Rosanna Sutherby, PharmD

The pipeline for hemophilia is brimming with novel treatments, and many have expected FDA approval dates within the next two years.

In a keynote talk at AMCP Nexus 2022 last month, Aimee Tharaldson, Pharm.D., senior clinical pharmacist at Emerging Therapeutics at Evernorth, discussed recently approved and up-and-coming specialty drugs. Among them was an abundance of gene therapies targeting several conditions, including hemophilia.

In her presentation, Tharaldson listed eight gene therapies for hemophilia, some with anticipated approval dates within the next few months. Of the eight, three are specific for hemophilia B, for which currently there are no approved gene therapies.

CSL Behring, in suburban Philadelphia, leads the pack with EntranaDez (etranacogene dezaparvovec) for the potential treatment of hemophilia B. In May 2022, the FDA accepted the company’s biologics license application (BLA), and a decision is anticipated toward the end of this month.

Following close behind is BioMarin’s valoctocogene roxaparvovec, a gene therapy for the potential treatment of hemophilia A. Valoctocogene roxaparvovec has been approved for conditional use in the European Union and is marketed under the trade name Octavian. In the United States, the FDA accepted a BLA for the investigational therapy in October of this year. A decision is expected by June 2023.

Other candidates for hemophilia B gene therapy include Genentech and Pfizer’s fidanacogene elaparvovec and Freeline Therapeutics’ verbrinacogene setparvovec. Fidanacogene elaparvovec is currently in phase 3 trials. Freeline Therapeutics plans to initiate phase 3 studies for verbrinacogene setparvovec in early 2023. Both companies are hoping for FDA approval in 2024.

Pfizer, Genentech, and Bayer also have gene therapy candidates in the pipeline for hemophilia A. These are expected in the market during 2024 and 2025.

Although gene therapy holds promise for improved quality of life for those living with hemophilia, Tharaldson points out that the annual cost of these one-time therapies could be as high as $25 billion by 2034. She also notes that, although some of these therapies have been hailed as potentially curative, there is currently not enough data to confirm this claim.

This article originally appeared on Managed Healthcare Executive.

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CSL Behring's gene therapy, called EntranaDez, may be approved later this month. BioMarin, Pfizer, Bayer and Freeline Therapeutics also have gene therapies for hemophilia in development.

Potential FDA Approval for Gene Therapy for Hemophilia Nears

For many with severe asthma, biologic therapy has changed the way they live with asthma. Biologics have been shown to reduce the frequency of asthma exacerbations, hospitalizations, emergency room visits, and the need for oral corticosteroids in individuals who once had poor asthma control and difficult to treat symptoms. Rather than treating symptoms and exacerbations after they occur, biologics target different cytokines, antibodies, and pathways to prevent asthma symptoms and exacerbations.

However, a patient’s response to a biologic depends on their asthma phenotype. Therefore, choosing the right biologic is crucial for ensuring therapy success. Challenges in determining patient phenotypes can lead to switching or stopping biologic therapy.

In the CLEAR study, an observational, multicenter study, researchers compared the clinical outcomes and emergency healthcare resource utilization in patients with severe asthma who switched, stopped, or continued biologic therapy. Findings were presented at the 

October 2022 American College of Chest Physicians (CHEST) Annual Meeting

The study included 1,859 adults with severe asthma enrolled in the International Severe Asthma Registry from December 2015 through August 2021. Eligible patients had initiated biologic treatment, and the researchers analyzed data from at least 12 months before and 6 months after therapy initiation. Patients were grouped according to whether they continued biologic use (used the first biologic for 6 months or longer), switched biologics (stopped the first biologic less than 6 months after treatment initiation and began using a different biologic), or stopped biologic use (discontinued the first biologic less than 6 months after initiating treatment and did not begin therapy with a new biologic).

The study found that patients who switched or stopped biologic therapy had a higher risk of asthma exacerbation compared with participants who continued treatment. These groups were also more likely to have uncontrolled asthma than those who continued biologic therapy. Additionally, participants who switched biologics had more hospitalizations and emergency room visits and were less likely to have long-term oral corticosteroid dose reduction than patients who continued treatment.

The researchers concluded that switching or stopping biologic treatment in patients with severe asthma leads to worse clinical outcomes and higher emergency healthcare resource utilization versus continuing treatment with the same biologic. They emphasize “the importance of selecting the right initial biologic for continual therapy.” The authors also suggest that “Biologics targeting multiple inflammatory pathways may address the limitations of phenotyping, which may reduce therapy stopping or switching.”

Findings from research presented at the American College of Chest Physicians suggest the importance of selecting the right biologic from the start.

