Crinetics Pharmaceuticals’ Oral ACTH Antagonist, CRN04894, Demonstrates Pharmacologic Proof-of-Concept with Dose-Dependent Cortisol Suppression in Single Ascending Dose Portion of Phase 1 Study

SAN DIEGO, CA, USA I August 10, 2021 I Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, today announced positive preliminary findings from the single ascending dose (SAD) portion of a first-in-human Phase 1 clinical study with CRN04894 demonstrating pharmacologic proof-of-concept for this first-in-class, investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist that is being developed for the treatment of conditions of ACTH excess, including Cushing’s disease and congenital adrenal hyperplasia.

“ACTH is the central hormone of the endocrine stress response. Even though we’ve known about its clinical significance for more than 100 years, there has never been an ACTH antagonist available to intervene in diseases of excess stress hormones. This is an important milestone for the field of endocrinology and for our company,” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “I am extremely proud of our team that conceived, discovered and developed CRN04894 this far. This is the second molecule to emerge from our in-house discovery efforts and demonstrate pharmacologic proof of concept. I am very excited to see what it can do in upcoming clinical studies.”

The 39 healthy volunteers who enrolled in the SAD cohorts were administered oral doses of CRN04894 (10 mg to 80 mg, or placebo) two hours prior to a challenge with synthetic ACTH. Analyses of basal cortisol levels (before ACTH challenge) showed that CRN04894 produced a rapid and dose-dependent reduction of cortisol by 25-56%. After challenge with a supra-pathophysiologic dose of ACTH (250 mcg), CRN04894 suppressed cortisol (as measured by AUC) up to 41%. After challenge with a disease-relevant dose of ACTH (1 mcg), CRN04894 showed a clinically meaningful reduction in cortisol AUC of 48%. These reductions in cortisol suggest that CRN04894 is bound with high affinity to its target receptor on the adrenal gland and blocking the activity of ACTH. CRN04894 was well tolerated in the healthy volunteers who enrolled in these SAD cohorts and all adverse events were considered mild.

“We are very encouraged by these single ascending dose data which clearly demonstrate proof of ACTH antagonism with CRN04894 exposure in healthy volunteers,” stated Alan Krasner, M.D., chief medical officer of Crinetics. “We look forward to completing this study and assessing results from the multiple ascending dose cohorts. As a clinical endocrinologist, I recognize the pioneering nature of this work and eagerly look forward to further understanding the potential of CRN04894 for the treatment of diseases of ACTH excess.”

Data Review Conference Call
Crinetics will hold a conference call and live audio webcast today, August 10, 2021 at 4:30 p.m. Eastern Time to discuss the results of the CRN04894 SAD cohorts. To participate, please dial 800-772-3714 (domestic) or 212-271-4615 (international) and refer to conference ID 21996541. To access the webcast, please visit the Events page on the Crinetics website. The archived webcast will be available for 90 days.

About the CRN04894-01 Phase 1 Study
Crinetics is enrolling healthy volunteers in this double-blind, randomized, placebo-controlled Phase 1 study of CRN04894. Participants will be divided into multiple cohorts in the single ascending dose (SAD) and multiple ascending dose (MAD) phases of the study. In the SAD phase, safety and pharmacokinetics are assessed. In addition, pharmacodynamic responses are evaluated before and after challenges with injected synthetic ACTH to assess pharmacologic effects resulting from exposure to CRN04894. In the MAD phase, participants will be administered placebo or ascending doses of study drug daily for 10 days. Assessments of safety, pharmacokinetics and pharmacodynamics will also be performed after repeat dosing.

About CRN04894
Adrenocorticotropic hormone (ACTH) is synthesized and secreted by the pituitary gland and binds to melanocortin type 2 receptor (MC2R), which is selectively expressed in the adrenal gland. This interaction of ACTH with MCR2 stimulates the adrenal production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved for example in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation, and excess adrenal androgen production can result in hirsutism, menstrual dysfunction, infertility in men and women, acne, cardiometabolic comorbidities and insulin resistance. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, has exhibited strong binding affinity for MC2R in preclinical models and demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH, while maintaining mineralocorticoid production.

About Cushing’s Disease and Congenital Adrenal Hyperplasia
Cushing’s disease is a rare disease with a prevalence of approximately 10,000 patients in the United States. It is more common in women, between 30 and 50 years of age. Cushing’s disease often takes many years to diagnose and may well be under-diagnosed in the general population as many of its symptoms such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity can be incorrectly attributed to other more common disorders.

Congenital adrenal hyperplasia (CAH) encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis with a prevalence of approximately 27,000 patients in the United States. This lack of cortisol leads to a loss of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects from improper gonadal development to life-threatening adrenal crisis.

