No, see post on history of FDA evaluation of drugs for orphan disease since 2010, and
Sasinowski, Quantum of Effectiveness Evidence, found on an FDA website as relevant
to how they exercise flexibility and scientific judgment. Multiple instances of administrative
flexibility or case by case judgement. No dangerous precedent.
Historically, need for adequate and well controlled trials. Guidance in May 1998 about evidence for effectiveness, at about the same time FDAMA 115 modified to 1 adequate and well controlled trial and confirmatory evidence. 2012 FDASIA Sec 901 adopted by legislation AA standards formerly set forth in Subpart H, allowing use of 1) surrogate endpoint or 2) ICE Intermediate Clincal Endpoint. FDA updates 1998 Guidance by Guidance for Expedited Approval, breakthrough therapy, and, relevant here, Accelerated Approval. Study of orphan drug approvals since 2010 indicates, 8 used conventional evidence standard, 19 administrative flexibility, 5 case by case flexibility and exercise of judgement.
Factors FDA uses to determine AA flexibility and exercise judgement include A) knowledge of underlying disease process B) relationship between surrogate or ICE and clinical benefit (the reasonably likely to show clinical benefit issue) and C 1 and 2 C1 strength of evidence about surrogate or ICE and c2 strength of evidence about clinical benefit. For Eteplirsen, we have: A) Good knowledge about disease -caused by lack of dystrophin B) dystrophin-debate about relationship of dystrophin and clinical benefit, but logically, if you make dystrophin, muscles will stabilize C1) Range of evidence about dystrophin - .09WB but 16-20% PDPF, 100% mRNA C2) 6Mwt, LOA, Pulmonary- appear to be much better than NH disease course; PRO and Physician reports say benefits remarkable. Overall - strong case for "flexibility" within context of FDA history and legislation providing for use of surrogates/ICE/scientific judgement.
From Sasinowski Quantum of Effectiveness Evidence, for background, conclusions about Eteplirsen inferred by this poster, use your own due diligence, but FDA can clearly act within its mandate and precedent to
approve this drug for significant unmet medical need.
The results of this study show that for just over two-thirds of all
noncancer orphan drugs approved between July 1, 2010, and
June 30, 2014, FDA did not require the orphan drug applica-
tions to provide the conventional level of proof of effectiveness
that is ordinarily expected.
Also cites Woodcock testimony to Congress. Worth a read Sasinowski (sic)
Quantum of Effectiveness is actually quite positive for a case like Eteplirsen and DMD
If you go to the Sarepta website, and the tab on genetics, you can find out what is going on for "your" exon.
And if you specify Exon 45, you get
Clinical trials will be starting in Europe shortly, or something like that.
This suggests,although not certain, that their Pediatric Investigation Protocol (PIP) agreement with
Europe medical agency is almost ready. If they get approval in US, and get a PIP for clinical studies of
other exons in Europe, they will own the worldwide Duchenne space for a while.
Holding off this PIP until the US plays out is smart.
Muntoni Mendell McDonald, Barry Byrne Kathryn Wagner Ann Connelly, Sue Fletcher , "I discovered Drstrophin" Kunkel, A Reghan Foley, Ovbiagele, Rommitti, Green, Hoffman, Dupree, Gunvalson, "I know it produces dystrophin" Woodcock, aaaannnnnd. Adam Feuerstein. yep, people want to be on the right side of history.
Cheri Gunvalson, talking about dystrophin, was saying, I know hundreds of boys with DMD, and these boys are obviously benefitting from this drug (ie, confirming drug effect from whatever dystrophin produced) but
the "Chair" cut her off, saying we're talking about dystrophin we'll talk about benefits later. THIS IS WRONG, CLINICAL BENEFITS WERE RELEVANT TO DYSTROPHIN ISSUE OF WHETHER ENOUGH PRODUCED.''
2) Vote: Has the Applicant provided substantial evidence from adequate and well controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit?
This is the standard for AA.
Is Eteplirsen likely to meet the standard for approvability.
Must factor in clinical data. What weight does it give to the decision?
Whether or not dystrophin is increased?
Reasonably likely – no standard established.
Threshold – not established for DMD.
Does the clinical experience in these pts: Is it reasonably likely to predict clinical benefit?