Severe Asthma Clinical Outcomes Worsen After Stopping or Changing Biologics

Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition that occurs in some people after experiencing or witnessing traumatic events, such as military combat trauma, childhood trauma and physical or sexual assault. PTSD is associated with several uncontrolled and debilitating symptoms typically triggered by trauma reminders, including nightmares, intrusive thoughts, flashbacks, hypervigilant behaviors, avoidance of traumatic reminders and sleep disruptions. People with PTSD are often burdened with coexisting disorders, including depression and substance use disorder. An estimated 30% of those with PTSD will die by suicide.

According to the U.S. Department of Veteran Affairs, approximately 12 million adults in the United States have PTSD in a given year. This figure has been rising throughout the COVID-19 pandemic as rates of anxiety and depression increase.

Currently, the gold standard for PTSD treatment is trauma-focused psychotherapy, which can include cognitive-behavioral therapy (CBT), eye movement desensitization and reprocessing (EMDR), cognitive processing therapy and imaginal exposure.

In PTSD, fear extinction deficits contribute significantly to hallmark symptoms of the disorder, such as reexperiencing the trauma through intrusive thoughts, flashbacks or nightmares. Current psychotherapy treatments promote fear extinction learning and can successfully establish new, safe associations with the original memory. However, they do not eliminate the initial fear memory, which often resurfaces.

Paxil (paroxetine) and Zoloft (sertraline) are the only two drugs approved by the FDA in the last 20 years to treat PTSD. These antidepressants can relieve some symptoms of PTSD, but they do not address the core pathology of the condition.

Drugs in development aim to amplify psychotherapy treatments by enhancing fear extinction during exposure therapy. Three agents have novel mechanisms of action and have been granted fast track designation by the FDA. Fast track designation is used to expedite a drug’s development and review process and is given to drugs that treat serious conditions and potentially address unmet medical needs.

Evidence suggests that the endocannabinoid system is critically involved in PTSD pathology. Endocannabinoids are chemicals produced in the body that bind to cannabinoid receptors. Studies have shown that elevated levels of anandamide, a fatty acid neurotransmitter and cannabinoid, promote fear extinction and memory consolidation. Researchers have found that inhibition of fatty acid amid hydrolase (FAAH), the primary catabolic enzyme for anandamide, results in elevated anandamide levels.

Jazz Pharmaceuticals, headquartered in Dublin, Ireland, is developing a FAAH inhibitor for the potential treatment of PTSD. This first-in-class investigational molecule was initially developed by Pfizer under the name PF-04457845. In 2017, Pfizer licensed the agent to Connecticut-based SpringWorks Therapeutics. Pfizer dropped the drug a year after a death occurred during a phase 1 trial of an experimental FAAH inhibitor. It was established that the issue involved off-target activity and is not linked to the drug class. In October 2020, Jazz acquired worldwide rights to the drug from SpringWorks and is now developing it as JZP150.

JZP150, which was granted fast track designation, is currently in a phase 2 trial for the potential treatment of PTSD in adults. The drug is designed to address the fear extinction deficit, which is the root cause of PTSD, as well as anxiety and sleep disturbances associated with PTSD. The trial is enrolling 270 adults with diagnosed PTSD. The primary endpoint will measure changes in clinician-administered PTSD scale, 5th edition (CAPS-5) scores from baseline to week 12. Participants will receive either placebo or one of two once-daily oral doses of JZP150. If things go according to plan, the study will be completed in June 2023.

Research findings have suggested that one possible way of treating disorders such as PTSD would target cholinergic activity and, as a result, quell hyperactivity in the amygdala, a part of the brain involved in emotion and motivation. One of the leading agents with this mechanism of action is BNC210, which, in more technical terms, is a negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. Under development by Bionomics Limited, an Australian biopharmaceutical company, it has also received fast track designation from the FDA for the potential treatment of PTSD and other anxiety disorders.

The ATTUNE phase 2b clinical trial currently underway is evaluating the safety and efficacy of BNC210 oral tablet in adults with PTSD. The primary endpoint is the change in CAPS-5 scores after 12 weeks of treatment compared with placebo. Results are expected in the first half of 2023.

Aptinyx Inc., based in suburban Chicago, has also received fast track designation for its investigational drug NYX-783, an N-methyl-D-aspartate (NMDA) receptor modulator in phase 2 trials for the treatment of PTSD in adults. NMDA receptors play a critical role in the extinction of fear memories. The novel mechanism of NYX-783 works in the brain’s prefrontal cortex, which is central to cognition, to activate glutamate, a major excitatory neurotransmitter.

In a preclinical study, NYX-783 significantly reduced the resurfacing of fear memories in PTSD models. Data from this study were presented at the Society of Biological Psychiatry Annual Meeting in April 2022.

Harald Murck, M.D., Ph.D., vice president of clinical and medical affairs at Aptinyx, said in a press release that “activation of NMDA receptors in the prefrontal cortex is understood to contribute to addressing the underlying glutamatergic dysfunction associated with PTSD. The approach provides an opportunity for a new class of therapeutics.”

