Welcome to the Alexander Yule Consulting Blog

Saturday, 25 March 2017

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) 

Thursday, 9 March 2017

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.

Monday, 6 March 2017

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

Thursday, 2 March 2017

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.

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 28th February 2017. http://tinyurl.com/js7293j

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