10 Rare Diseases Specialist Stocks

Rare Diseases – Curing The Incurable

While not entirely solved, a lot of major deadly illnesses that have plagued humanity have become more manageable over the last century, from bacterial (antibiotics) and viral (vaccines) infections to diabetes (insulin).

There is, however, a wide array of rare diseases which are still mostly incurable. Most of the time, this is because these diseases are not caused by an external threat, but by a biological dysfunction inside the very cells of the patient. This is quickly changing, thanks to progress in biosciences.

On one hand, with the human genome sequenced and much more advanced analytical methods, scientists can finally understand what are the root causes of rare diseases. Even AI is now helping interpret the data and provide new insights.

On the other hand, new technologies like gene editing open the possibility of fixing deficient cells or organs, restoring normal function.

Rare diseases each affect less than 1 in 2,000 people, with more than 6000 different rare diseases. Despite their individual rarity, together, they affect around 4% of the population, with as many as 30 million people in just Europe.

3/4 of rare diseases affect children, 72% are genetic in origin, and it takes on average 5 years for rare disease patients to get a diagnosis.

1. CRISPR Therapeutics

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a recently discovered tool for genetic editing. It allows for very precise and directed gene editing, and its discoverers have won the 2020 Nobel Prize.

Source: Lab Associates

What sets CRISPR Therapeutics apart is the all-star team of founders, including Dr. Emmanuelle Charpentier, one of the co-discoverers of CRISPR-Cas9 technology.

CRISPR Therapeutics is developing an efficient and versatile CRISPR/Cas9 gene-editing platform for therapies to treat hemoglobinopathies, cancer, diabetes, and other diseases.

The first therapy that they were advancing was targeting the blood diseases β-thalassemia and sickle cell disease.

They have now been approved under the commercial name of Casgevy for both applications, making it the first-ever approved CRISPR gene therapy. Sickle cell and beta-thalassemia are major rare diseases, and the treatment comes with a $2.2M per therapy price tag.

In the long run, they are working on making this gene therapy doable in-vivo (instead of the current ex-vivo approach, requiring expensive and complex extraction of the patient marrow cells first).

The company is working on several other rare diseases, notably:

• Duchene’s Muscular Dystrophy (DMD): IND-enabling stage (Investigational New Drug)
• Acute hepatic porphyria: IND-enabling stage.
• Myotonic Dystrophy Type-1 (DM1): preclinical
• Cystic Fibrosis: Pre-clinical
• 2 other undisclosed rare disease programs.

The company’s first allogeneic CAR-T program targeting B-cell malignancies (cancer) is also in clinical trials.

Another major potential for CRISPR Therapeutics, although not about rare diseases, is in curing type-1 diabetes. This was previously done in collaboration with Vertex but this link was severed in January 2024.

You can also read more about CRISPR Therapeutic in our article “Gene Editing: CRISPR Therapeutics vs. Beam Therapeutics.”

2. Bluebird Bio

Together with CRISPR Therapeutics, Bluebird was the other company granted approval in December 2023 for a gene therapy on sickle cell disease, under the commercial name Lyfgenia. The same therapy is also approved for beta-thalassemia, under the commercial name Zynteglo.

Lyfgenia didn’t make use of CRISPR. Instead, it went the “traditional” route of gene therapy treatment by utilizing a lentiviral vector (LVV), a family of viruses, to modify genes.

Here, the blood stem cells of SDC patients are genetically modified to produce a special hemoglobin HbAT87Q, which functions much like any normal adult hemoglobin but is gene-therapy derived and delivered to the patient.

The company’s success in approval of Lyfgenia has not really translated into success for its stock price. However, the success of the company in getting a total of 3 approved gene therapies using LVV is an indication of its expertise in using viruses for gene therapy.

The commercial success of Lygenia/Zyntelo will be crucial to the future of the company, as its pipeline seems to not contain many other products.

3. Editas Medicine, Inc.

Editas was founded by CRISPR-Cas9 discoverer Jennifer Doudna. Editas started working with Cas9 but is now focused on a proprietary version of Cas12 that they engineered: AsCas12a.

You can read more about Cas12a’s unique properties in our dedicated article “What Is CRISPR-Cas12a2? & Why Does It Matter?”.

To resume it shortly, Cas12as is unique because:

• Hard-to-solve problems with Cas9 could be workable with Cas12a
• It results in higher chances of gene editing happening than with Cas9.
• More than one gene can be modified at once with CAs12a.

Source: Editas

You can also read an overview of all of Jennifer Doudna’s companies in the corresponding article “Top Jennifer Doudna Companies to Watch.”

Editas is most advanced in Sickle Cell Disease (SCD), with 40 patients in a clinical trial at phase 1/2. The first results are expected by the end of 2023 but are still not announced as of May 2024. Overall Editas is behind its competitors in gene therapy for SCD.

Source: Editas

As this therapy and innovative treatments for this disease are seemingly becoming a little crowded, investors will want to look in-depth at the clinical trial results and assess if AsCas12a is producing superior results to “classic” CRISPR Therapeutics Cas9 technology, which is already approved.

