Gene therapy and fair value.

Retinal pigment epithelial cells in
RPE65-mediated retinal disease

Back in March, I wrote a piece regarding the coming impact of high ticket gene therapies on healthcare budgets. December saw the FDA approval of Spark Therapeutic's Luxturna™ (voretigene neparvovec), a unique treatment for biallelic RPE65-mediated inherited retinal disease, a form of Leber's congenital amaurosis, which results in early onset, progressive loss of vision.

Predictably, Luxturna's approval has reopened the debate around the cost of leading edge therapies. At around $850,000 to treat both eyes, Luxturna™ pricing is somewhat lower than the $1 million plus price tag anticipated by industry analysts, although it's still the most expensive drug in the US by list price.

Justifiable? Perhaps. Gene therapy product approval is not a guaranteed path to riches. As with other genetic disorders, the potential treatment population is small, being around 1000-2000 sufferers in the US, with around the same number in Europe. Moreover, Luxturna™ is a one-time treatment. While even modest uptake should cover Spark's development costs, the overall return to Spark will be, by pharma standards, unremarkable.

Spark appears pragmatic in its approach to reimbursement, offering insurers rebates should patients fail to achieve an agreed degree of benefit, although with only limited and short-term study data available, defining a improvement for rebate purposes will not be easy. Spark is also thought to be considering an annuity model, allowing insurers to pay over time [see update of 12th January below]. 

So much for cost, but what about value? Although not an easy calculation, tallying the lifetime benefit accruing from reduced direct and indirect medical costs, increased individual economic activity and quality of life improvement, might come close to justifying Luxturna’s price tag.

A draft assessment published by the Institute for Clinical and Economic Review published just prior to Luxturna's approval concluded that, although likely to result in better outcomes than standard care, Luxturna would probably not prove to be cost-effective at an assumed acquisition cost of $1 million.  Another crank of the spreadsheet incorporating the actual drug price and post-approval efficacy data, particularly the durability of benefit, could tip the balance in Luxturna's favour.

The UK's National Institute for Health and Care Excellence (NICE) recently concluded that, compared with the cost and risk associated with stem cell transplantation for the treatment of adenosine deaminase deficiency–severe combined immunodeficiency (ADA-SCID or "bubble boy" syndrome) GSK's gene therapy, Strimvelis™, provided both the best treatment option and value for money, despite its  €594,000 (around £505,000) price tag.

Although invariably flawed, cost-effectiveness analysis needs to be at the centre of gene therapy pricing and adoption debates. Such analyses may not always prove favorable, but without an objective means of establishing fair pricing and reimbursement, gene therapies could become out of reach for many patients. The commercial abandonment of Glybera™,a gene therapy for lipoprotein lipase deficiency and announcement of GSK's intention to abandon Strimvelis® (and rare disease therapy development in general) are portents that should not be ignored.

Photo credit: National Eye Institute, National Institutes of Health.

Are IDO inhibitors still the next big thing in immuno-oncology?

Metastatic melanoma cells

It's a safe prediction that immuno-oncology (IO) drug development activity is unlikely to diminish in 2018, with a major objective being the validation and approval of agents that synergise with the established anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors.

Much has been written on the broad utility of inhibitors of indoleamine-2,3-dioxygenase-1 (IDO), an intracellular enzyme present in both immune cells and cancer cells and  which regulates tryptophan levels in the tumour microenvironment (TME). 

Depletion of tryptophan by upregulated IDO expression starves cancer-antigen specific T cells, while a rise in the concentration of tryptophan metabolites triggers the development of immunosuppressive Treg cells.

This central role in local immunosuppresion and the prospect of synergy with immune checkpoint inhibitor treatment and other immunotherapies has made IDO (along with a similar enzyme, tryptophan-2,3-dioxygenase 2- TDO)  an attractive target for IO drug development, and a variety of  orally available small molecule inhibitors have entered clinical evaluation as both monotherapy and in combination with immunotherapies or cytotoxic cancer drugs.

Big pharma interest in  IDO and TDO inhibitors has fuelled several “big headline” partnering deals, including  BMS and Flexus Biosciences ($1.25 billon); Roche and CuraDev Pharma ($555m); Roche and NewLink Genetics ($1 billion), and Incyte Pharma and Roche, AstraZeneca, Merck and BMS (undisclosed terms).

 

IDO inhibitor progress has been mixed. In June last year, Roche returned the rights to NewLink's navoximod (GDC-0919), the latter failing to meet any of the primary study objectives (overall survival, progression-free survival or objective response rate) when combined with taxane chemotherapy in breast cancer patients.  Combination with Roche's ant-PD-L1 immune checkpoint inhibitor, Tecentriq® did not achieve an overall response rate better than Tecentriq® alone in patients with advanced solid tumours. Absence of efficacy was cited by iTeos Therapeutics today as the reason for termination of an IDO development partnership with Pfizer following analysis of interim trial data from a Phase I monotherapy study in patients with malignant glioma.

Failure in cancer drug development is, unfortunately, the norm rather than the exception, and it's possible that other IDO inhibitors with different chemistries and better bioavailability may prove capable of either upping the response to immune checkpoint inhibitors or being valuable treatments in their own right. Phase II data from a study of Incyte's epacadostat in combination with anti-PD-1 (Keytruda®) hinted that the combination might prove superior to, and safer than, combined anti-CTLA-4 (Yervoy®) and anti-PD-1 therapy in patients with advanced melanoma. A Phase III study (NCT02752074) is underway in collaboration with Merck, with primary data anticipated around the middle of 2018.

AstraZeneca, a company which could stand some good IO related news, recently expanded its collaboration with  Incyte to include lung cancer studies in combination with the anti-PD-L1 checkpoint inhibitor, Imfinzi®; other companies, including Kyowa Kirin, Jubilant Biosys, Kyn Therapeutics and e-Therapeutics have recently entered the IDO/TDO inhibitor game.

The apparent failure of ITeos's  candidate might not give immediate cause for concern (glioma is a very hard target), but it's reasonable to suppose that there are many fingers crossed in pharma management meetings in the hope that Incyte's Phase III study leads to registration and paves the way for the first small molecule IO treatments.

Photo credit: National Cancer Institute

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.