Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors, today announced the initiation of a Phase 1, double-blind, randomized, placebo-controlled, single and multiple-dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CRN01941 in healthy volunteers.
What is CRN01941?
It’s an oral nonpeptide somatostatin receptor subtype 2 (sst2) biased agonist* designed for the treatment of neuroendocrine tumors (NETs) that originate from neuroendocrine cells commonly found in the gut, lung, or pancreas. From the detail contained in the clinical trials document (see below), it appears to involve a capsule. I’m guessing that the use of terms such as ‘non-peptide’ means that it may not be the same as a somatostatin analogue, but the method of operation appear to be similar in that it wants to bind to somatostatin receptor 2 (SST2). I will bring more technical detail once I have it. * chemical that binds to a receptor and activates the receptor to produce a biological response.
This trial launch follows other products including a similar capsule based somatostatin receptor product for treating Acromegaly called CRN00808, currently undergoing two Phase 2 clinical trials. The company is also developing oral nonpeptide somatostatin agonists for hyperinsulinism, as well as oral nonpeptide ACTH antagonists for the treatment of Cushing’s disease.
On the basis that the CRN00808 Phase 2 trial for Acromegaly is using patients previously treated with somatostatin analog based treatment regimens, I suspect this drug is designed for the same market as Sandostatin LAR/Octreotide and Somatuline (Lanreotide). For more information, please visit www.crinetics.com.
The Phase 1 Clinical Trial of CRN01941 for NETs
The trial is initially only based in Perth Western Australia, it is not yet known if there are any plans to expand locations in subsequent phases or parts of the trial. It also appears they are trialling the use of a capsule based drug and another delivery method as yet unknown, the clinical trial only mentions “Oral Solution” so it isn’t an injection. Read more at ClinicalTrials.gov using the identifier NCT03936166.
This is not the first somatostatin receptor based product in the pipeline, please also check out my article about Somatostatin Analogues and Delivery Mechanisms in the pipeline – click here.
Lenvatinib has just completed a Phase 2 trial in Gastrointestinal (GI) and Pancreatic Neuroendocrine Tumours. The trial was sponsored by Grupo Espanol de Tumores Neuroendocrinos (Spanish NET scientific organisation) and the manufacturers. A European venture with sites in Austria, Italy, Spain, UK. Headline: The responses are better than Everolimus (Afinitor) and Sunitinib (Sutent).
What is Lenvatinib?
It is a type of targeted therapy known as a multikinase inhibitor. The brand name is ‘LENVIMA‘. These work by inhibiting multiple intracellular and cell surface kinases, some of which are implicated in tumour growth and metastatic progression of cancer, thus decreasing tumour growth and replication. A range of receptor kinases are involved in these processes, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (c-KIT), Flt3, fibroblast growth factor receptor (FGFR), which can be hyperactivated during tumour formation and progression. Tumour growth may be prevented by inhibiting the action of these hyperactivated receptor kinases, and as tumour progression usually involves the action of multiple kinases rather than just one, it is logical to target multiple kinases.
The Lenvantinib mechanism of action is similar to targeted therapy drugs already in use (or in trial) for Neuroendocrine Tumours:
Sunitinib (Sutent) – a targeted therapy receptor protein-tyrosine kinase inhibitor. It inhibits the actions of vascular endothelial growth factor (VEGF) and is an angiogenesis inhibitor (i.e. the development of blood vessels to supply the tumour with nutrients, which they need to grow). It is a mutlikinase in inhibitor.
Everolimus (Afinitor) – a targeted therapy kinase inhibitor that inhibits mammalian target of rapamycin (mTor) kinase, an enzyme required for cell growth and survival. By blocking this enzyme, the medication prevents cell division and, in turn, tumor growth. The medication can also interrupt angiogenesis.
Cabozantinib, an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL, and currently on trial for Neuroendocrine Cancer. Click here.
Multikinase inhibitors such as Lenvatinib, may be used to treat advanced kidney cancer as well as other specific types of cancer (in my research I also noted that in addition to kidney cancer, the drug is already approved for liver and thyroid cancers). Worth also noting that the 3 examples of targeted therapy above are not just in use/in trial for Neuroendocrine Cancer, they are also in use/in trial for others including Renal (Kidney) Cancer, Breast Cancer. Often more than one single kinase inhibitor can be given as a combo treatment, perhaps in sequence, to tackle multi kinases.
