RTRX – Notes on Retrophin’s PKAN program

August was a month full of news for Retrophin (RTRX): financing, PR on preclinical results of their PKAN candidate (RE-024), PR on agreement to negotiate a candidate for autism and schizophrenia. In addition, rumors came out on Alexion making an offer for $10 a share, motivated by the strong preclinical results of RE-024.

All this convinced me that it was time to stop procrastinating and look into Retrophin more in depth. Being a neuroscientist, a neurphysiologist by training and trade, I am particularly fascinated by the strong focus of the company on neurological and psychiatric diseases. I can’t say anything about their move on autism and schizophrenia, as no detail is available on the potential compound that they are negotiating. A bit more is available on their PKAN program, and that’s what I’ll focus on in the next few lines.

Martin Shkreli, Retrophin’s CEO, was very smart in targeting this disease: it’s an orphan disease, very severe, monogenic and potentially addressable (at least as a first approach) with replacement therapy.

Panthothenate Kinase-Associated Neurodegeneration (PKAN) is a genetic disease associated with movement deficits and retinal degeneration [1]. It exists in early-onset (the most diffuse) and later-onset forms, both are progressive, with the early onset leading to loss of ambulation within a decade and death by the third decade. The neurologic symptoms (dystonia and Parkinson’s like symptoms) are related to degeneration of neurons in the basal ganglia with accumulation of iron.

The disease is caused by mutations of the gene for the pantothenate kinase 2 (PANK2) [2]. This is an enzyme necessary to synthesize phosphopantothenate a compound needed for coenzymeA (CoA) biosynthesis. The pathogenesis is linked to deficit of CoA and accumulation of cysteine. Deficit of CoA leads to mitochondrial deficits and cell death. Accumulation of cysteine leads to iron accumulation, oxydative stress and cell death.

The enzyme is mutated in all the cells (PANK2 is predominant in the brain), but degeneration affects mostly retina and basal ganglia (specifically the globus pallidus and the substantia nigra pars reticulata). The cause of this selectivity is unknown, it could be that the areas affected rely strongly on PANK2 (and not other isoforms) or it could be related to high levels of iron in basal ganglia and their high metabolic requirements.

No therapy exists at the moment. The approach chosen by Retrophin is to develop a replacement therapy. Administering phosphopantothenate (the physiological product of PANK2) would allow cells to synthesize CoA. However, phosphopantothenate has issues of bioavailability and it is ineffective when administered as is. Retrophin has developed RE-024 as a bioavailable form of phosphopantothenate.

The studies they performed so far, in collaboration with a strong group at St. Jude Hospital specialized in PANK, are on mice. I could not find many details on the studies (it is still early and no peer reviewed article on RE-024 is available yet) so I’ll try to put together the information I found from Retrophin’s website and interpret it against the background of results from the literature.

Retrophin tested RE-024 on a PANK1 knockout mouse (a mouse that constitutively lacks of the PANK1) [3], these mice have reduced CoA in the liver. RE-024 administered to PANK1 knockout mice restores liver levels of CoA to control levels. They also tested RE-024 on a different mouse model, a mouse that was given a global PANK inhibitor [4]. RE-024 massively increased survival in these mice. In both cases RE-024 was found to be safe and non toxic.

All this is certainly encouraging and positive. Very positive if one thinks that phosphopantothenate is ineffective as a replacement therapy, and Retrophin has developed a compound that restores levels of CoA and promotes survival in mice. However I think it is a bit too early to be too positive about the possible effectiveness in relieving the neurological symptoms of PKAN. Particularly if one considers these issues:

1) The replacement experiments were performed either on mice constitutively lacking PANK1 (note that this is not the isoform mutated in PKAN) or on mice where all the isoforms of PANK were inhibited pharmacologically. Neither of these preparations is a model for the disease, these animals show neither the retinal degeneration nor the neurological symptoms. So these experiments don’t really tell us whether RE-024 is effective in preventing the neurodegeneration of basal ganglia and neurological deficits.
Now testing the effectiveness of RE-024 on neurological symptoms in better animal models of PKAN is far from trivial, mostly because there isn’t a good model of the neurological pathology of PKAN. There is a PANK2 knockout mouse [5,6], but while this animal has retinal degeneration, it does not have basal ganglia degeneration and movement disturbances. Thus, testing the ability of RE-024 to act as a neuroprotective agent in vivo and to rescue motor symptoms would require the development of a mouse model capturing the neurological features of PKAN. There might be some straightforward ideas to address this, and efforts from other research group might help, but it might take some time. This means that as of now RE-024 effectiveness on the central nervous system is unproven.

2) Basal ganglia degeneration is associated with PANK is accompanied by iron deposits. Iron deposits are believed to be due to accumulation of cysteine. It is not entirely clear why cysteine accumulates in PKAN. Phosphopantothenate is known to condense cysteine, hence adding RE-024 (the phosphopantothenate replacement) might reduce free cysteine. This would be great news! However, cysteine could be coming also from other sources. PANK2 deficit leads to accumulation of substrates that contain cysteine. If these compounds are also responsible for iron accumulation (hence toxic), then it might be a problem for Retrophin’s approach. Indeed, replacement therapy is not effective in reducing these compounds since it does not restore the enzymatic function of PANK2. [On a side note, small pilot trials have been run using deferiprone, an iron chelator, on PKAN patients [7,8,9]. A P2 pilot showed a reduction in globus pallidus iron content, but no clinical improvement [8]. A second small pilot provided hints at some improvement in neurological function [9]. A large multi-center, placebo controlled trial using deferiprone is currently being run [7] – http://www.tircon.eu/index.php – and depending on the results it could represent possible good news for PKAN patients and potential competition for Retrophin from ApoPharma]

So, where does all this leave us in evaluating Retrophin’s PANK program? I applaud Martin Shkreli’s decision to target PANK. This is a disease in need of a therapy and it is potentially tractable. The mutations that lead to PKAN are multiple and a genetic approach might not be as straightforward as a replacement therapy. In addition PANK could be an entry point to a family of related neurological disease related to iron accumulation (NBIA, neurodegeneration with brain iron accumulation)[10]. Success in PANK could potentially lead to much more; also in consideration is the fact that PANK has Parkinson’s like symptoms.
The good safety profile might make for a smooth move to clinical trials, which will increase the visibility of Retrophin. That said, the preclinical work has not yet demonstrated the effectiveness of RE-024 in preventing basal ganglia pathology and rescuing neurological deficits.

