Taking a Look at Trends in Biotherapeutics

Scientist DNA

It’s not easy to predict trends in drugs, especially with breakthroughs in immunology and genetic engineering often causing dramatic changes in how biopharma companies approach new drugs. It was pretty obvious four or five years ago that early work in immuno-oncology was going to have a huge effect, and it did, when in 2017 the U.S. Food and Drug Administration (FDA) approved two chimeric antigen receptor (CAR) T-cell therapies, Gilead Sciences and Kite Pharmas Yescarta (axicatagene ciloleucel) and NovartisKymriah (tisagenlecleucel).

A number of companies will undoubtedly produce new immuno-therapies, particularly if they focus on a different type of cancer marker. For example, loosely speaking, both Yescarta and Kymriah target CD19 proteins. But late last year, researchers at Stanford University, School of Medicine and the National Cancer Institute (NCI) identified another cancer-surface molecule, CD22. Companies will undoubtedly spend resources developing immuno-oncology therapies that focus on CD22, or potentially even both CD19 and CD22. And next-generation immuno-oncology approaches will look at improving how well they work and minimizing side effects.

The holy grail of immuno-oncology at the moment is to develop off-the-shelf CAR-T products. The current approaches are labor-intensive—a patient’s blood is taken and sent to a laboratory, where it is engineered to focus on the patients’ specific cancer cells, and then sent back to the patient’s physician, who transfuses the engineered cells back into them. Juno Therapeutics and Celgene are leading the charge in this area, working on a more generic, off-the-shelf CAR-T product.

Nucleic acid therapies are also a big, relatively new field, with a popular area being antisense oligonucleotides. Science Trends notes, “In 2016, two first-in-class antisense RNA drugs were approved, Sarepta Therapeutics Exondys 51 (eteplirsen) to treat Duchenne muscular dystrophy and Biogen/Ioniss Spinraza (nusinersen) to treat spinal muscular atrophy, both rare genetic disorders.”

Less successful to date are gene therapies. In many ways, Sarepta’s Exondys 51 is a type of gene therapy, where the therapeutic causes the cells to “skip” over the deletion, leading to a truncated but functional version of the protein. Dystrophin is too large a gene to be completely transferred using current vector technologies. One of gene therapies approved is GlaxoSmithKlines Strimvelis, which is marketed by Orchard Therapeutics. It was approved in Europe in May 2016 for severe combined immunodeficiency due to adenosine deaminase deficiency. In April 2018, GSK transferred its rare disease gene therapy portfolio to Orchard, which included Strimvelis, two late-stage clinical programs for metachromatic leukodystrophy (MLD) and Wiskott Aldrich syndrome (WAS), and one clinical program for beta thalassemia.

In December 2017, the FDA approved Spark Therapeutics Luxturna (voretigene neparvovec), a gene therapy for children and adults with retinal dystrophy caused by a mutation of the RPE65 gene. Retinal dystrophy results in severe visual impairment and eventual blindness. It was only the third gene therapy approved in the U.S.

Science Trends also mentions regenerative medicine as a trend, “generally comprised of a differentiated or specialized cell type combined with some sort of scaffold.” To date, four tissue products in this area have been approved: LAVIV (azficel-T) for improving moderate to severe nasolabial fold wrinkles in adults; Carticel (autologous cultured chondrocytes) for the repair of symptomatic cartilage defects of the knee; GINTUIT (allogeneic cultured keratinocytes and fibroblasts in bovine collagen) for gum disease; and MACI (autologous cultured chondrocytes on porcine collagens membrane) for knee cartilage repair.

Another area expected to explode is RNA silencing. On August 10, the FDA approved Alnylam Pharmaceuticals Onpattro (patisiran) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is the first and only RNA interference (RNAi) therapeutic to be approved.

RNAi was discovered about twenty years ago by researchers Andrew Fire and Craig Mello, who received the Nobel Prize for their discovery in 2006. The basic premise is that RNAi “silences” genes, so they don’t produce the protein they code for. Most drugs treat problematic proteins after they exist or accumulate. RNAi prevents the production of those proteins in the first place.

hATTR amyloidosis is a rare disease that affects about 50,000 people worldwide. In addition to polyneuropathy, or a degeneration of peripheral nerves, the disease can lead to significant disabilities that include loss of ambulation that can lead to the inability to walk and a decline in cardiac function.

And in related work, messenger RNA (mRNA) has the potential to revolutionize new therapeutics. The work here is most well-known by Moderna Therapeutics, although they have yet to have a product approved. mRNA’s job is to transport genetic information from DNA to the ribosome, providing the amino acid sequence of the eventual proteins the DNA is coded for. In Moderna’s tech platform, the company engineers mRNA to then deliver whatever protein codes they want the cells to produce, turning the cells into vaccine- or drug-manufacturing factories. The company currently has 19 therapies in development, 10 of which are in human clinical trials.

These are all areas of intense interest by the biopharma industry, but the next area of intense enthusiasm is only a single scientific discovery away.

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