Innate Possibilities

Might modulation of the innate immune
 response turn up the heat on "cold" tumours?

It's been (another) good year for cancer immunotherapy, marked by approval of the first autologous T cell therapies for otherwise untreatable haematological cancers, additional label indications for immune checkpoint inhibitors and even glimmers of hope around personalized cancer vaccines.

All of these advances exploit adaptive immunity- the body's capacity to recognise tumours (and invading pathogens) as "not self" and to programme the immune system to bring exquisitely specific antibodies and effector cells into the attack. A downside to this biological sophistication is that mounting an adaptive immune response takes time and can be deliberately misdirected. We rely on a more primitive and less selective innate immune response as a first defence against rapidly multiplying bacteria and viruses and to prime adaptive immunity.

Bringing the innate immune response into play as a means of increasing the efficacy of cancer immunotherapy is attractive. Non-responsiveness to immune checkpoint inhibitor therapy appears to correlate with tumour inflammation, rather than with immune checkpoint expression or the degree of tumour mutation. Turning “cold” (uninflamed) tumours “hot” (inflamed) might offer patients initially refractory to immunotherapy an additional treatment option.

A signature of tumour inflammation is the presence of IFN-β, a potent cytokine, the production of which is  triggered by STING ("stimulator of interferon genes") in response to molecules ("cyclic dinucleotides"- CDNs) that signal the presence of pathogen or host double-stranded DNA. CDNs produced in response to double-stranded DNA leaking from cancer cells are capable of activating STING and triggering IFN-β production, which in turn, stimulates cancer antigen-specific T cells.

STING activation has attracted the attention of Merck and BMS, rivals in the immune checkpoint inhibitor space. Two investigational STING activators (MK-1454: Merck and ADU-S100: Aduro Biotech/Novartis) are in early clinical evaluation. Both are synthetic CDNs, designed to be more potent than "natural" CDNs but, due to their chemistry, must be delivered directly into the tumour. Spring Bank Pharmaceuticals, BMS (through the acquisition of IFM Therapeutics), iTeos Therapeutics, Invivogen and GSK are also pursuing intratumoral CDN candidates, while Nimbus Therapeutics and CuraDev Pharma are developing small molecules that may allow oral dosing.

Other components of the innate immune system are of interest to immunotherapy developers.  "Toll-like receptors" (TLRs) recognise an array of bacterial and viral debris and are known to be expressed by various cancers. Past clinical studies with TLR-directed agents have been largely disappointing, although a TLR9 agonist, IMO-2125, developed by Idera Pharmaceuticals is under evaluation in combination with immune checkpoint inhibitors in melanoma patients who have previously failed immunotherapy.

"RIG 1 (retinoic acid inducible gene)-like receptors" (RLRs) sense viral infection and can eliminate infected cells, opening the possibility that RLR activation might be exploited to directly kill cancers. RLRs are largely activated by RNA and while perhaps not easily druggable, they offer a promising enough prospect for Merck to have acquired Rigontec, a pioneer in RLR research, for a headline figure of over $500 million.

Inflammasomes are multiprotein complexes of signalling molecules and enzymes that initiate and maintain inflammatory processes in infection and autoimmune disease. Inflammasomes are activated by various "NOD-like receptors" (NLRs), the most widely studied being NLRP3, a trigger sensitive to a wide range of microbial and "damage-associated" molecules, also environmental irritants (silica, asbestos) and amyloid-β, the hallmark protein of Alzheimer's disease. NLRP3 activation may prove to be a practical means of warming up cold tumours and BMS has ambitions to begin clinical studies with an NLRP3 activator in the next 12 months.

Inflammasome activation may not be without risk, being associated with both tumour promotion and suppression in different cancers. Certain tumour-expressed TLRs appears to contribute to development of a benign tumour microenvironment and promotion of metastasis and the STING signalling pathway can contribute to tumour development.  

"Pro-inflammatory" drug development faces the general challenge of achieving an effective degree of tumour inflammation without provoking potentially life-threatening "cytokine storms" or autoimmune adverse events. A better understanding of how the innate immune response might be modulated through the targeting of STING, TLRs, RLRs, inflammasomes or other elements could conceivably lead to novel or improved treatments for a spectrum of conditions that have chronic inflammation at the heart of their pathology. 

Photo credit: Rawich at FreeDigitalPhotos.net

Yet more on bugs and cancer

T-cells (red) on the attack

A Research Highlights piece in December’s Nature Reviews Cancer reports on another intriguing aspect of the interplay between our immune systems and the bugs we carry, namely how gut flora might influence the effectiveness of cancer immunotherapy.

Two international research groups set out to determine  whether the composition of the gut microbiome might influence the response to immunotherapy  directed against  PD-1, a so-called “immune checkpoint “ expressed by activated T cells and macrophages and which is exploited by cancer cells to switch off immune attack. Antibody-mediated blockade of the interaction between PD-1 and its ligand, PD-L1 can restore the anti-cancer response. The anti-PD-1 antibodies pembrolizumab and nivolumab (Opdivo® and Keytruda®, respectively) have proved their worth in the treatment of metastatic melanoma and a variety of other solid tumours.

Genetic analysis of faecal bacteria collected from cancer patients before and after anti-PD-1 immunotherapy found a correlation between gut bacteria diversity and the duration of progression-free survival in cancer patient after treatment.

A collaboration between US and French researchers found differences in the abundance of certain gut bacteria, with Faecalibacterium being enriched in melanoma patients responsive to anti‑PD1 therapy: Bacteroidales was enriched in those patients not responsive to immunotherapy. Differences were also found between responders and non-responders in regards to bacterial metabolism and the composition of immune cells found in the tumour microenvironment. Tumour-infiltrating “killer” T cells were more likely to be found in patients carrying an abundance of Faecalibacterium, while  immunosuppresive cells were more common in individuals carrying abundant Bacteroidales.

