(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)