Ibalizumab (Trogarzo) Has a Reasonable Chance of FDA Approval

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TAIMED BIOLOGICS & THERATECHNOLOGIES (THERF)

Trogarzo (ibalizumab), a novel HIV medication, has a PDUFA action date of 4/3/2018.

In one form or another, Trogarzo’s history of preclinical development goes back to 1993. In the early 2000s a phase I clinical trial for the drug was run by Tanox Inc., a U.S. biopharmaceutical company.

Tanox was acquired by Genentech, Inc. in 2006. By 2007, TaiMed Biologics Inc. (a Taiwanese firm) licensed the medication from Genentech.

STATUS & DESIGNATION

In 2003, the FDA granted ibalizumab Fast Track status, then Orphan Drug designation in 2014, and Breakthrough Therapy designation in 2015. Combined, this means:

  1. Ibalizumab has been recognized as a drug that is intended to treat a serious or life threatening condition (HIV/AIDS in this case).
  1. The FDA recognizes that ibalizumab has the potential to safely and effectively treat a condition (or subset thereof) that affects fewer than 200,000 people in the U.S. Ibalizumab is most likely going to be used in patients who have HIV that is resistant to other medications.
  1. Preliminary evidence suggests that ibalizumab may be substantially better in one or more relevant ways when compared to existing treatments for HIV.
  1. TaiMed can submit information in its Biologics License Application (BLA) for FDA review as it comes in, instead of submitting it all at once as most companies do when seeking FDA approval.
  1. As a result, the FDA will work along the way to speed up the development and review of this drug with greater organizational commitment. In other words, the FDA will work quickly yet just as thoroughly in order to get this drug approved so long as it’s truly safe and effective.

PRIORITY REVIEW

In 2016, Theratechnologies Inc. (Ticker: THERF) and TaiMed Biologics Inc. partnered to market and distribute ibalizumab (Trogarzo) in the U.S. and Canada.

A year later, the two companies reached an agreement whereby THERF obtained the commercial rights to Trogarzo in other territories, including the European Union and Russia.

In June of 2017, the FDA granted Trogarzo priority review for its BLA, with an expected PDUFA action date of January 3, 2018. This was delayed until April 3, 2018.

That’s because in October of 2017, the FDA requested TaiMed submit additional manufacturing information. TaiMed complied and the FDA had to extend the action date because the information TaiMed provided constituted a major amendment it needed more time to review.

WHAT IS TROGARZO (IBALIZUMAB & TMB-355)?

Fluorescent Antibodies

Antibodies bound to a green fluorescent molecule have attached to a very specific portion of each cell in this image.

Trogarzo is the trade name for an HIV medication known generically as ibalizumab. During its very long history of development, Trogarzo has alternatively been referred to as TMB-355, TNX-355, and hu5A8.

Trogarzo is a monoclonal antibody. Antibodies are protein molecules produced by white blood cells in our body known as plasma cells.

Naturally, antibodies attach to very specific portions of something the body considers to be foreign, like a virus. After attachment, the antibody can trigger a sequence of molecular events that destroy the virus.

Alternatively, the antibody may serve as a beacon for other white blood cells to come and destroy the virus instead.

The fact that Trogarzo is a monoclonal medication means that all of the antibodies found in Trogarzo are exactly the same. As a result, all of the antibodies in Trogarzo bind to the same exact spot on a cell.

HOW DOES IBALIZUMAB WORK?

HIV & T Cells

In this image, HIV viruses (green) are seen escaping a T cell (blue).

Trogarzo is designed to treat people infected with the human immunodeficiency virus (HIV); the virus responsible for causing AIDS.

HIV uses white blood cells, known as CD4+ T cells, to replicate itself in the human body. HIV also destroys these same T cells via numerous different mechanisms.

This is a serious problem because T cells are responsible for keeping us safe from other infections. And so, as a person loses more and more T cells due to HIV, they risk succumbing to infections caused by other microorganisms.

So this is where Trogarzo comes in.

Unlike natural antibodies, which would normally attach to foreign entities like viruses, Trogarzo has been genetically engineered to attach to a specific part of the T cell that’s known as the CD4 T cell receptor.

The T cell receptor is like a “lock” to a T cell. HIV must first open this main lock in order to be able to insert the keys to “co-locks” thereafter.

Trogarzo doesn’t stop HIV from inserting its key into the main lock. However, Trogarzo jams this lock and prevents HIV from opening up the co-locks thereafter as a result. This is why Trogarzo is known as an “entry inhibitor”.