Another (again, predominantly American and French) research group found that the abundance of the gut bacterium Akkermansia muciniphila in non-small cell lung cancer and renal cancer patients correlated with a positive response to anti-PD-1 immunotherapy.

Both groups looked for possible mechanistic links between gut bacteria abundance and treatment response. When patient-derived gut bacteria were transplanted into germ-free mice, a variety of favourable effects on tumour growth and immune response were observed, including higher numbers of killer T-cells  and other, immune effector cells, along with changes in the expression of  T- cell receptors for key immune signalling molecules (“chemokines”).

The response to immunotherapy is difficult to predict and involves a variety of tumour factors (PD-L1 expression, tumour burden, degree of mutation) and host factors (immune system genetic makeup, T cell infiltration of the tumour). Analysis of the gut microbiome is unlikely to improve prediction of response, but preservation or manipulation of the gut microbiome through avoidance of antibiotic treatment prior to immunotherapy, or probiotic treatment to encourage “good” bacteria could conceivably translate into better and more sustainable response rates for at least some individuals.  

Photo credit : Rita Elena Serda.  National Cancer Institute \ Duncan Comprehensive Cancer Center at Baylor College of Medicine

More on bugs and cancer

A publication in the December issue of Cancer Research points towards another complicated relationship between bacteria and cancer risk.

A group headed by researchers at the Perlmutter Cancer Center (NYU Langone) looked at data gathered from more than 120,000 subjects already enrolled in an ongoing NCI-sponsored study looking at the link between nutrition and certain cancers.

The presence of a mouth-dwelling bacterium, Tannerella forsythia,  was associated with a 21% increase in the risk of oesophageal adenocarcinoma after adjusting for other known risk factors including smoking, drinking and body mass index.

In contrast, the presence of various Streptococcus and Neisseria species was associated with a 24% decrease in cancer risk. The presence of Porphyromonas gingivalis, a bacterium associated with gum disease, appeared to correlate with a higher risk of another form oesophageal cancer, oesophageal squamous cell carcinoma.

How mouth bacteria influence oesophageal cancer risk is not clear. An association between poor oral health and a higher risk of oesophageal cancer has been suggested in epidemiological studies. Neisseria are capable of partially detoxifying tobacco smoke, with lower numbers of Neisseria found in the mouths of smokers than in non-smokers.  Bacterial metabolism analysis hinted at an increase in oesophageal adenocarcinoma risk associated with some pathways but a lower risk with others. Certain metabolites produced by Neisseria sp correlated with the observed protective effect.

While cause and effect remains elusive, it’s possible that analysis of oral flora might eventually serve as a useful marker for oesophageal cancer risk and that manipulation of the oral flora could reduce occurrence in those already at higher risk through other behaviours.  What’s clear is that “local” microbiomes, whether mouth or gut, can have a profound effect on distant organs.

Bugs and cancer? The plot thickens...

An item from the New York Times gives me the chance to write about two great interests in the same blog piece: bacteria (once a microbiologist, always a microbiologist) and cancer.

Fusobacterium nucleatum, an
accomplice of colorectal cancer

That bacterial infection might cause or promote cancer was debated for most of the 20^th century, but with little solid evidence emerging to support the notions. During the 1980s, Barry Marshall and Robin Warren (the former famously swigging down a flask of culture broth to prove his hypothesis) established that Helicobacter pylori, a common corkscrew-shaped found in the stomach, was an undisputable cause of gastric inflammation and ulcers.

Epidemiological studies involving British, American and Japanese subjects confirmed that H.pylori carriage was indeed associated with an almost four-fold increase in the likelihood of developing gastric cancer and resulted in the WHO designating H.pylori as a Class I carcinogen.

Continuing research has established that the relationship between  H.pylori and cancer is not a simple one of cause and effect,  with H.pylori infection being a factor in some, but not all, forms of stomach cancer and that H.pylori  strains expressing a particular cytotoxin, “CagA”,  are more strongly associated with an elevated risk of cancer than are non-producing strains. Perversely, H.pylori infection appears to be associated with a lower risk of oesophageal cancer.

A more recently uncovered “smoking gun” is the presence of Fusobacterium nucleatum, a common mouth-dweller, found in higher numbers in around half of colorectal tumours than in the surrounding tissue. F.nucleatum- induced inflammation is cited as a plausible contributor to CRC initiation and progression.

But, as with the Helicobacter story, there is no clear-cut cause and effect between infection and cancer. Bacterial species are rarely solitary and the inhabitants of the local milieu or “microbiome” may be more important with respect to cancer initiation and/or progression than the presence of F.nucleatum alone.

CRC may spread to other organs and give rise to tumours in the liver. According to a recent Science publication, if F.nucleatum and its microbiome buddies are present in the original tumour, then they can accompany the metastasizing cancer and pitch up in the liver. CRC dwelling F.nucleatum remained associated with tumours even after their transplantation into mice. Moreover, dosing of tumour-bearing mice with an F.nucleatum-killing antibiotic slowed tumour growth.

Does this make a case for antibiotic therapy or vaccine development to reduce CRC rates? Well, not yet. Antibiotics therapy tends to ablate both the good and bad and, as is hinted at in immuno-oncology studies, certain gut bacteria might positively influence anti-cancer immune responses. And not all F.nucleatum strains might be bad guys. However, it’s feasible that getting a better handle on the mechanism(s) involved in the bacterial promotion of cancer might identify new interventions to improve outcomes or recurrence rates.

