Acthar and Questcor pharmaceuticals is a 2-3Billion dollar company with an inferior product
itunes...@gmail.com
The only melanocortin receptor agonist on the market in the US is Acthar (Questcor Pharmaceuticals). This is a pig pituitary derived peptide without an exact known composition but mainly ACTH. The company describes a “complex formulation which includes adrenocorticotropic hormone(ACTH) and potentially other active peptides reported to bind to a variety of important receptors in the human body”. Synthactin, is a synthetic ACTH and is approved in Europe and elsewhere.
ACTH is a 39 aa polypeptide and the first 13 aa sequence is identical to MSH. (MSH is cleaved from ACTH). ACTH is an agonist on all 5 MC receptor subtypes. MSH is equal or greater than ACTH in its agonist activity on MC1,3-5R, in particular it is greater in MC1R. NDP-MSH or afamelanotide (Scenesse) is a known superpotent agonist, up to 1000 times with a much longer half life. MSH does not bind to MC2R, binding to MC2R causes release of cortisol from the adrenal glands, and this was the believed mechanism of action when the drug was developed 50 years ago. However with the increase in knowledge of the melanocortin receptors the company is now exploiting its position as a melanocortin receptor agonist.
Importantly this means that many of the effects of MSH will be the same as ACTH, with the exception of cortisol release,( this is no longer desirable as oral synthetic steroids have become available cheaply since acthar was developed).
From the Questcor website “adrenocorticotropic hormone (ACTH) and potentially other active peptides reported to bind to a variety of important receptors in the human body. These receptors appear to be found, for example, in the central nervous system, the kidney, and on certain immune cells. They are also found in the adrenal gland, where their binding by ACTH stimulates the production of the natural steroid cortisol. Thus, there appear to be multiple Acthar mechanisms of action, of which only one element is steroid-related. For this reason, Acthar seems to be effective in some patients who do not adequately respond to steroid treatment. Acthar has been misunderstood and underestimated, and what many physicians think they know about the drug is not up-to-date. We are working hard to change this. As such, Acthar is now undergoing a renaissance in multiple fields of medicine. This represents our opportunity and our challenge in rescuing and reviving this old drug.”
The Questcor business story is interesting reading, the drug was bought for a song (around $100k) from major pharma as it was considered obsolete by the introduction of cheap oral synthetic steroids. Following the result of aggressive marketing and a “failure” of the FDA regulatory system which has allowed marketing of this drug for non approved indications because Acthar was initially approved for use in 1952, before the Food and Drug Administration required clinical trials to show a drug is effective for a particular disease. Acthar is essentially grandfathered in.
In 2007, the price was more than $28,000 a vial, from as low as $40 in 2000. This was done on the justification that it was only approved for a rare (orphan) indication, infantile spasms.
The market cap was as high as 3.2billion in 2012, it has dropped to 2.1billion now as a large insurer has refused to pay for the drug for indications other that infantile spasms.
This story shows some of the potential in the melanocortin agonist space. This drug which is probable only weakly effective is now the only product for a 2-3Billion dollar company. Whether Clinuvel ever get anywhere near exploiting this market or are even aware of it remains unknown. There is going to billions made, perhaps the pigmentary effects of afamelanotide will ironically be the effect that prevents its global acceptance.
Uhohinc
Big Pharma lost slot of money here with deafened in research and commercial venturing.
King and lastly Astra Zenica called it quits and they know alot more about melanocortins.
Urging Palatin is just playing out the money and I do not think management believes it's stock is worth anything.
FDA is roadblocking it.
Attar appears to slipped by half a century ago befor thalidomide reforms.
I think it would take 5 years to reformulate and then they are probably where Palatin is.
Clinuvels dissolving implant with extensive half life may be what's to copy.
I think doctors may consider prescribing Scenesse in place of Athcar offlabel. And this may be a off label fortuity for Clinuvel in the future
Uhohinc
Uhohinc
Questcor Pharmaceuticals, Inc. (QCOR): Long Thesis & Emerging Trends On ACTH In Primary Literature
Questcor represents deep value; short interest = 28%, forward PE 7.89, no debt, expanding R&D, expanding therapeutic relevance, and a 1.9% dividend.
Questcor Pharmaceuticals, Inc. (QCOR) is a biopharmaceutical company focusing on the treatment of patients with autoimmune and inflammatory conditions. Information on their drug portfolio can be found here.
I advise all would be investors considering to go long QCOR to read the letter from the CEO Don Bailey, found on the company website.
THE SHORT THESIS
Below, as I will illustrate briefly, claims presented by Citron Research aka Andrew Left verbatim from his website here.
"Questcor is Deceiving the FDA and Investors H.P. Acthar Gel's Specified Active Ingredient Less Than 20% of the Label Specification Bioactivity of Deamidated Hormone Fragment Far Lower than Pure ACTH The FDA has been Notified Citron reports on further lab data submitted to FDA, that the contents Questcor's only revenue-generating drug product, H.P. Acthar Gel, does not match its label or the official product insert the label. Questcor spins one story for Wall Street, and another for the medical community, but the regulatory risk here cannot be overstated."
