This is my live blog post covering new developments in the area of new Somatostatin Analogues and new delivery systems.
As most of you will be aware, there are currently two main types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide and Lanreotide. You can click on the links for information on both of these well-known NET treatments. This post will focus on the not so well known and anything in the pipeline including different delivery systems.
Those who have read the Octreotide/ Lanreotide patient leaflets will know those SSAs are also used in the treatment of a condition known as Acromegaly. You can see why the drug is used for both as they control the release of excess secretions of various substances, a problem that has an effect on both conditions. In the case of Acromegaly, the condition is typically caused by pituitary tumours that oversecrete the growth hormone leading to elevated levels of IGF-1. Like NETs, Octreotide/Lanreotide is currently the mainstay non-surgical treatment for this condition. For those not aware of Acromegaly there is a nice infographic explaining it here.
The new syringe for Lanreotide is slowly being rolled out – read more here
Delivery methods discussed in this post include: a smaller, faster and easier Octreotide injection, an Octreotide capsule, an Octreotide nasal spray. Other somatostatin analogues includes Pasireotide which has already been approved for Cushing’s Syndrome and Acromegaly (core NET possibilities have been investigated) and a new kid in the pipeline called Veldreotide for Acromegaly but potential additional applications in Cushing’s syndrome and neuroendocrine tumors. Finally for those with an interest in Cushings, a drug currently in phase 3 trials called RECORLEV™ (Levoketoconazole) which is not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor.
It’s important to understand that NETs and other conditions including Cushing’s and Acromegaly, very often share the same hormone inhibiting drugs, thus why any development for these type of drugs is of interest to all physicians and patients in the associated conditions.
It’s also useful to understand that many of these drugs/delivery mechanisms are driven by availability of funding and are subject to the vagaries of the market. For example, one entry on the previous version of this article has been removed as the company manufacturing it went into administration (Solid Dose Injections).
Article feature: New Octreotide Delivery Method – Chiasma Capsule
Updated 13th January 2020. Chiasma Pharma announced that the U.S. Food and Drug Administration (FDA) accepted for review the New Drug Application (NDA) resubmission for its oral octreotide capsules investigational product candidate, conditionally trade named MYCAPSSA® The FDA assigned a Prescription Drug User-Fee Act (PDUFA) target action date of June 26, 2020, which is a six-month review.
Acromegaly appears to be in the lead in terms of new delivery methods. Chiasma is working on a daily oral version of Octreotide for this condition. You can check out the technology here. The manufacturer Chiasma, completed an international Phase 3 trial of octreotide capsules (conditionally trade named Mycapssa®), the results of which have been published in the Journal of Clinical Endocrinology and Metabolism. Read the Chiasma press release. This Phase 3 clinical trial was conducted under a Special Protocol Assessment agreement reached with the U.S. Food and Drug Administration for its octreotide capsules product candidate for the maintenance therapy of adult patients with acromegaly. The trial, referred to as “CHIASMA OPTIMAL” (Octreotide capsules vs. Placebo Treatment In Multinational centers), is a global, randomized, double-blind, placebo-controlled, nine-month trial. The trial is designed to evaluate the proportion of patients who maintain their biochemical response to octreotide capsules compared to placebo. The company completed enrollment with 56 adult acromegaly patients in CHIASMA OPTIMAL in October 2018 and anticipates the release of top-line data from this Phase 3 clinical trial in Q3 2019.
Chiasma also is conducting an international Phase 3 clinical trial under a protocol accepted by the European Medicines Agency (EMA) for the company’s octreotide capsules product candidate for the maintenance therapy of adult patients with acromegaly. The trial, referred to as MPOWERED™ (Maintenance of Acromegaly Patients with Octreotide Capsules Compared with Injections – Evaluation of REsponse Durability), is a global, randomized, open-label and active-controlled, 15-month trial. Chiasma plans to enroll up to 150 adult acromegaly patients into the trial, of which at least 80 patients who are responders to octreotide capsules following a six-month run-in will be randomized to either octreotide capsules or injectable somatostatin receptor ligands (octreotide or lanreotide), and then followed for an additional nine months. Patients are only randomized into the nine-month randomized controlled phase of MPOWERED if they are qualified as responders (IGF-1 <1.3 x ULN and GH<2.5 ng/mL) to octreotide capsules in the study at the end of the six-month run-in phase. The trial was initiated in March 2016 and has enrolled 135 patients as of July 2018 (of which the EMA-required minimum of 80 patients have been randomized). In October 2018, Chiasma announced it had elected to resume enrollment in the trial in an effort to enroll up to 150 additional patients exclusively located in the United States in order to gain further U.S. investigator and patient experience with octreotide capsules. Chiasma now anticipates the trial to complete enrollment into the run-in phase in Q2 2019 and expects to release topline data from this Phase 3 clinical trial during the second half of 2020.