Photo credit: CDC Public Image Library

(Almost) all quiet on the sepsis front

UC Riverside researchers
Meera Nair and Jessica Jang

Sepsis, a massive systemic immune response to infection leading to multiple organ damage and, more often than not, death, has proved resistant to drug development efforts over the last four decades. 

Spectacular late stage clinical study failures in the early 90s of drug candidates developed by some of the then brightest stars of the sector, including Centocor, Xoma, Synergen and Chiron led to sepsis treatment development being tagged as a "biotech graveyard".

Large  pharmaceutical companies have fared no better in sepsis therapy development and commercialisation. Eli Lilly's Xigris®, the first (and only) sepsis treatment to receive regulatory approval was pulled in 2011 after a decade in the market as growing clinical evidence indicated that it was of no significant benefit. In the following year, AstraZeneca abandoned development of the BTG Group's CytoFab®. More recently, Eritoran®, a synthetic lipid developed by Eisai failed to show sufficient efficacy in a pivotal clinical study.

Historically, sepsis treatment development attempts were aimed at blocking events which initiate the inflammatory cascade, such as the binding of bacterial lipid to "toll like" receptors which trigger our first line of defence, the innate immune system, or on neutralizing the cytokines (tumour-necrosis factor, interleukin-1) that ramp up the inflammatory response. Sepsis involves a variety of runaway biological processes, including vascular leakage and activation of the complement and coagulation systems, and, with hindsight, strategies that target any single contributing factor are not likely to element of the storm is likely to have only a minimal effect.

Sepsis remains a major problem, with a mortality rate somewhere in the 30% to 50% range and is the cause of around 37,000 deaths each year in the UK alone. It goes without saying that better interventions are required, but the combination of biological complexity, the challenges in designing and executing meaningful clinical studies and a history of high profile failures means that the pipeline is slender.

Work on new therapies is more or less confined to a handful of small-cap biopharmas, although several once promising although candidates with novel modes of action, such as Altor Biosciences’s anti-tissue factor antibody ALT-836 and InflaRx's anti-complement antibody, IFX-1, appear to have been quietly ditched. AM Pharma is currently evaluating a recombinant version of alkaline phosphatase in sepsis patient with acute kidney failure, although the reason for the apparent protective effect of the enzyme remains a mystery.

The lack of anything newsworthy in the sepsis field made two recent articles stand out. Critical Pressure Ltd, a UK start-up received funds to evaluate a small molecule selective inhibitor of nitric oxide (NO) synthesis. Nitric oxide is a potent vasodilator and contributes to vascular collapse. At the same time, NO also protects against the effects of infection, chiefly through macrophage and cardiomyocyte activation. Critical Pressure is banking on the selectivity of its candidate enzyme inhibitor to reduce the unwanted consequence of NO production.

A research paper from a group at the University of California (Riverside) suggests that resistin, a hormone associated with insulin resistance in diabetes and the accumulation of “bad” (low-density lipoprotein) cholesterol might actually have a protective effect in sepsis through binding to a toll-like receptor and preventing cytokine release. Resistin was shown to provide 100% protection from mortality in an animal model of sepsis. A synthetic analogue of resistin, “Retn N-Pep” is undergoing laboratory development as a possible sepsis treatment.

Photo credit:  Ross French, UC Riverside.

Roche’s lampalizumab disappoints- is the "dry" AMD pipeline about to dry up?

Ageing has many biological consequences, ranging from the merely annoying through to conditions that profoundly affect everyday living. The eye is a complex organ and susceptible to a variety of age-related conditions, including cataract formation, glaucoma, dry eye syndrome and loss of retinal function. 

Age-related macular degeneration (AMD) is a progressive loss of function of the macula, the central portion of the retina responsible for precise vision.  The condition starts with the accumulation of fat and protein waste- "drusen" in the subretinal space, causing a loss of essential pigmentation in the retina. The majority of individuals with AMD experience a slow decline in visual acuity- "dry" AMD, but around 10-20% experience acute and catastrophic loss of vision through the formation of new, leaky blood vessels below the retina- neovascular or "wet" AMD.

New blood vessel formation in AMD (and in several types of solid tumours) is stimulated by vascular endothelial growth factor (VEGF). Anti-VEGF drugs have proved reasonably effective over the last decade in slowing the progress of wet AMD when injected into the eye . A variety of other agents targeting VEGF are in clinical development, including brolucizumab (Novartis); RG7716 (Genentech) and abicipar (Allergan).

Unfortunately, no single point of attack is established for dry AMD. Nutritional supplements can slow AMD progression, presumably through reducing oxidative stress (diet, smoking and cardiovascular disease are all implicated as risk factors for drusen formation), but, being an inflammatory condition, a variety of immune mechanisms are likely to contribute to macular damage. 

The alternative complement pathway serves as a first line defence against infection and kicks in before the body mounts a specific immune response. On the back of a strong correlation between AMD and genetic changes in complement regulatory proteins, targeting various complement proteins provides a rational basis for AMD therapy development.

A clinical study with eculizumab, an antibody approved for another complement-mediated condition, failed to show benefit but some progress has been made with other complement-directed agents. Until last week, lampalizumab (Roche) was widely regarded as the first drug to be approved for late-stage dry AMD; unfortunately, treatment for 48 weeks did not show any improvement over placebo. A second Phase III study in ongoing but further development (and a marketing approval submission) will depend on establishing beneficial effects on visual acuity. 