About Crinetics Pharmaceuticals
Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. The company’s lead product candidate, paltusotine, is an investigational, oral, selective nonpeptide somatostatin receptor type 2 agonist for the treatment of acromegaly, an orphan disease affecting more than 26,000 people in the United States. A Phase 3 program to evaluate safety and efficacy of paltusotine for the treatment of acromegaly is underway. Crinetics also plans to advance paltusotine into a Phase 2 trial for the treatment of carcinoid syndrome associated with neuroendocrine tumors. The company is also developing CRN04777, an investigational, oral, nonpeptide somatostatin receptor type 5 (SST5) agonist for congenital hyperinsulinism, as well as CRN04894, an investigational, oral, nonpeptide ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are new chemical entities resulting from in-house drug discovery efforts and are wholly owned by the company.

SOURCE: Crinetics Pharmaceuticals

From https://pipelinereview.com/index.php/2021081178950/Small-Molecules/Crinetics-Pharmaceuticals-Oral-ACTH-Antagonist-CRN04894-Demonstrates-Pharmacologic-Proof-of-Concept-with-Dose-Dependent-Cortisol-Suppression-in-Single-Ascending-Dose-Port.html

Home cortisol tests: 3 of the best

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Cortisol is a hormone with various functions throughout the body. However, if a person’s body cannot regulate their cortisol levels, it could lead to a serious health condition. In these cases, home cortisol tests may be useful to indicate when someone might need medical attention.

A person sitting at a desk, holding an at-home cortisol test tube, typing on a laptop.

This article discusses:

  • what cortisol is
  • what a home cortisol test is
  • why a person might buy a home cortisol test
  • some home cortisol tests to purchase online
  • when to see a doctor

What is cortisol?

Cortisol is the stress hormone that affects several systems in the body, including the:

The adrenal glands produce cortisol. Most human body cells have cortisol receptors, and the hormone can help in several ways, including:

  • reducing inflammation
  • regulating metabolism
  • assisting with memory formation
  • controlling blood pressure
  • developing the fetus during pregnancy
  • maintaining salt and water balance in the body
  • controlling blood sugar levels

All these functions make cortisol a vital part of maintaining overall health. If the body can no longer regulate cortisol levels, it can lead to several health disorders, such as Cushing’s syndrome and Addison’s disease. Without treatment, these conditions could cause life threatening complications.

The body requires certain cortisol levels during times of stress, such as:

  • in the event of an injury
  • during illness
  • during a surgical procedure

What are home cortisol tests? 

A cortisol test usually involves a blood test. However, some may require saliva and urine samples instead.

There are several home cortisol tests available to purchase over the counter or online. These allow a person to take a sample of blood, urine, or saliva before sending it off for analysis.

After taking a home cortisol test, people can usually receive their results within 2–5 days online or via a telephone call with a healthcare professional.

However, there are currently no studies investigating the reliability of these home cortisol tests. Therefore, people should follow up on their test results with a healthcare professional.

Why and when do people need them? 

A person should take a home cortisol test if they feel they may have a cortisol imbalance.

If cortisol levels are too high, a person may notice the following:

  • rapid weight gain in the face, chest, and abdomen
  • high blood pressure
  • osteoporosis
  • bruises and purple stretch marks
  • mood swings
  • muscle weakness
  • an increase in thirst and need to urinate

If cortisol levels are too low, a person may experience the following symptoms:

  • fatigue
  • loss of appetite
  • unintentional weight loss
  • muscle weakness
  • abdominal pain

Additionally, low cortisol levels may lead to:

A test can help individuals check their cortisol levels. If the test results show these levels are too high or too low, people should seek medical advice.

A cortisol imbalance may be a sign of an underlying condition, which can lead to serious complications without treatment.

If a person cannot carry out a home cortisol test, they should speak to a medical professional who can arrange a cortisol test at a healthcare facility.

What to look for in a home cortisol test

At a clinic or hospital setting, a medical professional will usually take a blood sample and analyze it for an individual’s cortisol levels.

Home cortisol tests involve a person taking a sample of blood, urine, or saliva. There are currently no studies investigating the accuracy of these results.

However, home cortisol tests may be faster and more convenient than making an appointment with a doctor to take a sample.

People may consider several factors when deciding to purchase a home cortisol test, including:

  • Sample type: Some tests require a blood sample, while others need a sample of urine or saliva. With this in mind, a person may wish to buy a product that uses a testing method they are comfortable providing.
  • Test analysis: A person may wish to purchase a product from a company that sends tests to Clinical Laboratory Improvement Amendments (CLIA)-certified labs for analysis. The Food and Drug Administration (FDA), Center for Medicaid Services, and the Centers for Disease Control and Prevention (CDC) regulate these labs to help ensure safety and accuracy.
  • Accuracy: Individuals may wish to speak to a pharmacist or other healthcare professional before purchasing to ensure the test is reliable and accurate.