Clearly, we want drugs to be safe and the announcement is another reminder of why drugs take so long to be approved. Chiasma’s investigational oral octreotide uses their proprietary TPE® (Transient Permeability Enhancer) technology to facilitate gastrointestinal absorption of the unmodified drug into the bloodstream safely (i.e. it keeps the drug safe until it reaches its destination). Hopefully, the trials can convince the FDA/EMA to approve.
This is an exciting development given that both Acromegaly and Neuroendocrine Tumours have historically had access to the same somatostatin analogues) so there is always the hope that NETs might be next in line if the capsule version is finally approved. Separate trials would be required for NETs.
New Syringe for Lanreotide (Somatuline)
click on picture to read news
Crinetics Pharmaceuticals Initiates Phase 1 Study of CRN01941 for the Treatment of Neuroendocrine Tumors
Updated 21 May 2019. Click here to read about this exciting development.
New delivery system for Octreotide LAR – “Q-Sphera” (MDT201)
(awaiting confirmed graphic of the product)
Updated 8th January 2020.
An unnamed Asian ‘pharma giant’ has signed a deal with Midatech Pharma Plc that will see it evaluate the latter’s Q-Sphera drug delivery platform.
Midatech’s Q-Sphera™ is an advanced microencapsulation and polymer-depot sustained release (SR) drug delivery platform produced using a novel and disruptive printing based process, with numerous and distinct advantages over conventional reactor based technologies. From a manufacturing perspective Q-Sphera™ is a precise, scalable, efficient, and environmentally friendly microparticle platform. From a clinical perspective Q-Sphera™ ensures monodispersed microparticles that release active drug compounds into the body in a superior linear tightly controlled and predictable manner over an extended period of time from 1 – 6 months. Most recent study has proven sustainability of the injection for up to 6-8 weeks (see full article for details). Read more here in my article dedicated to this project – click here
Intranasal administration of Octreotide Acetate
Updated 14 May 2017. Dauntless Pharmaceuticals, Inc., a privately held biopharmaceutical company focused on the development of specialty therapeutics, announced the outcome of a Phase 1 clinical study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) injection in healthy volunteers. DP1038 (octreotide acetate for intranasal administration) is being developed via the 505(b)(2) regulatory pathway for the treatment of acromegaly and neuroendocrine tumors. DP1038 leverages patented technology for enhanced intranasal absorption developed by Aegis Therapeutics, LLC, a drug delivery and drug formulation company that has successfully licensed its technology to leading pharmaceutical and biopharmaceutical companies whose partners have multiple late stage clinical programs under development. The drug will most likely use an administration system patented by Aegis called Intravail® Aegis Therapeutics LLC announced last year that it has been awarded U.S. Patent No. 9,446,134 providing non-invasive metered nasal spray delivery of Octreotide (click here to view the announcement). The enabling Aegis Intravail formulation technology is broadly applicable to a wide range of small molecule and biotherapeutic drugs to increase non-invasive bioavailability by the oral, nasal, buccal, and sublingual routes and to speed attainment of therapeutic drug levels in cases where a non-invasive (i.e., non-injectable) form of the drug is unavailable or where speed of onset is important. A description of Intravail delivery systems can be found by clicking here.
About the Phase 1 Trial
The Phase 1 trial was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) Injection in healthy volunteers. In Part 1 of the study, each of 12 subjects received three doses of DP1038 plus 100 micrograms of subcutaneous octreotide acetate in a randomized 4 x 4 Latin square design. DP1038 was well tolerated across all doses and demonstrated a consistent, dose-proportional pharmacokinetic profile with significant nasal bioavailability. In Part 2 of the study, a single dose of DP1038, which was selected to exhibit a similar pharmacokinetic profile to subcutaneous octreotide acetate, was evaluated in 20 subjects in a cross-over design to compare the pharmacodynamic effect to 100 micrograms of subcutaneous octreotide acetate. Subjects were given a GHRH-arginine challenge, a standard test to stimulate growth hormone release, followed by administration of DP1038 or subcutaneous octreotide acetate. DP1038 showed comparable growth hormone suppression to the subcutaneous reference product. The news announcing the output from the Phase 1 clinical trial can be found by clicking here. Clearly, this is very early days and the product would need to go through the normal drug approval and acceptance routes etc. However, a Phase 1 trial using patients is very exciting.
