, “The mutation is an ideal goal but it is not mandatory. In the presence of typical symptoms, a low enzymatic activity is diagnostic, even with absent U-BP.” You can’t make this stuff up.

None of you need this type of harassment/abuse on top of all you already deal with. You’ll likely know if/when you fell through that trapdoor because the treatment(s) you’d poured your hopes into receiving will not materialize; your doctor may suddenly become adamant that you don’t have acute porphyria (a “mistake” was made); becomes silent or might even stop seeing you altogether (referring or “transferring” your case to another physician). This has been happening to TOO MANY people. From reports, it’s also been going on in Canada, the UK, South Africa and Australia and other countries (though certain dedicated porphyria experts have not been cowed by “arrogant porphyria experts’” tactics).

To the perps involved, shame on you for acting like the middle school troublemakers that taunted and pummeled my daughter when she was so sick. As adults, you should know better. Participating in the violation of  healthcare privacy laws (in US, HIPAA law) can lead to prosecution.

In conclusion, I leave you with a quote “straight from source” as Desiree Lyon APF “Global Director” likes to say. It was uttered by Dr. Robert J. Desnick’s during the 2017 APF-sponsored FDA “Voice of the Patient” meeting. As you read it (or better yet, view the video in its entirety—it’s a treasure trove of enlightening information) refer to the previous paragraph about your doctor’s potential reticence and loss of the diagnosis.

Video Timestamp: [2:57:53] DR. DESNICK: “in America, no doctor wants to have a malpractice suit and sometimes that happens because they [the patient] never got diagnosed…It takes many—sometimes years—before the diagnosis is made and multiple different doctors until you find the one that says…oh! “I saw that patient,” or “I heard about that” or “oh! That urine in that cup is port-wine red—I got the diagnosis!” And that’s how it happens.”

In America, medical fraud is defined as “…a crime that involves misrepresenting information, concealing information, or deceiving a person or entity in order to receive benefits, or to make a financial profit.” Within Desnick’s quote are certain points that cannot be dismissed. Most important is the veiled threat of a “malpractice suit” (in the guise of medical fraud) because the “patient never got diagnosed” (meaning the diagnosis was not made or confirmed by so-called EXPERTS). What Desnick (and APF et al) suavely appears to be implying is that a non-expert physician dared to diagnose acute porphyria—and therefore misrepresented information (by saying that the patient had acute porphyria when the “real” experts (in America) said no it isn’t. Because of APF et al’s arrogant insistence that the (“accidental, intermittent occurrence”–according to Waldenstrom/Vahlquist findings, which have yet to be publically confirmed or refuted) port-wine red urine is the diagnostic [still unscientifically proven] gold standard for acute porphyria—and the patient didn’t produce it. In the end, urine excretion was the common factor in virtually every case that had/has been denied and diagnosis withheld by the experts.

Fini ###


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Day 7 NPAW 2021 PURPLE CANARY COMMENTARY: CAN PORPHYRIA EXPERTS’ INFORMATION REALLY BE RELIED ON?; WRAP-UP ON RARITY/PREVALENCE; HEME DEFICIENCY; DIAGNOSTICS

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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.

RARITY/PREVALENCE WRAP-UP

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)

HEME DEFICENCY

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.


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DAY 6 – 2021 NATIONAL PORPHYRIA AWARENESS WEEK: An AIP PATIENT ODYSSEY

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Please note the author/patient posted his odyssey on a FB forum a couple of years ago. He agreed to participate in this Purple Canary NPAW compendium in hopes that the information and his experience might help other patients in managing their AIP.

My first AIP attack occurred in late summer 1956 at age nine. To clear up a bout of tonsillitis before my tonsillectomy I was given a sulfa drug. Almost immediately it hit like a hammer blow to the back of my head. My central nervous system lit up like an incandescent lightbulb just before it burns out. Then everything went dark. I collapsed.

I was likely given more porphryinogenic drugs in the hospital. The next several months my body ached all over. My visual world was back and white with shades of grey, my inner space dark and painful. I was withdrawn, depressed, miserable. The attack gradually dissipated.

Over the next sixteen years, I had numerous much less dramatic attacks. Hunger pangs would turn my belly on fire. Breathing malathion overspray triggered intense headaches. I would frequently feel disconnected from the world around me, just barely able to maintain a grasp on reality. I “whited out” once. I collapsed and briefly lost all muscular control. My inner and outer visual field become one uniform white light, eyes open or closed. I recovered quickly.