Products

Several online retailers offer home cortisol tests. It is important to follow all test instructions to ensure a valid result.

Please note, the writer has not tested these products. All information is research-based.

LetsGetChecked – Cortisol Test

This cortisol test uses the finger prick method to draw blood for the sample.

Here are the steps to take and send off a blood sample:

  1. Individuals fill in their details on the collection box and activate their testing kit online at the LetsGetChecked website.
  2. People need to wash their hands with warm soapy water before using an alcohol swab to clean the finger that they will prick.
  3. Once the finger is completely dry, individuals pierce the skin using the lancet in the test kit. A person must wipe away the first drop of blood before squeezing some into the blood collection tube.
  4. After closing the tube, individuals must invert it 5–10 times before placing it in the included biohazard bag, which they then place in the box.

After following these steps, people can send the sample back to LetsGetChecked using the kit’s prepaid envelope. Test results usually come back within 2–5 days.

LetsGetChecked tests samples in the same labs that primary care providers, hospitals, and government schemes use. These labs are CLIA-certified and CAP-accredited.

The company also has a team of nurses and doctors available 24 hours a day, 7 days a week, to offer ongoing support. These healthcare professionals are on hand to discuss a person’s results with them over the phone.

Everlywell At-Home Cortisol Levels Test Kit – Sleep & Stress Test

This Everlywell product uses a urine sample to test a person’s cortisol levels.

The test measures the levels of three hormones in a person’s body: cortisol, cortisone, and melatonin. It also measures a person’s creatinine levels.

There are three steps with this test:

  1. Individuals register their testing kit on Everlywell’s website.
  2. A person follows the instructions carefully to take their urine sample.
  3. Once they have their urine sample, they place it in the prepaid package and send it off to Everlywell’s labs.

Within a few days, individuals will receive their results digitally via the Everlywell website. Medical professionals can also offer helpful insights via their secure platform.

As well as sending a personalized report of each marker, Everlywell also sends detailed information about what the results mean.

The labs where Everlywell tests samples all carry certification with CLIA. The company also ensures that all results are reviewed and certified by independent board-certified physicians within the person’s specific state.SHOP NOW

Healthlabs Cortisol, AM & PM Test

Healthlabs offers a cortisol test that tests a person’s cortisol levels twice — once in the morning and once in the evening.

The company says they do this because a person’s cortisol levels fluctuate throughout the day. Therefore, by testing twice, they can gather information on this fluctuation.

This test uses a blood sample, which a person takes once in the morning and once in the afternoon. They must follow the instructions clearly to ensure they take suitable samples.

The manufacturer says that people should collect a morning sample between 7–9 a.m. and an evening sample between 3–5 p.m.

They then need to send off their sample for analysis. After testing is complete at a CLIA-certified lab, a person will receive their results, which usually takes between 1–2 days. SHOP NOW

When to speak with a doctor

A person should undergo a cortisol test if they believe they may have high or low cortisol levels.

They can do this at home or speak with a medical professional who can carry out the test for them.

People may also wish to seek medical help if they show signs of too much or too little cortisol. This could indicate a potentially serious underlying health issue.

Summary

Cortisol is an important hormone that affects almost all parts of the body. It has many functions, including reducing inflammation, regulating metabolism, and controlling blood pressure.

If a person believes they have high or low cortisol levels, they may wish to take a cortisol test. Usually, these tests take place at a medical practice. However, several home cortisol tests are available to purchase.

A person can take these tests at home by providing a urine, blood, or saliva sample. Once a lab analyzes the test, people usually receive their results within a few days. Individuals should follow up any test results with a healthcare professional. No clinics, no stress. Test your cortisol levels from home

Test your cortisol level from home with LetsGetChecked. Get free shipping, medical support, and results from accredited labs within 2–5 days. Order today for 30% off. LEARN MORE

Last medically reviewed on April 29, 2021 at https://www.medicalnewstoday.com/articles/3-of-the-best-home-cortisol-tests

Largest-ever analysis of its kind finds Cushing’s syndrome triples risk of death

WASHINGTON–Endogenous Cushing’s syndrome, a rare hormonal disorder, is associated with a threefold increase in death, primarily due to cardiovascular disease and infection, according to a study whose results will be presented at ENDO 2021, the Endocrine Society’s annual meeting.

The research, according to the study authors, is the largest systematic review and meta-analysis to date of studies of endogenous (meaning “inside your body”) Cushing’s syndrome. Whereas Cushing’s syndrome most often results from external factors–taking cortisol-like medications such as prednisone–the endogenous type occurs when the body overproduces the hormone cortisol, affecting multiple bodily systems.

Accurate data on the mortality and specific causes of death in people with endogenous Cushing’s syndrome are lacking, said the study’s lead author, Padiporn Limumpornpetch, M.D., an endocrinologist from Prince of Songkla University, Thailand and Ph.D. student at the University of Leeds in Leeds, U.K. The study analyzed death data from more than 19,000 patients in 92 studies published through January 2021.

