New treatments – and maybe a cure – for hemophilia

Haemophilia is a rare, usually inherited, blood-clotting disorder. Patients with the most severe forms of the disease may bleed uncontrollably following even a simple scratch. Internal bleeds into the joints can cause irreversible damage; bleeding into the brain may be fatal. Thus these patients have little choice but to regularly administer replacement versions of the protein, or clotting factor, that they are missing. This two-to-three times a week treatment is life-saving for many.

Most patients have a version of the disease called hemophilia A, and need to take clotting factor VIII throughout their lives. Those with a rarer form, hemophilia B, need clotting factor IX. Several forms of both clotting factors are available – including Bayer’s factor VIII Kogenate (octocog alfa), or Pfizer’s BeneFix (nonacog alfa), a factor IX.


But replacing missing clotting factor does not work for about a third of patients with hemophilia A. These patients’ bodies reject the externally-administered protein as foreign, and develop antibodies against it. This group is typically given bypassing agents, which help blood clotting via a different mechanism. But these agents aren’t as effective as clotting factors, so patients are much more likely to suffer from bleeds and resulting complications – costing lives, and significant healthcare resources.

Roche/Chugai’s Hemlibra (emicizumab), approved in the US in 2017 and in the EU in early 2018, offered treatment-resistant hemophilia A patients another life-line. Hemlibra activates the blood clotting system differently again, by binding together two other coagulation proteins, Factors IX and X. Hemlibra has since been approved for all severe hemophilia A patients, not only those with Factor VIII inhibitors. Trials show that the treatment can significantly reduce bleeding in both groups of patients, considerably expanding the market for the drug. Hemlibra, given as a subcutaneous injection, also offers more flexible dosing options than Factor VIII – including a once-a-month prophylactic regime.


Hemlibra has drawbacks, though: regulators slapped a black-box warning – the most severe kind – on the drug for thrombosis, unwanted and potentially dangerous blood clots. Appropriate dosing and monitoring are vital.


Gene-therapy has the potential to provide an even safer, more convenient option for hemophilia patients. By introducing a working version of the defective F8 gene, it may offer a one-time treatment that reduces or even removes the need for regular injections or infusions, allowing patients to lead close to normal lives. BioMarin has a Phase III hemophilia A gene therapy candidate; Spark Therapeutics (recently acquired by Roche) has a Phase III hemophilia B program with partner Pfizer, and a hemophilia A program on the cusp of Phase III.


These programs are not yet proven. Nor indeed is the longer-term efficacy and safety of gene therapy as a class.


Yet if they are approved, these potentially more effective, and more convenient treatments will come at a cost. Payers are already likely to balk at Hemlibra’s sub-$500,000 per-year price if carried over to all hemophilia A patients, let alone the likely up-front cost of gene therapy. Competition may help: Alynlam/Sanofi’s Phase III fitusiran lowers levels of anti-thrombin, a protein that inactivates coagulation enzymes. It might serve patients with both Hemophilia A and B, both with or without inhibitors.


Fitusiran will not come cheap either, though – it is among the first of a new class of RNAi drugs. Still, this potential new treatment era in hemophilia is unlikely to be a re-play of Sovaldi in Hepatitis C, which caused massive short-term cost increases and threatened many payers’ sustainability. With more than one option for hemophilia patients that can’t use replacement clotting factors, payers will have some leverage.

Sniffing out Parkinson’s Disease

The number of people suffering from Parkinson’s disease, already over 10 million worldwide, is set to double within 50 years as populations age. This chronic, progressive condition is caused by the degeneration of dopamine-producing cells in the brain, leading to both physical and cognitive symptoms. Parkinson’s patients may experience tremors, difficulties walking and moving normally, mood-changes and sleep disturbances, making their lives miserable. The disease is not in itself fatal. But its consequences can be.

The most effective treatment today is levodopa, a chemical developed 60 years ago. It converts in the body into dopamine, the neurotransmitter that Parkinson’s patients lack. Several brands are available including Sinemet, Duopa and Parcopa.


But Levadopa has side-effects, and does not address the root causes of Parkinson’s. And it is often administered too late to meaningfully reduce symptoms. Parkinson’s can be tricky to diagnose early, before significant neural damage occurs.


A handful of new approaches, from antibodies to cell- and gene-replacement, may help to stop – and even reverse – the brain damage characteristic of Parkinson’s. Some target alpha-synuclein, a protein that mis-folds to form clumps called “Lewy bodies” in parts of the brain. These clumps are thought to contaminate normal, healthy neurons, causing wider damage.


Biogen’s antibody, BIIB054, is designed to target the mutated forms of alpha-synuclein, thereby reducing the spread of Lewy bodies. A Phase II trial is recruiting. Meanwhile, scientists continue to work on ways to transplant dopamine-producing cells, grown from stem cells ex-vivo, into the brain. Various clinical trials are underway. Researchers at Edinburgh University are using gene-editing tools like CRISPR to strip out the DNA thought to be responsible for abnormal alpha-synuclein and Lewy body formation. Such ‘Lewy-resistant’ cells may help limit the spread of neuronal damage, making cell-therapy approaches more effective and long-lasting.


The gene-therapy revival has also reached Parkinson’s. Voyager Therapeutics’ VY AADC, which carries the gene for an enzyme involved in dopamine production, is beginning Phase II/III testing. The therapy is injected directly into the region of the brain where the neurotransmitter is normally active. A Phase Ib trial of 15 patients showed a reduced need for levodopa treatment and improved motor function and quality-of-life scores in some patients. Axovant Sciences’ AXO-Lenti PD, licensed from Oxford BioMedica, recently began a Phase II clinical trial in the UK. This product delivers genes for three enzymes required for dopamine production. The hope is that a single administration of such gene therapies may provide multi-year benefits to patients – though longer-term safety and efficacy data is required to prove that.


Meanwhile, Parkinson’s may soon be much easier to catch early – using our noses. In a widely-reported story, former nurse Joy Milne was able to smell a musty scent on her husband over a decade before he was diagnosed. She noticed in support group meetings that everyone smelt the same. Scientists are now looking to isolate substances in sebum – oily secretions from our skin – that may provide an early-warning of the condition, allowing early intervention to protect dopamine-producing cells before they die. One candidate substance that may be causing the aberrant smell: alpha-synuclein.