CONCLUSIONS
1) The information presented on the assays performed may be accurate. However there is no way for Citron to know how or what activity assays exist in the manufacturing protocol for Acthar.
In 1998, Left was found by the National Futures Association to have "made false and misleading statements to cheat, defraud or deceive a customer", and disbarred for three years; here.
In 2002, his then employer Detour Media sued Left for "fraud and deceit, negligent misrepresentation, breach of fiduciary duty and unlawful monetary conversion"; here.
2) Citron Research is not privy to, and therefore has absolutely no basis for presenting Biological Activity assays concerning Current Good Manufacturing Practices (cGMP) criteria for clinical grade H.P. Acthar® Gel.
cGMP refers to the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA). Questcor knows how to manufacture FDA compliant H.P. Acthar® Gel, those existing within the SOP portfolio for an already clinically approved naturally-derived formulation of adrenocorticotropic hormones.
Anyone who plans an investment strategy around Andrew Left aka Citron Research, should require him to do something that should be incredibly simple; he should disclose the lab performing the assay, and indicate proof that this is exactly as written Standard Operating Procedure (SOP) for FDA compliant H.P. Acthar® Gel.
A BRIEF HISTORY
The CEO Don Bailey in his open letter, on the website; "The upgrading and transfer of the manufacturing process had taken years of work and significant financial investment to be successful and be approved by the FDA."
Questcor purchased Acthar in 2001 for an attractive price relative to it's current and growing significance in the clinic. The effective criteria prior to 2001, was how well Acthar could elicit a corticosteroid response. In essence, Big Pharma believed that an upstream ligand to stimulate corticosteroid response would make a good drug, and it did. However the breadth of indications were limiting, and when recombinant protein technology hit the forefront of Biopharma, and exogenous corticosteroids entered the clinic, they became the de facto front runner as a therapeutic for the same indications profile, thereby putting Acthar off the radar.
This in no way undermines the clinical relevance of ACTH. This was an artifact of conventional knowledge at the time.
Since 2001, there are 1367 articles published on ACTH, as it exerts an effect through the anterior pituitary gland as a component of the hypothalamic-pituitary axis. Human understanding of the therapeutic significance of ACTH is emerging in primary literature TODAY, and thanks in part to Questcor who brought a forgotten drug, back into the therapeutic spotlight.
Primary literature (pubmed.gov) is a resource to better understand reasons ACTH has an increasing and integral role in the clinic, and why I believe QCOR is a compelling pharmaceutical company. The ACTH story is compelling.
THE LONG THESIS
Questcor currently holds 2 closely related compounds; Adrenocorticotropic hormone (ACTH).
1) H.P. Acthar® Gel (repository corticotropin injection). Questcor purchased Acthar in 2001. Acthar is a naturally-derived formulation of adrenocorticotropic hormones. Up to 2001, no investment was being made to understanding drug etiology; how it could be safely and effectively used in the treatment of patients with autoimmune and inflammatory diseases.
2) Tetracosactide (marketed under the brand name Synacthen) is a synthetic analogue consisting of the first 24 amino acids of the naturally occurring adrenocorticotrophic hormone (ACTH)
LITERATURE SUMMARY
ACTH is released from the pituitary gland at the base of the brain, and classical biochemistry (1980's) indicates conventional effect as action on the adrenal glands to stimulate the production of steroid hormones (glucocorticoids). Modern understanding is clearly showing that steroidogenesis is only one aspect of ACTH influence within the greater melanocortin system.
The melanocortin system is a neuroimmunoendocrine hormone system that constitutes the fulcrum in the homeostatic control of a diverse array of physiological functions. Converging evidence unequivocally demonstrates that the melanocortin-based therapy using the melanocortin peptide adrenocorticotropic hormone (ACTH) is prominently effective in inducing remission of steroid-resistant nephrotic syndrome caused by various glomerular diseases, including membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis, suggesting a steroidogenic-independent mechanisms (PMID: 24602463)
Melanocortin peptides [ACTH and α-, β-, γ-melanocyte-stimulating hormones (MSH)] and their receptors (Melanocortin receptors, MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production (PMID: 23482896).
Adrenocorticotropic hormone (ACTH) has a renoprotective effect in chronic kidney disease; the additive renoprotective actions are achieved by 1) steroid-dependent mechanisms and 2) MC1R-directed anti-apoptosis pathway (PMID: 23482896, 24159603).
ACTH and MCs regulate processes relevant to MS, including anti-inflammatory and immuno-modulatory functions involving lymphocytes, macrophages, the sympathetic nervous system involved in inflammatory processes, and reduction of pro-inflammatory cytokines. The clinical implications of the mechanistic differences between corticosteroid and ACTH gel treatment remain to be elucidated. Recent data show that patients experiencing an acute exacerbation, who previously had suboptimal response to or were unable to tolerate MP treatment, showed positive clinical outcomes with fewer adverse events with ACTH gel (PMID: 24587825)
SUMMARY
ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. Melanocortin system receptors are widely distributed within the central nervous system and in peripheral tissues including immune cells. This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system.