Then the big one hit. My descent into AIP-induced dementia began at age 26 with two rounds of tetracycline in early autumn 1973. My first system was an awareness of the floor of my being was about to collapse and I was powerless to stop it. Soon I lay paralyzed on my bed. My mind was clear but I could not form a thought, let alone act on it. My mental faculties were as paralyzed as my body. The need to eat or go to the bathroom would temporarily end the paralysis. I would get up, walk to the diner a half mile away eat, then walk back to the house only to collapse again.

After several days the periods of paralysis were replaced by exhaustion, fogged mind, visual disturbances and excruciating headaches. In a moment of clarity I realized how deteriorated my condition had become and decided I’d best fly home to my father in Atlanta. I sought refuge. A fellow graduate student saw me onto the plane.

Once home, my dementia deepened. I was a zombie for four or five months. My body ached like a really bad case of the flu. Thinking and normal activities were impossible. I spent most of the day staring blankly out the living room window. Dad cooked for me. I ate, bathed, slept and stared out the window. I wasn’t capable of anything else.

At the time, my father was a research biochemist. He worked at a highly respected university medical lab where he learned that a colleague was studying the use of zinc sulfate to treat symptoms like mine. Dad brought some home and I ingested just a tiny amount. It instantly relieved my symptoms. The visual disturbances and body aches stopped. My mind cleared for the first time in months. I became functional again. During the next few months I had numerous small to moderate outbreaks of symptoms but promptly taking a small amount of zinc sulfate (10-15 mg) ended them quickly, in a few minutes at most. My AIP remained undiagnosed for two more years, but I began to lead a more normal life.

In May 1976 I returned home late one night and found medical texts and journals piled atop one another on the breakfast bar, each open to an article on AIP. A note from Dad said, “Son, we have this!” I made coffee and read for hours.

The next day Dad explained he’d made his discovery by accident. The hospital had asked him to help diagnose a family apparently suffering from a hereditary disorder. Dad tested the father for AIP, using his own urine as a control. He added a few drops of 10% Ehrlich reagent to each test tube. The wrong one turned red. Dad was AIP positive! Since I had exhibited extreme symptoms of AIP he concluded I was too. He brought home a rack of test tubes and an eye dropper bottle of Ehrlich reagent. I tested positive. I used the test tubes and Ehrlich reagent to test my urine frequently, during and after attacks. Dad identified the delta aminolevulinic acid (d-ALA) and porphobilinogen (PBG) in his urine by electrophoresis and showed me the results. Two of the articles Dad brought home reported using zinc sulfate to treat AIP, confirming my experience.

I have used zinc sulfate for the last 46 years to control my AIP symptoms, both the physical and the neuropsychiatric. I carry zinc sulfate with me at all times and have it within easy reach at my desk. I take it the moment I sense an attack coming on or when I find myself spiraling downward either emotionally or with physical symptoms of weakness or pain.

The articles my Dad brought home informed me of the importance of avoiding triggers. That has become my primary goal. I use zinc sulfate only when that strategy fails, for instance when I allow myself to become hungry or react to some food contaminated with pesticides or breathe an airborne chemical that triggers and attack.

I hope what I have written here will be of assistance to others.

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NPAW 2021 Day 5 PURPLE CANARY COMMENTARY: ACUTE PORPHRYIA INFORMATION: A COMBINATION OF ANECDOTE, MYTH AND TRUTH?

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Information about the porphyrias has been traveling through medical circuits since its earliest presentation—from patients’ anecdotal reports to medical scientific interests to society at large as a blend of anecdote, myth and fact.  According to the Merriam-Webster dictionary, an anecdote is “an interesting biological incident”; a myth is “a popular belief or tradition that has grown up around something or someone” and truth is “the state of being the case: fact”. “Fact” is further defined as “actual…hinges on evidence”. German philosopher Schnopenhaur states, “Truth goes through three stages. First, it is ridiculed, second it is violently opposed. Finally it is accepted as self-evident.” It appears what has been presented as factual information (hinges on evidence) by certain porphyria experts may actually learn more toward the anecdote or myth category.

So far this week, Purple Canary has presented two NPAW Acute Porphyria Patient Odysseys: Variegate Porphyria (VP) and Hereditary Coproporphyria Porphyria (HCP). On deck for Friday is an AIP Patient Odyssey. These patient odysseys often prompted research (sometimes quite intense) into topics that don’t necessarily appear in the patient stories that are presented by various porphyria advocacy groups:

RARE—REALLY??