MUST FACTOR IN CLINICAL DATA DOES CLINICAL EXPERIENCE IN THESE PATIENTS SUGGEST
REASONABLY LIKELY TO PREDICT CLINICAL BENEFIT. DENYING WEIGHT TO CLINICAL DATA
SKEWS DECISION AND VOTES.
PPMD IS RIGHT AND CHAIR OF FDA ADVISORY COMMISSION WRONG WRONG WRONG.
Correction, with Obviagel, there were 7 in favor in their view of the evidence on either accelerated or full approval, Foley was positive for both votes. But they need to heed those 7
We know Foley and Obviagale thought there was proof the drug works, R Foley voted for full approval, Ovbiagele said everything he heard said the drug works, but voted no, And 6 others voted for Accelerated Approval based on dystrophin production (which Woodcock acknowledged was proven in her remarks.) So a majority 8 was in favor of either accelerated or full approval, despite the lousy questions.
The ill-prepared FDA presentation on eteplirsen was accompanies by an irrelevant and improper attack on historical controls by referring to other trials, when the only issue was, were these historical controls, suggested by FDA, comparable to the degree possible within the rare disease data available, Confusion about the questions (NSAA - who's an expert on NSAA??) was palpable. And one standing member of the PCNS committee, Merit Cudkowicz, was missing. An expert on biomarkers and genetic diseases including ALS.
All in all, an extremely poor performance of the new FDASIA funded FDA. The only real (simple) questions were; Did eteplirsen produce dystrophin -yes using multiple measures; Was dystrophin production associated with clinical benefits - yes. Does the corroboration of dystrophin production and significant clinical benefits provide substantial evidence of efficacy - yes. Testimony of 13 boys (Max + Austin) proved it.
The clearest path to approval is based on the Addendum, which wasn't discussed - they only had an AA question on dystrophin, and a full approval Question based on who knows what each panel member thought.
But the Addendum, which provoked the Major Addition and PDUFA extension, was over the non Loss of Ambulation data. LOA can be considered an intermediate clinical endpoint, and a basis for AA in itself. So if the
FDA wants to save face, it can say, based on the new LOA data, and combined with the dystrophin, although uncertain, and the patient reports and the significant unmet need, we are granting Accelerated Approval with the following conditions, report ongoing Exon 51 efficacy, report any safety issues, etc.
LOA to AA to Phase IV confirmatory trials. May 25 is a Wednesday. Anytime that week is possible.
There was no question about the acceptability of its safety profile like there was in last question for drisapersen. You heard only positive stories from the patients and FDA on safety. Ace in the hole for Eteplirsen given FDA's oft stated 'commitment to getting new drugs to patients as long as they can be shown safe and effective' the last words from a panel member were everything I heard today says it works (but that wasn't the way FDA framed the question ((unfortunately))
Eggzactly - who on the panel of patient represenatives and stroke neurologists and biostatisticians is supposed to be an expert on the phenotype of Beckers Muscular Dystrophy and their dystrophin levels: Multiple types of individual deletions; multiple delections as well (45-49), severe, mild, and asymptomatic cases. You simply cannot say, if you are producing some dystrophin, whether 17% under immunofluoresence or 0.9% with range of 0.35-2% WB, that that is not producing an effect, especially where there is a clinical benefit of 6mwt/LOA/FVC all indicating delayed disease progression or stabilization. You cannot say Oh well, we know what BMD is and therefore can compare the results to our detailed knowledge of BMD.
Rather they should be saying, its clear its producing some dystrophin, we're not sure how much, but the
fact of dystrophin corroborates the apparent significant clinical benefits.
People are talking about you need this dystrophin level and that dystrophin level, but Sarepta, and the Moms
1. No one really knows what is the best way to measure dystrophin - so the fundamental logic is you look
at it in as many measurable ways as possible, and try to draw a conclusion from the bulk of the evidence
RTPcr evidence 100% of all measured patients showing MOA by rtPCR for MRNA 100%
Dystrophin positive fibers: Ash Rao of FDa has already acknowledged if the immunofluorescence
change is greater than about the 4% variability of the measure, its showing some change, read
increase, in the dystrophin levels. IF evidence +17% at very least, means WELL BEYOND
NOISE LEVEL IN INDICATING DYSTROPHIN PRODUCTION.
