Sosei Heptares Starts New Clinical Development Program

TOKYO and LONDONFeb. 20, 2019 /PRNewswire/ — Sosei Group Corporation (“the Company”; TSE: 4565), announces that the first healthy subject has been dosed with a novel small molecule HTL0030310 in a Phase I clinical study, marking the start of a new in-house clinical program targeting endocrine disorders, including Cushing’s disease.

HTL0030310 is a potent and selective agonist of the SSTR5 (somatostatin 5) receptor and the sixth molecule designed by the Company using its GPCR Structure-Based Drug Design (SBDD) platform to enter clinical development.

HTL0030310 has been designed to modulate the excess release of hormones from adenomas (benign tumors) of the pituitary gland. Highly elevated plasma levels of pituitary hormones result in a number of serious endocrine disorders, including Cushing’s Disease. Cushing’s disease is characterized by excessive cortisol release, crucial in regulating metabolism, maintaining cardiovascular function and helping the body respond to stress.

A key design feature of HTL0030310 is its significant selectivity for SSTR5 over SSTR2. This selectivity is expected to improve the balance of efficacy vs. dose-limiting side effects and therefore, presents an opportunity to develop a best-in-class medicine for patients with Cushing’s disease, in particular.

The clinical trial with HTL0030310 is a double-blind, randomised, placebo-controlled first-in-human study in which single ascending subcutaneous doses of HTL0030310 will be administered to healthy male and female adult subjects. The study is being conducted in the UK and will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of HTL0030310 in up to 64 subjects. Preliminary results are expected in the second half of 2019 and will provide a first insight into the effects of HTL0030310 on the control of glucose and other endocrine hormones and the potential to target Cushing’s disease and other endocrine disorders.

Dr. Malcolm Weir, Executive VP and Chief R&D Officer, said: “HTL0030310 is a novel and highly selective molecule, and is the sixth candidate originating from our SBDD platform to advance into human trials. We are not only pleased to begin this new study but also delighted with the productivity of our unique platform to generate attractive candidates targeting GPCRs involved in multiple diseases. These candidates present new prospects for our emerging proprietary pipeline, as well as unique opportunities for partnering, and provide a solid foundation to execute our strategy.”

About Cushing’s disease

Cushing’s disease is a debilitating endocrine disorder caused by the overproduction of the hormone cortisol and is often triggered by a pituitary adenoma (benign tumour) secreting excess adrenocorticotropic hormone (ACTH). Cortisol has a crucial role regulating metabolism, maintaining cardiovascular function and helping the body respond to stress. Symptoms may include weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. Cushing’s disease affects 10-15 million people per year, most commonly adults between 20 to 50 years and women more often than men. The first line and most common treatment approach for Cushing’s disease is surgical removal of the pituitary tumor followed by radiotherapy and drug therapy designed to reduce cortisol production.

Ref: American Association of Neurological Surgeons (AANS) 

About Sosei Heptares

We are an international biopharmaceutical group focused on the design and development of new medicines originating from its proprietary GPCR-targeted StaR® technology and structure-based drug design platform capabilities. The Company is advancing a broad and deep pipeline of partnered and wholly owned product candidates in multiple therapeutic areas, including CNS, immuno-oncology, gastroenterology, inflammation and other rare/specialty indications. Its leading clinical programs include partnered candidates aimed at the symptomatic treatment of Alzheimer’s disease (with Allergan) and next generation immuno-oncology approaches to treat cancer (with AstraZeneca). Our additional partners and collaborators include Novartis, Pfizer, Daiichi-Sankyo, PeptiDream, Kymab and MorphoSys. The Company is headquartered in Tokyo, Japan with R&D facilities in Cambridge, UK and Zurich, Switzerland.

“Sosei Heptares” is the corporate brand of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565).

For more information, please visit https://www.soseiheptares.com/

LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco

Forward-looking statements

This press release contains forward-looking statements, including statements about the discovery, development and commercialization of products. Various risks may cause Sosei Group Corporation’s actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

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SOURCE Sosei Heptares

Faster Adrenal Recovery May Predict Cushing’s Disease Recurrence

A shorter duration of adrenal insufficiency — when the adrenal gland is not working properly — after surgical removal of a pituitary tumor may predict recurrence in Cushing’s disease patients, a new study suggests.