As far as the acute porphryias go, it appears the description “rare” is a misnomer that has been overused for decades. Even Dr. Jan Waldenstrom, the “Father of AIP who named the disease in 1937” six years later determined that the “malady may be found much more often than was previously realized, if it is correctly diagnosed.”(1) This is in the country that has long been heralded as having the largest AIP population in the world. Porphyria “maladies” obviously crossed the ocean to America in the genes of European immigrants and by 1953, American researchers reported, “There have been an increasing number of case reports of the hitherto comparatively rare group of disorders included under the general term of porphyria.”(2) That statement, or variations of it, has been found in numerous medical articles.


PREVALENCE

A fellow nonprofessional porph researcher pointed out illogical comparisons found in APF’s literature concerning porphyria prevalence and noted, “Consistently “blending” European prevalence numbers is not only misleading, but disingenuous for a US-based operation to do.” She’s right. The organization’s website states, “The exact incidence and prevalence of symptomatic AIP is unknown [in U.S.]. But “in Europe the prevalence is estimated to be approximately 5.9 per million people in the general population.” While there is no report for U.S. prevalence of HCP, VP or ADP, the website notes, “VP is especially common in South Africa in individuals of Dutch ancestry, where it has been estimated that 3 in 1,000 of the white population are affected.[and] It is much less prevalent in other countries.”(3) She concluded, “Since this is the American Porphyria Foundation, why not provide prevalence figures for each of the above referenced types of porphyria?” Of course they should. Interestingly, during his 3/1/2017 FDA “Voice of the Patient” presentation, Dr. Herbert Bonkovsky cited AIP prevalence information for Sweden, Finland, UK & West Europe—and USA (which at 2-5/100,000 (for “symptomatic disease”) was in line with its UK & West Europe counterparts. It was not disclosed where that number came from. Recalling what patient “Mary” said during an Alnylam/Givosiran Roundtable session—reported on NPAW Day 3 Commentary (“one thing to realize is even if they’re all latent, every single one of those is potentially a porphyria patient because all they need is one dose of sulfonamide antibiotics like I had and their porphyria is woken up”).(4) Should that statistic be accurate—and realized, the acute porphyrias NIH rare status might well be in jeopardy.

“RARE’s” IMPORTANCE TO APF, its SAB AND ITS PHARMACEUTICAL PARTNERS, NIH and FDA

Maintaining the NIH rare disease category status for the porphryias is critical to these partners for many reasons; financial gain is certainly chief among them. As far back as 2014, an Alnylam press release noted, “The acute hepatic porphryias, including AIP, are ultra-rare orphan diseases….”(5) When, during a 2018 Earnings Call an investor analyst questioned how large of an opportunity the drug Givosiran would be, an Alnylam executive replied, “Let me emphasize that porphyria will remain an ultra-rare disease…we are working with the porphyria network to strengthen the next set of physicians that are coming up….”(6) Fast forward to 2019. An Alnylam executive assured an investor analyst that the number of “active disease patients was estimated to be 3,000 in US and Europe of which 1,000 are recurrent attack patients—obviously a larger number in the rest of the world.” It was emphasized that 5,000 was the “real number.”(7)  Hmmm. Only 5,000 acute porphyrics in the entire world?

ACTIVE/SYPTOMATIC VS. LATENT VS. ASYMTOMATIC

All of this leads to the muddled terminology defining the status of one’s acute porphyria which I believe began at the earliest of times (say Hippocrates’ era) when it was noted that some patients (the “sickest”) exhibited severe neurological symptoms and excreted darkened urine. I guess when others (even in the same family) exhibited symptoms, but didn’t excrete darkened urine, they were considered to be “having fits” and/or mentally ill. For clarity’s sake, the definition of Latent is hidden, dormant, inactive; Asymptomatic: absence of symptoms and Active/Symptomatic the exhibiting or involving symptoms. What apparently came to pass is that physicians and the earliest of porphyria experts determined that unless a patient excreted darkened urine, his or her porphyria was not active, but latent. Now this is a huge bone of contention not only between the ever-growing number of patients who either don’t excrete darkened urine during severe neurological attacks, and porphyria experts. It has also contributed to a growing number of doctors who attend to such patients questioning porphryia experts’ integrity. Why? Because in reality, it has been well documented that porphyrns and precursors end up in tissue, the bloodstream and/or are excreted via urine. And there are porphyria experts who contend that the latter piece is not a surety.

