052 – BATTLING for the Top Anti-VEGF Eye Therapy

UPDATE 11/29/2019: Check out this image from Clearside’s investor presentation about the different ‘back of eye’ delivery methods

Happy Thanksgiving! In this video, I talk about all things related to eye diseases caused by over-proliferating endothelial cells. These diseases are currently treated by monthly intravitreal injections but there are new therapies in clinical trials that are likely to unseat them. I touch on #RGNX, #ADVM and #KOD as well as some others that have made headlines in the last couple weeks.

Relevant publication: Ding et al. AAV8-vectored Suprachoroidal Gene Transfer Produces Widespread Ocular Transgene Expression. JCI. 2019

Image credit: https://ir.clearsidebio.com/static-files/c9c4b682-92aa-4f3d-84df-6343468e340c

*This is not investment advice, so please do your own due diligence before investing*


041 – Is REGENXBIO a buy after Zolgensma approval?

Today, I talk about REGENXBIO and their in-house gene therapy candidates. Their most important asset in early clinical trials is RGX-314, indicated for wet AMD (and hopefuily Diabetic Retinopathy). This gene therapy could replace blockbuster drugs that treat millions patients, but is it a buy today?

Follow me @matthewlepoire

*this is not investment advice*


027 – Amarin Sells Off Amid Positive Vascepa Data

Amarin recently published data from their REDUCE-IT cardiovascular outcomes trial. Their EPA medicine, Vascepa, showed a 25% relative risk reduction compared to placebo. EPA is an omega-3 fatty acid that previously showed a 19% relative risk reduction in cardiovascular outcomes in a Japanese study (JELIS, 2007). Amarin saw a hazard ratio of 0.75 in their primary endpoint, which evaluated cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina. In this video, I go through two critiques of the study:
1) Lack of mechanistic insight
2) Mineral oil use in the placebo group
I believe Vascepa is likely to get FDA approval for the indication of reducing cardiovascular disease in patients with over 150mg/dl Triglycerides on statin therapy.

This is not investment advice, do your own due diligence.

Relevant links:


IONS/AKCA receive thumbs down on Waylivra for FCS

“We are extremely disappointed with the FDA’s decision”, writes the Ionis Pharma press release in describing the Complete Response Letter (CRL) they received regarding their latest medicine, WAYLIVRA. They continue, “we feel strongly that WAYLIVRA demonstrates a favorable benefit/risk profile in people with FCS as was reflected in the positive outcome from our Advisory Committee hearing in May”.

Ionis and their affiliate, Akcea, have collected substantial evidence on the efficacy of WAYLIVRA (volanesorsen) for the treatment of familial chylomicronemia syndrome (FCS). This disease, which has no treatment, is due to a mutation in the lipoprotein lipase gene, leaving patients with supraphysiological levels of triglycerides of over 1000mg/dl. Chronic high triglycerides is associated with obesity, type 2 diabetes, atherosclerosis, xanthomas and pancreatitis. Ionis Pharmaceuticals’ drug volanesorsen is an antisense therapy against the messenger RNA of apolipoprotein C3, which has been shown to significantly decrease triglycerides in rodents, nonhuman primates and humans (1). The Phase 3 clinical trial conducted by IONS and AKCA showed a 77% reduction in triglycerides in the treatment group compared to +18% in placebo (p<0.0001, NCT02211209). One would expect that a success like this will require significant side effects for the FDA to deny approval.

RNA technology has long been used in basic science research to artificially alter the expression of specific genes of interest. Simply put, a gene that is transcribed into messenger RNA (mRNA), can only be translated to protein if it is single-stranded. Complementary binding of the target mRNA by an antisense oligonucleotide will prevent the nascent mRNA from translating and instead target the complex for degradation. This technology is particularly useful for genetic disorders such as muscular dystrophy or spinal muscular atrophy (the latter, which Ionis has an FDA-approved medication).

The price of both Ionis and Akcea dropped in light of the volanesorsen CRL news, since it was previously expected to be approved. Unfortunately, the public was not provided with any details of the CRL. We can only assume the reason for this is they still need to have a conversation with the FDA in order to clarify a path towards approval. Studying the data from their Phase 3 and the minutes from the FDA advisory committee meeting provides us some clues, however.

Two things are noticeable that are likely to be the reasons for the CRL:

  1. FCS patients happen to have variable platelet levels throughout the course of their disease. Many have significantly reduced platelets, and treatment with WAYLIVRA exacerbated this leading to some severe adverse events. Thankfully, these events reversed themselves after drug cessation, but the FDA may be concerned that drug treatment will cause life-threatening bleeding.

fig.1 platelets

  1. Surrogate endpoint. Despite the profound effect of WAYLIVRA on lowering triglycerides, it remains a surrogate endpoint. The FDA may be concerned that reducing triglycerides by 77% is not enough to create a significant clinical impact. This includes reductions of abdominal pain or number of pancreatitis events. The Phase 3 trial did include some pain metrics, but they may not be considered sufficient to satisfy the review panel.

If these are the reasons for the CRL, I am confident IONS/AKCA will eventually prevail. The platelet issue can be overcome if they restrict the drug to patients with normal or above-average levels of platelets. Physicians are likely to already monitor platelets of FCS patients since the disease presents with abnormal platelets. Alternatively, a different dosing mechanism could be analyzed in order to minimize side effects, while still ensuring positive efficacy. This might take time, since additional trials would be needed to determine a new dosing regimen. Further, lowering the effectiveness of the drug will only lead to greater questions to the clinical benefit of WAYLIVRA. To mitigate these concerns, I would bet that the FDA wants IONS/AKCA to be much more thorough in their analysis of clinical outcomes of FCS. This will require another trial, but if done correctly, would demonstrate the bigger picture in improving clinical outcomes. It looks like the FDA will require Risk Evaluation & Mitigation Strategies (REMS) to be imposed if WAYLIVRA were approved, to ensure that the benefits of the drug outweigh the risks.

Overall, I think IONS/AKCA will be successful in this endeavor, but it’s a matter of time before they can satisfy all the concerns raised by the FDA. FCS happens to be a rare disease, with only about 5000 patients worldwide. Losing this revenue stream will not be detrimental to the future of IONS/AKCA, but getting this technology in more patients will help with the long-term adoption of antisense therapy. Ionis Pharma has a substantial pipeline of antisense therapies, targeting a variety of diseases with a large patient population. SPINRAZA is the only FDA-approved therapy for spinal muscular atrophy with global sales of $423 million in Q2-2018. Anyone who is looking for an opportunity to expand their portfolio to include a company with a novel treatment technology should use this current price drop as an excuse to buy.

Let me know what you think in the comments!


  1. https://www.ncbi.nlm.nih.gov/pubmed/23542898









Is Tandem Diabetes Care really worth $13?

Today I go through TNDM and their business model to see if they truly deserve the crazy run up we’ve seen the last few days.

Relevant links:

*This is not trading advice*

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