Thomson Reuters Market Insight:

1. Duchenne muscular dystrophy drugs face
tough path to approval
Lisa Hodgkinson, Thomson Reuters, London
18th February 2016
Thomson Reuters Forecast
Market Insight
Highly anticipated as new disease-modifying treatments for Duchenne
muscular dystrophy (DMD), therapeutics by BioMarin Pharmaceutical
(Kyndrisa; drisapersen) and SareptaTherapeutics (eteplirsen;AVI-4658)
both recently received negative FDA reviews and are now facing battles
for approval in the US. At present, BioMarin is committed to working
with the FDA to forge a pathway to approval following the failure of
its NDA, while Sarepta awaits the formal decision on its NDA, which is
expected by late May 2016. Despite the critical nature of both reviews,
analysts consider that there is still a narrow possibility of approval of
both drugs. According to Consensus forecasts from Thomson Reuters
Cortellis for Competitive Intelligence, Kyndrisa is forecast to achieve
sales of $533.71 million in 2021.
Exon-skipping oligonucleotide-based therapeutics
for DMD
DMD is caused by an absence or near absence of dystrophin – a muscle
protein crucial for maintaining muscle integrity - caused by defects in
the dystrophin gene. The condition affects 1 in every 3500 to 5000
boys, and causes progressive muscle weakness, loss of ambulation,
pain, cardiomyopathy, lung deterioration, some degree of learning
disabilities and death by around 20 years of age. It is the commonest
fatal genetic disorder diagnosed in childhood. Current therapies include
glucocorticoids, which have been associated with Cushingoid syndrome
and obesity, or supportive treatments such as physical therapy and
assisted ventilation.
The therapeutic approach of the oligonucleotide drugs Kyndrisa and
eteplirsen is based on the observation that the genetic defects in the
related dystrophinopathy, Becker muscular dystrophy, produce a
truncated, but functional, dystrophin protein, with milder and slower
symptom progression, later disease onset and a near-normal life
expectancy. By acting as genetic patches to skip over the damaged
exons in the dystrophin gene in DMD, these drugs restore production of
functional, albeit shorter, dystrophin in patients who previously lacked
this crucial protein.
Kyndrisa
Kyndrisa was first developed by the Dutch biotech company Prosensa,
which was spun out of Leiden University Medical Center, and
subsequently acquired by BioMarin. Early in the drug’s development
it was granted Orphan product designation in the US, EU, Japan and
Australia. The program was licensed by GlaxoSmithKline in October
2009. The FDA designated Kyndrisa as a Breakthrough Therapy in
mid-2013, based on positive results from the phase II DMD114117 study.
However, in January 2014, the phase III DMD114044 trial failed to
show a statistically meaningful difference from baseline in the primary
endpoint of distance walked in 6 minutes (6MWD) and GlaxoSmithKline
terminated its collaboration with Prosensa.
The FDA accepted an NDA for Kyndrisa in June 2015, and granted
the filing Priority Review with a year-end PDUFA date. However, in a
November 2015 briefing document prepared by FDA reviewers for
the Peripheral and Central Nervous System Drugs (PCNSD) Advisory
Committee, “clinical efficacy was not established”. The reviewers
stated that biomarker assessment using Western blotting failed to
show increased levels dystrophin with Kyndrisa treatment. Of the three
clinical trials reviewed, the conclusions were almost wholly negative.
Although the phase II DMD114117 trial that assessed continuous or
intermittent treatment with the drug showed an increase in 6MWD

2. of 35 m at 24 weeks in patients receiving continuous treatment, no
clinical benefit was shown with intermittent treatment. Data at the 48-
week timepoint, which the reviewers described as “arguably of greater
interest for understanding efficacy of chronic therapy”, were nominally
negative. The phase II DMD114876 trial also showed negative data, with
a P value of 0.07 in the 6-mg/kg arm for a treatment difference of 27 m,
and numerically inferior results in the 3-mg/kg arm versus placebo.
Results from the larger phase III DMD114044 study were also negative.