  • Acute Intermittent Porphyria: Prompt Response to Therapy with Corticotropin, Janoff et all; 1953
  • Studies on the excretion of porphobilinogen in patients with socalled acute porphyria, Waldenstrom & Vahlquist, 1943
  • APF website
  • Alnyam’s 7/24/2018 RNAi Roundtable: Givosiran, in Development for the Treatment of Acute Hepatic Porphyrias
  • Alnylam 5/21/2014 Press release: Alnylam and Collaborators Publish Pre-Clinical Results with ALN-As1, an RNAi Therapeutic Targeting Aminolevulinic Acid Synthase-1 (ALAS-10 for the Treatment of Hepatic Poprhyrias, in the Proceedings of the National Academy of Sciences
  • Alnylam Pharmaceuticals (ALNY) Q2 2018 Results – Earnings Call Transcript
  • Alnylam Pharmaceuticals (ALNY) Q3 2019 Earnings Call Transcript

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DAY 4 – 2021 NATIONAL PORPHYRIA AWARENESS WEEK:  An HCP PATIENT ODYSSEY, prepared by the patient’s mother/caregiver

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Two of my three children inherited Hereditary Coproporphyria (HCP) from their father’s lineage; last I

knew his family included more than ten HCP sufferers. My oldest child, a daughter, had episodes of pain in her abdomen and severe constipation from as soon as she could speak and tell me what she was feeling. She had taken numerous courses of antibiotics with little success. As the pain grew more and more severe my daughter was seen by numerous specialists and had been subjected to multiple tests to rule out everything the pediatrician could think of, even looking for signs of sexual assault as no cause could be found for her ongoing bouts of pain. One very hot summer’s day my daughter and I were gardening when she suddenly fell to the ground and stayed in the fetal position, not making a sound. I swept her up and took her to the nearest emergency room where a paternal family member, who happens to be a pediatric/genetic/metabolic specialist, is employed. She confided that porphyria was in the family and after thorough testing, gave an informal diagnosis of porphyria. Her professional opinion was that the disease was the best explanation for my daughter’s symptoms, despite the literature excluding the possibility of children having attacks before puberty. She explained that little was known about rare diseases and that the literature can often be incomplete, especially when it came to metabolic diseases. She stated that because porphyria is a genetic metabolic disease it would be more likely to be active from birth and noted that family accounts confirmed that porphyria activity had been reported in very young children from their family.

All of this happened before my daughter was 3. I remember this because she started preschool in a full leg cast after falling over on a family holiday. Thanks to the family specialist, I knew to keep her out of the sun and had learned from experience to hold her hand firmly as she would just suddenly collapse without warning, but she insisted on walking on her own this day so I let her walk through a park without holding her hand. Sure enough, she dropped to the ground with a thud and we soon found out she had broken her leg in the fall. There was no force or scream or even propulsion in the way she fell, just a hard whack onto the ground. These episodes, which I can only explain as fainting followed by severe stomach pain and two weeks of constipation had become a regular occurrence by the time she went to school. As I could not get a formal diagnosis for her due to the misinformation that children do not have acute attacks, she was left to her own devices at school and I was forever running to school after a phone call stating that she had fallen over in the playground, one day knocking out a front tooth and scraping her face. There were never any scrapes on her hands. She never guarded her face or broke her fall. She just dropped like a bag of potatoes.

My youngest child, a son, was diagnosed with epilepsy and a brain disorder at a very early age. He too

began exhibiting what I now knew to be porphyria symptoms. That’s when his treating neurologist insisted that genetic and biological testing be done on all three of the children in the family. This testing had previously been refused by a recommended porphyria specialist due to the assumption that children didn’t have acute attacks. All three children were tested–the two who were suffering symptoms came back with positive DNA and the stool biomarker indicating HCP (Copro III:I reversed). By that time, my daughter was sixteen and my youngest was seven. My seven year old also had high urinary PBG, which was determined to be due to years of taking unsafe epilepsy medications since his birth. Because he excreted U-BP, he was considered to be in an acute attack; removal of the offending epilepsy medications stopped the symptoms. While no treatment was offered by the porphyria specialist, my son was frequently placed on glucose IV by doctors at his regular hospital in order to avoid attacks.