WBlot: FDA says this is the most accurate, but at the most its semi-quantiative. Claiming
WB is the best evidence is like saying a shotgun is more accurate than a pistol. Truncated
exon-skipped dystrophin may not react to the antibodies the same way.
AND EVEN THE WB, SOME OF THE RESPONDERS ARE IN THE 2% LEVEL, NOT 0.9%
2. Even more important than using different measures, NO ONE KNOWS HOW MUCH
DYSTROPHIN IS NECESSARY TO PRODUCE A CLINICAL BENEFIT. The Karen Anthony, 2011
et al paper on dystrophin levels in DMD and Beckers MD, discusses patients with mild
symptoms, cramps, or asymptomatic with 40% levels. BUT WE DON'T NEED TO GET
TO MILD BMD OR ASYMPTOMATIC, we're just trying to keep the DMD patients
alive and functional for as long as possible. So there is A STAGE BETWEEN DMD
AND BMD where Eteplirsen can extend ambulation, enhance cardiac strength,
and stabilize pulmonary volume. That might be 1%, 2%, 5%, 8% 10% - nobody
knows what is necessary to delay disease progression and extend function.
3. If there is Dystrophin being produced (by at least 2 3 measures, maybe 3/3)
and if there is clinical benefit by 3 or 4 measures (6mWT/ LOA/Ejection fractions/pulmonary)
there is SUBSTANTIAL EVIDENCE
P. 7, 1. Expression of the Expected mRNA in Muscle
"....it does provide evidence that Eteplirsen causes at least some degree of exon 51 skipping as intended."
Immunofluorescence p. 9
The applicant argues that "duration of therapy was observed to be the critical variable when interpreting dystrophin levels. 12 weeks does not represent a clinically relevant duration of therapy." ...Applicant considered increases in dystrophin-positive fibers after 12 weeks of treatment as possible, and it remains that the negative findings at a higher dose of Eteplirsen at Week 12 weaken the findings at Week 24 . (This is of course, blatant nonsense by FDA. Protein restoration takes time, and Sarepta has, as indicated, said duration is more important than dose. )
3. Clinical Effects Reflecting Muscle Function. P12, 15
...in the context of an ongoing series of reports from the applicant and its academic associates describing marked effects on dystrophin production and stabilization of disease progression, many in the DMD community had strong reservations regarding the ethics and practicality of conducting another placebo-controlled trial of Eteplirsen....Considering the entirety of the data submitted, we seek the Committee's opinion on whether there is convincing evidence that the clinical course of the 12 patients participating in Study 201/202 differs appreciably from the expected natural history of DMD...Compring 6MW distance in eteplirsen-treated patients to control patients observed for a similar duration, the applicant describes nominally significant results in favor of Eteplirsen in Study 202, with a difference of 148 meters compared to the external control at Year 3, and 162 meters at year 4.
Clinical safety p. 21
NO SAFETY SIGNAL OF SIGNIFICANT CONCERN HAS BEEN IDENTIFIED FOR ETEPLIRSEN.
P. 86 Based on the CINRG data, about 25% of exon-skip-able patients maintain ambulation to age 16, and about 15% of patients to age 18. Fig 21 (not 100% ambulatory after 4 years 25%)
Merit Cudkowicz’s research and clinical activities are dedicated to the study and treatment of patients with neurodegenerative disorders, in particular amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Her clinical research team conducts experimental therapeutic trials of novel agents and biomarker studies in people with ALS and HD.
Rocket science is passé. In view of the current state of knowledge of sense, antisense, peptide morpholinos and exon-skipping, the current usage would be, It shouldn't take a gene jockey to understand that Exon 51 boys treated with Eteplirsen have experienced significant clinical benefits and show improvement in the dystrophin bio marker. The 21st century is the century of biology at the mRNA level. And this AdCom will be a landmark in precision medicine, leading to new clinical regime protocols for rare diseases and follow-on personalized medical therapy.
This comparison demonstrated a clinically significant 153 meter benefit in 6 minute walk distance after 3 years of treatment with eteplirsen relative to external controls. Evidence of persistent dystrophin
induction in serial muscle biopsies from treated boys establishes mechanism of
action and provided further support for a treatment effect
So a clinical benefit and corroboration by showing a protein mechanism of action produced.
