Looking good: industry sets its sights on retinal disease treatments

End stage retinitis pigmentosa

Some while back, I posted on the challenge, and lack of progress, in the development of drug treatments for the most common cause of adult blindness- “dry” age-related macular degeneration - dAMD (Roche’s lampalizumab disappoints- is the "dry" AMD pipeline about to dry up?). 

But, as a recent article in Nature Outlook reminded me, while pharmaceutical development may be lagging, a host of technologies now in clinical and commercial development offer hope for individuals with previously untreatable forms of inherited and non-inherited retinal degeneration. Author Simon Meakin lists four technologies with the potential to revolutionise treatment: retinal prosthetics (“bionic eyes”); gene therapy; optogenetics, and cell regeneration.

The “bionic eye” approach involves fooling the brain into interpreting electrical signals delivered by an implanted microchip placed over the retina as spots of light. A microprocessor converts images captured by a miniature camera worn on a spectacles frame to electrical impulses relayed by wireless to the implant. While this cannot match the resolution achieved by the millions of photoreceptors in a healthy retina, with training, recipients can distinguish light from dark and identify high contrast objects. 

The first commercial product (Argus II: Second Sight) received regulatory approval in 2011 in Europe (2013 in the US) for use in individuals with end-stage retinitis pigmentosa (RP).The device cost is widely cited as around $150,000, excluding surgical and training costs. Two other prosthetic systems in clinical development use implants placed underneath the retina; Prima (Pixium Vision) and Alpha AMS, a camera-free system developed by Retinal Implants AG, although the latter has recently entered administration. Pixium intends to begin trials of Prima in dAMD patients before the end of 2019. Second Sight is evaluating the feasibility of bypassing the retina by implanting electrodes into the visual cortex with its Orion system. 

Gene therapy is now established as a viable means of bringing some degree of vision improvement to those with certain inherited conditions, with the landmark approval of Luxturna® (Spark Therapeutics) in both the US (December 2017) and Europe (November 2018). Clinical trials of other gene therapies are underway, with the aim of correcting RP-associated defects and inherited retinal conditions including Leber’s hereditary optic neuropathy; Leber’s congenital amaurosis; Stargardt disease; achromatopsia, and X-linked retinoschisis.

While not associated with any single gene detect, the “wet” (neovascular) form of AMD is also the subject of gene therapy trials aimed at neutralizing a protein (vascular endothelial growth factor- VEGF) involved in blood vessel formation. Success could replace the current treatment of regular injection of anti-VEGF antibodies into the eye.

Treatments in development require injection of viral vectors to insert functioning genes but other strategies, including gene editing and gene silencing, could potentially expand the range of treatable conditions. At a cost of around $425,000 per eye, Luxturna® has featured in the “fair value” debate around drug pricing, although the recent acquisition of NightstaRx, a gene therapy developer with a portfolio of early and clinical-stage assets by Biogen for a headline value of around $800 million, and the acquisition of Quethera and its pre-clinical glaucoma programme by Astellas are likely only the beginning of big pharma interest in next generation ophthalmology.

   

Optogenetic approaches, which exploit light sensitive proteins (“opsins”) to modulate biological processes, are still in early clinical development but have the potential to address a number of ophthalmologic conditions in which there are too few cells left to exploit or repair through either restoring function or inducing other types of retinal cell to become light-sensitive. A start-up company, RetroSense, initiated the first clinical studies of a viral vector delivered opsin in RP patients and was acquired by Allergan in 2016: an early-stage clinical study is ongoing.

The downside of opsins is that they respond to a limited range of light conditions. Gensight Biologics, hopes to get around this by combining video capture and electrical stimulation of retinal ganglion cells made light-sensitive through insertion of a gene coding for opsin production. The first RP patient was treated in October 2018 and the ongoing clinical study will evaluate different doses of the viral vector bearing the opsin gene.

The replacement of damaged retinal pigment epithelium (RPE) through stem cell therapy may eventually become a viable treatment for RP and AMD. Mixed results have been obtained with injected cell suspensions but implantation of pre-formed sheets of RPE cells secured within a biocompatible matrix could prove to be a significant improvement. Early clinical studies have been completed in subjects with both the wet and dry forms of AMD, and a start-up, Regenerative Patch Technology, formed to take up the challenge of financing and commercialising development.

Repairing the circuitry linking photoreceptors to the brain presents an altogether different level of technical challenge but, on the basis that non-mammalian species are capable of some degree of retinal neuron regeneration, it’s not impossible that means of reproducing this trick in humans might be developed, possibly through re-programming other cells present in the eye to regenerate lost neurons.

Complexity, cost and necessary caution over gene therapy and stem cell procedures make it likely that only a small number of individuals will initially benefit from these treatments, but advances in viral vector and stem cell-derived product manufacture, together with growing industry involvement should eventually make these life-changing treatments available to a significant minority of vision-impaired individuals.

