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.