Since the HIV can’t enter the T cell, it can’t multiply itself and destroy the T cell in the process. Consequently, Trogarzo helps decrease the destruction of T cells and may decrease the chances a person with HIV/AIDS will come down with a lethal infection.

GENERAL ADVANTAGES & DISADVANTAGES OF MONOCLONAL ANTIBODIES

Monoclonal antibodies like Trogarzo have some major potential advantages when compared to traditional HIV medications:

  1. They last a long time in the body. This means they don’t have to be administered to patients very frequently. This helps improve patient adherence and quality of life.
  1. They can help treat HIV without suppressing the immune system. In fact, they might boost the immune system by stopping the destruction of T cells in the body.
  1. They can cut down on the number of significant side effects.

Potential disadvantages compared to other HIV medications include:

  1. The need to inject such medications into the body. They can’t be taken orally because they are pretty fragile and won’t survive the digestive processes in our stomach and intestines.
  1. Fluctuating pharmacokinetics (PK). Practically speaking, this implies it can be hard to figure out an effective dose for such a medication.
  1. A high cost of manufacture, passed on to consumers.

THE EVIDENCE FOR IBALIZUMAB’S SAFETY & EFFICACY

We’ll summarize the many known findings of phase I, II, and III clinical trials on ibalizumab as follows:

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  1. Ibalizumab (Trogarzo) decreases the amount of HIV in a person’s body, even in people with a high resistance to many other HIV medications.
  1. Ibalizumab increases the number of T cells in the body. In other words, it boosts the immune system.
  1. There is a relatively small chance of serious side-effects as a result of the drug’s use.

A more detailed discussion follows below.

DISCUSSION

PRECLINICAL STUDIES

We reviewed several “test-tube” and animal studies on ibalizumab. In sum, the data shows that ibalizumab is safe and effective.

We don’t have any concerns that are limited solely to the preclinical data. Any concerns we did have about this data are equivalent to some of those mentioned in the clinical section below.

CLINICAL SAFETY

While known safety issues do exist, the majority of them are either mild to moderate in nature, have little clinical relevance, or (if serious) occur very rarely and even less frequently than some alternatives.

Overall, we do not doubt that ibalizumab is generally safe over the short term.

CLINICAL EFFICACY

It must be emphasized that when the FDA grants a medication the special statuses and designations discussed before, it may be far easier (research-wise) to prove that a medication is effective.

In this case, the data provided in numerous studies appears to support the case that Trogarzo is effective at decreasing the levels of HIV while simultaneously increasing the levels of T cells.

Overall we believe that, quantitatively-speaking, TaiMed has demonstrated that Trogarzo is effective for its main endpoints.

CONCERNS

However, we do have some concerns. We will outline them briefly:

  1. Given the published data, it appears there may be the potential for significant inter-patient variability with respect to the dose that is administered and the effect that ibalizumab will (or won’t) have. This is not surprising, given the type of medication that this is.

The FDA may bring up the need for further studies but given the scarce data on this very important point, we can’t be sure as to how significant of a problem this really is.

  1. While the quantitative proof of efficacy is undoubtedly there, if ibalizumab is rejected we believe it will be because the FDA will raise questions surrounding the quality of some of the evidence. In other words, while many of the results seem numerically solid, the level of evidence for even these good results may not be high enough to allay some of the safety/efficacy concerns.

Our opinion is only limited to some studies as others showed robust quantitative and qualitative evidence.

  1. There is evidence to suggest that Trogarzo will lose highly significant levels of efficacy in some patients relatively quickly. This particularly applies to patients who receive Trogarzo as their sole medication and/or patients who miss even a single dose of the medication. The potential for HIV developing resistance is also there.

To be fair, this is possible for any HIV medication.

The good thing is that Trogarzo can be used synergistically with other HIV medications and it doesn’t appear to promote the development of resistance to these other medications.

This means that, given appropriate labeling and use, Trogarzo will likely be an effective supplemental treatment (particularly over the short term) for people with multi-drug resistant HIV.

CONCLUSION

Given all of the studies and data we have gone over, we should emphasize that this medication and the special statuses it has earned make for a higher likelihood that it will be approved despite all of our concerns (especially #1 and #2 above).

As a result, our take is that Trogarzo has an above average chance of approval when compared to your run of the mill NDA or BLA but a below average chance of approval when compared to medications that have received the same designations.

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Published: 2/21/2018

Last Updated: 2/21/2018

No one associated with this article has any financial stake in, or ties to, THERF.

2018-12-05T16:12:50+00:00