Lampalizumab acts by targeting complement factor D, while other investigational agents are specific for other complement proteins. Opthotech's Zimura (a non-antibody drug) binds to C5, as does tesidolumab (Novartis) while APL-2 (Apellis Pharmaceuticals) targets C3. These other complement directed therapies might yet prove to be effective in AMD, although the decline in Opthotech's share price suggests investor nervousness over the approach.

Discontinuation of lampalizumab development could effectively dry up the AMD clinical (and pre-clinical) pipeline should it take the other complement inhibitors with it.  A few AMD studies with repurposed drugs are ongoing and stem cell implantation might eventually prove capable of restoring some degree of vision to a handful of fortunate individuals, but there is little in the late stage development pipeline that offers any cheer for the three million or so individuals in Europe and the US handicapped by late-stage AMD. 

A new generation of AMD candidates awaits better understanding of the retinal microenvironment in disease, particularly an unravelling of the role of macrophages in the inflammatory process, alongside the contribution made by genetic and environmental factors.   

Photo credit: National Eye Institute, National Institutes of Health

Safety concerns put the brakes on checkpoint inhibitor studies in multiple myeloma

While CAR-T therapy development has regularly been in the spotlight due to an association with lethal adverse events (AEs), immune checkpoint inhibitor therapies, with the exception of some combinations, have so far proved to be comparatively benign.

Severe AEs do occur with current PD-1/PD-L1 antibodies, most commonly with the CTLA-4 antibody ipilimumab (Yervoy®). Immune checkpoint inhibitors act by restoring the immune system’s ability to identify tumours as being “not self”: since the same mechanisms also serve to prevent unwanted immune responses to normal tissue, it’s not surprising that checkpoint inhibitor therapy can result in autoimmune-disease like effects involving the gut, liver, skin and thyroid gland. Severe immune related AEs can require intensive management with steroid and/or other anti-inflammatories, but fortunately occur in a minority of patients.

Studies leading to the approval of checkpoint inhibitors in melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer and bladder cancer progressed without the red flag of safety concerns, so it’s all the more surprising that a slew of multiple myeloma studies involving checkpoint inhibitor combinations have been brought to a halt by the FDA.

Three Merck studies involving anti-PD-L1 (Keytruda®: pembrolizumab) in combination with drugs already used in multiple myeloma treatment (pomalidomide or lenalidomide with dexamethasone) were placed on clinical hold as of early July following a higher number of deaths in the treatment arms. The FDA have since halted enrolment (although not dosing of enrolled subjects in similar studies involving combination with Bristol Myer Squibb’s anti-PD-1 checkpoint inhibitor, Opdivo® (nivolumab) plus either of two antibodies approved for multiple myeloma treatment.

The FDA’s caution also extend to six combination studies sponsored by Celgene, all involving AstraZeneca’s anti-PD-L1 antibody, Infinzi® (durvalumab),with one study being placed on full hold.

Lenalidomide (Revlimid®) and pomalidomide (Pomalyst®), chemical descendant of thalidomide, are approved for the treatment of multiple myeloma.  Lenalidomide and pomalidomide are potent immunomodulators but also act through a variety of other, non-immune mechanisms. It’s tempting to consider excessive up (or down) regulation of cytokines as a likely  smoking gun, but the combination of effects on tumour/immune system interaction with PD-1/PD-L1 may prove hard to unravel.

No approved cancer treatment is effective (or necessarily safe) for all tumour types: clinical experience with checkpoint inhibitors is still at a early stage, so perhaps safety (or efficacy) issues arising with one or more form of malignancy and/or with a number of the various checkpoint inhibitor combinations under study should perhaps not be unexpected and will not derail the advance of immuno-oncology.

The current generation of checkpoint inhibitors might never make for better multiple myeloma treatment but each setback represents an opportunity to gain better insight into what might work, and what’s to be avoided in the ongoing development and deployment of cancer immunotherapy.

Image courtesy of sheelamohan at FreeDigitalPhotos.net

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First flagged in:  UPDATED: Safety fears spur FDA to pause checkpoint combo studies by Bristol-Myers, Celgene. John Carroll. Endpoints News, online 7^th September 2017. http://tinyurl.com/ybekxrzl

Bristol-Myers Squibb Provides an Update on Three Opdivo-based Combination Clinical Studies in Multiple Myeloma. Company press release online 6^th September 2017. http://tinyurl.com/y9wv3h3g

Merck Provides Further Update on Three Multiple Myeloma Studies Evaluating KEYTRUDA® (pembrolizumab) in Combination with Pomalidomide or Lenalidomide. Company press release online 5^th July 2017. http://tinyurl.com/ya9z2tfs

Parkinson's disease drug development: moving beyond L-DOPA

False colour MRI scan. 

It's been several years since I was engaged in licensing a treatment for Parkinson's disease (PD), but I recall being struck by the heavy reliance on just a handful of drugs and how empty the PD development pipeline then was. 

In this, the two hundredth year since James Parkinson first described the clinical features of the condition, it's good to see the emergence of potential new treatment options and signs of increasing big pharma involvement in PD drug development.

Like Alzheimer's disease, PD is age-related, with prevalence increasing some 20-fold between ages 60 and 80 in Europe and the US (the rise in PD cases is significantly greater in men than in women, prompting speculation on possible environmental causes of PD). And, again in common with Alzheimer's disease, the future burden of PD care constitutes a demographic time bomb.

The discovery that PD is associated with low levels of dopamine, a key neurotransmitter, resulted in the introduction of l-3,4-dihydroxyphenylanine ("L-DOPA"), a precursor of dopamine, in the 1960s. L-DOPA remains the cornerstone of PD treatment but at a price: long term use results in "off" effects, manifesting as stiff or slow movement and an increased frequency of involuntary movement ("dyskinesia"). Less commonly, L-DOPA can result in episodes of impulsive/compulsive behaviours. Additional medications are often needed to alleviate nausea and other L-DOPA side effects. The other main classes of PD drugs either substitute for dopamine or act by slowing down the biochemical breakdown of dopamine or of L-DOPA. 