TECHNICALS & GRAPHICS
Consolidation in the low 60's
(click to enlarge)
Courtesy Stockcharts.com
28% of shares are short / outstanding
Uhohinc
Uhohinc
importance of melanocortin 4
Uhohinc
Uhohinc
Athcar has 19 approved indications. There is strong basis to state the "good" therapeutics that Athcar causes is all and only from the small and very intermittent melanocyte stimulating hormone that is one of the two major biochemical that make up Athcar or POMC similar to humans. And there is stronger basis to ascribe all the negative effects as well as all the warnings are caused by the other hormone cleaved from POMC/Athcar called cortotropin. Cortotropin works on different recptors which induce stress responses system wide. But the side effects have to be watched for Scenesse as they could be from the msh. Longterm use of Athcar, or even a human under constant stress constantly making Pomc natural is very detrimental to health overall. It can induce Addisons like or Graves like syptoms.
Uhohinc
Uhohinc
Mallinckrodt settles investor lawsuit for $38 million
Mallinckrodt will pay $38 million to settle a shareholder lawsuit filed in 2012 against Questcor, a company that Mallinckrodt bought last year for $5.6 billion.
Mallinckrodt maintains the plaintiffs’ claims “are without merit” and that the company was “entering into the settlement to eliminate the uncertainties, burden and expense of further protracted litigation,” according to a filing with the U.S. Securities and Exchange Commission.
Investors claimed the California drug company and top executives had made false and misleading claims about the effectiveness of its drug H.P. Acthar.
The lawsuit alleged there was no clinical evidence to support the use of the drug beyond its intended use for infantile spasms.
The suit also alleges Questcor executives engaged in questionable tactics to promote the drug for the treatment of multiple sclerosis and nephrotic syndrome in order to turn it into a “blockbuster drug.”.
Those misleading and false statements ultimately led to inflated stock prices, the lawsuit alleged, which reached a high of $57.64 on July 9, 2012.
The suit said an investment website reported that Aetna, one of the nation’s largest insurers, determined that clinical research showed that Acthar was “medically necessary” for only the infantile seizures and not for the other 18 indications.
After this news, Questcor’s stock plummeted 48 percent to close at $26.35 per share on Sept. 19, 2012, the suit states. Then Questcor announced the U.S. government had launched an investigation into the company’s promotional practices. Questcor’s stock price dropped to $19.08 per share.
Mallinckrodt later acquired Questcor in a cash-stock deal that valued the shares at about $86.10.
Samantha Liss • 314-340-8017
@samanthann on Twitter
sl...@post-dispatch.com
Copyright 2015 stltoday.com. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Uhohinc
Uhohinc
Mar. 12, 2019 7:11 PM ET | About: Mallinckrodt plc (MNK)
Subscribers Only
Earning Call Audio
Unidentified Analyst
Let’s switch gears and look at the branded business a bit. So what’s the outlook for 2019? And could you give us some commentary on the performance of the -- each of the hospital products?
Steve Romano
Sure. Absolutely. So if you go back to our last earnings call, we provided guidance, obviously, for the overall specialty brand business of 1% to 4% on top line growth. When you look at the hospital products, I think, those have grown very well throughout 2018. And we expect that growth to continue as we move into 2019, and we would expect the growth collectively between those assets to be in the mid to single digits. I think we saw that bore out in 2018, and we would expect that to continue again into 2019. Specific to Acthar, the commentary that we made there is we expect the asset to generate greater than a billion dollars in net sales in 2019. I think, if you look at the phasing of that performance throughout the year, the expectation is that the products will be a bit softer in the first half of the year as compared to the back half of the year, and much of that really is determined based off of the data generation strategy that we have employed and we got a lot of a data that’s coming. And maybe Steve can talk about things we have coming from a data perspective.
Daniel Speciale
Yes, I'm happy to do that. So with Acthar, we set off on sort of an evidence generation strategy when we acquired the product few years ago. So over the last few years, I would say that we would segment that effort into three components. The first was generating health economics and outcomes research data on the promoted indications, which we were able to generate fairly rapidly and provide a helpful tool for evaluating the value of Acthar in each of the indications for which it was promoted. The second component was pre clinical data because this was an older product, and there was sort of lumping of this product into corticosteroid. And it is distinctly different from a corticosteroid. It's actually a melanocortin receptor agonist and it has effected all five melanocortin receptors that go well on distribution of gland goes through other organs in the body as well, certainly immune components. So it is more of an immune-modulating effect potentially than an immunosuppressive effect, which is more common with the corticosteroids. So we generate some really nice data. In the preclinical space, in animal models that were relevant and are beginning to show a distinction between how Acthar expresses how a corticosteroid work. The third arm -- a third component of that evidence generation was clinical trial. Now clinical trial is naturally take the longest time to execute. So we initiated seven clinical trials now and we are at the leading edge of the readout of those trials. And we think that's very important because when you have a product that is in the market and challenge with regards to data, the one thing that will help tremendously is to prove that data to bear. So that prescribers, patients and as important the payers have some guidance that they can offer the use of the drug to the folks that prescribe it.
