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