In an exploratory phase 2a study, adults with PTSD receiving 50 mg of NYX-783 achieved significantly greater improvement in CAPS-5 scores compared with those in a placebo group. NYX-783 is currently in phase 2 and 3 trials with an estimated completion date at the end of next year.

The pharmaceutical companies Otsuka Pharmaceutical Co., Ltd., and Lundbeck produce and market the atypical antipsychotic Rexulti (brexpiprazole). The companies are currently evaluating a combination treatment of Rexulti and Zoloft (sertraline) for the treatment of PTSD in adults. Rexulti is approved to treat depression in combination with selective serotonin reuptake inhibitors (SSRIs), and schizophrenia as a monotherapy. Zoloft, an SSRI, is approved for PTSD and other psychiatric conditions.

In a phase 2 trial, neither Rexulti nor Zoloft showed significant improvement in PTSD symptoms when used alone. However, when used as a combination, there was significant improvement in CAPS-5 scores after 12 weeks compared with placebo. Although no new safety concerns emerged from the study, it is worth noting that common side effects of Rexulti include insomnia and agitation, conditions that commonly occur among people with PTSD.

The companies are now conducting a more robust phase 3 trial comparing the combination of Rexulti and Zoloft with Zoloft alone or placebo in adults with PTSD. The primary endpoint is the change in CAPS-5 scores 12 weeks after baseline.

The study’s primary results are anticipated in December 2023. If approved, the agent may provide a more affordable option than other drugs in development, given that Rexulti is already on the market and Zoloft is available as a generic.

Several drugs with novel mechanisms of action have been put on the pathway for speedier approval decisions by the FDA. Phase 2 and 3 trials are underway.

PTSD Therapies on the Fast Track

Asthma exacerbations can wreak havoc in patients’ lives. Difficulty breathing can result in frequent trips to the emergency room visits, absences from work and a host of other problems. Asthma exacerbations are also associated with healthcare costs, burdening patients — and society overall — staggeringly high medical bills.

Exacerbations are believed to be a significant but potentially modifiable cause of declining lung function in some people.Loss of lung function over time is associated with comorbidities, including chronic shortness of breath and premature death.

 in August 2022, researchers investigated whether asthma exacerbations are associated with age-specific decline in lung function over time. Using data from the U.K. Optimum Patient Care Research Database (OPCRD), the researchers conducted an observational cohort study of 109,182 patients with active asthma ages 5 to 50 years. The primary outcome was peak expiratory flow rate (PEF) measured in liters per minute (L/min) and an analysis of the correlation between PEF and forced expiratory flow in 1 second (FEV1).

The investigators found that, compared with patients who had no exacerbations, those with exacerbations lost an estimated additional -1.34 L/min PEF per year with each episode. Young adults aged 18 to 24 years with asthma exacerbation rates of 2 or more per year lost an additional -5.95 L/min versus those who did not experience exacerbations. The results were similar with an FEV1 analysis. Increasing age was associated with increasingly smaller differences between the groups, and the correlation was stronger in patients ages 18 to 39 years.

The authors concluded that more frequent asthma exacerbations are associated with faster lung function deterioration. They suggest that early interventions might preserve lung function, particularly in younger patients with frequent asthma exacerbations. They wrote, “This finding underlines the need for a review of the management of patients at risk of accelerated decline before reaching 40 years of age.”

Early interventions might preserve lung function, particularly in younger patients with frequent asthma exacerbations, say authors.

Poor Lung Function Tied to Asthma Exacerbations

Anticipated agency approvals of emerging innovative hemophilia treatments are bound to disrupt healthcare organizations and patient care management. The pipeline includes subcutaneously administered coagulation factor replacements, treatments with a longer duration of action and potentially curative gene therapy.

 in September 2022, researchers evaluated the perceived impact of up-and-coming hemophilia treatments on healthcare organizations. The study took place in a hemophilia treatment center in Chambery, France. The investigators arranged a multidisciplinary expert group in hemophilia care management consisting of three physicians, three nurses, two pharmacists, one physiotherapist, and one psychologist. Using the multiple criteria decision analysis (MCDA) approach, a tool used to facilitate decision-making when various criteria need to be considered, the researchers used the following seven steps to complete the study: 1) defining the decision problem, 2) selecting and structuring criteria, 3) weighing criteria, 4) measuring performance alternatives, 5) generating a performance score, 6) calculating aggregate scores, and 7) deliberation.

Healthcare professionals in the study answered questions regarding hemophilia treatment innovations and their anticipated impact on their organization. An online software was used to weigh each answer, and aggregate scores were generated. The criteria with the strongest weight were “acceptability for patient/care-giver/association” (weight of 31.4%), “number of emergency or unscheduled consultations” (weight of 20.3%), and “complexity of the innovation choice” (weight of 16.6%).