So the bottom line is the first study that's going to readout is rheumatoid arthritis. So we did a large trial, 260 patients enrolled in a RA study. And in each of the cases for Acthar, we look for the most challenging to treat sub population. So we’re not looking at the overall population. This is not a first line therapy. It’s a late wide intervention. And it's for use in patients who have already been on other medicines and haven’t actually progressed or been helped by those medicines, and it's usually added on. So the bottom line is we pick the population of patients with rheumatoid arthritis who had high disease activity level, they were on multiple medications including foundational therapies like methotrexate, on steroids also DMARDs both oral and biologics. And we added Acthar to that population. And what we have been reporting on is that we are getting very robust effects. Now that trial had a 12-week open label portion, which was then followed by a 12-week randomized withdrawal portion. So we will be able to answer a number of questions. First, who response to the drug? So the appropriate population of the patients. What dose is necessary? And what kind of duration -- durability of effect you have? So after 12 weeks, we randomized the responders to continued therapy for another 12 weeks or blinded withdrawal. That way you get a sense of how durable that effect is. Now you go then into the payer with very different information that can actually guide them as sort of appropriate use of the product in RA. So RA data is going to readout this year, MS data from a very large registry of nearly 160 patients is going to readout midyear as well. We are going to complete the enrollment of two other studies, one is in lupus and one is in uveitis, a condition of an inflammatory condition of the eye. And then into 2020, we will get the results of those trials and we will complete the other trials that are ongoing, including keratitis, sarcoidosis, and eventually the FSGS trial, which is a component of the nephritic syndrome. So this is a large data set. The beginning wave of that clinical trial data is just now pressing if you will. So we are very excited about that.
Like this article
Single page view « Previous | page 3 / 7 | Next »
Uhohinc
Three Athcar patients with multiple sclerosis give a antecdotal 11 out of 12 score as to effectiveness
Uhohinc
A variety of therapies show promise for those with a tuberous sclerosis complex diagnosis, but their long-term side effects are unknown.
When Griffin Moritz of Scottsdale, AZ, was born with a white patch of hair, the maternity ward nurses said it was nothing to worry about. Five months later, Griffin began pulling his hands and feet up and collapsing into a fit of tears—repeatedly. At the time, his mother, Debora Moritz, had no idea the two symptoms were related. Three days later, she was sitting in a pediatric neurologist's office with a diagnosis for her son: tuberous sclerosis complex (TSC), a genetic disease affecting one in 6,000 births.
White patches of hair, reddish skin, and infantile spasms—a specific type of seizure that begins in infancy and is linked to later cognitive problems—are common among people with TSC. But the hallmarks of the disease are non-cancerous brain tumors called cortical tubers because of their shape. Some people may have just one or two, while others have tubers covering nearly every portion of their brain. Many individuals also have subependymal giant cell astrocytomas (SEGAs), another type of benign brain tumor that puts people at risk for increased pressure on the brain and other potentially fatal problems.
Almost all people with TSC have treatment-resistant epilepsy, and many are cognitively impaired or autistic. What's more, the disease causes benign tumors to grow outside the brain as well as inside. Heart tumors, called cardiac rhabdomyomas, may result in arrhythmia (irregular heartbeat), obstruction, or murmurs (usually prenatally or within the first year of life). Kidney tumors, called angiomyolipomas, can grow very large; some may bleed. Lung tumors can develop into a potentially fatal disease, called lymphangioleiomyomatosis, that causes holes in the lungs.
"Having TSC is like walking in a minefield," says Elizabeth Thiele, M.D., Ph.D., director of the Pediatric Epilepsy Program and the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital in Boston. "You get over one thing, and you walk right into another. That's what sets this disorder apart from epilepsy. It's not just the seizures. It's not just the brain involvement. It's everything."
Yet some people with TSC have few symptoms or may not even know they have the disorder. As a result, neurologists tend to prescribe treatments for each symptom as it strikes.
During the past decade, however, researchers have made tremendous strides in treating TSC after stumbling upon the two proteins that cause the uncontrolled growth of tumors. That discovery enabled researchers to move from simply managing TSC symptoms to developing new approaches for treating the underlying disease.
Seizing ControlSeizures, such as infantile spasms, are often the first sign that a person has TSC. In fact, nine out of 10 patients with TSC have them. Like Griffin, many of these patients have their first seizures during infancy, when they're easily mistaken for colic because the baby doubles up during the spasm and cries afterward. At first, spasms may be as subtle as a slight bob of the head or a thrust of the chin. But over time, they usually become more pronounced.
Unfortunately, once a child begins having these spasms, he or she will often fail to meet new developmental milestones and may even lose mental or physical skills learned before the spasms began. Social interaction may also diminish, and the child may seem irritable and stop smiling.
"Infantile spasms are huge risk factors for cognitive impairment and autism," says Dr. Thiele, "so being vigilant about spasms and aggressive in treating them is really important." A study published in the medical journal Psychological Medicine in 2003 found that approximately 45 percent of TSC patients have learning difficulties—and for all of these patients, a history of seizures, particularly infantile spasms, predicted the degree of intellectual impairment.
