IP Verse

Corticotropin Releasing Factor Receptor Antagonists

Patent No. US10849908 (titled "Corticotropin Releasing Factor Receptor Antagonists") was filed by Spruce Biosciences Inc on Apr 18, 2019.

What is this patent about?

’908 is related to the field of pharmaceutical compositions and methods for treating congenital adrenal hyperplasia (CAH) . CAH is a genetic disorder that causes the adrenal glands to produce excess androgens and insufficient cortisol. Current treatments involve glucocorticoids to normalize hormone levels, but these can lead to adverse side effects. The invention addresses the need for alternative or adjunctive therapies to manage CAH and reduce reliance on high-dose glucocorticoids.

The underlying idea behind ’908 is to use a CRF1 receptor antagonist to modulate the hypothalamic-pituitary-adrenal (HPA) axis, thereby reducing the production of ACTH and subsequently decreasing androgen production in the adrenal glands. By blocking the CRF1 receptor, the drug aims to interrupt the signaling cascade that leads to excessive androgen synthesis, offering a more targeted approach to managing CAH.

The claims of ’908 focus on methods of treating CAH by administering a CRF1 receptor antagonist to a human. Claim 1 specifies that the administration of the CRF1 receptor antagonist results in a reduction of the adrenocorticotropic hormone (ACTH) level by at least 10% from baseline. Claim 11 specifies that the administration of the CRF1 receptor antagonist results in a reduction of the 17-hydroxyprogesterone (17-OHP) level by at least about 10% from baseline.

The invention works by administering a pharmaceutical composition containing a CRF1 receptor antagonist, such as 3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine, to a patient with CAH. This antagonist binds to the CRF1 receptor in the pituitary gland, blocking the action of corticotropin-releasing factor (CRF) . This blockade reduces the release of ACTH, which in turn lowers the production of androgens like androstenedione and testosterone in the adrenal glands. The reduction in these hormones helps to alleviate the symptoms of CAH.

This approach differs from traditional treatments that rely on glucocorticoids to suppress ACTH production. While glucocorticoids can be effective, they often require high doses that lead to significant side effects. By using a CRF1 receptor antagonist, the invention aims to achieve similar therapeutic benefits with potentially lower doses of glucocorticoids, thus reducing the risk of adverse effects associated with long-term, high-dose steroid therapy. The patent also explores combination therapies with glucocorticoids and mineralocorticoids to optimize treatment outcomes.

How does this patent fit in bigger picture?

Technical landscape at the time

In the late 2010s when ’908 was filed, pharmaceutical compositions were commonly formulated as capsules or tablets, and the characterization of drug release profiles (e.g., Tmax) was a standard practice. At a time when bioavailability was typically addressed through formulation strategies, controlling particle size and using excipients to enhance absorption were well-established techniques. Systems commonly relied on traditional methods for assessing drug stability, such as evaluating appearance, assay, related substances, and disintegration over time under various temperature and humidity conditions.

Novelty and Inventive Step

The examiner approved the application because the applicant demonstrated a reduction in adrenocorticotropic hormone (ACTH) and 17-hydroxyprogesterone (17-OHP) hormone levels in humans with congenital adrenal hyperplasia (CAH) over a six-week period. This result was considered unexpected compared to the closest prior art, which only disclosed measuring ACTH and 17-OHP levels within a 24-hour post-dose period, without maintaining the reduced hormone levels over an extended period.

Claims

This patent contains 25 claims, with claims 1 and 11 being independent. The independent claims focus on methods of treating congenital adrenal hyperplasia by administering a CRF1 receptor antagonist to reduce adrenocorticotropic hormone or 17-hydroxyprogesterone levels. The dependent claims generally specify details such as dosage amounts, formulations, types of CAH, and combination therapies.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
17-hydroxyprogesterone
(Claim 11)		“In some embodiments, the hormone is 17α-Hydroxyprogesterone (17-OHP), adrenocorticotropic hormone (ACTH), testosterone, or androstenedione. In some embodiments, the hormone is 17-OHP, and the pre-determined range is from about 200 ng/dL to about 400 ng/dL.”A hormone, the level of which is reduced by the claimed method.
Adrenocorticotropic hormone
(Claim 1)		“Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In some embodiments, the pharmaceutical composition is administered at or before the expected circadian release of adrenocorticotropic hormone (ACTH). In some embodiments, the pharmaceutical composition is administered about 3-4 hours before the expected circadian release of adrenocorticotropic hormone (ACTH).”A hormone produced by the pituitary gland, the level of which is reduced by the claimed method.
Congenital adrenal hyperplasia
(Claim 1, Claim 11)		“The present invention provides novel pharmaceutical compositions comprising 3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods using such pharmaceutical compositions for treating congenital adrenal hyperplasia (CAH). In one aspect, the present disclosure provides a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound 1.”A genetic condition affecting the adrenal glands, treatable by the methods described.
Crf1 receptor antagonist
(Claim 1, Claim 11)		“Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. The present invention provides novel pharmaceutical compositions comprising 3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods using such pharmaceutical compositions for treating congenital adrenal hyperplasia (CAH).”A compound that inhibits the corticotropin releasing factor 1 receptor. The specification identifies Compound 1 as such an antagonist.
Therapeutically-effective amount
(Claim 1, Claim 11)		“In one aspect, the present disclosure provides a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound 1: or a pharmaceutically acceptable salt or solvate thereof, wherein Compound 1 is administered at a dose between about 50 mg/day and about 1600 mg/day.”An amount of the CRF1 receptor antagonist sufficient to treat congenital adrenal hyperplasia.

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US10849908

SPRUCE BIOSCIENCES INC
Application Number
US16388620
Filing Date
Apr 18, 2019
Status
Granted
Expiry Date
Aug 14, 2038
External Links
Slate, USPTO, Google Patents