- U.S. Food and Drug Administration requests additional Phase
3 study
- Issues raised in CRL echo those discussed in FDA Advisory
Committee hearing
- The Company intends to pursue all available regulatory
pathways to expeditiously bring a potential new treatment to the 13
million Americans who live with PTSD, a condition that has not had
new treatments available for nearly 25
years1,2
SAN
JOSE, Calif., Aug. 9, 2024
/PRNewswire/ -- Lykos Therapeutics ("Lykos"), a company dedicated
to transforming mental healthcare, announced that the U.S. Food and
Drug Administration ("FDA") has issued a complete response letter
("CRL") for the new drug application ("NDA") for midomafetamine
capsules for the treatment of post-traumatic stress disorder
("PTSD") in adults. The FDA communicated that it had completed its
review of the NDA and determined that it could not be approved
based on data submitted to date. The FDA has requested that Lykos
conduct an additional Phase 3 trial to further study the safety and
efficacy of midomafetamine. Lykos plans to request a meeting with
the FDA to ask for reconsideration of the decision and to further
discuss the agency's recommendations for a resubmission seeking
regulatory approval for midomafetamine capsules.
The issues expressed in the CRL echo those raised during the FDA
Advisory Committee meeting on June 4,
2024. The Company and other stakeholders have expressed
concerns around the structure and conduct of the Advisory Committee
meeting, including the limited number of subject matter experts on
the panel and the nature of the discussion, which at times veered
beyond the scientific content in the briefing documents. FDA itself
has acknowledged potential problems with the Advisory Committee
process and has opened a public docket seeking comments on how it
can be improved.
Lykos has previously published its response to the substantive
issues discussed at the Advisory Committee hearing. Among others,
this included concerns that Lykos' clinical data were insufficient
to demonstrate durability along with questions about expectancy
bias stemming primarily from participants with prior MDMA use.
Lykos believes that the data included in the NDA provide sufficient
evidence of efficacy and durability in line with the relevant FDA
guidance. FDA's draft guidance for industry on psychedelic
drugs3 indicates that endpoint data should be
collected at 12 weeks; Lykos' Phase 3 studies collected endpoint
data at 18 weeks, with additional exploratory endpoints collected
six months or more later. In addition, Lykos had aligned with the
FDA in the Special Protocol Assessment ("SPA") in 2017 on a variety
of bias minimization measures in the study design. Prior MDMA use
among participants was not previously viewed as detrimental. As an
example, nearly 30% of participants in Lykos' Phase 2 studies
reported prior use, which was shared with FDA before establishing
the inclusion and exclusion criteria in the Phase 3 trial
design.
The Advisory Committee panelists also raised psychotherapy as a
concern, with some recommending to further characterize the extent
to which psychotherapy contributes to treatment benefit and if it
is even necessary. Lykos acknowledges that midomafetamine-assisted
therapy represents a novel combination of drug and therapy that
raises unique research questions and will continue to engage the
FDA as appropriate on these challenges. Lykos remains committed to
continuing development of this integrated approach.
"The FDA request for another study is deeply disappointing, not
just for all those who dedicated their lives to this pioneering
effort, but principally for the millions of Americans with PTSD,
along with their loved ones, who have not seen any new treatment
options in over two decades," said Amy
Emerson, Chief Executive Officer of Lykos Therapeutics.
"While conducting another Phase 3 study would take several years,
we still maintain that many of the requests that had been
previously discussed with the FDA and raised at the Advisory
Committee meeting can be addressed with existing data,
post-approval requirements or through reference to the scientific
literature."
Lykos will work diligently in the coming months to address FDA's
concerns and to take advantage of agency processes to resolve
scientific disagreements. Following the FDA
meeting, Lykos expects to provide an update on next steps
for the resubmission.