During the last two years, the U.S. Food and Drug Administration (FDA) approved two medications to treat infantile spasms: adrenocorticotropic hormone (ACTH) and vigabatrin (Sabril). Both medications have serious side effects. Vigabatrin can cause irreversible damage to the retina of the eye, impairing a patient's peripheral vision. Adrenocorticotropic hormone is associated with high blood pressure (hypertension), irritability, gastrointestinal problems and bleeding—even death.
Several studies show that infantile spasms are better controlled with vigabatrin than ACTH. "Sometimes even just a few doses of vigabatrin controls the spasms," says Mustafa Sahin, M.D., assistant professor and clinic director at Children's Hospital at Harvard Medical School in Boston, MA, and member of the American Academy of Neurology (AAN). In 2000, researchers at the National Institutes of Health Tuberous Sclerosis Complex Consensus Conference stated that vigabatrin should be the first treatment doctors prescribe for infantile spasms in children with TSC—even though the medication wasn't yet FDA approved for any use and wasn't even available in the United States.
"We learned Griffin had TSC on Monday, and we drove to Mexico for vigabatrin on Wednesday," Moritz recalls. "The neurologist said the faster you can get it under control, the better the outcome." (Please note: Medications should only be purchased outside of the United States with caution and under the direction of a medical doctor.) Unfortunately, vigabatrin didn't work for Griffin. He had one good day without any spasms, but then no matter how his neurologist adjusted the dose, the spasms kept coming.
So the Moritzes turned to ACTH. The steroid caused Griffin to lose all muscle tone and become ravenously hungry. "He looked like this big, red, cranky blob," says Moritz of her son, who weighed 30 pounds by the time he was nine months old.
After six weeks on ACTH, Griffin's infantile spasms gradually stopped. But, as with many children who have TSC, Griffin began experiencing another kind of seizure as he grew older—in his case, simple partial seizure, during which a person remains alert. The Moritzes never got complete control over these seizures. "We were constantly trying different medications in various combinations and dosages. Yet we were told by neurologists that when several medications fail, the chances of other medications working begins to diminish," says Moritz.
Non-Drug TreatmentsWhen drug cocktails fall short, many families investigate other options, including the ketogenic diet, which is a strict, medically supervised nutritional regimen that contains a large amount of fat, adequate protein, and very small amounts of carbohydrates. Typically, the diet requires eating four times as much fat as protein and carbohydrates. (The typical American diet is 34 percent fat, 50 percent carbohydrate, and 16 percent protein.) Under normal circumstances, the body uses carbohydrates for energy, but on a ketogenic diet, fat becomes the primary fuel. The goal is to force the body to produce ketones, which may improve seizure control and can be detected in the blood and urine. (Ketones are also made if your body cannot use blood sugar properly, which is why people with diabetes are tested for them.)
"Kids who go on the ketogenic diet, regardless of the type of seizures they're having, often become seizure-free—and those are kids that have been on at least four medications before trying the diet," claims Dr. Thiele. "It's the most successful treatment we have for seizures caused by TSC." (Find out more about the ketogenic diet.)
Unfortunately, the ketogenic diet is extremely difficult to maintain, especially if there are other children in the household. Staples include butter, heavy whipping cream, mayonnaise, and oils. Because carbohydrates and protein have to be severely restricted, everything the child puts in his mouth has to be monitored. Even toothpaste has sugar in it!!
In a small study of 12 children with TSC published in the medical journal Epilepsia in 2005, 11 children had a greater than 50-percent reduction in their seizures at six months on the ketogenic diet, and eight had a greater than 90-percent response. Five children were seizure-free for five months. Diet duration ranged from two months to five years, with an average of two years.
In terms of side effects, Dr. Thiele says patients may experience constipation, increased acidity in the blood (acidosis), and kidney stones due to the dietary restrictions. She's not aware of any health-related risks as a result of the excess fat from this diet—lipid profiles of kids on the ketogenic diet are usually not significantly elevated, she says.
Another option is vagal nerve stimulation (VNS), which sends regular, mild pulses of electrical energy to the brain. Think of it as a little pacemaker for the brain that's implanted under the skin on the chest. A wire extends from the device to the vagus nerve in the neck, which relays messages between the brain and the organs. The neurologist programs the strength and timing of the impulses and can adjust the settings with a programming wand connected to a laptop computer.
For all patients, the device runs continuously, usually with 30 seconds of stimulation followed by five minutes of no stimulation. For patients who experience warnings or auras before a seizure, holding a special magnet near the implanted device can abort a seizure before it happens. Researchers aren't clear why VNS works, but for up to 40–60 percent of patients with epilepsy, it does reduce seizure frequency.