Anything special about Lenvatinib for Neuroendocrine Cancer?
Recent reports from oncology conferences indicate that Lenvatinib showed significant antitumor activity and a favourable toxicity profile in progressive advanced NETs. This is the highest reported ORR with a targeted agent, confirmed by central radiology assessment in pancreatic NETs and Gastrointestinal (GI) NETs with promising progression free survival (PFS) in a pre-treated population; further evaluation is warranted.
Adverse events were mild to moderate in 90% of patients, the most frequent being fatigue, diarrhea and hypertension.
Lenvatinib showed the highest reported overall response rate (ORR) by central radiology assessment with a targeted agent in advanced NETs:
pNETs: 40.4% (95% CI 27.3-54.9),
GI NETs: 18.5% (95% CI 9.7-31.9.
Worth noting that Everolimus and Sunitinib were approved with ORRs much less than these figures.
Given the responses in comparison to other approved targeted agents, a phase 3 trial should be anticipated. Studies are “currently ongoing” and “further evaluation warranted”. I will keep this article live to provide updates.
New Trial using Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Neuroendocrine Tumors
Under ClinicalTrials.gov Identifier: NCT03950609, there is a trial being setup at MD Anderson in Texas USA. Use of a combo of Lenvatinib along with Everolimus (Afinitor) in treating patients with advanced, unresectable Neuroendocrine Tumors (the word ‘Carcinoid’ is used in the trial documentation).
Reference material used in the compilation of this article:
1. Annals of Oncology – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors: Results of the international phase II TALENT trial (GETNE 1509) 23 Oct 2018 – click here.
2. ESMO Congress 2018 – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors – click here
3. Prime Oncology Slide Show – click here (useful)
4. Clinical Trials Document NCT02678780 – click here
6. Clinical Trials Document NCT03950609 for the trial of combo treatment Lenvatinib and Everolimus. Click here. As at 15 May 2019, the trial was not recruiting but see document for contact details, quite often these documents can be behind in updating. Trial start date recorded as 30 June 2019.
In my article listing the somatostatin analogues and their drug delivery systems pipeline (click here), there has been a very interesting development in a product called Q-Sphera (was previously known as Q-Octreotide). In a press release, it was announced that an unnamed ‘pharma giant’ has signed a deal with Midatech Pharma Plc that will see it evaluate the latter’s Q-Sphera drug delivery platform. Later in Feb 2019, the pharma was identified as China Medical System Holdings Limited (based out of Hong Kong). Adding to the excitement behind this development, it was announced in Mar 2019 that the Spanish Government had conditionally approved a €6.6m loan that will be used to help commercialise this flagship drug.
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. An injection lasting 6 months sounds very exciting but I have no more detail on the feasibility or likelihood of such a change in frequency with Octreotide or Lanreotide but the press release does mention the possibility, i.e. “Q-Sphera allows drug compounds to be released into the body in a “highly controlled manner” over a prolonged period of time; potentially from a few days to up to six months.”
What’s the main differences?
The current trials are based on the use of Sandostatin LAR (Octreotide) using the Q-Sphera delivery system (previously known as Q-Octreotide). The key aspects of usability are reconstitution and needle size but there is also an inference that less frequent injections could be possible. A comparison of the trial output is as follows:
Reconstitution: For Sandostatin LAR (SLAR)™ the procedure to prepare the product for injection is a complex 30 step error prone process, taking up to 40 minutes and, once reconstituted, the product has to be given immediately to prevent solidifying and wastage of the injection. For MTD201™ Q-Octreotide the preparation process is a simple 5 – 7 minute procedure, after which the product is stable up to 2 hours. For the nurse preparing and giving the injection, the short and flexible process of MTD201™ has clear advantages over the all consuming SLAR process™.
Needle size: For SLAR, a large 19G needle is prescribed for the injection to prevent blockage, and often an even large 18G needle is required for successful injection. For MTD201 Q-Octreotide the precision microencapsulation technology means that a much smaller 21G needle can be used, and there are no blockages. Other Q-Sphera products use even finer needles as small as 27G. The importance of this is evident from the first-in-human phase I data where MTD201 had lower injection pain – 8% for MTD201 versus 25% for SLAR™, and much lower injection site
tenderness – 8% for MTD201 versus 83% for SLAR.
This is an exciting development and I will keep this article live with further information as I receive it.