Emerson added, "Our heart breaks for the millions of military
veterans, first responders, victims of sexual and domestic abuse
and countless others suffering from PTSD who may now face more
years without access to new treatment options. We intend to work
tirelessly and use all available regulatory pathways to find a
reasonable and expeditious path forward for patients who deserve
access to midomafetamine-assisted therapy for PTSD."
As noted above, Lykos negotiated a SPA with the FDA in
2017. Breakthrough Therapy designation was granted that same year.
On February 9, 2024, the FDA accepted the company's
NDA for midomafetamine used in combination with psychological
intervention for adults with PTSD and granted the application
Priority Review.
"Developing the first-ever clinical trial design to assess the
safety and efficacy of midomafetamine-assisted therapy with
patients suffering from moderate to severe PTSD is an enormously
complex undertaking," said Jennifer
Mitchell, Ph.D., Professor of Neurology and Psychiatry
and Behavioral Sciences at UCSF. "Over the course of many years,
the researchers, with the support of our sponsor, Lykos, developed
and executed Phase 3 studies that we believe demonstrated
the approvability of this treatment. We did so in consultation
with the FDA and with an agreed Special Protocol Assessment in
place. The FDA's decision to request another Phase 3 study is a
major setback for the field."
Midomafetamine capsules have not been approved by any regulatory
agency. The safety and efficacy of midomafetamine have not been
established for the treatment of PTSD. Investigational
midomafetamine is also being studied in other
indications.
About PTSD
Prevalence and symptoms
PTSD is a serious mental health condition that can develop when a
person experiences or witnesses a traumatic
event.4 PTSD affects approximately 13 million
Americans each year with women and disadvantaged or marginalized
groups more likely to be
affected.5,6 Military personnel also
have a greater prevalence of PTSD than the general
population.7 However, it may not be as widely known
that the largest cause of PTSD is non-combat-related trauma (e.g.,
sexual violence, unexpected death of a loved one, life-threatening
traumatic event or interpersonal violence).8 PTSD
results in debilitating symptoms including nightmares and intrusive
thoughts related to the trauma, mental and/or physical distress in
response to trauma-related stimuli, avoidant behaviors, negative
thoughts and feelings, and hyperarousal.9 These
symptoms can impact nearly all aspects of a person's life,
including their interpersonal relationships.4 PTSD can
also be a chronic condition with a World Health Organization study
showing that after ten years post-trauma, nearly a quarter of
people had not recovered.10
Co-morbidities and economic impact
People with PTSD frequently experience anxiety, depression,
substance use disorder and suicidal ideation.11,12 They
also may have a greater incidence of medical conditions that impact
their physical health, including heart disease, metabolic syndrome
and asthma.13,14,15,16 U.S. Army
veterans who developed PTSD after military service have been shown
to have approximately two times greater risk of mortality than U.S.
Army veterans who did not develop PTSD after military
service.15 In addition to the significant personal
impact, PTSD has an enormous economic impact, resulting in an
estimated annual cost of over $232 billion in the
United States.13
PTSD treatment
Trauma-focused talk therapy,
which concentrates on memories of the traumatic event or thoughts
and feelings associated with the traumatic event is first-line
treatment for PTSD, which can be used alone or in combination with
medication.17 There are two SSRIs approved for the
treatment of PTSD (sertraline and
paroxetine).18 Studies have shown talk therapy
lessens the severity of PTSD symptoms, however, improvements in
functioning and quality of life have been
modest.19,20 Trauma-focused talk
therapy is associated with a high risk of dropout and lingering
symptoms which occur in as many as two-thirds of people who
complete treatment.21,22 Current
treatments for PTSD are "reasonably efficacious" (Bryant, 2019,
p.265), however many people don't respond to treatment or stop
treatment early, underscoring the urgent need for new
evidence-based therapies and approaches to address this important