Meanwhile, my daughter continued to suffer severe HCP symptoms and attacks; she never did excrete first-line U-BP so was denied treatment for eighteen long years. Having left school, unable to eat or

sleep, often being taken to emergency via ambulance, she was left to suffer due to a lack of high urine

PBG, despite her having seen a multitude of specialists over more than a decade who ruled out common

causes for her symptoms, despite her family history of porphyria and even despite the expert-confirmed

DNA result! In 2016, she became deathly ill. I sought contact with an experienced porphyria expert from another state who confirmed that my daughter was indeed suffering from porphyria. He cited the DNA result combined with the stool ratio indicating HCP plus symptoms and triggers synonymous with an acute attack of porphyria and began treating her with glucose/hemin treatments. Her condition improved considerably. Previously in a wheelchair, she resumed her ability to walk but her HCP remains chronic, needing numerous treatments with heme infusions per year. She currently has another excellent specialist who regularly tests her heme levels and organizes treatment when these levels are reduced or depleted and symptoms worsen. She also has been found to have high urinary ALA during most attacks–something never tested previously when urinary PBG was assumed to be the only relevant indicator. She has never had high U-PBG yet her doctors are now well aware that it is not a good indicator of acute attacks in her case and she receives hematin as she needs it. It is her specialist’s opinion that she has been heme deficient for years and will need many years of treatment before her body recovers from years of medical neglect.

A final point:

It is still commonly stated in academic papers that infantile acute attacks are extremely rare. It is also completely unrecognized by most ‘experts’ that sun exposure can cause acute attacks in porphyrics who are susceptible. I only recently realized this when representatives from two major international porphyria organizations stated bluntly that the sun only ever causes skin reactions, much to the chagrin of the many HCP and VP sufferers who, like my daughter, have had life-long neurological attacks from sun exposure. There is still so much misinformation circulating in porphyria academia which never seems to be challenged.

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Day 3, Purple Canary 2021 National Porphyria Awareness Week Commentary

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In a perfect world, every acute porphyria patient would be identified, receive adequate and effective treatment as necessary (high-ticket, budget-busting pharmaceutical orphan drugs need not be the only option(s))–and maybe have a chance at retaining his/her position as a contributing member of society, even if it means in a non-traditional sense. But of course, this world is far from perfect.  And from where the ever-expanding number of expert-dismissed patients and their caregivers, family members and friends sit, “perfect” is not the word they would use to describe the rigmarole they and their doctors (if, that is, they are lucky enough to secure physician interest) are subjected to—sometimes for months, sometimes for years, sometimes for decades. The catastrophic VP PATIENT ODYSSEY presented yesterday is testament to that reality.

According to APF’s compilation of historical porphyria facts [website], in 1880 “MacMunn” observed/described reddish-colored urine excreted by a patient “with symptoms of an attack of acute Porphyria”. From that point it appears that reddish-colored urine became the “diagnostic touchstone” for acute porphryias. In fact, it remains the benchmark, evidently without scientific backing (US experts have gone so far as to brazenly dub it the “gold standard”) for diagnosing all of the acute porphryias.

Expert reliance on what Dr. Jan Waldenstrom (aka “Father of AIP”) determined to be “accidental” occurrences has caused considerable consternation for patients who are denied acute porphyria diagnoses. Further, the so-called “gold standard” ultimately resulted in a substantial breach between the two patient groups—the ones whose bodies produced quantifiable (measurable) amounts of “gold standard” imbued urine (preferably during attacks), and those who don’t. While members of the latter group eventually come to understand (some sooner, some later) that they have been dismissed by experts, the former group just doesn’t get it—because they don’t have to.  Why? Because by having excreted the coveted urine, they are welcomed into putative “porphyria clubs” (the foundations, organizations and associations created for advocacy and education) where they are provided support, access to experts and have an opportunity to participate in research. The latter group, lured by “Research is the Key to Your Cure!”1 the ones who would willingly turn their bodies inside out to find out “what is wrong with me” are left to their own devices in every way, shape and form.

Following are some illuminating quotes (followed by Purple Canary commentary); they were made by APF “members” of the “former group” mentioned in the previous paragraph:

“If we don’t advocate for ourselves, who will?” Posed by despairing VP patient/panel participant “S.D.” during the FDA, “The Voice of the Patient: Patient-Focused Drug Development Meeting” sponsored by APF (3/1/2017). This individual was one of five panelists to present clinical manifestations of [acute porphyria], effects on daily life, quality of life and family impact. To that query, Purple Canary offers: “Um…maybe your presence at and participation in this meeting is a clue that APF advocates for you and the others that were invited to attend and/or participate in the meeting?”

