Straight Dope on Medicine: As the Apraglutide Turns

Author

Scott Ganser
December 31, 2023

Soap Operas aren’t my cup of tea.

They plunge into unnecessary drama and crises and sell them as entertainment.

As the World Turns is one such venture.

It had a long run.

It aired on CBS for 54 years from April 2, 1956, to September 17, 2010.[i]

Irna Phillips was its creator. She constructed it as a slow-moving psychological character studies of families headed by legal and medical professionals. The personal and professional lives of doctors and lawyers remained central to As the World Turns throughout its run and eventually became standard fare on many soap operas.

"As the world turns, we know the bleakness of winter, the promise of spring, the fullness of summer, and the harvest of autumn—the cycle of life is complete."

 -Phillips

If you’ve been in the pharmaceutical/biotech realm for any period of time, you know that they are also a soap opera. There are personal and political hijinks galore, and they impact everybody. At times, it seems that scientific progress is made in spite of these entities, and not because of them.

One of the elements in the ongoing drama is merger and acquisitions. Smaller companies get eaten up by larger companies, and sometimes there are “mergers of equals.” There can also be a reverse-acquisition where the smaller eats up a larger. These are rare indeed, and are done for tax/economic advantage.

Why do I mention it?

In our case study today, it is part of the story.

Ironwood Pharma acquired VectivBio.

It wasn’t a simple story. Oftentimes acquisitions are accomplished by some transaction involving cash and stock. Sometimes there are hostile takeovers. In this case, the bone of contention bore the label: Squeeze-Out Merger.[ii]

All remaining outstanding ordinary shares of VectivBio not previously purchased by Ironwood have been cancelled and converted into the right to receive $17.00 per share in cash, subject to any applicable withholding taxes. The Squeeze-Out Merger was approved by shareholders of VectivBio at the extraordinary general meeting held on November 28, 2023.

People who don’t want to sell get squeezed-out.

As previously announced, Ironwood successfully completed a tender offer on June 29, 2023 to purchase an aggregate of approximately 97.5 percent of the outstanding Shares (the “Tender Offer”). Ironwood accepted for payment and promptly paid for all such Shares that were validly tendered and not validly withdrawn in accordance with the terms of the Tender Offer Statement on Schedule TO filed with the U.S. Securities and Exchange Commission on May 31, 2023, as amended. Following the Tender Offer, Ironwood caused VectivBio to voluntarily delist its shares from Nasdaq.

VectivBio was a global, clinical-stage biotechnology company focused on the discovery, development and commercialization of innovative treatments for severe rare conditions with high unmet medical need.[iii]

Now they are part of Ironwood Pharmaceuticals.

This was their pipeline:

Apraglutide was the crown jewel in the purchase. It theoretically will eventually bring in $1 billion annually.

Apraglutide, is a next-generation synthetic 33-amino-acid peptide, long-acting synthetic GLP-2 analog being developed for rare gastrointestinal diseases, including short bowel syndrome with intestinal failure (SBS-IF) as well as several earlier stage assets.

It contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance.[iv]

Apraglutide is administered via intravenous and subcutaneous routes.

Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life.

Glucagon-like peptide-2 (GLP-2) is an intestinotrophic factor released from L-cells in the ileum, a segment commonly resected or atretic in neonatal short bowel syndrome (SBS).[v] It acts in the intestine to stimulate growth, increase absorption, promote healing, and maintain intestinal epithelial integrity (Orskov et al., 1986; Xiao et al., 1999; Burrin et al., 2000, Brubaker, 2018).

Short bowel syndrome is a severe, chronic condition characterized by malabsorption due to physical or functional loss of significant portions of the small intestine (Jeppesen et al., 2011). Consequently, patients suffer life-threatening malnutrition, dehydration, and imbalances of fluids and salts resulting from severe diarrhea.

How much did Ironwood pay?

It amounted to a $1 billion cash deal.

Not bad, if Agraglutide lives up to billing. Anything more is just icing on the cake.

Should we believe the hype?

It’s looking good so far.[vi]

Abstract

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome-associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF.

Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6-10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period.

Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490-939; P < .05) and 795 ml/day (95% CI, 195-1394; P < .05), respectively, compared with placebo, with no significant differences between doses.

Conclusions: Once-weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS-IF.

Once‐weekly 5 mg apraglutide was well tolerated in patients with SBS‐II and SBS‐IF and significantly improved the absorption of fluids, electrolytes, and energy.[vii]

Competition?

The GLP-2 analog teduglutide (Revestive/ Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. It was the first therapy indicated in the EU for use in patients aged one year and above with SBS.[viii]

Takeda is now the official owner.

How did that happen?

See my original premise regarding soap operas.

Sales of GATTEX/REVESTIVE (for short bowel syndrome) were 56.6 billion JPY in the last quarter of 2021.[ix] Converting to dollars gives us $397,235,780. This is for one quarter, and so must be multiplied by four. This gives us $1,588,943,120.

Yes, one billion annually is no stretch.

Conclusion

The direct comparisons reported here for apraglutide versus native hGLP-2 and other GLP-2 analogs currently in the clinic (teduglutide) or in clinical trials (glepaglutide) for the treatment of SBS show that apraglutide has superior PK and pharmacodynamic profiles. In addition, they demonstrate that these translate to greater biological activity in vivo.

Ironwood currently has it in phase 3 clinical trials.

A second indication for apraglutide is acute graft versus host disease (GVHD).

Will it pan out? Will it defeat the competition?

Stay tuned for our next episode of “As the World Turns…”


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