The study, “Recovery of the adrenal function after pituitary surgery in patients with Cushing Disease: persistent remission or recurrence?,” was published in the journal Neuroendocrinology.

Cushing’s disease is a condition characterized by excess cortisol in circulation due to a tumor in the pituitary gland that produces too much of the adrenocorticotropic hormone (ACTH). This hormone acts on the adrenal glands, telling them to produce cortisol.

The first-line treatment for these patients is pituitary surgery to remove the tumor, but while success rates are high, most patients experience adrenal insufficiency and some will see their disease return.

Adrenal insufficiency happens when the adrenal glands cannot make enough cortisol — because the source of ACTH was suddenly removed — and may last from months to years. In these cases, patients require replacement hormone therapy until normal ACTH and cortisol production resumes.

However, the recovery of adrenal gland function may mean one of two things: either patients have their hypothalamus-pituitary-adrenal axis — a feedback loop that regulates ACTH and cortisol production — functioning normally, or their disease returned.

So, a team of researchers in Italy sought to compare the recovery of adrenal gland function in patients with a lasting remission to those whose disease recurred.

The study included 61 patients treated and followed at the Ospedale Maggiore Policlinico of Milan between 1990 and 2017. Patients had been followed for a median of six years (minimum three years) and 10 (16.3%) saw their disease return during follow-up.

Overall, the median time to recovery of adrenal function was 19 months, but while most patients in remission (67%) had not yet recovered their adrenal function after a median of six years, all patients whose disease recurred experienced adrenal recovery within 22 months.

Among those with disease recurrence, the interval from adrenal recovery to recurrence lasted a median of 1.1 years, but in one patient, signs of disease recurrence were not seen for 15.5 years.

Statistical analysis revealed that the time needed for adrenal recovery was negatively associated with disease recurrence, suggesting that patients with sorter adrenal insufficiency intervals were at an increased risk for recurrence.

“In conclusion, our study shows that the duration of adrenal insufficiency after pituitary surgery in patients with CD is significantly shorter in recurrent CD than in the persistent remission group,” researchers wrote.

“The duration of AI may be a useful predictor for CD [Cushing’s disease] recurrence and those patients who show a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored being more at risk of disease relapse,” they concluded.

From https://cushingsdiseasenews.com/2019/01/29/faster-adrenal-recovery-may-predict-recurrence-cushings-disease/

Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

Metastatic Pituitary Carcinoma Successfully Treated with Radiation, Chemo.

A man with Cushing’s disease — caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma — who later developed metastases in the central nervous system without Cushing’s recurrence, was successfully treated over eight years with radiation and chemotherapy, according to a case report.

The report, “Long-term survival following transformation of an adrenocorticotropic hormone secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma: Case report,” was published in the journal World Neurosurgery.

Pituitary carcinomas make up only 0.1-0.2% of all pituitary tumors and are characterized by a primary pituitary tumor that metastasizes into cranial, spinal, or systemic locations. Fewer than 200 cases have been reported in the literature.

Most of these carcinomas secrete hormones, with ACTH being the most common. Though the majority of ACTH-secreting carcinomas present with Cushing’s disease, about one-third do not show symptoms of the condition and have normal serum cortisol and ACTH levels. These are called silent corticotroph adenomas and are considered more aggressive.

A research team at the University of Alabama at Birmingham presented the case of a 51-year-old Caucasian man with ACTH-dependent Cushing’s disease. He had undergone an incomplete transsphenoidal (through the nose) resection of an ACTH-secreting pituitary macroadenoma – larger than 10 mm in size – and radiation therapy the year before.

At referral in August 1997, the patient had persistent high cortisol levels and partial hypopituitarism, or pituitary insufficiency. He exhibited Cushing’s symptoms, including facial reddening, moon facies, weight gain above the collarbone, “buffalo hump,” and abdominal stretch marks.