Some patients aren't good candidates for VNS because of where their seizures originate in the brain, which is why a thorough examination is required first. Side effects of VNS include a worsening of obstructive sleep apnea and, in rare cases, behavioral problems or an increase in seizure activity. For TSC patients, the most significant "side effect" is the inability to perform MRIs (with an implanted device, MRIs aren't possible). This is a problem for people with TSC, because physicians follow the health of their kidneys and other organs with imaging tests such as MRIs. (Cyberonics, a VNS manufacturer, claims that although full-body scans should not be done with the implant, brain MRIs can be done with proper equipment.)
SurgeryUntil recently, undergoing surgery to remove TSC tubers was considered only after all other methods, including the ketogenic diet and VNS, had failed. Now, many patients undergo surgery early in the disease process—even months after birth. "If you target the network [the area responsible for the seizure activity] early, not only will the surgery results potentially be more durable, but also the developmental outcomes may be better," says Howard Weiner, M.D., professor of neurological surgery and pediatrics at New York University School of Medicine.
Kids with multiple hotspots in the brain generating seizures were once deemed poor candidates for epilepsy surgery. The reason is that the surgeon has to cut out multiple areas in the brain, so the risk of removing areas required for cognition and movement is increased. But now, these children are increasingly being considered for surgery.
"One of the big pushes over the last 10 years is the recognition that TSC patients who do not meet the classic selection criteria for epilepsy surgery may still benefit from surgery," says Dr. Weiner.
Seven-year-old Evan Moss is a good example. He had severe seizures and, upon first evaluation, he wasn't a clear candidate for surgery. But using extensive pre-surgical testing, Dr. Weiner and his colleagues identified the area in the brain causing Evan's seizures and realized they could operate without impacting important functions such as cognition and movement. They uncovered a group of tubers in a specific part of Evan's brain as well as seizure-causing tissue in the area around the tubers.
"We removed the areas generating seizures and the surrounding area that could lead to seizures down the line," says Dr. Weiner, who performs these procedures in three separate operations during a single hospital stay. Step one involves implanting electrodes into the brain to find the main area that's causing the seizures (the seizure focus). During step two, the surgeons remove the seizure focus and introduce new electrodes to identify other areas of the brain that might generate seizures. Then, after additional days of monitoring, the patient undergoes a third operation to remove any additional tissue that could give rise to seizures (as well as the electrodes). The three-step process allows Dr. Weiner to preserve as much healthy brain tissue as possible.
In one study that included 15 patients who did not meet traditional surgical criteria because several areas in their brains generated seizure activity but underwent surgery after careful evaluation, eight remained completely seizure-free during the 10-year follow-up period.
Evan wasn't as fortunate. Initially, his seizures stopped completely, but they returned—though on a much lesser scale—within a few years. "Since Evan's seizure focus was in close proximity to the part of the brain that controls his motor function, we were limited by how much tissue we could remove without creating problems for him," says Dr. Weiner. "While we had a good strategic attack of the network causing Evan's seizures, it somehow found a way to reactivate itself. Sometimes that happens spontaneously, or sometimes it happens from a patient experiencing a head trauma, or missing medication, or experiencing some other stressor that reactivates the system." No one knows for sure. What they do know is that even with a return of seizures, most parents claim the surgery is worthwhile.
According to a study published earlier this year in the medical journal Epilepsy and Behavior, most parents of children with TSC who had surgery to treat seizures were happy with the results. Of the 39 families interviewed, 77 percent had greater than 90 percent reduction in disabling seizures, and 46 to 85 percent had at least a moderate improvement in quality of life—including families whose seizures didn't resolve.
Brain surgery is not a risk-free endeavor, to be sure. Every surgery comes with risks, including unexpected reactions to anesthesia or medications, which may cause major injury or death. Brain surgery carries added risks of damage to nerves or blood vessels, which can cause stroke or neurologic impairments that may be either temporary or permanent. The risk of such complications, while very small, varies according to the type of procedure and is different for each individual. On the other hand, uncontrolled seizure activity poses its own serious risk.
A New FrontierAll of the problems caused by TSC—from epilepsy and autism to kidney and lung problems—seem to stem from mutations in two genes, TSC1 and TSC2. Scientists discovered the genes during the 1990s. Until recently, researchers hadn't unraveled the process through which the proteins synthesized by TSC1 and TSC2 (hamartin and tuberin) cause the runaway growth fueling TSC tumors. It involves something called the mTOR pathway, which exists in every cell of the body and serves as a master switch to regulate normal cell growth. In the brain, for example, mTOR controls the synthesis of proteins needed to form synapses, which allow cells to communicate with one another and are important in learning and memory. But when defects in TSC1 or TSC2 prevent hamartin and tuberin from doing their job—acting as a brake to control cell growth—mTOR is left in the "on" position. As a result, cells divide uncontrollably, leading to the development of TSC tumors.
When Griffin was 10 years old, a routine MRI revealed an explosion of tumors on both sides of the brain that were increasing pressure in his head at an alarming rate. Treatment for tumors of this size is usually surgery, but Griffin wasn't a candidate because his were so widespread.
Moritz knew researchers were investigating mTOR inhibitors in clinical trials. She found a trial at Cincinnati Children's Hospital that had been open for two years and submitted Griffin's medical records. The next day she received a call, and within a week, Griffin was enrolled in the trial. Within the first week of starting the medication, everolimus (Afinitor), Moritz began noticing changes in Griffin.