However, Editas seems ahead in another rare disease, Leber Congenital Amaurosis (LCA). After a break in 2022,  Editas Medicine announced in May 2024 that the clinical trial for EDIT-101 has seen 79% of the 14 clinical trial participants experience measurable improvement after receiving the experimental gene therapy. We discussed these results and the overall news about CRISPR-based gene editing in our article “From Blindness to Meat Substitutes: CRISPR Gene-Editing Continues to Produce Promising Results”.

4. Beam Therapeutics

The company was founded in 2017, focusing on developing the technology of “base editing.” This promises more precise gene editing than traditional CRISPR-Cas9 technology. It could also edit multiple spots in a gene or multiple genes at once.

“Many existing gene editing approaches are like ‘scissors’ that cut the genome. Base editors are like ‘pencils’ that enable erasing and rewriting one letter of the genome at a time.” – Giuseppe Ciaramelle, President & CSO at Beam Therapeutics

Beam Therapeutics is at an earlier stage than other CRISPR companies, with its manufacturing facilities expected to start only in late 2023. Most of its pipeline is still at the research stage of entering phase 1 of 2 of clinical trials.

It has pretty much the same focuses as CRISPR therapeutics: hematology (sickle cell disease), oncology, and rarer genetic diseases (impaired glycogen metabolism and Alpha-1 Anti-trypsin Deficiency – AATD), as well as undisclosed diseases in collaboration with Appelis and Pfizer.

Source: BEAM Therapeutics

With SCD becoming an increasingly crowded therapeutic space (somewhat ironic for a disease incurable until very recently), the future of BEAM Therapeutics will rest on the potential technical superiority of base editing over Cas-9 gene editing. And its programs in other rare diseases.

5. Sangamo Therapeutics

The company is both a gene therapy and a stem cell company. Its two flagship programs are:

• A hemophilia A gene therapy, in partnership with Pfizer, in clinical trial phase 3. The Biologics License Applications (BLA) is anticipated for the end of 2024.
  • The first results have been very positive, with ”Pfizer announced at Q4 earnings that this remains one of their most promising assets.’
• A gene therapy for Fabry disease, in phase 1/2.

Its 2 main stem cell therapies in development are:

• A stem cell therapy to remove the risk of kidney transplant rejection, in phase 1/2.
• It had an SCD therapy in plans, that was shelved in early 2023

The research pipeline also includes 5 more stem cell therapies and 9 genome engineering therapies.

Genome engineering could be used to solve neurological issues like Prion disease (like mad cow disease), Huntington’s, etc. These programs are developed in partnership with Pfizer, Novartis, Biogen, and Takeda.

Source: Sangamo

Of all these programs, hemophilia is by far the more advanced one.

Overall, Sangamo is an investment opportunity providing exposition to gene and cell therapy technologies. Its financial position is relatively solid, thanks to non-dilutive partnerships with some of the largest pharmaceutical companies, which provide cash when reaching scientific and clinical milestones.

6. UniQure

UniQure is the company that developed HEMGENIX the first hemophilia type-B gene therapy, approved in 2022 in the USA and the EU, costing $3.5M/dose.

The company does not use a CRISPR-like technology, preferring Adeno-Associated Viral Vectors (AAVV), and had the first ever approved AAV therapy.

The company hopes that the recent success in hemophilia can be expanded to other pathologies, notably:

• Huntington’s disease.
• Temporal Lobe Epilepsy (TLE)
• Fabry disease
• ALS (SOD1)

Source: Uniqure

The debate between using AAV or CRISPR technology for gene therapy is still ongoing, with virus-mediated techniques that may be getting a boost from discoveries, as discussed in “Super Charging Gene Therapy with Electric Pulses”.

So while less at the news forefront than CRISPR competitors, UniQure still has the potential to make a difference for many rare disease patients.

7. Sarepta Therapeutics

Sarepta is a company focused on genetic diseases, most of which are rare diseases.

It is the current leader for Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), with 4 therapies approved and on the market.

The prevalence of DMD is approximately 1 in 3,500 – 5,000 newborn males worldwide. LGMD is affecting  2.27-10 per 100,000 individuals.

The company uses the technology of Phosphorodiamidate Morpholino Oligomers (PMOs). It added to PMOs at the end of 2023 a gene therapy, ELEVIDYS.

Source: Sarepta

Its pipeline is equally focused on the same diseases, making the company a strong specialist in this segment. The various LGMD gene therapies in the pipeline would ultimately cover 70% of known patients.

Source: Sarepta

8. RegenXBio

RegenXBio is a gene editing company with a technological focus on modified adeno-associated viruses (AAVs) and rare diseases.

Its AAV platform is looking at solving most of the limitations of previous generations of AAVs, which have reduced their usefulness for gene editing therapies for rare diseases. The target is stronger transgene expression, less immune reaction, and simpler manufacturing.

