I’ve posted extensively about this subject on Facebook early last year, focused on the ongoing Neuroendocrine Cancer trial in Uppsala Sweden. I wanted to incorporate this information into a single article ready for future news, whilst at the same time updating you on further developments in the field of Oncolytic Viruses for Neuroendocrine Cancer.
What exactly are Oncolytic Viruses?
Oncolytic Viruses infects and breaks down cancer cells but not normal cells. Oncolytic viruses can occur naturally or can be made in the laboratory by changing other viruses. Certain oncolytic viruses are being studied in the treatment of cancer. Some scientists say they are another type of immunotherapy whilst others say it’s too early to classify as such. The good news is that Neuroendocrine Cancer seems to figure in this work with two of these viruses apparently working on mice to date. Listed below are two active projects involving NETs, one directly and one indirectly.
The Uppsala Trial – AdVince
There has been no real update on what is happening since I posted last year. Hopefully, positive thinking indicates no news is good news. If anyone has anything more than what I’ve written or linked to in this article, please let me know. I’ll briefly described what’s happening and then you can link to my Facebook article if you need more background.
The trial is called AdVince after Vince Hamilton who funded it. Unfortunately he died before he saw any output but his forward thinking and benevolence lives on and might hopefully help NET patients in the longer term. It’s quite a small trial and is being conducted in Uppsala University Sweden, a famous European NET Centre of Excellence and where many people from across the world attend to take advantage of PRRT availability and experience and is home to famous NET specialist Kjell Öberg, MD, PhD, a professor of endocrine oncology.
A Swedish man (Jan-Erik Jannsson) was the first to get the virus to their cancer (NETs) using a genetically modified virus.
Unfortunately, I was given the news from a source close to the trial that Jan died last year of pneumonia. I have no evidence to suggest his death is in anyway connected to the trial but I’m told he was an ill man prior to the trial commencing. I have therefore dedicated this post to him. RIP Jan.
The initial data presented by the trial indicated that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET. The last I heard from the trial is that they are trying to recruit a further 12 patients to Phase IIa (the trial document allows for up to 36).
Read more background on my Facebook post here: Click here
The trial document on Clinical Trials Website: Click here
This is an oncolytic viral therapy currently in phase III and phase Ib/II clinical trials for use against primary liver (Hepatocellular Carcinoma) and Colorectal cancers, respectively. Pexa-Vec is a weakened (or attenuated) virus that is based on a vaccine used in the eradication of smallpox. The modified virus is injected directly into the cancer tumour, to grow inside these rapidly growing cancer cells and hopefully kill them.
According to the Colorectal Clinical Trial, the aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition i.e. they are testing it in conjunction with Immunotherapy drugs (Durvalumab, and a combination of Durvalumab and Tremelimumab).
The Hepatocellular Carcinoma trial (Phocus) is at Phase III where the sponsors are evaluating Pexa-Vec to determine if it can slow the progression of advanced liver cancer and improve quality of life.
The work is a collaboration forged between University of California San Francisco (UCSF) vascular researcher Donald McDonald, MD, PhD, and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.), a subsidiary of SillaJen, Inc., headquartered in Korea.
So what’s the Neuroendocrine Connection with Pexa-Vec?
As part of the research, McDonald’s lab injected it intravenously into mice genetically modified to develop pancreatic neuroendocrine cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction.
“At first small spots of the tumor were infected, but then most of the tumor started to die,” McDonald said. “We were able to show that while only about five percent of cells were infected by the virus, the number of cells that were killed was more than ten times higher. As far as I know, no one has ever done this kind of analysis.”
McDonald’s team wondered whether they could improve the efficacy of the virus by adding in a second drug called Sutent (sunitinib) that blocks blood vessel growth and alters immune function. The combination worked, with significantly greater tumor killing than with the virus alone. When the researchers examined the tumors, they discovered that the second drug acted by making the immune system hyper-alert to tumor proteins released by the viral infection, rather than through effects on tumor blood vessels.
Clearly it’s still early days in the Oncolytic Virus field with minimum breakthrough in terms of success on humans. In terms of the Neuroendocrine connection, it is exciting that two programmes are showing results (albeit in mice). We wait to hear from Uppsala on how the human test of AdVince is coming along. My agents are scanning the internet every day looking for any comment. If you want to learn more about Oncolytic Viruses in general – there’s a great summary here.