PD drug development efforts have produced a variety of useful formulations and add-ons to increase and prolong the usefulness life of L-DOPA treatment but new therapies are needed to address the spectrum of PD non-motor and motor symptoms and to halt,  or at least substantially slow, disease progression. The first treatment to address L-DOPA associated dyskinesia (Gocovri™: Adamas Pharmaceuticals) has received FDA approval, although the FDA were less enthusiastic about accepting a marketing approval submission for Inbrija® (Acorda), an inhaled L-DOPA formulation that may reduce “off" symptoms.

As might be expected in a condition that manifests itself as a variety of not obviously connected symptoms, the pathophysiology of PD involves multiple mechanisms, a better understanding of which could lead to new classes of therapeutics.

The recently announced collaboration between AstraZeneca and Takeda is of note as it signals further big pharma involvement in PD drug development.  Efforts will be focused on a widely touted drug target, alpha-synuclein, a protein found in Lewy bodies- aggregates which accumulate in parts of the brain in PD patients and which may be central in spreading PD related  changes throughout the nervous system. AstraZeneca has also entered into an alliance with Berg Health to apply artificial intelligence to identify novel druggable targets in PD and other neurological diseases.

It's hoped that preventing  alpha-synuclein folding and aggregation might slow or even reverse PD progression. Trials of other anti-alpha-synuclein antibodies (developed by Prothena/Roche and Biogen) are underway, as is a study of a vaccine designed by an Austrian biotech, AffiRis AG, to elicit antibodies against alpha-synuclein. Neuropore, in partnership with UCB is evaluating an orally administered small molecule drug candidate, NPT200-11, which may prevent the accumulation of alpha-synuclein. Another alpha-synuclein modulating small molecule, PBT434 (Prana Biotechnology) has shown promise in animal studies.

The observation made around 40 years ago that certain synthetic opioids resulted in PD like symptoms in drug addicts suggested that mitochondrial defects might  be involved in PD, although no compelling case for a genetic basis for mitochondrial involvement  can be made. Edison Pharma believe that vatiquinone, an antioxidant which is in clinical development for inherited mitrochondrial disease may also have a role in PD treatment, with Phase II study results being announced last year.

Another candidate with a novel mode of action is Foliglurax (Prexton Therapeutics), which acts by modulating the metabotropic glutamate receptor 4 (mGluR4) to restore the imbalance in neurotransmitters believed to cause PD dyskinesia.  A recently published study in which exenatide, an injected synthetic peptide drug used in the treatment of Type 2 diabetes, brought about improvements in PD patients adds weight to the hypothesis that reduced insulin signalling in the brain plays a role in PD and other neurodegenerative conditions.

PD drug development has a historically high failure rate but, between new targets and improved clinical study design, perhaps aided by validated PD biomarkers, it’s reasonable to expect an expansion of PD treatment options over the next ten years, with a realistic prospect of being able to slow disease progression in at least some individuals.

Photo credit: NIH Image Bank

Athauda D et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 2017; published online 3rd August 2017. http://dx.doi.org/10.1016/S0140-6736(17)31585-4.

RNAi drug development: Twilight or a new dawn?

A recent conversation brought to mind a blog piece I wrote back in early 2011 about the exit of big pharma, en masse, from interfering RNA (RNAi) drug development, with the canning of internal development or strategic partnerships, due in part to the technical challenge of delivering effective quantities of small oligonucleotides and the availability of less rocky paths to targeted therapies, both biologic and small molecule.

RNAi works by throwing a spanner into the cellular mechanism which translates the information encoded by DNA into proteins: small, double stranded pieces of synthetic RNA (siRNAs) bind to messenger RNA to dial down expression of disease-related proteins. Although simple in concept,successful RNAi drug development involves selection of the right mRNA binding sequence, chemical toughening of the double-stranded oligonucleotide so that it resists degradation, and efficient delivery to the target cell. The latter has proven to be the most difficult element and the early promise of lipid-based oligonucelotide delivery has long since evaporated. High hopes are now pinned on carbohydrate conjugate delivery ("GalNac" conjugation), which offers an easier route to liver and other cell types and more patient-friendly dosing. 

Fast forwarding from 2011 to the second half of 2017, has enthusiasm for RNAi been rekindled? Well, sort of, although with reservations. Big pharma has, in the main, not changed its collective mind over RNAi,  but the remaining exponents (largely small and mid-cap biopharmas) have made significant progress in the clinic and in pre-clinical pipeline expansion. 

Leading the pack is Alnylam, with four late-stage (Phase III) candidates, fitusiran, inclisiran and givosiran, indicated in the treatment of  the rare genetic disorder hereditary ATTR amyloidosis, hypercholesterolemia, haemophilia and rare bleeding disorders and acute hepatic porphyrias, respectively. Positive Phase II data was recently reported for an open label inclisiran study where haemophilia patients were treated once a month for up to 20 months without safety or tolerability issues.  

Alnylam needs continued good news. A higher than expected death rate in the study arm forced the company to abandon late stage development of revusiran, then in evaluation for another form of ATTR-amyloidosis, last October, causing the share price to tank by 50% as investors considered the implications for the rest of the RNAi pipeline. Arrowhead Pharmaceuticals abandoned its clinical RNAi hepatitis B programme after primate deaths occurred in toxicology studies, necessitating a return to the pre-clinical drawing board. 

