Algenpantucel-L immunotherapy by Newlink Genetics

 

This drug hi-lights the pancreatic cancer cells so that the immune system recognises them. For unknown reasons the immune system doesn’t attack those abnormal proteins produced by pancreatic cancer cells (normally the immune system would attack abnormal proteins). In the Phase 2 trial of 64 patients, improved overall survival (OS) was 55 months with 55% survival rate in the responder group (those with anti-CALR antibodies). In those without increased anti-CALR antibodies the OS was only 19%. In resected pancreatic cancer Newlink says that there has been no change in outcomes for over 3 decades. Median OS for resected pancreatic cancer is around 19 months. This Phase 3 trial involves up to 722 patients with surgically resected pancreatic cancer. The first interim analysis was on 3rd March 2014 at 222 events. The second interim analysis (at 333 events) was in May 2015 and the DSMC (data safety monitoring committee) recommended continuation without modification. The final analysis is at 422 events (planned 'if needed' - which it was). Perhaps this analysis will occur around May 2016, although the trial may produce results sooner.

 

Jakafi (Ruxolitinib) by Incyte

 

On the 21st Aug 2013 Incyte was up 33% (by $1.4bn or $9 per share on the day) due to results of a phase 2 (n=136) proof of concept trial with Capetitabine, where 6-month survival in the Jakafai arm was 42% vs 11% for placebo. Durable tumour responses were only observed in patients receiving Jakafi, and Jakafi patients achieved a significant improvement in body weight relative to placebo. The Jakafi combination with Capecitabine was generally well tolerated in this study. There was12% who discontinued therapy for an adverse event, compared with 20% who received Capecitabine alone. Incyte sees 'an opportunity to bring Jakafi forward into Phase III development in a population with no attractive treatment options.' They look forward 'to working with the FDA to define the core components of the Phase III program in pancreatic cancer as rapidly as possible, and in parallel, leveraging these results to expand their Jakafi and JAK1 inhibitor programs into additional solid tumour populations, including those that may benefit from selective JAK1 inhibition.' Extracts from company press releases. For the subgroup with elevated C-reactive protein Incyte released phase 2 results for second-line metastatic (advanced) pancreatic cancer on 2nd June 2014 showing 11% survival at 12 months versus 0 % in the group taking capecitabine alone. Median time to death was 83 days versus 55 days. In October 2014 Incyte said that there are two Phase 3 trials here with data from both expected in 2016. Comments on Incyte market reaction: Possibly fair to say half (750m) of the market capitalisation move in August 2013 was for pancreatic and the other half (750m) was for the opportunity in other solid tumours. It did move up further after this, so each could be close to a 1bn opportunity. The market appeared to ascribe a relatively high success rate to this drug, which gives a sense of the size of the opportunity in pancreatic in general, as well as the threat that Incyte might be to Celgene, who makes Abraxane for pancreatic cancer.

 

Evofosfamide (Evo) by Threshold targets cancer cells in low oxygen environments. Cancer cells may divide more slowly in low oxygen environments and metabolism differs hence the treatment for fast-dividing cells may not work. Initially on 21st February 2012 when the company revealed top-line results, Threshold went up 70%. On 18th November 2015 Threshold announced it entered into a co-promotion agreement for Evofosfamide with Merck so that Threshold can co-promote Evo in the US. A Phase 3 trial for Evofosfamide (previously TH-302) was initiated with Merck Germany following results from the randomized Phase 2b trial of Evofosfamide in patients with pancreatic cancer. Fast track designation was granted for the combo in May 2015. At the ESMO 2012 Congress (European Society for Medical Oncology) on 28 September 2012) updated pancreatic cancer results were presented confirming a significant improvement (p=0.008) in progression free survival (PFS) associated with 41% reduction of risk for disease progression or death for patients treated with evofosfamide 340 mg/m2. This represented a 2.4-month increase in median PFS for patients receiving evofosfamide. The 12-month overall survival rates were also in favor of the Evofosfamide treatment group compared with the control arm (38% vs 26% (p=0.13)). (Source: press release and slide presentation 29 Sep 2012.) Fast track was given for the Evofosfamide combo with doxorubicin in Nov 2014 in soft tissue sarcoma. Threshold has one other Phase 3 trial in soft tissue sarcoma after 2-year survival rates of 44% were shown. Other Phase 2 trials include Non-small Cell Lung Cancer, Non-squamous non-small cell lung cancer, and advanced melanoma, head & neck squamous cell carcinoma. Some are with the drug TH-4000. Phase 1/2 trials are underway in multiple myeloma, astrocytoma and RCC/HCC (according to their pipeline on the website). Finally there are Phase 1 trials of RCC/GIST/PNET and various solid tumours. There is also a diagnostic with various solid tumours in Phase 1. Responses of around 30% observed in advanced multiple myeloma patients, reported on 6th Dec 2014 and 30 May 2015, add weight to the case for Evofosfamide. It was interesting that objective responses were observed in heavily pretreated patients including prior treatment with proteasome inhibitors like bortezomib (Velcade®.) The combination regimen of TH-302 and proteasome inhibitor bortezomib (Velcade®) was to be investigated in the final stage of an ongoing trial according to the Threshold press release on 30th of May 2014.