“Cured” – In cancer, this word can evoke a number of emotions. Interestingly, not all these emotions will be as positive as you might think. If you want to spark a heated debate on a Neuroendocrine Cancer patient forum, just mention that you’ve been cured.
I’ve been living with Neuroendocrine Cancer for 8 years so I must be cured, right? Unfortunately not as straightforward as this, and I’m guessing this is the case for many cancers. Doctors clearly need to be careful when saying the word “cured‘ even if there is a small likelihood that a cancer will recur. There’s plenty of ‘conservative’ and alternative terms that can be used, such as ‘stable’, ‘no evidence of disease (NED)’, ‘in remission’ or ‘complete response’. However, I don’t see the latter two much in Neuroendocrine disease circles.
So with all these ‘ifs’ and ‘buts’, what exactly is a cure?
Answering this question isn’t a simple case of ‘yes’ or ‘no’, because it depends on the way that the term ‘cancer’ is defined. It should actually be viewed as an umbrella term for a collection of hundreds of different diseases. They all share the fundamental characteristic of rogue cells growing out of control, but each type of cancer, and each person’s individual cancer, is unique and comes with its own set of challenges.
That’s why it’s very unlikely that there will be one single cure that can wipe out all cancers. That doesn’t mean individual cases of cancer can’t be cured. Many cancers in fact already can be. Scientists aren’t actually on the hunt for a ‘silver bullet’ against all cancers, Quite the opposite. The more scientists get to know each type of cancer inside and out, the greater the chance of finding new ways to tackle these diseases so that more people can survive. Thanks to a much deeper understanding of cell biology and genetics, there exist today a growing number of targeted therapies that have been designed at a molecular level to recognise particular features specific of cancer cells. Along with chemotherapy, surgery and radiotherapy, these treatments—used singly and in combination—have led to a slow, but steady, increase in survival rates. You can definitely count Neuroendocrine Cancer in that category.
Cancer is seen today less as a disease of specific organs, and more as one of molecular mechanisms caused by the mutation of specific genes. The implication of this shift in thinking is that the best treatment for, say, colorectal cancer may turn out to be designed and approved for use against tumors in an entirely different part of the body, such as the breast. We’re certainly seeing that with certain targeted therapies and more recently with Immunotherapy.
Surely a cure is more possible if cancer is diagnosed earlier?
To a certain extent this is true for many types of cancer, not just for NETs. In fact the same scientists did say ….”We detect those attacks when they’re still early, before the cancers have widely spread, at a time when they can still be cured simply by surgery or perhaps surgery and adjuvant therapy, which always works better on smaller tumors.”.
What about Neuroendocrine Tumors (NETs)? Clearly I’m not qualified to make such statements except to say that I am of the opinion that earlier diagnosis is better for any curative scenario. When you read NET guidelines (ENETS/NANETS etc), the word ‘cure’ and ‘curative’ is mentioned in relation to surgery. Bearing in mind that our most expert NET specialists are involved in the drafting of these guidelines, perhaps we should pause and think before dismissing these claims. Having checked ENETS publications, I can see it’s related to certain conditions and factors such as localisation within the organ, tumour size, good resection margins, and a suitable follow-up surveillance.
Clearly with advanced disease, the cancer becomes incurable but treatment for many being palliative to reduce tumor bulk and reduce any symptoms and/or syndrome effects. Despite this, the outlook for metastatic NETs at the lower grades is good. While we’re talking about palliative care, do not confuse this with end of life, that is only one end of the palliative spectrum. It can and is used at the earliest stage of cancer.
Immunotherapy will eventually cure cancer, right?
Immunotherapy will play a huge part in cancer treatment in the future, that we know. But to suggest that it’s a cure is probably overstating its current success. Neuroendocrine Cancer has not been forgotten – you can read more about Neuroendocrine Cancer and Immunotherapy here.
I heard the Oncolytic Virus at Uppsala is a cure for NETs?