New Somatostatin Analogues
Somatostatin Analogue – Pasireotide
Updated 14 Dec 2017. Not really new but I wanted to include it because it’s not very well-known. Pasireotide is also known as Signifor and SOM230. This drug is already in the pipeline but only for Acromegaly and Cushing’s Syndrome. I found it interesting that is able to function as a multireceptor-targeted SSA by binding with high affinity to 4 of the 5 somatostatin receptors (sstrs 1, 2, 3 and 5), with the highest affinity for sstr5, resulting in inhibition of adrenocorticotropic hormone (ACTH) secretion (Octreotide only binds to sstrs 2, 3 and 5). In fact, Signifor represents the first specific treatment for ACTH-secreting pituitary adenomas. Moreover, it is the first approved medical treatment for Cushing’s disease. If you’ve read my blog on NET Syndromes, you will see the connection – both involve pituitary tumours and this drug is designed to cater for scenarios where surgery has not solved the problem or is not an option. Interestingly Novartis describes it as a second generation SSA, inferring that Octreotide is first generation. It comes in short and long acting (LAR) forms with a similar delivery system to Octreotide. It is a US FDA approved orphan drug and is also approved for use in the EU. Novartis has also submitted additional regulatory applications for Signifor LAR worldwide. You can read more by clicking here.
However, there have been studies in its use for advanced NETs where Octreotide is not working or has not sufficiently controlled the effects of the syndrome. You can read a full text article about the study results by clicking here (you will recognise some of the authors including Edward M Wolin, Christos Toumpanakis, John Ramage, Kjell Öberg). My interpretation of the trial conclusion is that there does not appear to be any significant advantages of Pasireotide over Octreotide. The attachment also confirmed studies are ongoing including a potential combination treatment of Pasireotide and Everolimus (Afinitor). There does not appear to be a study comparing it to Lanreotide.
Jonathan R. Strosberg, MD, associate professor at H. Lee Moffitt Cancer Center, discussed pasireotide as a potential treatment for patients with neuroendocrine tumors (NETs). He said “Pasireotide is a somatostatin analog similar to octreotide (Sandostatin) and lanreotide (Somatuline). However, pasireotide targets 4 out of the 5 somatostatin receptor subtypes, which may provide it with an advantage over the other 3 agents. Thus far, there has not been enough evidence showing that pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. Pasireotide may be an appropriate choice for patients in later lines of therapy. In the future, he envisions that patients could be selected for therapy based on their somatostatin receptor profile.”
New Somatostatin Analogue – Veldoreotide (COR-005)
Updated 14 Dec 2017. There is another new drug in the pipeline currently known as Veldoreotide or COR-005 (although I can see the term ‘Somatoprim’ used on other searches). COR-005 is an investigational SSA in phase 2 development for treatment of patients with Acromegaly. Although the page on the manufacturer’s website does not mention NETs, an announcement of its progress has just been made at the Endocrine Society’s annual conference for 2016. The announcement states that the drug has “potential additional applications in Cushing’s syndrome and neuroendocrine tumors”. COR-005 targets somatostatin receptors 2, 4 and 5. Read about the drug here.
COR-005 has received orphan drug designation (only for Acromegaly) in the US and EU. There is not enough data to understand how this might benefit NETs and what the differences would be. Hopefully, an update will be available later which will result in an update to this post.
For those interested in Cushing’s Syndrome, (hypercortisolism or high levels of cortisol), the same manufacturer working on Veldoreotide is also working on a new drug in Phase 3 trials known as RECORLEV™ (Levoketoconazole). Not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor
This information is provided for information only. There is no intent to indicate at this point that these new drugs will eventually be approved for NETs. However, it’s another indication that people are working on new treatments which might end up being available at some stage.
The pipeline for new treatments and methods of delivery continues to grow!
Thanks for reading