 

Peptide Vaccines for RAS mutations by Targovax

 

Peptide Vaccines have failed in the past. Targovax maintained that their Phase 1/2 drug TG01 has longer peptides and so activates cells that are dependent on major histocompatibility complex 2 (MHC2,) not just MHC1. In Phase 1 they showed an immune response although serious adverse events were high. A small Phase 2 trial was initiated with interim read-outs due in the second half of 2015. Given the failure of past peptide vaccines, and a relatively high serious adverse event profile in Phase 1, probability of success is seen (by me) as low. In presentations Targovax associates itself with the Immuno-oncology drugs, which is a huge opportunity, but as yet does not extend to vaccines. In the drug's favour is an old and small trial conducted from 1994 to 2000 to investigate safety and immune response to RAS peptides. In this study 20% survived 120 months (10 years). This compares to a control group of only 7.7%. In addition follow-up showed median survival was 28 months instead of 20 months in the control.

 

RNA Interference Therapy by Dicerna

 

Dicerna is developing an RNA interference therapy meant to target the “undruggable” Myc gene, which is mutated in several forms of cancer. As of May 12, 2015, 26 patients were treated with DCR-MYC, with 18 patients evaluable for response. Anti-tumour activity was seen in two out of three patients with advanced, treatment refractory PNET (pancreatic neuroendocrine tumours). Specifically, evidence of a complete metabolic response based on imaging was seen in one patient, and a partial tumour response (34% reduction in tumour size) in another (press release 13 May 2015). This data was presented at ASCO 2015 on 1 June 2015. On 14 May 2015 Dicerna announced it is expanding its ongoing Phase 1 study of DCR-MYC in solid tumours, multiple myeloma, or lymphoma to include a cohort of patients with pancreatic neuroendocrine tumours (PNETs) following the early signs of clinical and metabolic response and tumour shrinkage in PNET patients. Dicerna says, despite recent improvements in treatment, advanced PNET remains an incurable disease. In the United States, says Dicerna, the incidence of PNET has increased approximately 80% from 2007-2012, with PNETs representing an estimated 5.7% of all pancreatic tumours (National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) Program 2015, research data 1973-2012.) There are only two approved targeted therapies (Sutent® and Afinitor®) for advanced PNET, both with modest response rates, and there are no approved treatments for patients who progress after standard therapies. Therefore there remains a clear unmet medical need for patients with advanced PNET. This was only a minor update from Dicerna’s ASCO abstract in mid-May, however, a more substantial update on Dicerna’s RNAi efforts in cancer is expected later in the year (source: Dicerna press release 14 May 2015 and Xconomy Asco round-up June 2nd 2015). About RNAi: Rather than targeting and binding to proteins to inhibit their activity, RNAi exerts its effects one step earlier in the process by targeting the mRNA, the instruction set that directs the building of the protein. In this manner, RNAi can potentially attack any target. Potential targets include disease-causing genes that are expressed exclusively inside cells and which lack good small-molecule binding pockets, putting them beyond the reach of traditional antibody and small-molecule technology. RNA interference (RNAi) is a biologic process in which certain double-stranded RNA molecules inhibit the expression of disease-causing genes by destroying the messenger RNAs (mRNAs) of those genes (Source: Dicerna press release.)