About two years later, the man was weaned off ketoconazole — a medication used to lower cortisol levels — and his cortisol levels had been effectively reduced. He also had no physical manifestations of Cushing’s apart from facial reddening.

In May 2010, the patient reported two episodes of partial seizures, describing two spells of right arm tingling, followed by impaired peripheral vision. Imaging showed a 2.1-by-1-cm mass with an associated cyst within the brain’s right posterior temporal lobe, as well as a 1.8-by-1.2-cm mass at the cervicomedullary junction, which is the region where the brainstem continues as the spinal cord. His right temporal cystic mass was then removed by craniotomy.

A histopathologic analysis was consistent with pituitary carcinoma. Cell morphology was generally similar to the primary pituitary tumor, but cell proliferation was higher. Physical exams showed no recurrence of Cushing’s disease and 24-hour free urinary cortisol was within the normal range.

His cervicomedullary metastasis was treated with radiation therapy in July 2010. He took the oral chemotherapy temozolomide until August 2011, and Avastin (bevacizumab, by Genentech) was administered from September 2010 to November 2012.

At present, the patient continues to undergo annual imaging and laboratory draws. He receives treatment with hydrocortisone, levothyroxine — synthetic thyroid hormone — and testosterone replacement with androgel.

His most recent exam showed no progression over eight years of a small residual right temporal cyst, a residual mass along the pituitary stalk — the connection between the hypothalamus and the pituitary gland — and a small residual mass at the cervicomedullary junction. Lab results continue to show no Cushing’s recurrence.

“Our case is the first to document a patient who initially presented with an endocrinologically active ACTH secreting pituitary adenoma and Cushing’s disease who later developed cranial and spinal metastases without recurrence of Cushing’s disease and transformation to a silent corticotroph pituitary carcinoma,” the scientists wrote.

They added that the report is also the first documenting “8 years of progression-free survival in a patient with pituitary carcinoma treated with radiotherapy, [temozolomide] and bevacizumab.”

Adapted from https://cushingsdiseasenews.com/2019/01/03/successful-treatment-pituitary-carcinoma-radiation-chemo-case-report/

Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature

 2018 Nov 28. doi: 10.1007/s00381-018-4013-5. [Epub ahead of print]

Abstract

AIM:

Pituitary adenomas are rare in childhood in contrast with adults. Adrenocorticotropic hormone (ACTH)-secreting adenomas account for Cushing’s disease (CD) which is the most common form of ACTH-dependent Cushing’s syndrome (CS). Treatment strategies are generally based on data of adult CD patients, although some difficulties and differences exist in pediatric patients. The aim of this study is to share our experience of 10 children and adolescents with CD.

PATIENTS AND METHOD:

Medical records, images, and operative notes of 10 consecutive children and adolescents who underwent transsphenoidal surgery for CD between 1999 and 2014 in Cerrahpasa Faculty of Medicine were retrospectively reviewed. Mean age at operation was 14.8 ± 4.2 years (range 5-18). The mean length of symptoms was 24.2 months. The mean follow-up period was 11 years (range 4 to 19 years).

RESULTS:

Mean preoperative cortisol level was 23.435 μg/dl (range 8.81-59.8 μg/dl). Mean preoperative ACTH level was 57.358 μg/dl (range 28.9-139.9 μg/dl). MR images localized microadenoma in three patients (30%), macroadenoma in four patients (40%) in our series. Transsphenoidal microsurgery and endoscopic transsphenoidal surgery were performed in 8 and 2 patients respectively. Remission was provided in 8 patients (80%). Five patients (50%) met remission criteria after initial operations. Three patients (30%) underwent additional operations to meet remission criteria.

CONCLUSION:

Transsphenoidal surgery remains the mainstay therapy for CD in pediatric patients as well as adults. It is an effective treatment option with low rate of complications. Both endoscopic and microscopic approaches provide safe access to sella and satisfactory surgical results.

KEYWORDS:

Cushing’s disease; Endoscopic pituitary surgery; Pediatric; Transsphenoidal microsurgery

PMID:
30488233
DOI:
10.1007/s00381-018-4013-5

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