Source: RegenXbio

The company pipeline covers Duchenne muscular dystrophy (DMD), Mucopolysaccharidoses (MPS)/Sanfilippo disease, a neurodegenerative disease, and retinal diseases (one product for 3 different diseases in partnership with AbbVie).

Source: RegenXbio

The global retinal disease market is expected to reach $17B in the next 5 years, in large part driven by diabetic retinopathy, the DMD market $7B in the next 5 years, and MPS $1B.

With MPS the most advanced treatment in the pipeline, it could bridge the gap in funding necessary to turn RegenXBio from pre-commercial biotech to a rare disease therapy company also active in DMD and retinal diseases (with regulatory submissions for subretinal wet AMD expected in late 2025).

9. Vertex

Vertex is the leader in Cystic Fibrosis treatment, a deadly genetic disease, with 4 different treatments targeting different patient profiles. Patients who cannot be treated with the current therapy have a drug in phase III of clinical trials, Vanzacaftor. They are also developing gene therapy for cystic fibrosis using mRNA technology.

However, its main involvement in gene editing is twofold.

First, with therapies developed in tandem with CRISPR Therapeutics for blood disease and now approved: beta-thalassemia and sickle cell disease.

As a whole, Vertex is very R&D-focused, with 70% of operating expenses dedicated to finding new drugs and therapies.

Source: Vertex

They partner with CRISPR Therapeutics to help develop the blood disease gene therapy mentioned above. As mentioned, the partnership with CRISPR Therapeutics regarding diabetes has been canceled.

This leaves Vertex with several other R&D programs in the pipeline:

• Their VX-548 treatment for acute pain is in the last stage of development and might be a new alternative to opioids without the risk of addiction and fewer side effects.
• Inaxalpin, a drug for APOL1-mediated kidney disease, is also in phase 3 of clinical trials.
  • Another kidney disease, Autosomal dominant polycystic kidney disease, is in phase 1 of clinical trials.
• Myotonic dystrophy type 1 is in phase 1/2
• Duchenne muscular dystrophy
• All the pipeline of Alpine Immune Sciences, focused on autoimmune diseases and acquired for $4.9B in cash in early 2024.

Source: Vertex

Vertex can rely on its stable income stream from its leading position in cystic fibrosis (a rare disease untreatable before Vertex success) to finance all of its expansion into new therapeutic fields. It should also benefit from the recent approval of Exa-cel CRISPR gene therapy for blood diseases.

10. Amgen

Amgen is maybe the poster child of success in biotechnology, both for its technological achievement and from an investing point of view. It went from a price of $0.11/share in 1984 to a recent price in the $225-$285/share range in 2022.

Its first achievement was creating the first recombinant human erythropoietin in 1989. It would follow with treatments for rheumatoid arthritis in 1998 and osteoporosis and cancer in 2010, among other protein and biological-based therapeutics.

It currently has a total of 27 approved treatments, treating 11 million patients. Its most quickly growing products (9 products worth $ 10.5B in sales) have grown their sales volume by 16% in 2022.

It has 39 potential drugs in its pipeline, of which 18 are already in clinical trials phase 3, with a strong predominance of inflammation and oncology for these most advanced clinical trials.

This also includes multiple rare diseases, including:

• Sjögren’s Disease with DAZODALIBEP, a fusion protein therapy in phase 3 of clinical trials, and AMG 329, a monoclonal antibody in phase 2.
• Pediatric Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis with TAVNEOS, a small molecule in phase 3 of clinical trials.
• Thyroid Eye Diseasewith TEPEZZA, a monoclonal antibody therapy in phase 3 of clinical trials.
• IgG4-related disease& Myasthenia Gravis with UPLIZNA, a monoclonal antibody therapy in phase 3 of clinical trials.
• Discoid Lupus Erythematosus& Dermatomyositis and Anti-synthetase Inflammatory Myositis with DAXDILIMAB, a monoclonal antibody therapy in phase 2 of clinical trials.
• Diffuse Cutaneous Systemic Sclerosis& Idiopathic Pulmonary Fibrosis with FIPAXALPARANT, a small molecule in phase 2 of clinical trials.
• Thyroid Eye Diseasewith TEPEZZA, a monoclonal antibody therapy in phase 3 of clinical trials.

Another innovation is AMG 133, an obesity treatment that is hoped to be more powerful than the existing therapies. AMG 133’s unique advantage would also be a long half-life, with a dosage every 4 weeks instead of the required weekly treatment of Wegovy. With Wegovy becoming quickly one of the largest blockbusters in the pharmaceutical market, this could be important for Amgen’s future.

The company also has a biosimilar department (the equivalent of generic drugs for biotech treatments), with 5 approved drugs and 3 drugs in the R&D pipeline.

Amgen has historically been one of the most innovative pharmaceutical companies ever made, almost single-handedly creating the biotech sector.

Its impressive R&D pipeline shows Amgen is determined to keep that reputation intact, including by venturing into new segments like the obesity market and tackling rare diseases with a wide range of different solutions not relying on gene therapy.