Sickle Cell Disease: The hope for new treatments

For a disease that hasn’t seen a new development implemented since 1998 ,the news of a complete cure or treatment to alleviate the pain to those affected is one we are all hoping for and will single handily change the lives of so many.

Sickle cell disease will always make news headlines and bring up an intense range of emotions. It is a debilitating genetic disease that has been carefully campaigned for in the UK by Sickle cell society — through educating the workforce and dispelling negative stereotypes about black patients and supporting them through hospital admissions, treatments and general wellbeing.

Sickle cell mainly affects black people who rightfully have a very complicated relationship with the healthcare system. As a black woman in the UK, it’s almost second nature to expect health headlines highlighting my demographic to end in negativity. This distrust in health systems is a wound yet to be healed that starts with knowing there is a high chance of receiving a different level of care . A fresh wound constantly reopened on a global scale highlighted by racial disparity findings during the height of the Covid-19 Pandemic.

This post breaks down current treatment options for sickle cell patients and explains the disappointment of recently revoked ‘new treatment’ — Crizanlizumab — Landmark sickle cell drug axed by regulators

Sickle cell is a genetically determined blood disorder where blood cells have a sickle shape which affects how oxygen is transported to organs and due to the shape can also build up in areas of the body leading to a painful crisis . In people without sickle cell, blood cells are disc shaped and can easily flow through blood vessels.

Crizanlizumab( commercial name: Adakveo) would have been the first new sickle cell drug introduced in the past 20 years. Current sickle cell treatments aim to reduce the pain experienced by patients to ultimately decrease the need for hospital visits. The current medication offered under the NHS is Hydroxycarbamide (Hydroxyurea) which lowers the number of ‘sticky cells’ ( white blood cells and platelets), reducing the chances of a build up of blood cells that leads to a crisis.

How do these drugs work?

Hydroxycarbamide : lowers the number of cells that clot (white blood cells and platelets and preventing the formation of sickle shaped red blood cells) — NHS

2. Crizanlizumab( Adakveo) : prevents blood from sticking to the walls of blood vessels , less crisis for patients.

The withdrawal of Adakveo was responded to on X(formerly twitter) with wavering disappointment yet again for sickle cell patients and ultimately a deep sigh where black patients don’t feel treatments are being developed at a pace we desperately need.

While the news headlines may describe it as a major loss — it is more of a disappointment which is part of the long drug development process. It’s worth noting now that Adakveo is not the only treatment being trialled and inclacumab is currently in Phase 3 trials awaiting results that will further be described in this post.

The different phases of a clinical trial taken from(https://www.cam.ac.uk/stories/clinicaltriallists)

‘ Though no safety concerns were identified, the MHRA concluded the drug is not sufficiently effective, despite evidence suggesting that it eases symptoms for those living with the illness.’ — MHRA 2024

The extract from the independent article leaves many questions as to what ‘sufficiently effective’ means and why a drug with ‘no safety concerns’ has been withdrawn. The revocation comes at a review of interesting Phase 3 results announced in early 2023 by NOVARTIS- the pharmaceutical company responsible for the development. To which for them the previous Phase 2 trial showed to be more effective over no treatment (placebo).

A key factor in drug trials is ensuring the new treatment being developed has an advantage of either the current treatment offered or having no treatment whatsoever. Drug companies tend to compare patients receiving regular treatment in order to not decrease patient wellbeing during the trial.

A detailed look at the Phase 2 trial publication in Feb 2017 shows a few things:

What was the aim? The overall aim is to have the patients on the drug visit the hospital less than those not taking the new drug.

What did they do? In 198 patients over 60 sites in three countries: United States (151 patients), Brazil (40), and Jamaica (7).They compared two doses ( high and low) of this new treatment Crizanlizumab against a placebo( not having the drug) to investigate how often patients were hospitalised .

What were the results?: The phase 2 results showed a lower rate of hospital visits in patients given a higher dose for a long time than those with the placebo treatment and a longer time between crises needing hospital visits. 10% of patients also had a high frequency of side effects:arthralgia( joint pain) , diarrhoea, pruritus(itching), vomiting, and chest pain.

Why has it been withdrawn from the UK and EU ?

“ Adakveo does not reduce the number of painful crises requiring a healthcare visit or treatment at home in patients with sickle cell disease.” — EMA ( European Medical Authority) May 2023

Following Phase 2 trials, NOVARTIS decided to move to Phase 3 trials in a larger group of patients to hopefully identify the same findings. The findings of the phase 3 results didn’t show the same results . Given Novartis Phase 3 results, regulatory bodies of different countries can then decide the wider role out of the medication. In the US Adakveo was approved by the FDA it did not meet the requirements for European regulators EMA in May 2023.This led to its subsequent revoking for use of patients in the UK . Even though its the end of the road in Europe, Phase 4 trials are likely to follow in the US where the drug is still available.

This may seem frustrating; but the scientific concept behind Adakveo is still being developed by other researchers. A drug is more than the concept and different researchers will have different formulations and ways to deliver similar therapies.

What is the concept?

As early as 2001 researchers began to identify the importance of a molecule called P-selectin. P-selectin in very simple terms promotes the sticking of blood cells on vessel walls. Understanding this interaction has led researchers to develop therapies that block P-selectin and hence prevent the build up of blood cells and improve blood flow , which for sickle cell patients will hopefully reduce the number of crises.

Will Inclacumab provide the answers?

With clinical trials just because one fails doesn’t mean all hope is lost. Inclacumab is a another drug that also works by targetting P-selectin currently under Phase 3 trials . Interestingly in a study from NOV 2023 on blood samples of 6 sickle cell patients. The effectiveness of both drugs were compared on a chip, researchers found Inclacumab to be more effective at preventing the sticking of blood cells than Adakveo. This is promising as we wait for the results from the Phase 3 trails.

Other new treatments

The revoking of Adakveo has also caused some confusion with the recently announced CRISPR -gene editing therapy for sickle cell patients. The gene editing therapy is a one-time treatment that has already had positive effects in a handful of trial patients. Its major downside is the million dollar price tag placed on the technology. Adakveo is $2357 in the US , and most patients will require 3 to 4 vials per month ($7071 to $9428).

As we patiently wait for new therapies we are reminded that will still come at a cost, reducing the number of people that benefit from life changing treatment.