There's nothing to indicate that RNAi drugs have inherent safety issues. Quark Pharmaceuticals and Arbutus Biopharma have not encountered problems with their respective Phase II/III RNAi candidates and Alnylam's analysis of the revusiran data has not uncovered an obvious association between treatment and increased mortality. But, as a 20 year old development platform that has still to produce an a single approved drug, it's not surprising that investors and potential global pharma partners remain largely unconvinced about RNAi technology and are tuned into negative news.  

The future of RNAi drug development hangs on Alnylam's patisiran, currently in Phase III development, with top-line data expected in September. Submission of US and/or EU marketing applications before the end of 2017 would go a long way to (re)build confidence in RNAi as a platform. On the other hand, significant delay in regulatory submissions or abandonment of patisiran will impact heavily not only on Alnylam but, perhaps unfairly, its RNAi peers.  

Perhaps most galling for those companies that have the kept the faith is that clinical and regulatory success may not translate into sustainable commercial success,  as even in the orphan and niche indications being targeted by Alnylam and its peers, RNAi drugs will need to compete with small molecule, monoclonal antibody and antisense oligonucleotide therapies.  

Group B Streptococcus vaccine development: an eighty year old challenge

Group B streptococci 

Group B Streptococcus (GBS) and I go back a long way.  In the late 90s and early 2000s, I worked for several companies with ambitions to develop a GBS vaccine, only for hopes to be abandoned as an appreciation of the technical (and commercial) challenge sunk in.

GBS vaccine development has been kept alive over the last couple of decades largely by academic investigators and the odd small-cap biopharma, so it’s good to see a company the size of Pfizer getting involved, albeit with development being subsidised by the Bill and Melinda Gates Foundation.

GBS is a not uncommon resident of the guts and vaginas of healthy women, and is harmless until it turns up in the wrong place at the wrong time. Transmission of the bug to newborns can result in life-threatening, sometimes fatal, sepsis and meningitis. 

Microbiological screening, along with attention to risk factors such as preterm delivery and rupture of the protective amniotic membrane, can give a heads up as to the risk of delivering and infected infant and direct appropriate prophylactic antibiotic therapy. However, not every GBS case is prevented, even in well-resourced countries.

GBS is well-adapted for evasion of the immune system. Spreading bacteria express a variety of virulence factors which help them to set up house and deflect the unwanted attention of patrolling white cells. One of these factors, “capsular polysaccharide” (CPS) naturally elicits a generally ineffectual antibody response and was first investigated as a possible vaccine candidate during the 1930s. 

The immunogenicity of CPS can be boosted by chemically linking it to tetanus toxoid or other proteins (a strategy that works for Haemophilus Type B, Neisseria meningitidis and Streptococcus pneumoniae vaccines).  Investigational   glycoconjugate vaccines have resulted in reduced GBS carriage rates in healthy volunteers but not to the extent necessary for useful vaccination. A small scale study conducted in pregnant women had no beneficial effect on outcome. 

Over the last 15 years or so, whole genome sequencing and recombinant DNA technology have allowed researchers to identify bacterial surface proteins that might potentially protect against infection from a variety of GBS strains.   

MinerVax, a small Danish biotech which receives funding from the EU “Neostrep” project, reported positive results in a Phase I study of an all-protein vaccine,  with antibody responses in group of 240 healthy women elicited at all dosage levels. Pfizer’s candidate, which has just entered Phase I studies, is more old-school, being a conjugate vaccine designed to mimic multiple GBS serotypes. 

Any (potentially) preventable condition that causes infant death is rightly emotive, but harsh as it may seem, it’s not a certainty that GBS vaccination will actually prove to be universally cost-effective. Deployment may not make economic sense in countries where the incidence of GBS infection is low, but payback will hopefully prove substantial in countries such as South Africa, where the incidence of GBS infection is around five times higher than that of the UK. 

What’s more certain is that the technical challenge of effective GBS vaccination will be resolved well within the next 80 years. 

Image courtesy of James Archer, Medical Illustrator US Centers for Disease Control and Prevention 2013

The Body Electric

A not unpleasant consequence of being a generalist is that work regularly brings me into contact with unfamiliar areas of science and medicine or otherwise forces me take a fresh look at new takes on old ideas.

"Take 20,000 volts and call
me in the morning"

Such is the case with neurostimulation, a catch-all term for the controlled application of external stimuli (electrical, light or vibration) to bring about localised or systemic effects on health by acting on disease-associated“neural circuits”. Sounds a bit “out there”? Well, yes, but a surprising number of major pharmaceutical companies and funding agencies now have a stake in bioelectronic development.

GlaxoSmithKline is a high-profile exponent of bioelectronic healthcare, with the shift in focus from pills and potions being championed by Moncef Sloui, a former head of research.  A division dedicated to “electroceutical” research and development was established almost five years ago, followed by a GSK backed venture fund, Action Potential, which has since invested in several bioelectronic start-ups.

A joint venture, Galvani Bioelectronics, was formed in 2106 between Google’s life sciences spin-off, Verily, despite Verily’s “big on promise, short on delivery” reputation with respect to advanced medical device development. Lead indications have not been disclosed although  initiation of clinical trials sometime in 2017 has been hinted at.

Action Potential investments include CVRx Inc, which has secured European marketing approval for Barostim Neo™, a minimally invasive implanted device which acts on receptors in the carotid artery to lower blood pressure. Another portfolio company, SetPoint Medical is developing implantable devices to exploit the “inflammatory reflex”, described as a natural mechanism by which the central nervous system regulates the immune system. Studies involving vagus nerve stimulation in patients with rheumatoid arthritis and inflammatory bowel disease have shown some degree of efficacy.