"His skin looked less red, he was sleeping better, and his behavior began to change," says Moritz. "He fidgeted a little less, he walked a little more calmly, and he responded a little more quickly." The first follow-up MRI 90 days later revealed remarkable results: The increased pressure on Griffin's brain was resolving, and he already had a 30-percent reduction in tumors.
Results like Griffin's prompted the FDA to approve everolimus in 2010, after a study revealed that one-third of the 28 patients studied experienced a reduction of 50 percent or greater in the size of their largest tumor within six months of starting everolimus treatment (and none of the patients developed a new tumor while taking the drug).
"The most dramatic reduction in tumor volume occurs within the first three months of everolimus therapy," says Dr. Sahin. "It continues to improve out to six months, and the response is sustained—or even improved—for up to two years."
Originally approved only for tumors, mTOR inhibitors are showing promise in other aspects of TSC, including seizure activity, cognition, and autism. When infant mice engineered to have brain disorders resembling TSC are given the mTOR inhibitor rapamycin, they usually do not develop seizures. "Researchers have also treated adult mice with TSC with rapamycin just for five days, and the mice perform better in tests of learning and memory," says Dr. Sahin, who is currently screening patients to participate in the first controlled trial on everolimus and cognition.
Rapamycin has been used in children requiring kidney transplants for the past two decades, so there's well-documented evidence about safety and side effects, which include mouth ulcers, immune suppression, and increases in blood lipids (fats). "They're not benign medications," says Dr. Thiele. And this area of research is so new that scientists aren't sure what the long-term effects of the medications are.
Griffin has been on everolimus for two-and-a-half years and, according to Moritz, every month he's on the drug, his seizures become less severe. "It didn't happen overnight, but each month he had fewer and fewer seizures, and they were less intense," she says. During the sixteenth month, Griffin didn't have a single seizure, and 2010 was practically clear. He had a few little blips—mild seizures, lasting no longer than 15 seconds—but Moritz has not used any "rescue" seizure medication on him in more than a year.
"Right now, treatment for TSC continues to be symptomatic, but the preliminary evidence we're seeing with the rapamycin-like drugs is very encouraging," says Dr. Thiele. "However, none of us thinks these are the silver bullets." When people go on these drugs, they might see the tumors shrink, but once they stop the drug, there's rapid re-growth, she says, so decades of treatment can be expected.
The good news: The peak onset of TSC tumors is during the first two decades of life. "That's one of the positive things about the natural course of this disease," says Dr. Sahin. "But the question becomes, if you treat these tumors with everolimus, can you take patients off the drug after age 20?" At this point no one knows.
For Griffin, mTOR inhibitors have dramatically improved his physical, mental, and emotional health with negligible side effects. He's even communicating with a device that allows him to deliver common phrases with the touch of a button. "When we were sitting in the waiting room for Griffin's speech therapy, the therapist he used to see came out to do some paperwork," says Moritz. "He reached to his device and said, 'Hi, how are you?' Two years ago, he would have thrown that device across the room when he saw her."
Moritz now views Griffin's explosion of tumors as a blessing because it gave him access to medication that would not have been offered to him otherwise—medication that has dramatically altered the course of his life.
Missing The DiagnosisMany clinicians still don't recognize tuberous sclerosis complex in patients. A study published in the medical journal Pediatrics earlier this year found that 39 percent of TSC patients reported missed symptoms or signs of TSC that should have led to an earlier diagnosis. Seizures were the most commonly missed symptom and were noted in 19 percent of patients. Other missed symptoms included infantile spasms, family history of TSC, cardiac rhabdomyomas, and skin disorders.
"TSC is not uncommon, and there needs to be a heightened awareness of the disease among all types of clinicians," says Dr. Thiele. "New treatments are emerging, but even with the treatments we have now, if we know a person has TSC, there's a lot we can do to keep him or her healthy."
Signs and Symptoms of Tuberous Sclerosis Complex- Difficult-to-control seizures
- Brain tubers
- Kidney tumors
- Heart tumors
- Skin abnormalities
- Cognitive delay
- Behavioral disorders
However, symptoms of tuberous sclerosis complex vary widely from one person to the next, with some experiencing only minor skin abnormalities, and others experiencing severe seizures, cognitive disabilities, and behavioral disorders. Symptoms of TSC also typically change over time within the same individual. This variability and unpredictability is a hallmark of TSC and can make accurate diagnosis difficult. It also presents challenges to those who have been diagnosed, their family, and their doctors.
Source: Living with TSC at Massachusetts General Hospital
Uhohinc
Uhohinc
Uhohinc
Uhohinc
With Mallinckrodt facing a proposed $1.6 billion opioid settlement and bankruptcy of its specialty generics unit, the Irish drugmaker is digging deep for promising signs in what's left of the business. One source of hope? None other than controversial H.P. Acthar Gel, which Mallinckrodt said it's working to prop up amid the opioid fallout.