public health issue.2 While there have been advancements
in the management of PTSD, there have been no new drug treatments
approved by the FDA in over twenty years.23
About Midomafetamine-Assisted Therapy
Midomafetamine (MDMA) is commonly known to mental health
professionals. In the 1970s and early 1980s, MDMA was used in
conjunction with talk therapy by mental health providers to help
enhance patients' access, processing and communication of difficult
emotions and experiences.24 MDMA is an entactogen—
a class of psychoactive compounds that are differentiated from
classic psychedelics (i.e., psilocybin, mescaline and LSD) and are
defined based on their mechanism and demonstrated effects of
increasing self-awareness leading to introspection and personal
reflection.25,26
In 1985, the U.S. Drug Enforcement Administration ("DEA")
made MDMA a Schedule I drug under the Controlled Substances Act,
preventing it from being used for recreational or medical
use.27 Since then, research has suggested that MDMA
may have potential as a catalyst to support psychotherapy by
helping diminish the brain's fear response, allowing people to
access and process painful memories without being
overwhelmed.28
Lykos, with longstanding roots in advocacy for psychedelic
medicine, was the first company to pioneer randomized,
double-blind, placebo-controlled clinical trials evaluating the
efficacy and safety of MDMA-assisted therapy as an investigational
modality using midomafetamine (MDMA) in combination with
psychological intervention and submit an NDA to the FDA seeking
approval for the treatment of PTSD in adults.
Lykos Therapeutics
At Lykos Therapeutics, a public benefit corporation ("PBC") founded
by the Multidisciplinary Association for Psychedelic Studies
("MAPS"), our mission is to transform mental healthcare. We're
applying decades of evidence-based research to develop
investigational psychedelics to catalyze therapeutic approaches for
mental health conditions. We are relentlessly exploring and
reimagining novel approaches to address unmet needs in the mental
healthcare space, with an initial focus on PTSD. As a PBC, we are
focused on delivering positive impact on our people, communities
and society. To learn more visit us at www.lykospbc.com and on
LinkedIn, X, Instagram and Facebook.
1 VA National Center for PTSD. US Department of
Veterans Affairs. Accessed August 9,
2024.
https://www.ptsd.va.gov/understand/common/common_adults.asp
2 Stein MB, Rothbaum BO. 175 Years of progress in
PTSD therapeutics: Learning from the past. Am J Psychiatry.
2018 Jun 1;175(6):508-516. doi:
10.1176/appi.ajp.2017.17080955
3 Psychedelic Drugs: Considerations for Clinical
Investigations. Guidance for Industry (Draft Guidance).
https://www.fda.gov/media/169694/download
4 The Mayo Clinic, PTSD, symptoms and causes.
Accessed February 14,
2024. www.mayoclinic.org/diseases-conditions/post-traumatic-stress-disorder/symptoms-causes/syc-20355967c
5 VA National Center for PTSD. US Department of
Veterans Affairs.
https://www.ptsd.va.gov/understand/common/common_adults.asp
Accessed May 13, 2024.
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Psychiatr Epidemiol. 2016; 51(8):1137–1148.
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9 Bryant RA. Post-traumatic stress disorder: a
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Psychiatry. 2019;18(3):259–269.
10 Rosellini AJ et al. Recovery from DSM-IV
post-traumatic stress disorder in the WHO World Mental Health
surveys. Psychol Med. 2018 Feb;48(3):437-450. doi:
10.1017/S0033291717001817
11 Grinage B.D. Diagnosis and management of
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13 Edmondson D, von Känel R. Post-traumatic stress
disorder and cardiovascular disease. Lancet Psychiatry. 2017
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14 Krantz DS, Shank LM, Goodie JL. Post-traumatic
stress disorder (PTSD) as a systemic disorder: Pathways to
cardiovascular disease. Health Psychol. 2022
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Ann Epidemiol. 2006 Apr;16(4):248-56. doi:
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16 Nichter B, Norman S, Haller M, Pietrzak RH.
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21 Lewis, C., Roberts, N. P., Gibson, S., &
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SOURCE Lykos Therapeutics