Scientific ACTH and related research

macgyver

Well-known member
This thread will be added to as time and circumstance allows. I thought it was important to start this thread as I'm beginning to see a pretty compelling case for Clinvuel to enter the ACTH space. It remains to be seen whether Clinuvel intends to take on Mallinckrodt directly, but one thing is for sure: there is room for another competitor in the U.S. Mallinckrodt has engaged in price gouging of the worst kind, and controls two of the leading ACTH brands: HP Acthar Gel (worldwide) and Synacthen (outside of the US worldwide). Given the monopolistic practises of Mallinckrodt regarding ACTH, Clinuvel possibly sees a chance to take a slice of the US market by offering better pricing ('ethical pricing?') in which I think Medicare will gladly reimburse given its troubles with Mallinckrodt in recent times. Add to this Mallinckrodt's bankruptcy woes (of which PW talked at length in the AGM), the timing perhaps could not be better to enter the space. This drug is very valuable, and could end up being a surprise cash cow for Clinuvel in the near future.
 
Last edited:

macgyver

Well-known member
ANI Pharmaceuticals has an extensive range of drugs, and has recently added Cortrophin Gel, which had its sNDA approved by the FDA in November 2021. HP Acthar Gel was the sole ACTH product for related indications for 30 years, and now Cortrophin Gel is a competitor. (Note the NDA for Cortrophin Gel has been around for some time and was acquired by ANI pharmaceuticals from Merck in 2016).

ANI Pharmaceuticals has its own CDMO. It is NASDAQ listed with its share price sitting around $US42. Last financial year saw it operating in the red.
 
Last edited:

macgyver

Well-known member
HP Acthar Gel INDICATIONS AND USAGE

1.1 Infantile spasms:
H.P. Acthar Gel (repository corticotropin injection) is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age.

1.2 Multiple Sclerosis:
H.P. Acthar Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

1.3 Rheumatic Disorders:
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis, Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), Ankylosing spondylitis.

1.4 Collagen Diseases:
During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis).

1.5 Dermatologic Diseases:
Severe erythema multiforme, Stevens-Johnson syndrome.

1.6 Allergic States:
Serum sickness.

1.7 Ophthalmic Diseases:
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis; optic neuritis; chorioretinitis; anterior segment inflammation.

1.8 Respiratory Diseases:
Symptomatic sarcoidosis

1.9 Edematous State:
To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythema.
 

macgyver

Well-known member
HP Acthar Gel INDICATIONS AND USAGE

1.1 Infantile spasms:
H.P. Acthar Gel (repository corticotropin injection) is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age.

1.2 Multiple Sclerosis:
H.P. Acthar Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

1.3 Rheumatic Disorders:
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis, Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), Ankylosing spondylitis.

1.4 Collagen Diseases:
During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis).

1.5 Dermatologic Diseases:
Severe erythema multiforme, Stevens-Johnson syndrome.

1.6 Allergic States:
Serum sickness.

1.7 Ophthalmic Diseases:
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis; optic neuritis; chorioretinitis; anterior segment inflammation.

1.8 Respiratory Diseases:
Symptomatic sarcoidosis

1.9 Edematous State:
To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythema.
Since this drug has been around forever, the off label uses before the price gouging began would’ve been manifold. That might’ve tightened up a little since the price went up, it would be interesting to see what exactly this product is now mainly prescribed for. I’m guessing serious disorders only.
 

macgyver

Well-known member
Vasculitis as a potential candidate for Neuracthel. I don’t see it in the indications list for HP Acthar Gel, and the condition can lead to stroke among other outcomes. As an alternative to prednisone, it would be distinctly different from afamelanotide i.e. purely anti inflammatory versus vasoactive and reduction in atherosclerosis.

 

macgyver

Well-known member
The following article (19th August 2021) is a good summary of the potential therapeutic possibilities of ACTH. It mentions the following:

" However, after an initial number of studies on its potential as a therapeutic strategy in many diseases and conditions, researchers seem to have abandoned the “corticotropin path” and have focused more on its downstream hormone pathways (glucocorticoids and androgens)."

A timely reminder of why PW sees opportunity in pursuing ACTH therapies. Mallinckrodt has been distracted by their troubles, and possibly lost focus with their drug even when it brought in the dollars. Concerning new ACTH therapies, Clinuvel will hopefully be close in behind if not at the forefront alongside Mallinckrodt in researching and pursuing these.

From the authors (via Sapienza University of Rome)

"We performed a research of published literature with no time constraints. Only English papers were included. When possible, results from human studies were preferred over in vitro or animal studies. Being out of the main scope of this review, papers focusing on ACTH as a diagnostic marker for adrenal diseases were excluded."

The following areas where ACTH could play a therapeutic role as described in the article:

Adrenal effects:
  • Corticosteroid Rhythmicity
  • Effects on Steroidogenesis
  • Effects Against Reactive Oxygen Species
  • Effects on Adrenal Growth and Adrenal Blood Flow
  • Effects on Adrenal Medulla

Extra-adrenal effects of ACTH:
  • Osteoarticular System
  • Reproductive System
  • Adipocytes and Insulin Sensitivity
  • Immune System and Inflammation
  • Brain
  • Skin
Adrenal Disorders:
  • Genetic Forms of Adrenal Insufficiency
  • Acquired Adrenal Insufficiency

 
Last edited:

macgyver

Well-known member
Corticosteroid Rhythmicity: "It is well established that circadian changes in ACTH and glucocorticoids are associated with expression of clock-related genes (1519). In adrenal tumors, the clock machinery that mitigates the response to ACTH and stress favors a higher and more arrhythmic corticosteroid secretion when dysregulated, suggesting that hypercortisolism exerts effects on circadian genes, contributing to the worsening of disease-related comorbidities (16, 20, 21). Circadian gene expression is dysregulated in patients with adrenal insufficiency and normalize under more physiological timing of glucocorticoids, emphasizing the importance of synchronization of clocks to coordinate the endogenous and exogenous signals to achieve cellular homeostasis"

 
Last edited:

macgyver

Well-known member
Effects Against Reactive Oxygen Species: "ACTH-induced steroidogenesis reactions involve lipid peroxidation and production of reactive aldehyde metabolites that generate reactive oxygen species (ROS) and thus a considerable cellular oxidative stress. Consequently, several enzymes involved in the detoxification are mobilized in adrenal cells. Aldo–keto reductases participate into this detoxification process, and their expression is ACTH-dependent (35)".

"Moreover, in human and rat adrenal cells, seladin-1 (selective Alzheimer disease indicator 1, also named 24-dehydrocholesterol reductase) expression and redistribution to the nucleus occur after ACTH treatment (36). Finally, increased expression of SOD2, (mitochondrial superoxidase dismutase 2, a metalloenzyme involved in the scavenging of mitochondrial ROS) is also induced by ACTH (37)".

"Therefore, ACTH regulates the expression of enzymes responsible for steroid biosynthesis and nonsteroidogenic enzymes involved in preventing ROS-induced cell toxicity."



From the paper in the above link: "Nonetheless oxidative stress is implicated in several potentially lethal adrenal disorders including X-linked adrenoleukodystrophy, triple A syndrome and most recently familial glucocorticoid deficiency".
 
Last edited:

CUV Quote (Yesterday's close)

Time: 10:26AM AEDT
Price: 22.56
Volume: 23844
Top