The US Defense Advanced Research Projects Agency (DARPA) “Electrical Prescriptions” (ElectRx) initiative is supporting seven neurostimulation-focused research programmes, including work at Circuit Therapeutics, a start-up developing “optogenetics” for neurostimulation. This involves insertion of light-activated proteins (“opsins”) which act as ion channels or pumps to turn neural circuits on or off. Proof of concept is still at the laboratory stage but the company has got the attention of both Boehringer Ingelheim and Lundbeck, with collaborations in obesity and psychiatry, respectively.

Critics of electroceuticals point to the paucity of clinical data and to the limitations of current technology, such as the longevity and robustness of implanted devices which rely on battery power and that implantation itself requires skilled operators. Neuro/electro- stimulation has so far been confined to indications where there are no other options and device design and installation issues are of lesser importance. Driving the uptake of bioelectroncs on a larger scale and across a broader range of conditions will require multi-disciplinary input and exploitation of advances in materials technology and manufacture, with perhaps 3D printing allowing bespoke device design at acceptable cost. 

User-friendly, non-invasive bioelectronic treatments are only just beginning to move out of the fringe. Simple electroceutical treatments could conceivably play a useful role in the self-management of intractable chronic conditions. A UK start-up, Oxford Bioelectronics, has plans to evaluate a non-invasive electrostimulation device in patients with an otherwise untreatable eye condition, dry age-related macular degeneration. 

Image from Wikipedia ("Fair Use" rationale) 

Paying for gene therapy. No easy terms.

An early promise of biotechnology was gene therapy- the correction of Nature’s mistakes by re-writing the genetic code to restore normal function. The complexity of the task, even for single gene defects, has proved immense and several decades on, only two gene therapies have received approval in developed economies.

Glybera®, a treatment for lipoprotein lipase deficiency developed by UniQure, received European approval in 2012 and Strimvelis®,  a treatment for severe combined immune deficiency in children (“bubble boy” disease) developed by the San Raffaele Telethon Institute for Gene Therapy (and licensed to GSK), received European approval in 2016.

In addition to being the first approved gene therapy, Glybera® has the distinction of being the most expensive drug in the world at €1.1 million. Only one patient has ever been treated and the prescribing physician had to personally call the CEO of a German health insurance provider to secure payment.  Strimvelis® is more modestly priced at just under €600,000.

As Glybera® has demonstrated, monetizing gene therapy treatments is a problem. While there are upwards of 4,000 genetic disorders, the number of treatable patients afflicted with any single disorder is minute. Only around 1 in a million individuals suffers from lipoprotein lipase deficiency, with 14 or so “bubble boy” patients in Europe.

A report from the UK’s Office of Health Economics released earlier this week covers a policy summit convened in December 2016 which brought together healthcare payers and companies developing gene therapies to discuss the challenges involved in gauging effectiveness and assigning value. Such therapies do not lend themselves to blinded clinical studies and, with such small patient numbers,  the degree of effectiveness (and cost-benefit) may not become apparent for several years after approval.

Mooted mechanisms include those used with other high cost treatments (discount and rebate arrangements, restricting eligibility or reserving as the treatment of last resort, or outcomes-based agreements, although the latter would seem to be impractical given the difficulty in assessing outcomes. However, this has not prevented GSK offering a money back guarantee on Strimvelis®. Healthcare payers could lay off some of the risk through reinsurance although amortization, where the cost of treatment is spread over time could turn out to suit payers and developers alike.

Paying for gene therapy is far from abstract. Despite a history of failure and unknown commercial return, development continues and there are now over 20 gene therapies in Phase III development. At around €1 million or $1 million a pop, healthcare systems will feel the impact even on limited gene therapy approval. One of the front runners is Spark Therapeutics, which is on the cusp of submitting a rolling Biologics License Application to the FDA for its inherited retinal disease treatment, SPK-RPE65 (voretigene neparvovec) and could win approval this year.

Fishy. But in a good way.

Big tilapia. Or perhaps a small tilapia 

held close to the camera.

A recent and widely syndicated media piece (originally featured in STAT) described the experimental use of the skin of tilapia, an edible (if bland) freshwater fish farmed on a large scale, in the treatment of burns victims.

Severe burns destroy the epidermis and prevent it from regenerating, resulting in thick scar tissue that lacks the mechanical and functional features of normal skin. Healing can be encouraged by applying skin grafts to the damaged areas. Smaller burns can be treated using grafts harvested from the patient but this is rarely practical for large burns. Donated human skin and frozen pig skin are valuable substitutes, although both have their drawbacks, as do currently available synthetic and semi-synthetic skin replacement products.

The tilapia skin studies are being conducted in Brazil’s José Frota Institute with the hope that a common and easily processed waste product might help address the very limited availability of donated human and animal skin. There’s not much in the way of scientific rationale in the article, although the clinical investigator, Dr Edmar Maciel, cites the excellent mechanical and moisture-retaining properties of tilapia skin and its collagen content.

Research groups in China and Japan have looked at exploiting tilapia-extracted collagen in wound healing. Tilapia collagen meets the requirements for a useful material in regenerative medicine, being biodegradable, conducive to cell growth, and unlikely to be recognised by the immune system. Tilapia collagen nanofibres have been claimed to promote wound healing in an animal model (although the corresponding publication has since been retracted).

Skin from another table fish is being commercially exploited in wound care products developed and marketed by Kerecis Limited, a company situated in Ísafjörður, Iceland and close to cod-rich fishing grounds. The cod skin is minimally processed (“decellularized”) to provide a biocompatible matrix rich in omega 3 polyunsatured fatty acids and collagen. While fish oil has a long history of use as a health supplement, there’s currently little clinical evidence to indicate that topical application markedly improves wound healing or reduces scarring.