So what would I like to see next from Retrophin in their path to find a therapy for PKAN? It would be great to have a sense on whether RE-024 passes the blood-brain barrier (bbb) and restores CoA levels in the brain. Needless to say that passing the bbb would make targeting the basal ganglia much easier. I would also love to see whether RE-024 can rescue the retinal degeneration seen in PANK2 KO mice. Of course the ideal pre-clinical data would come from reducing basal ganglia iron deposits and rescuing the neurological symptoms of PKAN in a model (at the moment non existing) that captures these feature.

While an effective PKAN’s therapy is not behind the corner, RE-024 got off to a good start. As a scientist and MD I am looking forward to more results on RE-024 and deferiprone and more research on PKAN.

DISCLOSURE: I have no conflict of interest to declare, neither financial nor scientific. At present I have no financial position in Retrophin nor in any competing company developing drugs for PKAN. I have written this commentary for personal interest, in my free time and I have neither requested nor received any compensation for it.

Biography: I got my Medical Degree and PhD in Neuroscience from the Department of Pharmacology, University of Brescia (Italy). I did my PhD thesis research at Caltech, studying the neurophysiology of olfaction. After postdoctoral training at The Volen Center for Complex Systems – Brandeis University, I joined the faculty of the Department of Neurobiology and Behavior at Stony Brook University, NY. My research group studies the neurobiology of taste and emotion. Our research has been published on many peer reviewed journals, is funded by NIH and has been recognized with a Pecase Award from the White House, an Ajinomoto Award for Research on Taste and a Klingenstein Award.


1) Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration (PKAN) In: Singer HS, Kossoff EH, Hartman AL, and Crawford TO, editors. Treatment of Pediatric Neurologic Disorders. CRC Press, 2005: 355-359
2) Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001 Aug;28(4):345-9.
3) Leonardi R, Rehg JE, Rock CO, Jackowski S. Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state. PLoS One. 2010 Jun 14;5(6):e11107.
4) Zhang YM, Chohnan S, Virga KG, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Newgard CB, Lee RE, Rock CO, Jackowski S. Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. Chem Biol. 2007 Mar;14(3):291-302
5) Kuo YM, Duncan JL, Westaway SK, Yang H, Nune G, Xu EY, Hayflick SJ, Gitschier J. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum Mol Genet. 2005 Jan 1;14(1):49-57.
6) Garcia M, Leonardi R, Zhang YM, Rehg JE, Jackowski S. Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism. PLoS One. 2012;7(7):e40871.
7) Hayflick SJ, Hogarth P. As iron goes, so goes disease? Haematologica. 2011 Nov;96(11):1571-2.
8) Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, Longo F, Garavaglia B, Aquino D, Savoiardo M, Solari A, Nardocci N. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord. 2011 Aug 1;26(9):1756-9.
9) Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, Galanello R, Barella S, Matta G, Ruffinengo U, Bonuccelli U, Forni GL. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica. 2011 Nov;96(11):1708-11.
10) Rouault TA. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci. 2013 Aug;14(8):551-64.

12 replies added

    • Avatar photo

      It’s a very rare disorder, prevalence not completely certain- est at btwn 1-3 per million. My guess is low hundreds of millions.

  1. From Jason’s report in January, CEO Martin mentioned the plan to uplist in NASDAQ in 1H13?
    Anybody has follow-up about this uplisting? Thx.

    • Avatar photo

      Company hasn’t spoken of it since as far as I am aware. But it appears to meet the requirements to list under Nasdaq Capital Markets

  2. Does anyone have an idea what that press release about “Pursuant to the exclusivity agreement, Retrophin paid the major pharmaceutical company a non-refundable upfront fee and will have an exclusive period of 120 days to negotiate a license agreement. ” was about?

    They paid an upfront fee for the right to negotiate???? No guarantees or commitments that the negotiating partner will agree to any specific terms or that an agreement will be reached that is acceptable to Retrophin?

    I’ve never seen anything like this before and was wondering if I’m alone in thinking it sounded very, very odd.

    • Avatar photo

      I don’t find it too unusual for a small biotech to PR these type of things. They depend on a constant news flow to keep investors interested. The company has a $25 million PIPE and speak frequently of Autism. I think the negotiations are serious and Retrophin is willing to put up real money to make it happen.

    • Avatar photo

      Interesting Martin’s comment on twitter that the drug will not be given orally. Funny we kinda all seemed to assume it would be. If delivered directly into the spinal fluid via something like intrathecal injection, there would be no worries about crossing the BBB.

      • Avatar photo

        Considering this is replacement therapy I am not sure intrathecal is doable. I assume it would have to be given frequently. I agree with John and Patrick that bbb data are crucial. I think it will be very important also to show efficacy in rescuing neuro symptoms.

          • Avatar photo
            Alfredo Fontanini Aug 28, 2013

            Yep, you are right, Shire is doing it. It just seems to me way more complex than having an oral formulation. But it seems to offer a potential backup plan if it doesn’t pass bbb.

Leave your comment