This is my live blog covering new developments in the area of Somatostatin Analogues and delivery systems.
As most of you will be aware, there are currently two types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide and Lanreotide. Those who have read the drug patient leaflets for both 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 benign pituitary tumours that oversecrete the growth hormone leading to elevated levels of IGF-1. Octreotide/Lanreotide is currently the mainstay non-surgical treatment for this condition. For those who were aware of Acromegaly via their Octreotide/Lanreotide treatment, there is a nice infographic explaining it here.
Somatostatin Analogues – New Delivery Methods in the Pipeline
Intranasal administration of Octreotide Acetate – NEW in on May 5th 2017
Dauntless Pharmaceuticals, Inc., a privately held biopharmaceutical company focused on the development of specialty therapeutics, today 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.
Glide Solid Dose Injection (SDI®)
New Delivery Method – Glide Solid Dose Injection (SDI®)
(added 19 May 16). News in of an Octreotide dose to be delivered via a new needle-free solid dose injection system (SDI®). Glide Technologies, the pharmaceutical development and device company focused on solid dose formulations of therapeutics and vaccines, today announced that it has initiated a clinical proof-of-concept study comparing its novel solid formulation of Octreotide acetate with the currently marketed liquid product (Sandostatin). According to the company website, it has developed a hand-held ‘solid dose injector’ (“SDI®”). In use, all that is required is to push the end of the SDI® against the skin. The patented internal mechanism of the SDI® responds to the slight rise in pressure so created by ejecting the drug dose and pushing it into the subcutaneous layer of the skin, all in a fraction of a second. In order to make the SDI® reusable Glide has developed small disposable cartridges, each of which contains a single dose of the drug. It takes only four steps to load a cartridge onto the SDI® and to inject drug through the skin (Click here to see the video). Glide anticipates that the ease of loading and speed of injection will be features that patients and healthcare workers currently spending minutes injecting liquid drug or vaccine doses will appreciate – hence the likelihood of improved adherence. Clearly, this is very early days.
New Delivery Method – Chiasma Capsule
Acromegaly appears to be in the lead in terms of new delivery methods. A pharma company called Chiasma is working on an oral version of Octreotide for this condition and they are currently at Phase 3 trials but not without some more hurdles to jump. You can read the full announcement here.
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 new trial can convince the FDA to finally approve.
This is potentially an exciting development given that both conditions use the same drugs (Octreotide and Lanreotide injections) so there is always the hope that NETs might be next in line if the capsule version is finally approved. However, still early days.
New Somatostatin Analogues in the Pipeline
(added 31 May 16). Before listing the new stuff in the pipeline (both new SSAs and new delivery methods), I thought I’d also include a section on this ‘in service’ SSA which is not that well-known – Pasireotide (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 sst5, 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 (however, you should decide for yourself). 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.
There is news of ‘new kids on the block’ if the pipeline plans and clinical trial successes are realised. You can read below about two ‘new kids’ below:
New Somatostatin Analogue – MDT201 (Q-Octreotide)
“Midatech Pharma has reported good results from a pre-clinical study of Q-Octreotide, its treatment for the side effects of carcinoid tumours. The company’s speciality is drug delivery systems and MTD201 (Q-Octreotide) is a sustained release version of Octreotide designed to treat the incapacitating symptoms of metastatic Neuroendocrine Tumours, such as severe diarrhea and flushing. Q-Octreotide compared favourably with the standard Octreotide product and current market leader Sandostatin for acromegaly and carcinoid syndrome.”
Apparently, the delivery method (see picture) is smaller, faster, easier. Clinical trials due to start end of 2016/beginning of 2017. Midatech plans on submitting its investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA). Q-Octreotide is a wholly-owned asset of Midatech Pharma and will continue to be developed in-house. Midatech expects to commercialize Q-Octreotide in the United States through its Midatech Pharma U.S. subsidiary.
More to follow when known but in the meantime, please see a useful video here << Video about Q-Octreotide>>
New Somatostatin Analogue – COR-005 (Somatoprim)
There is another new drug in the pipeline currently known as 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 has received orphan drug designation (only for Acromegaly) in the US and EU. Read about the drug here. 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 a revised blog.
Read the announcement from the Endocrine Society Conference here. For those interested in Cushing’s Syndrome, (hypercortisolism or high levels of cortisol) this is actually the main driver behind this announcement with information about a new drug in Phase 3 trials known as COR-003.
This information is provided for information only. There is no intent to indicate at this point that these new drugs will 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
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