However, the results of studies of cod skin-derived dressings in patients with hard to heal wounds, including diabetic foot ulcers, communicated to date look promising and fish skin matrices may offer a viable alternative to animal-derived and synthetic wound care products. Kerecis has secured regulatory approval for its cod skin dressing and has attracted US Department of Defense funding with which to explore the treatment of burn and blast injury.

Fish skins are not the only marine waste products to have utility in wound healing. Crab and shrimp shells are largely composed of the polysaccharide, chitin. Chitin and its soluble derivative, chitosan , are incorporated into highly absorptive dressings and hydrogels which promote healing. 

Image courtesy of Anusorn P nachol at FreeDigitalPhotos.net

CAR-T: A wheel falls off, but still rolling

In the same week that Kite Pharma announced positive data from a pivotal study of its lead CAR-T candidate, KTE-C19 (easier to remember- and to spell- than the non-proprietary designation axicabtagene ciloleucel) in patients with B-cell non-Hodgkin lymphoma (NHL) refractory to other treatments, a one-time leader in the CAR-T race, Juno Therapeutics, pulled the plug on its lead candidate, JCAR015.

CAR-T (chimeric antigen receptor – the “T” is for T cell) is a form of adoptive cell transfer therapy which involves collection of T-cells from the patient and genetically engineering them to express receptors specific for a protein expressed on the tumour surface. After expansion in the laboratory, the transformed cells are infused back into the patient to seek and destroy tumour cells.

CAR-T therapy first made headlines by achieving unprecedented remission rates in patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and NHL where all available treatments had failed to slow disease progression. The other side of the coin was the accompanying high incidence of life-threatening adverse events arising from the massive release of cytokines (part and parcel of the anti-tumour response) and from immune-related neurotoxicity.

Juno’s JCAR015 was placed on clinical hold early in development following a death attributed to cytokine release syndrome and again twice in 2016 following five deaths from cerebral oedema during a Phase II study in ALL patients.  The company initially speculated that the deaths might be related to changes in a pre-treatment regimen involving two chemotherapy drugs but the decision to halt further development suggests that JCAR015 itself is now thought be the culprit. 

CAR-T candidates from Kite Pharma and Novartis have also resulted in high rates of cytokine release and neurotoxicity-related adverse events, but, so far, these have proved to be more manageable or of lesser severity than those occurring during the JCAR015 studies. No cerebral oedema occurred in the Kite Pharma pivotal study, with two treatment-related deaths probably arising from cytokine release.

Juno hope to stay in the game with an earlier stage CAR-T candidate, JCAR017, which showed a relatively low incidence of severe adverse events  in a small study conducted in NHL patients, but the abandonment of JCAR015 puts Juno a long way behind Kite Pharma and Novartis, with both shooting for regulatory approval in 2017.

CAR-T treatment will probably never be a “safe” option, although adverse event management would be expected to improve with experience. If regulators can be convinced that the benefits of CAR-T therapy outweigh risk, safety is likely to be a secondary concern for individuals cursed with otherwise untreatable B-cell malignancies. 

An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.

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Kite Announces Positive Topline Primary Results of Axicabtagene Ciloleucel from First Pivotal CAR-T Trial in Patients with Aggressive Non-Hodgkin Lymphoma. Company press release online 28^th February 2017. http://tinyurl.com/js7293j

Juno Therapeutics Reports Fourth Quarter and 2016 Financial Results. Company press release online 1^st March 2017. http://tinyurl.com/hunp9uh

Cancer vaccines: déjà vu all over again

News of two cancer vaccine clinical trial failures brought to mind the famous Yogi Berra quote “déjà vu all over again”.

"For the Win"

Argos Therapeutics was forced to halt a Phase III study of rocapuldencel-T in renal cancer patients when an interim data analysis indicated that continuing the study was futile. Agenus, somewhat shyly, announced the halting of a Phase II study of its Prophage G-200 vaccine in newly-diagnosed glioma patients for the same reason.

Both rocapuldencel-T and Prophage® are “personalized” vaccines which present cancer antigens derived from the patient’s own tumour.  In theory, these so –called “neoantigens” should be able to get around the problem of tumour-induced host tolerance and elicit cancer-fighting T cell responses.

Despite their sophistication, the Argos and Agenus candidates were unable to induce effective immune responses. A variety of other personalized cancer vaccines are in development but the complexity of neoantigen design is well-recognized and fine-tuning of epitope-predicting algorithms will require accumulation of a large body of clinical data. 

Although still a long way from validation, the prospect that the bespoke neoantigen approach might achieve the stunning outcomes observed in the minority of checkpoint inhibitor-treated individuals in a far larger percentage of treated patients has prompted several high-ticket licensing deals in the past year.

Cancer vaccine success has proved largely elusive over the past three decades, with only Dendreon’s ill-fated prostate cancer vaccine, Provenge®, managing to secure regulatory approval (call me a purist, but I don’t consider Amgen’s Imlygic® a vaccine. We can agree on “immunotherapeutic”). 

As someone whose professional interest in cancer vaccines goes back to the 90s, I’m hopeful that the broader renaissance in cancer immunotherapy will, directly or indirectly lead to useful cancer vaccines, either through combination with tolerance breaking biologics or small molecules or through a better understanding of the subtle interplay between tumours and the host immune system.

To quote Mr Berra once again, “It ain't over 'til it's over”. 

Image By Bowman Gum (Heritage Auctions), via Wikimedia Commons