“Our results found that death rates have fallen since 2000 but are still unacceptably high,” Limumpornpetch said.

Cushing’s syndrome affects many parts of the body because cortisol responds to stress, maintains blood pressure and cardiovascular function, regulates blood sugar and keeps the immune system in check. The most common cause of endogenous Cushing’s syndrome is a tumor of the pituitary gland called Cushing’s disease, but another cause is a usually benign tumor of the adrenal glands called adrenal Cushing’s syndrome. All patients in this study had noncancerous tumors, according to Limumpornpetch.

Overall, the proportion of death from all study cohorts was 5 percent, the researchers reported. The standardized mortality ratio–the ratio of observed deaths in the study group to expected deaths in the general population matched by age and sex–was 3:1, indicating a threefold increase in deaths, she stated.

This mortality ratio was reportedly higher in patients with adrenal Cushing’s syndrome versus Cushing’s disease and in patients who had active disease versus those in remission. The standardized mortality ratio also was worse in patients with Cushing’s disease with larger tumors versus very small tumors (macroadenomas versus microadenomas).

On the positive side, mortality rates were lower after 2000 versus before then, which Limumpornpetch attributed to advances in diagnosis, operative techniques and medico-surgical care.

More than half of observed deaths were due to heart disease (24.7 percent), infections (14.4 percent), cerebrovascular diseases such as stroke or aneurysm (9.4 percent) or blood clots in a vein, known as thromboembolism (4.2 percent).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism and good infection control and emphasize the need to achieve disease remission, normalizing cortisol levels,” she said.

Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to put the disease in remission, other treatments are available, such as medications.

Study co-author Victoria Nyaga, Ph.D., of the Belgian Cancer Centre in Brussels, Belgium, developed the Metapreg statistical analysis program used in this study.

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Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From https://www.eurekalert.org/pub_releases/2021-03/tes-lao031621.php

New study identifies the main genetic causes of autoimmune Addison’s disease

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.

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Contact information:

Professor at the University of Bergen, Eystein Husebye – Eystein.Husebye@uib.no – cell phone +47 99 40 47 88

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php

Thyroid cancer: Cushing syndrome is a lesser-known warning sign – what is it?

Thyroid cancer survival rates are 84 percent for 10 years or more if diagnosed early. Early diagnosis is crucial therefore and spotting the unusual signs could be a matter of life and death. A sign your thyroid cancer has advanced includes Cushing syndrome.

What is it?

What is Cushing syndrome?

 

Cushing syndrome occurs when your body is exposed to high levels of the hormone cortisol for a long time, said the Mayo Clinic.

The health site continued: “Cushing syndrome, sometimes called hypercortisolism, may be caused by the use of oral corticosteroid medication.

“The condition can also occur when your body makes too much cortisol on its own.

“Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between your shoulders, a rounded face, and pink or purple stretch marks on your skin.”

In a study published in the US National Library of Medicine National Institutes of Health, thyroid carcinoma and Cushing’s syndrome was further investigated.

The study noted: “Two cases of thyroid carcinoma and Cushing’s syndrome are reported.

“Both of our own cases were medullary carcinomas of the thyroid, and on reviewing the histology of five of the other cases all proved to be medullary carcinoma with identifiable amyloid in the stroma.

“A consideration of the temporal relationships of the development of the carcinoma and of Cushing’s syndrome suggested that in the two cases with papillary carcinoma these conditions could have been unrelated, but that in eight of the nine cases with medullary carcinoma there was evidence that thyroid carcinoma was present at the time of diagnosis of Cushing’s syndrome.

“Medullary carcinoma of the thyroid is also probably related to this group of tumours. It is suggested that the great majority of the tumours associated with Cushing’s syndrome are derived from cells of foregut origin which are endocrine in nature.”

In rare cases, adrenal tumours can cause Cushing syndrome a condition arising when a tumour secretes hormones the thyroid wouldn’t normally create.

Cushing syndrome associated with medullary thyroid cancer is uncommon.

The syndrome is more commonly caused by the pituitary gland overproducing adrenocorticotropic hormone (ACTH), or by taking oral corticosteroid medication.

See a GP if you have symptoms of thyroid cancer, warns the NHS.

The national health body added: “The symptoms may be caused by less serious conditions, such as an enlarged thyroid, so it’s important to get them checked.

“A GP will examine your neck and can organise a blood test to check how well your thyroid is working.

“If they think you could have cancer or they’re not sure what’s causing your symptoms, you’ll be referred to a hospital specialist for more tests.”

 

Adapted from https://www.express.co.uk/life-style/health/1351753/thyroid-cancer-signs-symptoms-cushing-syndrome

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