“There was that paper that Puy put out in France saying that 1 in, I think, 1,652(sic) [1,675] people in France have the gene for porphyria. And one thing to realize is even if they’re all latent, every single one of those is potentially a porphyria patient because all they need is one dose of sulfonamide antibiotics like I had and their porphyria is woken up.” Statement offered by unidentified participant (actually self-identified as “Mary”) during Alnyam’s 7/24/2018 RNAi Roundtable: Givosiran, in Development for the Treatment of Acute Hepatic Porphyrias.” Purple Canary offers: “This individual is obviously “all in” regarding the “latent” acute porphyria narrative presented by the experts. This misnomer will be discussed later this week as will the subjects of rarity and prevalence. In any event, she missed the point about “patient population”—clearly, Alnylam’s goal is to maintain the lowest population counts in order to sell ultra-expensive Givosiran (now Givlaari) through insurance companies and single payer healthcare countries.” To that end, the Alnylam representative politely thanked “Mary” for her information and quickly changed the subject.

Following are remarks made by patients who’ve been ignored, dismissed, gaslighted and abandoned by experts—and definitely not included in any expert’s research project(s). Their identities will remain anonymous. Note how the tone and despair differs from selection of previous quotes:

“I feel I am hanging on by a thread. It breaks my heart to know how many of us are suffering so greatly and dying slow, painful deaths and can’t get help. It’s criminal.”

“Letting parents suffer the hurt in their children’s eyes will information that could help them is purposely buried is pure evil.” – From a porphyric mother whose son died of unexplained seizures at eleven years of age.

“Most of us have been through the ringer with this disease. Doctors that are incompetent, emergency rooms not treating us and treating you as a drug seeker. When the largest foundation says they going to support you, you jump at the chance! [But they don’t (help).]”

Closing:

“the most demeaning is to be [told] “You’re being a drug seeker because your pain can’t possibly be that bad.” – Commented by APF director D. Lyon during FDA, “The Voice of the Patient: Patient-Focused Drug Development Meeting” sponsored by APF (3/1/2017). Purple Canary: No, D. Lyon….the most demeaning is to be told by a porphyria expert, “you don’t have AIP, VP, HCP or any type of porphyria.” Especially after you’ve been diagnosed (by porphyria expert(s), no less) and/or have a known family history of porphyria. The gaslighting of patients by medical professionals is far too common in this world.

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  1. https://porphyriafoundation.org/

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Day 2, Purple Canary 2021 National Porphyria Awareness Week: VP PATIENT ODYSSEY

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Although I was an early talker at 4 months three months later I was given a medical diagnosis of failure to thrive. During my early years (age 3-4), I frequently suffered bad tummy aches after being in the sun. Even so, my mother was ordered by doctors to subject me to sun therapy because they said I suffered from rickets. A tetanus shot at age 3 precipitated vomiting attacks for the next several years. At age five, I fainted while seated in school. Two years later, I nearly died of hypoxia while being treated with penicillin (I was not allergic to it) for strep throat and measles then developed pyelonephritis, a condition that years later a highly respected porphyria expert determined was an indicator of porphyria. I have memories of being about 8 years old and seeing my mother curled up in her bed, suffering with an attack. Sometime later, she went away for treatment where she was presumably diagnosed with porphyria. Evidently, her urine changed color and a doctor was alerted due to this interest in porphyria. However, the word “porphyria” was never uttered throughout my childhood. But after that hospitalization my mother always loaded me up with candies and other sweets to take back to boarding school (which suggested she knew about porphyria/sweets). At some point, she was hospitalized for a length of time (2x at 6 weeks each) for retinal detachment treatment; in those days they believed such patients were to be kept in a reclining position for the duration.

Beginning early and throughout my many years, my symptoms and illnesses ran a troublesome gamut: lactose intolerance, gluten intolerance, food allergies, stomach pains, “ovulation pains”, rheumatic fever, pneumonia, pleurisy, bronchiectasis, ringworm, petichae, erythema nodosum, sarcoidosis (with many relapses), diabetes, insulin intolerance, vision loss, broken toes (upon simply rising from bed), bladder infections, frequent UTIs with hematuria, fibromyalgia, hepatitis-like illnesses, mental distress, unexplainable “drop attacks”, vision loss, bouts of paralysis, pernicious anemia.