The difference in 6MWD of 10.33 m between Kyndrisa and placebo did
not reach statistical significance, and there was no treatment difference
in key secondary assessments of motor function - the 10-m walk/run
test, four-stair climb and North Star Ambulatory Assessment. The
trial had allowed enrollment of patients with more advanced disease
compared with the phase II trials, but a post-hoc analysis of data from
only the patients who met the enrollment criteria of the phase II trials
was also negative with a non-significant increase in walk distance of 5
m compared with placebo. Furthermore, the reviewers also expressed
concerns over the drug’s safety and recommended inclusion of a boxed
warning in the drug’s label, should it be approved. Noted were renal
toxicity in 61% patients, potentially fatal thrombocytopenia in 2% of
subjects and injection site injury (including ulceration, irreversible
scarring and atrophy) in 79% of patients.
Some positives were highlighted in analyst comments in response to the
document; an RBC Capital Market analyst said that the staff reviewers
had not included a vote on the potential approval of the drug in voting
questions put forward to the committee, so it was likely that BioMarin
could still have discussions regarding a path to approval. Similarly, a
Piper Jaffray analyst said that while the document was highly critical
of the drug, the reviewers had not recommended against the drug’s
approval. The FDA issued a Complete Response Letter in January of
this year stating it could not approve the NDF in its current form, and
BioMarin stated that it would collaborate with the FDA to decide the
next steps. While this is ongoing, the company’s Kyndrisa trials are to
continue,asareclinicaltrialsforitsotherexon-skippingoligonucleotides
for DMD: BMN-044; BMN-045; and BMN-053.
BioMarin also filed an MAA in the EU in June 2015, which was validated
by the EMA that month. The opinion of the Committee for Medicinal
Products for Human Use is expected in the second quarter of 2016.
Eteplirsen
Competing for access to the same market as Kyndrisa, and with the
same mechanism of action, is Sarepta’s eteplirsen, which also holds
Orphan designation in the US and EU. The FDA accepted an NDA from
Sarepta with Priority Review status in late August 2015; the conclusion
of the review process is eagerly awaited, and was originally given a
PDUFA date of February 26, 2016. The data under review included
two small exploratory studies (Study 28 and Study 33) assessing
eteplirsen’s potential to increase dystrophin expression, and a efficacy
study comprising a placebo-controlled part (Study 201) followed by an
open-label extension (Study 202).
However, as with Kyndrisa, a briefing document on eteplirsen in January
2016 from the FDA reviewers to the PCNSD Advisory Committee
raised significant concerns. The document questioned the methods
used to confirm both exon skipping and also dystrophin production in
muscle. Although exon skipping was confirmed by reverse transcriptase
polymerase chain reaction in all eteplirsen recipients, the reviewers
noted that the highly sensitive nature of the technique meant that
even a trivial signal could be interpreted as positive, and thus that that
biomarker provided little substantiation of efficacy. Methodological
concerns had been identified in the immunohistochemical methods
used to assess dystrophin production. Although two positive findings
wereseenatre-analysis,thelackofdose-andtime-responseeffectscast
doubt on the positive findings. Dystrophin production was also assessed
used Western blotting, but although increases in dystrophin from 0.3 to
0.9% of normal were seen, the correlation between the two methods
of dystrophin assessment was not strong. Thus Study 201 failed on the
prospective primary endpoint of percentage change from baseline in
dystrophin-positive muscle fibers, preventing the 6MWD clinical benefit
test from being anything more than an exploratory secondary endpoint.
In any event, no significant difference was seen in 6MWD. Various
issues with Sarepta’s post-hoc comparison with historical controls were
additionally identified by the reviewers. However, the reviewers did not
question the safety of the drug as they did with Kyndrisa, and some
analysts expressed the opinion that there was still a chance, albeit
small, of approval for the drug.
The PCNSD Advisory Committee was to discuss eteplirsen on January
22, 2016, but adverse weather warnings caused the meeting to be
postponed. Just prior to the committee date, Sarepta had submitted
4-year clinical effectiveness data, including 6MWD and loss of
ambulation data, to the FDA. In February 2015, the agency responded
that the data submission would result in an extension of the NDA-review
date to May 26, 2016.
Summary
The exon-skipping oligonucleotide-based therapeutics developed by
BioMarin and Sarepta thus have a long way to go before they might
claim to be the only approved disease-modifying drugs for treating
the Orphan disease DMD. Ultimately it remains to be seen whether
BioMarin will forge a pathway for the approval of Kyndrisa and whether
the review of the amended NDA from Sarepta will be more positive than
the review of the initial NDA data.