Welcome to the Alexander Yule Consulting Blog

Thursday, 23 August 2018

mRNA vaccine technology: industry is getting the message



Can mRNA technology take vaccine
design and development into a
post-Jennerian era?
Vaccination is second only to the provision of drinking water with respect to global public health benefit, and while  still some way short of universal  vaccine coverage, hundreds of millions of children and adults are protected each year  from formerly lethal  infections.

Vaccine development has never lacked ingenuity, but progress has arguably been evolutionary rather than revolutionary. The concept of injecting selected components of infectious agents rather than whole microorganisms would not greatly surprise Edward Jenner.

Twenty-first century vaccinology faces major challenges. Conventional manufacturing and deployment capabilities are taxed by the annual challenge of shifting influenza strains [A single shot] or in mounting a large-scale response to  “swine ‘flu”-like global pandemics; shorter development cycles are needed to tackle outbreaks of Zika and Ebola viruses, or whatever emerging pathogens tomorrow might bring; no effective vaccines exist for infections common in both developed and emerging economies, including HIV, Chlamydia, cytomegalovirus and tuberculosis.

Revolutions in vaccinology have proved elusive. The prospect of replacing expensive and complex vaccine manufacture with the injection of chemically-synthesised strands of DNA encoding one or more vaccine components has been pursued since the 1990s. Although simple in concept, and despite efforts to optimise DNA delivery, low potency and unresolved safety issues have confined DNA vaccination to a few animal health products. Synthetic peptide vaccines designed to mimic and present a desirable selection of antigenic sequences, struggle to elicit robust immune responses and confer effective protection.

High profile buy-ins by vaccine industry majors suggest that a true technological revolution might, finally, be on the horizon. Protein synthesis requires DNA code to be rewritten in the forma of another nucleic acid, messenger RNA (“mRNA”), which is then translated by ribosomes, the cell’s protein factories. That the transcription of DNA can be circumvented through direct injection of mRNA to produce the  corresponding protein has been known for decades, but the instability of mRNA,  and the complication that unmodified mRNA is itself highly immunogenic,  led to the exploration of mRNA vaccination  being sidelined by less technically demanding DNA and recombinant protein approaches.

Across the board advances in ease of delivery, chemical modification to improve stability and increased duration of protein production in vivo are rapidly making mRNA vaccination a viable proposition.  Clinical trials are underway in both infectious disease indications including influenza, Zika virus and HIV infection (the latter exploring therapeutic rather than prophylactic potential), and in solid and haematological cancers. The majority of cancer studies exploit the properties of specialised antigen-presenting cells (dendritic cells) which can be readily isolated from patients, loaded with tumour antigen encoding mRNA and then returned by infusion [Dendritic cell vaccines: back to the future].

Recent licensing agreements between mRNA vaccine developers and leading vaccine companies add to a growing list of industrial, governmental and non-for-profit collaborations aimed at leveraging  the benefits that mRNA technology might bring to infectious disease vaccination: higher immunogenicity; inherent safety and rapid, low-cost, scalable manufacture.

Pfizer’s $425 million headline collaboration with mRNA vaccine developer BioNTech is focused on building better flu vaccines which can be manufactured quickly and cheaply. Another mRNA vaccine pioneer, Translate Bio, entered in an $805 million headline agreement with Sanofi Pasteur in June covering five undisclosed infectious disease agents with the option to expand the collaboration to other pathogens. CureVac AG has infectious disease mRNA vaccine partnerships with both Sanofi Pasteur and Johnson & Johnson, while GSK and Novartis are collaborating on mRNA vaccine development.

Early clinical data obtained using directly injected flu and rabies mRNA vaccines can best be described as “modestly encouraging” and it will be several years before which, if any, of the various flavours of mRNA technology  can claim to be a viable route to cost-effective, large scale vaccination,  and/or  serve as a solution to  problem pathogens. The picture may become clearer with a second Phase I study of Moderna Therapeutics’s flu vaccine candidate and a Zika virus Phase I study due to complete before year end.

Image credit: Wikipedia (public domain image)

Wednesday, 15 August 2018

Tumour-treating fields: moving beyond glioblastoma treatment


Tumour treating fields: more than just
fun with physics

Glioblastoma (GBM), that most aggressive of brain cancers, is notoriously resistant to treatment and a variety of leading edge approaches, including immunotherapy, virotherapy and gene therapy  are under investigation as means of extending survival by a meaningful amount.

One of the few treatments to have gained regulatory approval in the last decade is a medical device, Optune™, a custom-made, shower cap-like array of electrodes worn constantly on a shaven scalp, which is claimed to disrupt and slow tumour growth through the application of low intensity, alternating electrical current- so-called “tumour treating fields (TTFs).

I’m probably not alone in being reminded of 19th century quackery and the various galvanic treatments advocated by the beauty industry, but Optunes’s developer, NovoCure, a publicly traded US-based company, has managed to navigate the rocky path of clinical development to satisfy both American and European regulators, although approval was not without controversy.

Optune™ (then designated NovoTTF-100A) received FDA approval for the treatment of recurrent GBM in April 2011, on the back of clinical data that hinted at, rather than conclusively established, a degree of benefit comparable to chemotherapy, a comparison in itself made complex by differences in investigator choices of chemotherapy regimen. The FDA panel was accused of being overly influenced by pleas from GBM patients and their families during an open public hearing. Approval did come with the rider that NovoCure conduct a post-approval study to establish non-inferiority of TTF treatment to chemotherapy.