I’ve endured numerous operations and medical procedures and received various vaccinations that turned out to have distressing side effects. There isn’t enough room here to list the number of medications (safe and unsafe) that have been tried out on me over many years. Despite my medical concerns, I earned a degree in Clinical Psychology and worked in that gratifying field for a number of years. I’ve been investigated for MS, Myasthenia gravis and other similar and/or related diseases, and yes, porphyria. In fact, in 1981, my case was written up in a highly respected medical journal that stated a “patient with known family history of porphyria.” At that time, although I presented with “severe abdominal pain and aching of lower limbs of three days duration,” my “blood pressure, pulse rate and mental state were normal.” But urine and fecal samples “gave a pattern diagnostic of variegate porphyria” and the porphyria experts who’d prepared the article stated, “this patient demonstrates the main features of variegate porphyria: a positive family history and chronic skin involvement with occasional transient episodes of acute abdominal and neurological manifestations.” In 1999 I received a clinical diagnosis of variegate porphyria from a highly acclaimed porphyria pioneer. Four years later I found myself in the presence of one of the porphyria experts who’d participated in the 1981 writing of my case study. But he inexplicably refused to order DNA testing and broke off contact with me. He turned my case over to genetic counsellors who were ready with an inexplicable argument, “Would DNA results change your treatment?” Knowing of the efficacy of glucose infusions and hematin treatments, I thought, “Of course it would!” However, other than the few times when I begged for oral glucose treatment (which did help), I received neither glucose nor hematin infusions. Given early enough and regularly, it is quite probable that the neuropathy and paralysis I’ve suffered since would have not have worsened into the frequent, unmitigated horror events I continue to suffer. Aggravatingly so, interference from the aforementioned porphyria expert has continued for years throughout my quest to obtain answers from numerous sources.

My family history is replete with sickly cousins and second cousins that present with similar symptoms to the family of Chester, UK, where I have ancestral ties.  I’ve dedicated considerable time and effort to research the acute porphryias—most notably variegate porphyria. Not impressed with information provided by so-called experts, I ventured down many trails to obtain treatment and/or medical advice. Now as an octogenarian here are some points I want to share with readers of this forum about what I’ve learned through experience about the acute porphyrias: 

1)        they are progressive disorders that worsen over time;

2)        chronicity is not a maybe—it’s a surety;

3)        acute porphyria patients can indeed suffer with anemia;

4)        blood sugar (especially low) can be an indicator of impending porphyria activity.  It is for me–I wear a continuous glucose monitor to alert me of blood sugar lows;

5)        blood cell abnormalities are not uncommon in acute porphyria;

6)        nutrition (including additional supplementation with minerals and/or vitamins) is critical for the management of acute porphyria;

7)        reducing or better yet, avoiding sunlight and blue light of computers, phones, etc. can help decrease skin rashes however, my skin afflictions can flare from other triggers such as stress, too.

Even though my case history was published back in 1981 and data from my brother’s, mother’s and my porphyria were included in a 2016 US study about acute porphyria, it is painfully obvious that experts intentionally turned their backs on me.  My husband, my rock, passed away in 2010, leaving me alone to manage as best I can. I find minimal relief by ingesting glucose, maintaining a higher than “normal” carb diet and relying on regular intake of supplements (such as B vitamins). At times I turn to cimetidine which was long ago proven through clinical trial to treat acute porphyrias. Some days (actually most days) none of this is enough.

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PORPHYRIA EXPERTS: FOR SOCIETIES’ SAKE…STOP DISMISSING, GASLIGHTING AND ABANDONING DESPERATELY ILL ACUTE POPHYRIA PATIENTS! Day 1, Purple Canary 2021 National Porphyria Awareness Week Commentary

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“What we have here is a failure to communicate.” This classic line from the American film Cool Hand Luke exemplifies the alarming and capacious disparity between information provided by certain acute porphyria experts and what doctors and patients need to know in order to make informed medical decisions. For decades, these experts have (willfully, it appears) spoon-fed select information to audiences (physicians, patients, society) and shrewdly excluded information they don’t want them to know. This has led to (and reinforced) an overabundance of withholding and/or revocation of acute porphyria diagnoses—a practice that continues to this day.