Innovations were given aggregate scores of 0 to 100, with the highest scores representing low impact on the healthcare organization. The two treatments with the highest aggregate scores were very long-acting recombinant replacement factor (88.8) and subcutaneous recombinant replacement factor (87). Low scores were associated with gene therapy (27.3) and anti-antithrombin RNA (21.9). Acceptability was perceived to be low for these treatments, and the therapy was considered complex and difficult to explain to patients.

Lead author Karen Beny and her colleagues suggest that discoveries made in this study can be used to guide organizational changes in anticipation of emerging hemophilia treatments. They emphasize that this type of sresearch should be repeated in other hemophilia treatment centers. The authors comment, “A better understanding of the nature and strength of the organizational impact of a therapeutic innovation should allow for a better match between therapeutic choice and individual’s health determinants (biological characteristics, family environment, local health system, cultural context, etc.), to understand the most suitable patient support, and to ensure an optimal healthcare pathway, reducing the risk of dropouts.”

Long-acting recombinant replacement factor gets favorable rating from multidisciplinary group. Gene therapy was viewed with some wariness.

Assessing Up-and-Coming Hemophilia Treatments

People with plaque psoriasis have a number of treatment options: topical agents, phototherapy, oral treatments and biologics. And now drugmakers are vying to create even more.

In front of the queue is Vtama (tapinarof) cream 1%, the first nonsteroidal topical agent approved to treat plaque psoriasis. Developed by Dermavant Sciences, a biotech company in Morristown, North Carolina, Vtama is a cream containing an aryl hydrocarbon receptor agonist. Aryl hydrocarbon receptors play a crucial role in the immune response and the body’s response to pollution and other exogenous factors.

Otezla (apremilast), an oral phosphodiesterase 4 (PDE4) inhibitor developed by Amgen, was approved by the FDA in December 2021 as a treatment for plaque psoriasis in adults. Adverse effects, such as severe vomiting and diarrhea or depression, may preclude certain patients from using this medication.

Roflumilast cream is a topical PDE4 inhibitor developed by Arcutis Biotherapeutics, a Southern California biotech company. PDE4 is an enzyme that promotes inflammation; inhibiting it downregulates the inflammatory cytokines responsible for symptoms of plaque psoriasis.

Following positive results from phase 3 trials DERMIS-1 and DERMIS-2, the company filed a new drug application with the FDA for the use of roflumilast cream 0.3 % once daily in the treatment of plaque psoriasis in adults and adolescents.

The FDA approved the roflumilast cream on July 29. The cream, which Arcutis is marketing under the brand name Zoryve, became available on Aug. 10, according to a company media release. Zoryve joins Vtama as a nonsteroidal topical agent for plaque psoriasis.

Meanwhile, Bristol Myers Squibb is developing deucravacitinib, an oral treatment that the company says would be the first tyrosine kinase 2 (TYK2) inhibitor. TYK2 is member of the Janus kinase (JAK) family. By homing in on TYK2, deucravacitinib inhibits signaling of interleukin (IL)-23, IL-12 and type 1 interferons, which are heavily involved in plaque psoriasis pathology. Bristol Myers Squibb says that deucravacitinib’s selectivity — it doesn’t affect JAK1, JAK2 or JAK3 — could mean that it won’t have the risk of serious side effects, such as heart attack and blood clots, that other JAK inhibitors do.

In phase 3 trials, more participants taking deucravacitinib achieved clear or almost clear skin compared with those taking placebo or Otezla. Moreover, fewer participants taking the TYK2 inhibitor discontinued treatment due to adverse events than those taking placebo or Otezla.

Deucravacitinib is under review by the FDA, with a decision expected by September 2022.

Bimzelx (bimekizumab) is a selective IL-17A and IL-17F inhibitor developed by UCB, a Belgian pharmaceutical company. IL-17A and IL-17F are highly active cytokines in the inflammatory process of plaque psoriasis. In phase 3 trials, bimekizumab, which is administered by injection, showed promising results compared with other systemic biologics.

But UCB has run into problems gaining FDA approval for Bimzelx. COVID-19 restrictions prevented the agency from inspecting the UCB manufacturing facility, and then the FDA issued a complete response letter because of problems it identified during the inspection. But Bimzelx has been approved as a treatment of plaque psoriasis in the European Union, Great Britain, Japan, Canada and Australia.

Pfizer has two plaque psoriasis drugs that are earlier in development. PF-07038124, another topical PDE4 inhibitor, is in phase 2 studies. PF-06826647 is an oral TYK2 inhibitor, and results from a phase 2 study showed that it was significantly more effective than placebo in treating plaque psoriasis.

Nonsteroidal topical agents and TYK2 inhibitors may join an already full armamentarium.