FDA approval for the treatment of newly-diagnosed GBM in conjunction with chemotherapy was granted in 2015 on the back of interim clinical data gathered from almost 700 GBM patients receiving radiotherapy and chemotherapy following surgery. The addition of TTF treatment increased the median time to progression, and overall survival, by almost three months over chemotherapy alone.

Neuro-oncologists remain divided on Optune™, being, with reason, critical of a pivotal clinical study that did not include sham treatment as a control, and the vagueness of the TTF mechanism of action, stated as involving “misalignment” of charged proteins critical to cell division. On the other hand, TTF in combination with chemotherapy is recommended in the authoritative National Comprehensive Cancer Center treatment guidelines. Despite the requirement of near constant wear (a minimum of 18 hours a day) and high treatment cost (around $20,000 per month with as yet limited reimbursement, Optune™ is currently in use by over 2,000 GBM patients in the US, Europe and Japan.

Recent data suggests that TTF may be of benefit in other forms of solid tumour. Two completed pilot studies of TTF in combination with standard chemotherapy in malignant mesothelioma and pancreatic cancer patients indicated improvements over historical progression-free survival and one year survival rates obtained with chemotherapy alone.

An apparent improvement in progression-free survival was observed in a small study conducted patients with recurrent ovarian cancer is more difficult to interpret due to difference in the treatment histories of individual patients and historical chemotherapy comparators.

Nonetheless, NovoCure is sponsoring three pivotal TTF studies in pancreatic cancer, non-small cell lung cancer (NSCLC) and in brain metastases arising from NSCLC, with final data from the latter study anticipated in 2020. TTF faces tougher competition in these indications from advances in precision chemotherapy and immuno-oncology, but should TTF even prove to be non-inferior to conventional therapies, it could find use in individuals intolerant of, or unresponsive to, other forms of cancer treatment.  Success may also serve to disarm TTF’s critics, as might elucidation of the putative mechanism(s) of action, along with the acid test of undertaking a  TTF study that includes a sham treatment control arm.

Image credit: Wikipedia(creative commons licence)

Tuesday, 7 August 2018

Holding back the years. Drug development takes on the ageing process.

Can the selective removal of old cells
 modify age-related conditions?
An oft-quoted Irish proverb advises “Do not resent growing old. Many are denied the privilege”.  Compared with the alternative, we should perhaps be more accepting of the physical (and cognitive) decline that time brings to all of us. But rising life expectancy has consequences, not least in healthcare costs: postponing or even reversing age-related decline has a societal importance far beyond personal vanity.

The impact of age is readily apparent at the cellular level, and a variety of alterations in the mechanisms which regulate normal cell division and function, including genetic stability; energy production, and cell-to-cell communication – collectively “cellular senescence” – have been identified. Ageing cells secrete a variety of pro-inflammatory proteins and are more abundant in failing hearts, joints and eyes. The relationship between senescence and organ dysfunction is misty, but animal studies in which an artificially-aged type of stem cell was transplanted into young mice resulted in a decrease in their physical capabilities and lifespan when compared to control animals.

Moreover, treatment with agents hypothesised to be capable of triggering programmed cell death (apoptosis) in senescent cells had a positive effect on physical function and lifespan in the stem cell-transplanted mice and on levels of secreted proteins associated with cellular senescence.

Drugs designed to selectively remove ageing cells- “senolytics”- are just beginning to make their way into clinical development. Unity Biotechnology’s strategy is the elimination of ageing cells in specific disease states. UBX0101 targets the interaction of the proteins MDM and p53, the latter being involved in cell-cycle arrest and apoptosis. A Phase I study is recruiting subjects with osteoarthritis, who will each receive a single intra-articular injection into the knee. A preclinical candidate, UBX1967 targets Bcl-2, another pro-apoptotic protein, and is intended for the treatment of age-related ophthalmological conditions.

Several other candidate senolytics are in preclinical evaluation. Two target the interaction between p53 and a DNA-binding protein: FOX04, a pro-apoptopic peptide (FOX04-DRI: Cleara Biotech), and an undisclosed small molecule (Antoxerene). Oisin Biotechnologies is developing a plasmid-based gene therapy to selectively ablate senescent cells.

Recently published results suggest that pharmaceutical intervention might be capable of bolstering ageing immune systems. RTB101, being developed by ResTORbio in partnership with Novartis has completed a Phase II study conducted in elderly volunteers. RTB101 is a combination of two drugs, both of which act on targets within a long-studied, multi-protein complex, “the mechanistic target of rapamycin” (TORC1), which is critical for the activation of protein translation.

The 264 study volunteers (65 years or over) received either the drug combination, one or other of the drugs or placebo tablets for six weeks and were then given a flu vaccination two weeks later. At 10-month follow-up, those receiving both drugs had the lowest rate of self-reported respiratory infection; blood tests indicated that the combination (but not single drug treatment) resulted in more complete TORC1 inhibition and that genes which control virus-fighting Type 1 interferon production were upregulated.  The authors postulated that other mechanisms might also contribute to this apparent reduction in “immunosenescence”.

Time to start planning for that 100th birthday celebration? Probably not (unless centenarians run in the family), but there’s a reasonable expectation that one or more of the current development strategies in, or close to, clinical study, will eventually lead to useful medications, although perhaps in specific age-related disease states rather than universal elixirs of youth.

Photo credit: Linnaea Mallette https://www.publicdomainpictures.net