 

Vismodegib (GDC-0449) by Roche-Genentech and Curis

 

The first oral hedgehog signal inhibitor to be approved, in January 2012 (in basal cell carcinoma.) It was discovered in collaboration with Curis. It may be a possibility for pancreatic in future. Most of Curis's solid tumour programs are in only Phase 1, but the approval for basal cell carcinoma adds weight. The hedgehog signalling pathway is considered a valid and important target in tackling the problem of resistant cancer stem cells that hide in the stem cell niche (refer research on resistance in leukemia). The drug suppresses the hedgehog-signalling pathway by binding to the SMO. Normally this pathway is turned OFF, but in pancreatic stem cells the hedgehog-signalling pathway is turned ON. Comments on company: Curis market capitalisation was around $400m on 29 July 2015 with share price of c $3.10. The share price was up more than 100% in the year to end July 2015. All other cancer programs are preclinical and phase 1, but in basal cell carcinoma the drug is already marketed with Genentech. There is a phase 2 with Idiopathic Pulmonary Fibrosis (IPF) to be modified against new standard of care for IPF, Esbriet.)

 

Sapacitabine combined with Seliciclib (CDK inhibitor) both by Cyclacel.

 

These two drugs may work for tumours with the BRCA mutation and are in a Phase 1 combination trial for solid tumours (including pancreatic.) These are heavily pre-treated patients with advanced solid tumours. To date, 38 patients with incurable solid tumours and adequate organ function have been enrolled, 16 of which were found to be BRCA mutation carriers. Stable disease of 12 weeks or more was observed in eight additional patients, including two with BRCA-deficient, ovarian and breast cancers, lasting 64 weeks and 21 weeks, respectively. With Sapacitabine there is also a Phase 3 programme with Sapacitabine alone in AML in older patients. And a Phase 2 programme further behind, but for the larger indication, myelodysplastic syndrome (MDS.) The valuation of the company around the end of July 2015 was $22m, indicating the market does not hold much hope of success despite that trials are fairly advanced. A surprise on the upside is possible. Minnelide from the thunder god vine When tested on mice it was found to be “highly effective in reducing pancreatic tumour growth.” Thunder god vine grows natively in China, Japan and Korea, and has been a mainstay in traditional medicine for hundreds of years. The plant is a favourite for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In 2007 it was found to prevent kidney cysts in mice. It was poorly soluble in water therefore Minnelide, a water-soluble version of triptolide was made. Note that Myriocin was isolated from the culture broth a type of fungus (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine. This is now the very successful Gilenya used for Multiple Sclerosis. (Extracts from an article in the Register, 18 October 2012, Phil Muncaster. Also cited was Science Translational Medicine. "A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer" Rohit Chugh Veena Sangwan etc 17 Oct 2012.)

 

The measles virus

 

The measles virus tested against a variety of tumours in animal models where it shows a broad spectrum of activity against lymphoma, multiple myeloma, ovarian cancer, brain cancer and pancreatic cancer. Ovarian cancer was one of the first cancers where activity was shown. (Ref: ‘Measles virus for cancer therapy’ Stephen J. Russell, M.D., Ph.D. and Kah Whye Peng, Ph.D. 17 Feb 2014, Pubmed.)

 

Metformin, stem cells and exercise James Watson suggests the use of Metformin (used for stopping progression of type 2 diabetes and the world’s most effective anti type 2 diabetic weapon) may result in 20-40% lower incidence of major cancers such as pancreatic, lung and colon. Harvard research found Metformin preferentially kills cancerous mesenchymal stem cells, the most untreatable of all cancer cells. Watson suggests we should measure antioxidant levels in cancer stem cells exposed to metformin as soon as possible. He suggests that diabetes; dementias, cardiovascular disease, and some cancers are linked to a failure to generate sufficient biological oxidants, called reactive oxygen species (ROS). “The prevalent view of type 2 diabetes,” Dr. Watson says, “is that an excess of intracellular oxidation causes inflammation, which in turn kills cells in pancreatic tissue.” Proper function of those cells, it is well understood, is critical for the maintenance of normal blood glucose levels. Watson does not question that pancreatic tissue in people with Type 2 diabetes is indeed inflamed, but he does present a novel theory of why. (Ref: The Lancet March 1-7, 2014. Extracts from Cold Spring Harbour Laboratory 27 Feb 2014.) “The fundamental cause, I suggest, is a lack of biological oxidants, not an excess,” he says. Exercise seemed to Watson the key to the puzzle: what was it about exercise that served to benefit people with high blood sugar? There were important clues, he speculated, in the chemistry of oxidation and reduction reactions. The body’s cells cannot survive without making both oxidants and antioxidants. “There is a delicate balance” between the two, Watson observes. Physical exercise prompts the body to make large numbers of oxidants – molecules called reactive oxygen species, or ROS. In a cellular organ called the endoplasmic reticulum (ER), one such “species,” the oxidant hydrogen peroxide (H2O2), helps forge chemical bonds (disulfide bonds), which stabilize proteins as they fold. When there is not enough oxidation in the ER, Watson says, proteins emerge unfolded, and cannot function. This, he proposes, causes the inflammation that harms the pancreas, sometimes causing Type 2 diabetes. Hence, Watson suggests, exercise, which promotes oxidation, plausibly can have a beneficial effect on those with high blood sugar. Such benefit would be lessened if not abolished, he speculates, if such an individual consumed large quantities of antioxidants – just as athletes who take large quantities of antioxidant supplements do not seem to benefit or benefit less from their exertions. In short Watson is saying that we need oxidants or reactive oxygen species (ROS) – in order to ensure apoptosis (death) in cancer cells, therefore we do not always need anti-oxidants since they can limit ROS. See more on James Watson at the beginning of the book on stem cells.

