2022’s Top Clinical Advancements: See Pivotal Data in NASH, Alzheimer’s, Sickle Cell Disease

2022 featured pivotal data that could change the landscape in non-alcoholic steatohepatitis, Alzheimer’s disease, sickle cell disease and many more indications.

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Though much of the attention in the biopharma industry focuses on FDA approvals, those cannot happen without what is arguably the most important - and underrated - news: clinical trial wins.

Without success in clinical trials, there would be no new treatments available to patients. Fortunately, 2022 saw pivotal data that may change the landscape in non-alcoholic steatohepatitis (NASH), Alzheimer’s disease, sickle cell disease (SCD) and many more indications. Some of these milestones could lead to approvals in the new year.

BioSpace takes a look at the top clinical advancements of 2022.

The First NASH Treatment?

On Dec. 19, Madrigal Pharmaceuticals announced that resmetirom, its investigational treatment for NASH, hit both primary endpoints and a key secondary endpoint in a pivotal Phase III trial.

If approved, resmetirom would be the first treatment on the market for this intractable disease, which is defined by an excessive build-up of fat in the liver.

Several companies, including Gilead Sciences, Novo Nordisk and Intercept Pharmaceuticals have tried and failed to conquer NASH. There are more than 300 clinical trials currently underway in the space.

Madrigal plans to submit the therapy to the FDA for accelerated approval in the first half of 2023.

Lecanemab Revives the Anti-Amyloid Theory

Results from Biogen and Eisai’s Phase III CLARITY AD study of lecanemab went a long way to reviving the deflated anti-amyloid approach to treating Alzheimer’s disease.

The data, presented in September, showed lecanemab, an anti-amyloid beta antibody, reduced clinical decline in patients with mild-to-moderate AD by 27% compared to placebo after 18 months based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment.

While the Alzheimer’s Association called the data “the most encouraging results in clinical trials treating the underlying causes of Alzheimer’s to date,” the trial has since been marred by reports of patient deaths attributed to lecanemab.

During the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, Marwan Sabbagh, M.D., a behavioral neurologist at the Barrow Neurological Institute, pointed to possible co-morbidities and said the two cases “show that the causality with lecanemab is a little difficult” to establish.

Nonetheless, the potential approval lecanemab is one of the most anticipated moments of 2023.

Donanemab Outduels Aduhelm

When a clinical advancement occurs, scientists will do their best to top it. That’s the beauty of science, and Eli Lilly’s donanemab is a perfect example.

The investigational antibody outperformed Biogen’s Aduhelm (aducanumab-avwa) – the first approved Alzheimer’s therapy in eighteen years – in the Phase III TRAILBLAZER-ALZ 4 study.

After six months, donanemab led to brain amyloid clearance in 37.9% of patients compared to 1.6% of Aduhelm-treated individuals. It was the first active comparator data on amyloid plaque clearance in patients with early symptomatic Alzheimer’s treated with amyloid-targeting therapies.

Donanemab also outperformed Aduhelm in a key secondary endpoint, reducing brain amyloid levels vs. baseline by 65.2% compared with 17% for Aduhelm at six months.

Exa-cel could Make History

The FDA could be on the cusp of approving the first CRISPR therapy for a genetic disease.

The regulator granted a rolling review for exagamglogene autotemcel (exa-cel), co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics.

Exa-cel is being developed as a one-time treatment for SCD and transfusion-dependent beta-thalassemia (TDT).

The decision to submit for regulatory approval follows encouraging follow-up data from 75 patients in the CLIMB studies presented at the 2022 European Hematology Association in June.

All 31 SCD patients had experienced an average of 3.9 vaso-occlusive crises during the previous two years. Following treatment with exa-cel, all were free of VOCs after 2 to 32.3 months.

Of the 44 TDT patients, 42 were transfusion-free 1.2 to 37.2 months after treatment with exa-cel.

The safety profile was generally consistent with myeloablative conditioning with busulfan and autologous stem cell transplant, Vertex and CRISPR reported.

Vertex intends to complete the FDA submission in Q1, 2023.

A New Day for Schizophrenia Treatment?

There has never been a therapy that effectively addresses the negative symptoms of schizophrenia – until Karuna Therapeutics’ KarXT.

In August, the Boston-based biopharma company announced its lead therapeutic candidate elicited improvements not only in the positive symptoms of the disease but also in the negative symptoms.

KarXT met the primary endpoint in the EMERGENT-2 trial. In 252 adults with schizophrenia experiencing psychosis symptoms, the therapy demonstrated a significant decrease in symptom severity as measured by the Positive and Negative Symptom Scale (PANSS).

A muscarinic receptor agonist, KarXT is designed to preferentially stimulate muscarinic receptors in the central nervous system. According to Karuna, research has shown activity in the M1 and M4 receptors indirectly affects dopamine neurotransmission in the brain, leading to the positive, negative and cognitive symptoms of schizophrenia.

Progress in PAH

The pulmonary arterial hypertension (PAH) space also saw progress as Merck’s activin receptor sotatercept produced positive results in the Phase III STELLAR trial.

In the study of 320 adults with PAH, sotatercept met all primary endpoints except one, falling short in the cognitive/emotional impacts domain of the PAH-SYMPACT questionnaire - a secondary endpoint.

Patients treated with sotatercept saw a statistically significant and clinically meaningful increase in 6-minute walk distance (6MWD) at the 24-week follow-up.

The late-stage win boosts Merck’s PAH pipeline, which already includes Adempas (riociguat). Merck picked up sotatercept in the $11.5 billion acquisition of Acceleron.

An RSV Vaccine could be Coming Soon

Respiratory syncytial virus (RSV) is hitting the world particularly hard this winter. RSV can be deadly for older adults, and there is currently no vaccine available for prevention.

In the race to develop a vaccine, Pfizer caught up to GSK when its candidate, RSVpreF, was granted FDA priority review following positive late-stage data.

Interim data from the Phase III RENOIR study showed RSVpreF elicited 85.7% efficacy in adults aged 60 and older. The vaccine was also well-tolerated with no safety concerns, Pfizer reported earlier this month.

In a pivotal Phase III trial, GSK’s RSV vaccine candidate showed an overall vaccine efficacy rate of 82.6%, though the vaccines performed differently in different subgroups and patient populations. In severe RSV-associated lower respiratory tract disease (LRTD), the vaccine was 94.1% effective.

Both candidates received priority review within weeks of one another.