Mallinckrodt is in the midst of an Acthar "modernization" to help drive growth in its branded drugs unit as the company works through the court-supervised restructuring––and possible future sale––of its generics business, executives said in a fourth-quarter earnings call with analysts Tuesday.
Acthar, long a source of legal issues for Mallinckrodt after its acquisition in 2014, hit $952 million in sales in 2019 at a 14.2% decrease from the previous year. Mallinckrodt tied that down year to "continued reimbursement challenges impacting new and returning patients and continued payer scrutiny on overall specialty pharmaceutical spending," the company said in a release.
But even with revenues down, Mallinckrodt is predicting a "long-term stabilization" of Acthar sales that could help the drugmaker weather the storm of its pending opioid settlement and generics restructuring.
"We continue to invest heavily in Acthar, continue to modernize the brand and that applies to enhancements to the label," CEO Mark Trudeau told analysts. "We've invested greater than $0.5 billion in research and development and other activities to modernize the brand."
RELATED: Mallinckrodt floats $1.6B opioid deal, bankruptcy for specialty generics unit
Tuesday, Mallinckrodt floated an "agreement in principle" to settle a raft of opioid lawsuits for a combined $1.6 billion, facilitated by a court-supervised restructuring of its generics unit. The deal already has the support of a plaintiff's executive committee including thousands of lawsuits and 47 state and territory attorneys general, Mallinckrodt said.
That restructuring––tentative, so far, without a full settlement signoff––would reform the generics unit into a public trust and allow for a "channeling injunction" against further opioid lawsuits as well as grease the skids for a future sale or hive-off.
Trudeau forecast the generics unit could enter Chapter 11 bankruptcy in the first half of the year, with the drugmaker looking at options for the business after it emerges from restructuring.
"We will ... be evaluating a whole range of strategic options to potentially separate the generics business post emergence from Chapter 11 of which sale could be one of a whole range of options that we could consider," Trudeau said.
RELATED: See you in court: Mallinckrodt takes on feds to fight $600M in back Acthar rebates
Mallinckrodt's embrace of Acthar's future role in its portfolio comes as the drug has proven a legal thorn in the company's side for years.
In June, the Department of Justice slapped federal kickback charges on Mallinckrodt, which acquired Acthar-maker Questcor Pharma in 2014 for $5.6 billion, accusing the company of funneling money through front funds to illegally subsidize Medicare copays and jack up the drug’s list price by 85,000%. The charges filed in Pittsburgh federal court fell on the same day the drugmaker agreed in principle to a $15.4 million settlement on separate charges tied to two whistleblower kickback suits the DOJ joined in early May.
Humana filed its own suit in August, claiming it overpaid for Acthar by $700 million because of Mallinckrodt’s widespread campaign to stifle competition and pay doctors and patients to choose the pricey med, the insurer said.
Despite the legal challenges, Mallinckrodt itself has been no stranger itself to fighting over Acthar in court.
In May, the company sued the U.S. Department of Health and Human Services and the Centers for Medicare & Medicaid Services (CMS), accusing the government of retroactively changing the drug’s average manufacturer price and putting it on the hook for $600 million in back rebates.
Mallinckrodt said the move, if left unchallenged, would undermine the company’s development work on a new-and-improved Acthar formulation. That project is a $500 million-plus proposition, the company said, and it includes clinical trials in hard-to-treat indications like rheumatoid arthritis.
Tuesday, Trudeau offered no updates on the CMS suit but said an August hearing with a federal judge "went very well."
Tuesday, November 9 | 1pm ET / 10am PT
Uhohinc
Clinuvel's regulatory path is an abbreviated new drug application (aNDA), which is a pretty low hurdle. No clinical trials, just proof of bioequivalency. However, as you mentioned, ACTH was approved by the FDA long ago, when my parents were still in diapers (1952) and Billy Boots was a young man still married to his first wife.
I doubt that the FDA has ANY data on file as a reference point for bioequivalency from 1952. For reference, in 1952, shoe salesman still used fluoroscopes.
So, it would seem that Clinuvel's main hurdle is a GMP inspection of their contract manufacturer, and FDA clearance of their excipients, which I believe they've stated is a non-issue (iirc, the NDA for Scenesse acknowledged that the excipients in the implant were polymers that were already in common use in medicine, and not subject to additional scrutiny).
So, IN THEORY, this could be a brilliant play. Clinuvel goes into competition with a bankrupt company with a gutter reputation, that company is spending $500 million to rehabilitate the Acthar brand, and then Clinuvel offers a superior product with 2021 technology against Acthar's 1950's technology. When a doctor has his prescription pad out, which one is he going to choose?
First year of sales in the US alone could easily exceed that of Scenesse worldwide.
FWIW, the only FDA actions I can see since approval in 1952 are related to labelling, CMC, and a single REMS modification letter, in which the FDA removed the sole REMS requirement for the drug.
But I've been wrong before.
Edit: this only references Acthar. I'll look into Synacthen in the US market shortly.
Second edit: Synacthen is only labeled for diagnostic use in the US, and is a synthetic, truncated version of ACTH.