There is currently no scientific evidence that the Oncolytic Virus (AdVince) can cure humans with Neuroendocrine Cancer. So far it has only been proven in destroying neuroendocrine tumours in mice. The Oncolytic Viruses developed in Uppsala are now being evaluated in phase I clinical trials for neuroendocrine cancer. If you’re not up to speed with this trial, read more here – Oncolytic Virus Uppsala
Isn’t prevention better than a cure?
This old adage is still relevant BUT latest thinking would indicate it is not applicable to all cancers. Scientists claim that 66% of cancer is simply a form of ‘bad luck’ and if the claim is accurate, it follows that many cancers are simply inevitable. The thinking suggests that random errors occurring during DNA replication in normal stem cells are a major contributing factor in cancer development confirming that “bad luck” explains a far greater number of cancers than do hereditary and environmental factors. This scientific thinking is a tad controversial so it’s worth remembering that even if, as this study suggests, most individual cancer mutations are due to random chance, the researchers also admit that the cancers they cause may still be preventable. It’s complex!
The newspapers are always talking about breakthroughs and cures for cancer?
Newspapers looking for a good headline will use words such as ‘cure’. Sadly, headlines are generally written by sub-editors who scan the article and look to find a ‘reader-oriented angle’ for the heading. They either can’t or don’t have time to understand what’s actually being said. Unfortunately this then leads to people sharing what is now a misleading article without a thought for the impact on those who are worried about the fact they have cancer and whether it can be cured or not. There’s also a lot of fake health news out there – check out my article series about the problems with the internet and ‘Miracle Cures’.
To cure, they must know the cause?
To a certain extent, that’s very accurate. Have you ever wondered what caused your NETs? I did ponder this question in an article here. The only known cause of NETs is currently the proportion of patients with heredity syndromes – see my article of Genetics and Neuroendocrine Cancer. Interestingly, the NET Research Foundation recently awarded funding to look at the causes of Small Intestine (SI) NETs (one of the most common types). A scientific collaboration between UCL, Dana-Farber Cancer Institute, UCSF Medical Centre and the UCL Cancer Institute / Royal Free Hospital London. The team’s approach has the potential to identify inherited, somatic (non-inherited) genetic, epigenetic and infectious causes of SI-NETs. The research is questioning whether SI-NETs are caused by DNA changes in later life or by aberrant genes inherited at birth; environmental influences or infectious agents – or is it a combination of all these factors? Very exciting. Read more here.
What would a cure mean to those living with NETs?
This is something that has crossed my mind, even though I don’t believe it will happen in my lifetime. I guess it would be good to get rid of the known remnant tumors left behind from my treatment (and any micrometastases currently not detectable). However, many NET patients are living with the consequences of cancer and its treatment, including surgery, chemotherapy, biological therapy, somatostatin analogues, radionuclide therapy, liver directed therapy, and others. Many of these effects would remain – let’s face it, a cure is not going to give me back bits of my small and large intestine, liver and an army of lymph nodes. So support for those living with NETs would need to remain despite a cure.
The emotional aspect of the word ‘cured’ seems to be an issue across many cancers and it’s certainly very controversial in NET circles. The world has still not cured the many cancers that exist. But over the next five to ten years the era of personalised medicine could see enormous progress in making cancer survivable. I think both doctors and patients need to take a pragmatic view on the ‘cured’ word and to end this article I wanted to share an interesting quote I found whilst researching.
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.
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 andLanreotide. 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.
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 Cushings 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. One entry on the previous version of this article has been removed as the company manufacturing it went into administration (Solid Dose Injections).
Somatostatin Analogues – New Delivery Methods in the Pipeline
New delivery system for Octreotide LAR – “Q-Octreotide” (MDT201)
Updated 20 Dec 2018.
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. Only a guess from me, but I suspect it’s either Novartis or Ipsen.
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.
Apparently, the delivery method (see picture) is smaller, faster, easier with the possibility of less frequent injections. More to follow when known but in the meantime, please see a useful Video about Q-Octreotide. Apologies for the use of the out of date term ‘carcinoid‘.
New Octreotide Delivery Method – Chiasma Capsule
Updated 14 Dec 2017. 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. You can check out the technology 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. The trial is currently only Acromegaly based and details are here.
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 very early days as the company does not anticipate the release of top line date from the Phase 3 trial until 2020.
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 studyto 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 in the Pipeline
New 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!