By denying diagnoses and not providing truthful, complete and inter-connected information about acute porphyria “rarity”; prevalence; chronicity; progression; the (unproved)diagnostic “gold standard”; latent and/or asymptomatic versus manifest presentations; heme deficiency and efficacious, safe  treatment options, such experts have–individually and collectively–needlessly contributed to steep, persistently burdening medical costs to (and anguish for) patients, their families, insurers and indeed, societies throughout the world. Interfering with physician/patient relationships by undermining medical professionals who are intent on doing the job they trained for is highly unethical—not to mention doing so raises the specter of potential manslaughter/murder charges. Seriously.

To that end, this year’s Purple Canary’s 2021 National Porphyria Awareness Week commentary takes a cue from American poet Maya Angelou’s “You shouldn’t go through life with a catcher’s mitt on both hands; you need to be able to throw something back”. Patient voices will provide clarification with highlights from hard-fought odysseys. Citations from peer-reviewed medical journals and/or textbooks will offer what amounts to court-worthy expert testimony. Finally, declarations proffered by certain experts will appear throughout the week and provide context for the state of affairs that has confused too many for far too long. In this way, patients and caregivers will “throw something back.” All readers (especially experts) are welcome and encouraged to respond.


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International Rare Disease Day, 2021

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Although Rare Disease Day technically is observed each year on the last day of February each year, this year NIH announced it will hold a virtual Rare Disease Day on Monday, March 1, 2021.

A bit of history

On February 29, 2008, EURORDIS (the European Organisation for Rare Diseases) organized the first Rare Disease day. According to Wikipedia, “the date was chosen because February 29 is a “rare day” and 2008 was the 25th anniversary of the passing of the Orphan Drug Act in the United States.”[1] Nine months later (almost to the day) my daughter was diagnosed with AIP via DNA testing by Robert J. Desnick—a member of the American Porphyria Foundation’s Scientific Advisory Board, NORD’s Porphyrias Consortium and revered (by APF at least)  geneticist at Mount Sinai, NYC.

The next year (2009), US and 23 other countries joined the first global observance of Rare Disease Day.[2] By then, my daughter’s condition had severely deteriorated, necessitating my taking a wide berth around APF and its experts to get medical treatment that essentially saved her life. Since then, a lot has “gone down” that required me (with the help of so many others) to do some “deep diving”—the findings of which made me wonder: when it came to porphyria, just what the hell was really going on in my beloved USA with all of its “medical excellence”?

Back to Rare Disease Day

In occurring once every four years, one might argue that February 29 is more of a mathematical/scientific and perhaps human ego[2]-combined anomaly rather than an actual rarity.  But in the US, without any bona fide, unbiased scientific proof, porphyria is still considered to be a “rare” disease. Yet over its 39 or so years of being in business, APF has intoned that for a disease/illness/disorder to be considered rare in the US, it must affect less than 200,000 [patients]. Hmm. On its website, this foundation lists nine different types of porphyria yet has never offered a breakdown for how that <200,000 patient population is arrived at.

“Rare” and Orphan Drug Prove Robust for Alnylam

Alnylam and its investors, inventors of intellectual property, consultants, recipients of research grants, and the many who received (and still receive) support for accommodations, travel and other expenses did damn well with its orphan drug entry into the realm of porphyria treatment (in this case treatment for acute porphyrias—less than half of the porphryias identified by APF). In fact, according to its fourth Quarter Earnings Call Report, Alnylam “achieved $55.1 million in global Givlaari revenues for the full year 2020.”[4]

Yet my mind is drawn to the multiples of patients across the globe, in order to maintain that medically-coveted “rare disease” diagnosis, aren’t counted. Their lives and families are in ruins. Each’s character is repeatedly degraded by those “in power.” They are left to suffer inhumanely and lose their status as contributing members of society–just so experts and non-experts (pharmaceutical companies) profit by sustaining serious conflicts of interest.

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[1] https://en.wikipedia.org/wiki/Rare_Disease_Day

[2] https://ncats.nih.gov/news/events/rdd

[3] https://www.kiro7.com/news/trending/leap-year-2020-what-is-leap-year-how-did-it-start-why-feb-29/377CELP2VNDZDMBM7BEQEPB5E4/

[4] https://www.fool.com/earnings/call-transcripts/2021/02/11/alnylam-pharmaceuticals-inc-alny-q4-2020-earnings


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