Photo credit: Christian Hamel [CC BY 2.0]

Gene editing: off the bench and into the clinic

As the first sponsored CRISPR-Cas9 clinical study gets underway,
industry has high hopes that genome editing will eventually make gene
therapy a mainstream treatment for both inherited and non-inherited
diseases. 

Recent progress in gene therapy, with successful proof of concept being reported in a range of otherwise untreatable conditions and the grant of marketing authorisations for commercially-developed treatments makes it easy to forget that these successes were built on almost three decades of endeavour and regular disappointment.

Gene therapy restores aberrant or missing biological functions through the introduction of functional genes carried into the cell using engineered viruses or by zapping with electrical pulses. A more involved process is the alteration of specific nucleotide sequences within a faulty gene to restore or 
modify function- so-called “gene editing”. 

Around the turn of the millennium, certain bacterial genomes were observed to have multiple copies of repeated DNA sequences which read the same in both directions -“clustered regularly interspaced palindromic repeats” (CRISPR), which were subsequently found to be responsible for the exquisitely specific recognition of infecting viruses. In 2012, it was shown that CRISPR could be exploited to edit genes in mammalian cells, prompting an explosion in translational science, patent wrangles and an influx of venture funding. 

Reduced to its bare bones, CRISPR gene editing utilises a short piece of “guide” RNA, designed to bind to a specific sequence of DNA, complexed with an enzyme able to cut double-stranded DNA, with the bacterial enzyme “Cas9” being widely used. Once within the nucleus, the guide RNA latches onto its complementary DNA sequence, directing the enzyme to cut in the right place: the cell’s DNA repair mechanism completes the editing process. 

CRISPR-Cas9 (and other CRISPR based systems) have brought relative simplicity and low cost to gene editing, providing a powerful research tool with application across biological disciplines and a route to significant advances in agriculture and the treatment of both inherited and non-inherited disease.

American and European regulators have been understandably cautious with respect to CRISPR clinical studies. As with other forms of gene therapy, CRISPR-Cas9 editing is not without potential risk, such as unwanted alteration of DNA sequences other than the target gene sequence, or the triggering of immune responses to the Cas9 enzyme (obtained from one or other of two common skin bacteria) or through introduced RNA being recognised as being  “foreign”. 

Chinese investigators have been less troubled by the unknowns surrounding CRISPR clinical development:  first in man studies began in 2010, with around 80 subjects being treated in cancer and HIV gene editing studies by February this year. Several Chinese research groups have explored  gene editing in non-viable, and most recently, viable human embryos.  

CRISPR Therapeutics, in partnership with Vertex,  successfully addressed undisclosed FDA concerns raised in May this year and are now recruiting beta thalassemia patients for a Phase I/II gene editing study. Like sickle cell disease, beta thalassemia arises from an inherited defect in the gene encoding the oxygen-carrying protein, haemoglobin. 

Rather than directly editing the haemoglobin gene, the CRISPR-Cas9 complex (designated CTX001) is designed to alter a DNA sequence responsible for the shutdown of foetal haemoglobin production, in the hope that turning the switch back on will produce sufficient levels of functional haemoglobin. The editing process is performed ex vivo, with blood-forming stem cells being extracted from the patient, transfected with the CRISPR-Cas9 complex, expanded and then returned by infusion. 

CRISPR Therapeutics and its peers, Editas Medicine and Intellia Therapeutics have ambitions to develop gene editing therapies for a range of genetic conditions that result in metabolic dysfunction (Hurler syndrome, glycogen storage disease, alpha-1 antitrypsin deficiency, transthyretin amyloidosis) and visual impairment (Leber congenital amaurosis, Usher syndrome), as well as cystic fibrosis and Duchenne muscular dystrophy (DMD). Exonics Therapeutics recently published data indicating that their “SingleCut” CRISPR technology was able to  restore near normal levels of dystrophin expression in an animal model of DMD. 

CRISPR may prove to be more efficient and flexible means of engineering “off the shelf” (allogeneic) cancer-fighting T cell therapies, reducing the cost and complexity of current patient-specific CAR-T therapy  [ASCO Clinical Cancer Advances 2018. And the winner is...].

Pre-CRISPR era gene editing methodologies may also prove to have therapeutic application. Sangamo Therapeutics has used a zinc finger nuclease-based approach to achieve “in body” editing of a faulty gene in four individuals with Hunter syndrome, an enzyme disorder that prevents the breakdown of complex sugars, leading to harmful accumulation. A decrease in urinary complex sugar level was observed in two individuals, although not an increase in normal enzyme levels in the blood. Full interpretation of the significance of these results will take time but importantly, “in body” editing raised no safety issues. 

Clinical development of  gene editing-based therapies will continue to advance cautiously (at least in the West), but is likely to can to benefit from experience gained in viral and non-viral vector design now being exploited in other forms of gene therapy and growing regulatory familiarity with gene therapy risk-benefit assessment. 

Image credit: Credit: Jill George, NIH.

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.

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.