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Within the next month, the US Food and Drug Administration (FDA)
is set to review a landmark gene therapy product, Zolgensma
(onasemnogene abeparvovec), touted by its developer (AveXis, a
Novartis subsidiary) as a potential one-off cure for a rare
inherited neuromuscular condition, spinal muscular atrophy (SMA).
Zolgensma has been designed to overcome the genetic mutation in SMA
type-1, the most common subtype, which is associated with a high
infant mortality rate and is severely debilitating.
While the launch of this product has been hotly anticipated by
patient groups and physicians, there has also been much animated
discussion over its expected US price tag - estimated at well over
a million dollars per patient. Opinion is divided on whether such
high prices are sustainable within the US healthcare system, and
conversely, whether it would be ethical to deny patients access to
a lifesaving treatment purely on grounds of cost.
Does it work, and is it safe?
Certainly, the supporting clinical evidence has been working in
Zolgensma's favor so far. Most recent data from the STRIVE trial in
22 infants with SMA-1 revealed "early and rapid" improvements in
neuromuscular function and motor milestones, following a single
Zolgensma infusion. This supported previous data from the START
trial, which had created a stir when Novartis announced
"unprecedented" positive developments such as rolling over and
unaided sitting at the 24-month mark. It should be remembered that
untreated SMA-1 generally results in mortality or a requirement for
permanent ventilation in 90% of untreated cases, by two years of
age.
Regarding safety, reports so far have been generally favorable -
with the most common adverse event being a (manageable) increase in
serum aminotransferase levels. However, the picture was clouded
recently by reports of two infant deaths during trials. One of
these has already been considered by an independent monitor to be
non-treatment-related, although a second, from a severe respiratory
infection with neurological complications, remains open, with
investigations continuing. Novartis's most recent statement
indicated that the company did not predict this event to have a
negative impact on the timing or outcome of the FDA's decision.
The problematic question of pricing
In bringing such a treatment to SMA patients, a balance clearly
needs to be struck between avoiding unnecessary delays (especially
in a fatal condition) and spending a large portion of the entire
healthcare budget on only one drug. This dilemma is especially
acute in the field of gene therapy, where there is little precedent
on which to base a pricing decision.
With such considerations in mind, last November Novartis pitched
a tentative US price point at around USD4-5 million per patient, as
a "cost-effective" estimate for the one-off treatment, although
more recent communications have broadened the range downwards. In
April, CEO Vas Narasimhan stated in an analyst call that he would
consider USD4-5 million per-patient a cost-effective price if a
cut-off value of USD500,000 per quality-adjusted life year (QALY)
were used but could consider values down to USD1.5 million in the
case of a USD150,000 per QALY threshold. The actual price point
will remain to be seen once the treatment is approved.
It is noteworthy that these company estimates chime closely with
expected threshold prices for cost-effectiveness quoted only last
month by the US Institute for Clinical and Economic Review (ICER)
advisory body - and this may well work in favor of acceptance.
Indeed, ICER recently endorsed Novartis's pricing of another gene
therapy product, the chimaeric antigen receptor T-cell (CAR-T)
therapeutic Kymriah for cancer, at USD475,000 per patient for a
one-off treatment - although sustainability of payments for such
expensive treatments will still need to be carefully re-evaluated
over time.
How does it line up against Spinraza?
No discussion on SMA would be complete without considering
Biogen's rival product Spinraza (nusinersen) - which was the
first-ever SMA product to reach the market, back in December 2016.
While Spinraza also addresses the underlying mutation of SMA, and
has also shown clear effectiveness in improving motor function, it
has the disadvantage of being a small molecule requiring multiple
lifelong dosing, and carries a hefty reported US price tag of
USD750,000 per patient for the first year, followed by USD375,000
per year (according to our PharmOnline International [POLI] -
Pharmaceutical Pricing & Reimbursement Database).
While the price estimates for Zolgensma appear likely to be much
higher, it must be remembered that it this is for a one-off
treatment, whereas Spinraza requires repeated lifelong repeated
administration, compounding costs over time - a factor which has
restricted its reimbursement in several key markets. Indeed, ICER's
recent study ruled that it considered Spinraza a "low long-term
value for money" option at current prices, and that it would
require an 83% discount to meet the USD150,000 per QALY threshold.
Once Zolgensma hits the market, Biogen will have to re-evaluate
their pricing package carefully, if it is to compete effectively
with a one-off gene therapy.
The next month will be crucial both for Zolgensma and its rival
Spinraza. Certainly, if Zolgensma lives up to its advance
publicity, and is approved this month with pricing at a level which
could be considered sustainable, it has the potential to
out-compete Spinraza - unless any long-term efficacy, patient
acceptance or safety issues emerge over time. With gene therapy
still in its infancy as a strategy, this long-awaited event for SMA
groups still carries its risks, both in practical and financial
terms.
Posted 03 May 2019 by Janet Beal, Senior Research Analyst, Life Sciences, IHS Markit