Pfizer hit by DMD delay & halts BCMA trials; Sarepta’s drug shows promise in Phase II; Human organ chips enable COVID-19 drug repurposing; AbCellera takes new antibody into clinic

Posted on May 6, 2021 by Delveinsight

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Pfizer suffers a DMD delay and halts BCMA trials amid safety woes 

Pfizer has paused after seeing three cases of peripheral neuropathy in an early-stage study, enrollment in a critical analysis of its anti-BCMA bispecific antibody. Big Pharma shares news with details of delays to the start of the US part of Duchenne Muscular Dystrophy (DMD) Phase 3.

In February, Pfizer announced a crucial phase in the strength of the overall response rate of 80% seen in 20 patients treated with BCMA bispecific elanatamab, also known as PF-06863135, in Phase 1. 2 Incorporated into research. In a study of patients with relapsed and refractory multiple myeloma, Pfizer suspended the survey to give them time to garner information about safety signals.

The pause was caused by the discovery of three cases of peripheral neuropathy in a phase I trial. As of the end of last year, Pfizer had Phase 1 data on 30 patients, but recruitment continued after the update. Researchers aim to recruit 80 patients.

In its December update, Pfizer does not mention cases of peripheral neuropathy known as polyneuropathy, which affects many nerves. However, adverse events were previously associated with BCMA bispecific antibodies. 

Faced with its own BCMA safety concerns, Pfizer suspended medication in a critical trial while sharing additional information about FDA cases of peripheral neuropathy. Patients who are already benefiting from treatment can continue their medication.

Sarepta’s second Muscular Dystrophy drug shows promise in Phase II

Sarepta Therapeutics declared that its next-generation peptide phosphorodiamidate morpholino oligomer (PPMO) candidate, SRP-5051, showed promise in a Phase II trial when utilised as a treatment for Duchenne muscular dystrophy in patients amenable to exon 51 skipping. 

Sarepta probes SRP-5051 as a follow-up to its other Duchenne muscular dystrophy drug, Exondys 51 (eteplirsen). The company’s currently marketed eteplirsen for the muscle-wasting disorder is not exactly a robust competitor – the drug only develops modest dystrophin amounts and got controversial approval in 2016 after leaders with the U.S. Food and Drug Administration (FDA) overruled its scientists. 

The company’s PPMO chemistry and exon-skipping technology created SRP-5051 to jump exon 51 found in the dystrophin gene. As per the company, the candidate binds to exon 51 in dystrophin pre-mRNA, subsequently leading to the debarring of the exon during the processing of mRNA. Likewise, skipping up the exon offers the production of a truncated dystrophin protein. Around 13% of patients with Duchenne muscular dystrophy present with genetic mutations, making them susceptible to exon 51 skipping. 

Human organ chips enable COVID-19 drug repurposing

A Wyss Institute-led collaboration spanning four research labs and hundreds of miles has utilised the Institute’s organ-on-a-chip (Organ Chip) technology to recognise the antimalarial drug amodiaquine as a potent inhibitor of infection with SARS-CoV-2, the virus that is responsible for COVID-19.

The Organ Chip-based drug testing ecosystem established by the collaboration dramatically simplified the process of assessing the safety and efficacy of current drugs for new medical applications and proffers a proof-of-concept for the utilisation of Organ Chips to quickly repurpose existing drugs for new medical applications, including future pandemics. The research is outlined in Nature Biomedical Engineering.

While many groups globally have been assessing existing drugs for efficacy against COVID-19 using cultured cells, it is well established that cells grown in a dish do not behave like the cells in a living human body. Many drugs that appear effective in lab studies do not work in patients. The Wyss team assessed eight existing drugs, comprising hydroxychloroquine and chloroquine, that they and others had found active against SARS-CoV-2 in conventional cell culture assays.

When examined in their more sophisticated microfluidic Lung Airway Chip, which had been infected with a pseudotyped SARS-CoV-2 virus, they observed that most of these drugs, including hydroxychloroquine and chloroquine, were ineffective. Nevertheless, another antimalarial drug, amodiaquine, was highly effective at prohibiting viral entry. These results were then confirmed in cultured cells and a small animal model of COVID-19 using infectious SARS-CoV-2 virus. Amodiaquine is currently in clinical trials for COVID-19 at several sites in Africa, where this drug is inexpensive and widely available.

Lilly’s Covid-19 partner AbCellera takes a new antibody into the clinic

Eli Lilly has commenced clinical development of an anti-SARS-CoV-2 antibody designed to work against all currently known circulating variants of concern. The action comes weeks after the FDA cancelled the single-use emergency authorisation of Lilly’s first COVID-19 antibody due to the rise of variants. 

Researchers have shown COVID-19 antibodies, including Lilly’s bamlanivimab, are less effective against variants of concern such as B.1.351 than the original SARS-CoV-2 virus when given as monotherapies. The research, coupled with the emergence of variants of concern as the dominant causes of COVID-19 in parts of the world, has led to reassessments of the use of antibodies as single agents.

AbCellera, which worked with Lilly on bamlanivimab, responded to variants by searching the blood of a patient who recovered from COVID-19 for an antibody that is effective against them. The result is LY-CoV1404, an antibody that binds to a conserved part of the receptor-binding domain. 

The targeted region is different from the mutations observed in variants and the parts targeted by current neutralising antibodies. To evaluate whether that translates into the neutralisation of variants, AbCellera, Lilly, and their collaborators pitted LY-CoV1404 against the original SARS-CoV-2 and the B.1.1.7, B.1.351, P.1, B.1.526, B.1.427, and B.1.429 versions that have arisen around the world.

LY-CoV1404 retained full neutralisation potency against all the tested variants. Against the original SARS-CoV-2, LY-CoV1404 had potency values ranging from 9 ng/mL to 22.1 ng/mL. Bamlanivimab and S309, a Vir Biotechnology antibody that fared well against variants in another study, were found to be less potent. The potency opens the door to subcutaneous administration. 

Lilly is now set to test whether the preclinical promise translates into clinical efficacy. Big Pharma has added LY-CoV1404 to BLAZE-4, a clinical trial testing multiple antibodies as single agents and combinations in patients with mild-to-moderate COVID-19

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