Sage Therapeutics receives fast track designation for status epilepticus therapy

Sage Therapeutics (Originator)

Sage Therapeutics

For Epilepsy, status epilepticus

SGE-102; SAGE-547; allopregnanolone; allosteric GABA A receptor modulators (CNS disorders),

Sage Therapeutics receives fast track designation for status epilepticus therapy
Ligand Pharmaceuticals announced that its partner Sage Therapeutics has received fast track designation from the US Food and Drug Administration (FDA) for the Captisol-enabled SAGE-547 to treat status epilepticus.

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http://www.pharmaceutical-technology.com/news/newssage-therapeutics-receives-fast-track-designation-for-status-epilepticus-therapy-4324543?WT.mc_id=DN_News

SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

In 2014, orphan drug designation was assigned in the U.S for the treatment of status epilepticus. In July 2014, fast track designation was received in the U.S. for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat life-threatening, rare central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has granted fast track designation to the SAGE-547 development program. SAGE-547 is an allosteric modulator of GABAA receptors in development for the treatment of adult patients with refractory status epilepticus who have not responded to standard regimens (super-refractory status epilepticus, or SRSE). SAGE is currently evaluating SAGE-547 in a Phase 1/2 clinical trial for the treatment of SRSE. Preliminary data indicate that the first four patients enrolled in the clinical trial met the key efficacy endpoint, in that each was successfully weaned off his or her anesthetic agent while SAGE-547 was being administered. There have also been no reported drug-related serious adverse events in these four patients to date.

“The fast track designation for SAGE-547 recognizes the significant unmet need that exists in the treatment of super-refractory status epilepticus,” said Jeff Jonas, MD, chief executive officer of SAGE Therapeutics. “The receipt of orphan drug designation earlier this year for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547, and we will continue to work closely with the FDA to advance our lead compound and the additional programs in our pipeline for the treatment of life-threatening CNS disorders.”

Fast track designation is granted by the FDA to facilitate the development and expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

About SAGE-547

SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE.

About Status Epilepticus (SE)

SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.1 We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.

About SAGE Therapeutics

SAGE Therapeutics (NASDAQ: SAGE) is a biopharmaceutical company committed to developing and commercializing novel medicines to treat life-threatening, rare CNS disorders. SAGE’s lead program, SAGE-547, is in clinical development for super-refractory status epilepticus and is the first of several compounds the company is developing in its portfolio of potential seizure medicines. SAGE’s proprietary chemistry platform has generated multiple new compounds that target GABAA and NMDA receptors, which are broadly accepted as impacting many psychiatric and neurological disorders. SAGE Therapeutics is a public company launched in 2010 by an experienced team of R&D leaders, CNS experts and investors. For more information, please visitwww.sagerx.com.

Allopregnanolone
IUPAC name 1-(3-hydroxy-10,13-dimethyl- 2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro- 1H-cyclopenta[a] phenanthren-17-yl)ethanone
Other names 3α,5α-Tetrahydroprogesterone
Identifiers
PubChem	262961
ChemSpider	17216124
ChEMBL	CHEMBL38856
Jmol-3D images	Image 1
Properties
Molecular formula	C21H34O2
Molar mass	318.49 g/mol

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone), generally abbreviated as ALLO or as 3α,5α-THP, is an endogenous inhibitory pregnane neurosteroid.^[1] It is synthesized from progesterone, and is a potent positive allosteric modulator of the GABA_A receptor.^[1] Allopregnanolone has effects similar to those of other potentiators of the GABA_A receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.^[1]

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions.^[1]

Biosynthesis

The biosynthesis of allopregnanolone starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.^[1]

Depression, anxiety, and sexual dysfunction are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.^[2]

Mechanism

Allopregnanolone acts as a potent positive allosteric modulator of the GABA_A receptor.^[1] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.^[1] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear.^[3][4] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,^[5] and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor.^[6] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.^[7]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).^[7] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.^[8] In addition, allopregnanolone has recently been found to be an agonist of the newly-discovered membrane progesterone receptors (mPR), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABA_A receptor.^[9][10] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.^[9][11] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.^[7][12]

Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),^[13] including α₁ subtypes Ca_v1.2 and Ca_v1.3.^[14] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.^[14] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.^[14] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).^[15] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.^[15]

Function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,^[16] prosocial,^[17] antiaggressive,^[18] prosexual,^[17] sedative, pro-sleep,^[19] cognitive and memory-impairing, analgesic,^[20] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.^[1]

Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.^[21][22][23]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.^[24][25][26] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.^[24][25] This seems to be a common effect of many GABA_A receptor positive allosteric modulators.^[26][21] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.^[27]

Therapeutic applications

Allopregnanolone and the other endogenous inhibitory neurosteroids have very short half-lives, and for this reason, have not been pursued for clinical use themselves. Instead, synthetic analogs with improved pharmacokinetic profiles, such as ganaxolone, have been synthesized and are being investigated. However, exogenous progesterone, such as oral micronized progesterone (OMP), reliably elevates allopregnanolone levels in the body with good dose-to-serum level correlations.^[28] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.^[28] As a result, there has been some interest in using OMP to treat catamenial epilepsy,^[29] as well as other menstrual cycle-related and neurosteroid-associated conditions.

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http://www.google.com/patents/WO2006037016A2?cl=en

Materials and Methods

[0181] The materials and methods used for the follwing experiments have been described in Griffin L.D., et al, Nature Medicine 10: 704-711 (2004). This reference is hereby incorporated by reference in its entirety.

Example 1: Allopregnanolone Treatment of Niemann Pick type-C Mice Substantially Reduces Accumulation of the Gangliosides GMl, GM2, and GM3 in the Brain [0182] Mice were given a single injection of allopregnanolone, prepared in 20% βcyclodextrin in phosphate buffered saline, at a concentration of 25 mg/kg. The injection was on day 7 of life (P7, postnatal day 7). Concentrations of gangliosides GMl, GM2, GM3, were measured as well as other lipids such as ceramides and cerebrosides.

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WO-2014031792 OR EQ

http://www.google.com/patents/US20140057885?cl=en

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WO-2013112605

http://www.google.com/patents/WO2013112605A2?cl=en

References

Additional reading

• Herd, MB; Belelli, D; Lambert, JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol. Ther. 116(1):20-34. doi:10.1016/j.pharmthera.2007.03.007.