Forthcoming article - I would not say "proof," but rather consistent, cumulative empirical evidence
From Nov 24 transcript about p. 396 on they ask about dystrophin. Bagiella: Are there precliniccal studies that show drug actually increases the level of dystrophin? 405 Onyike: Are there studies of dystrophin in lab animals which resulted in a measurable amount? 405 Farkas: there looked to be support for the mechanism in non-clinical trials that there was detectable dystrophin and a change in condition of the animals. 417 Nuckolls
I think that increased dystrophin above noise levels is a required signal for function of this drug.
So Sarepta, and experts will have to be prepared to say
1. Yes, prior studies, animal stuideshave shown the increased dystrophin is related to improvement in function
See Effective rescue of dystrophin improves cardiac function in dystrophin deficient mice, Wu, Moulton, Sep30 2008, and the videos of dogs. Its a good biomarker, it may be an ideal biomarker.
2. The dystrophin produced is clearly above the noise level, it is not a negligible increase. As Dr. Rao has
previously noted, an increase in immunofluorescence of more than than the 4% assay variability is an indication of actual dystrophin increase. (Rao tends to get caught up in weeds of measurment complexity)
3. Finally, again and again, duration is more important than dose. 12 weeks of dosing cannot be considered
enough to say dystrophin is not produced, 24, 48 weeks, the longer dosing the better.
In sum, actual, non-negligible dystrophin production corroborates, not controverts, the significant clinical benefits seen in eteplirsen treated patients.
Now lets see if the briefing documents reflect common sense about rare disease therapy and trials.
There is no specific minimum number of patients that should be studied to establish effectiveness
and safety of a treatment for any rare disease. The number of patients to establish effectiveness
and safety is determined on a case-by-case basis,taking into consideration the persuasiveness of
the data (e.g., comprehensiveness and quality), the nature of the benefit provided (or expected in the case of surrogate endpoints), the length of treatment or exposure, the patient population that
would be treated after marketing approval, and the concern for potential of harm from the the treatment
Reading up from the bottom
Eteplirsen, no serious adverse effects, a neutral charged PMO
Length of treatment: 4 years for initial group, now 100 plus with other exon trials
Benefit: serious unmet medical need to prevent progressive loss of walking, pulmonary function, cardiac function and ultimately mortality
Persuasiveness of data: dramatic improvement in walking ability, + 150 meters v. untreated
comparable cohort; No loss of ambulation v 80% loss in untreated natural history group; pulmonary function
Significant Clinical benefits corroborated by multiple forms of proof of production of key protein which
demonstrated Mechanism of Action, ie restore dystrophin, even in truncated, form, and while
difficult to measure, clearly shown as produced by drug at above noise level, 18-25% dystrophin
positive fibers, 100% shown by rt-PCR.
This is empirical evidence for approval based on efficacy and safety. If the RDR guidance is applied,
should be approvable.
I don't know that a change in authorship has or will occur, but it is clear that there is a hierarchy something like this: Cailiff is the Sec of Defense, Woodcock is the Captain of the Carrier, Dunn is the CAG (Air Group Commander) and Farkas is a squadron leader-does what is told, carries out the mission. But if you read the Nov 24 transcript very carefully, you will see that Dr. Dunn clarifies points when necessary - at Tr. 361 Paul Romittee asks, when do we get to talk about totality of data, and Dunn, 362, says Q 9 where you get to discuss all the different aspects discussed today' then Tr371-375, Farkas says we'll do whatever is scientifically supportable for indications on labeling, AdComChair Alexander summarizes FDA would not object to effect of 10 meters if real, Farkas adds, certainly risk benefit too, and Dunn ends with 6minute walk test and any "clinically meaningful difference" would be an acceptable outcome measures. So they're looking for efficacy, any meaningful clinical benefit, and acceptable risk/benefit profile. Which is what they'll see April 25, and what the mothers should repeat -clinically meaning benefit for 6Mwt and no Loss of Ambulation and no SAEs, along with MOA proof through dystrophin production
FDA really going after opioids, new guidance just issued General Principles for
Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products Guidance for Industry
probuphine is right up the alley of the FDA's initiatives to deal with the crisis of use and
overuse of these drugs.