 

MEDI4736 Plus Treme combination from Astrazeneca On a press release on the 2nd June 2015 at ASCO AstraZeneca said it is exploring the potential clinical benefit of the combination of MEDI4736 and tremelimumab in additional tumour types including squamous cell carcinoma of the head and neck (SCCHN), and announced new tumour types, including gastric, bladder cancer and pancreatic cancer, with the aim of changing the treatment paradigm for patients with a chemotherapy-free regimen.

 

Y-clivatuzumab tetraxetan by Immunomedics

 

In the Immunomedics August 2015 presentation they showed Y-clivatuzumab tetraxetan + gemcitabine (Arm A) in Phase 1b in refractory (advanced) pancreatic cancer after 2 or more therapies showed 10% of patients were still alive after 12 months (0% were alive in the Y-Cliv monotherapy arm).

 

Questions related to Pancreatic Cancer

 

Are cancer cells produced because the body is not receiving sufficient oxygen? Does the body produce cells that grow and survive in a low oxygen environment? Will low-oxygen cancer cells stop growing if we have sufficient oxygen? If we receive sufficient oxygen, cells in the stem cell niche may also have to stop growing and we may need to wait for this to occur. If they have already been grown or seeded, we may need to wait longer for new cancer stem cells to stop growing.

 

Could blood clots found in pancreatic cancer be linked to insufficient oxygen? Some malignant cancers (gland-based) of the pancreas and lung show a tendency to form blood clots, for reasons that are not understood. Could blood clots found in pancreatic cancer be linked to infection? Some malignant cancers (gland-based) of the pancreas and lung show a tendency to form blood clots, for reasons that are not understood.

 

Can genetics and molecular analysis unravel which mechanisms cancer cells use to resist treatment? For instance bacteria put up a cell wall, which remain even after harmful characters have been destroyed. Can we identify which genetic material enables bacteria to regrow the cell wall potentially contributing to their resistance to treatment? Does cancer use a similar resistance mechanism? What are the possible viral and bacterial causes in pancreatic cancer? There is a link between viruses and bacteria, because a virus offer lowers the immune system so that bacteria can settle in (this can then trigger an exacerbation, in lung disease for instance).

 

Could anti-virals be given to chronic obstructive pulmonary disease (COPD) patients in order to prevent viral triggers of exacerbations? Pneumonia is a frequent infection in COPD that might be triggered by a virus lowering the immune system. Since this can be fatal in COPD anti-virals may be justifed. Or can we strengthen the immune system? Will vaccines help?

 

When pancreatic cancer has been resected or taken out, it may be worthwhile giving a vaccine. Targovax in Norway quoted an intriguing study in which 20% of patients given a vaccine in a small study were still alive after 10 yrs (in the "comparator" group none were alive.) Below see an extract from this study: "Strikingly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of nonvaccinated patients treated in the same period. Three patients mounted a memory response up to 9 years after vaccination. The present observation of long-term immune response together with 10-year survival following surgical resection indicates that K-ras vaccination may consolidate the effect of surgery and represent an adjuvant treatment option for the future." Refer to Targovax to see more on their vaccines. (Source: Pubmed abstract or alternatively see the full study on Wiley online library: - "Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras." Synne Wedén, Marianne Klemp et al. International Journal of Cancer 128. Article first published online: 12 May 2010.)