Exelixis Again. The Road to Defeating DMD. Two New Important IPOs


They said: Sell EXEL, as no partner is interested in the firm’s FDA approved cabozantinib to date.

What really happened: It did not take long for IPSEN to come forward and take the responsibility of marketing cabozantinib abroad and pay $200 million upfront payment to Exelixis.

They said: Although the FDA approved Cabometyx (cabozantinib) for advanced renal cell carcinoma (RCC), the drug will not be able to compete with a checkpoint inhibitor approved for the same.

The fact is: For the first time, a kidney cancer drug Cabometyx demonstrates robust and clinically meaningful improvements in all three key efficacy parameters, Overall survival, progression free survival, and objective response rate in a large Phase 3 pivotal trial on advanced RCC.

Cabometyx label cites all the statistical significance in the three key efficacy parameters cited above. No company can lie in their approved drugs’ labels. Also cited in the label is the fact that Cabometyx will be used in case the checkpoint inhibitor drug fails to treat advanced RCC carcinoma.

Another fact is that Exelixis’ CTEP collaborators are already conducting a Phase 1b study evaluating the combination of cabozantinib plus the checkpoint inhibitor Opdivo (nivolumab)with or without ipilimumab in patients with genitourinary cancers including RCC.

They said: Cabometyx has adverse effects that might deter oncologists from using it.

The Fact is: Cabometyx side effects are predictable and oncologists have become familiar with them through previous use in the real market after the same drug was approved for Thyroid cancer. Oncologists know how to manage Cabometyx’ adverse effects, making the reward by-far outweighs the risk. More important is that following the overall survival results, and, prior to Cabometyx approval, three hundred prescriptions for RCC have been filled. And two days following the approval, prescription for the drug started to come.

The Investigative Sponsor Trial (IST) program and the CTEP program have a total of 45 planned or ongoing trials. This include randomized Phase 2 trials as well as single agent studies and combination studies with targeted agents, as well as with immune checkpoint inhibitors in a variety of indications.

For Liver cancer: Ongoing Phase 3 study in second line treatment of hepatocellular cancer or (HCC) continues to accrue patients globally in the CELESTIAL trial – a randomized placebo controlled study in patients with advanced HCC who have received prior sorafenib. The primary end point is overall survival (OS) and results of the study is expected in mid 2017 timeframe.

More for Cobimetinib combination results are scheduled for presentation at the next American Society of Clinical Oncology (ASCO) meeting. These presentations are important as the combinations aim at amassing more people to respond to treatments.

Eight presentations at ASCO, covering cobimetinib results. They include:   

– Cobimetinib with Roche’s anti PD-L1 product atezolizumab in colorectal cancer.

– Cobimetinib plus vemurafenib in the BRAF-mutant melanoma program and;

Cobimetinib + paclitaxel in triple negative breast cancer. The results are from an ongoing Phase 2 trial

More for EXEL:

XL888: Results from a Phase 1b study of XL888 will be presented in combination with vemurafenib for advanced BRAF-mutant melanoma.

Important to note that Exelixis future growth rests on its capability and creativity in designing new entity oncology drugs. That’s what the firm has been busy doing in spite of its crowded schedule comprising hectic clinical trials, marketing Cometriq® for progressive, metastatic medullary thyroid cancer (MTC), sharing in the marketing of cobimetinib combination for melanoma, readying itself to market Cobimetyx for RCC and designing clinical trials for adding more indications to its initially approved drug’s indications.

Recent news announced that ASCO accepted 18 abstracts featuring Exelixis’ discovered compounds for presentation in its next meeting.

We are staying with EXEL. We heard the same nonsense said when Amgen was trading at $4, Regeneron at $2 and Illumina at $5.

We now, more than ever, appreciate the fact that, in spite of the analysts’ persistent negative speculations and campaigns of fear that used to cause long-term paralysis of the best biotechnology stocks, we remained loyal to the mere palpable facts.

– – – – – –  – – –

Duchenne Muscular Dystrophy

The latest news about the authorities’ opinions and actions in the U.S. and Europe regarding the approvability of Duchenne muscular dystrophy (DMD) treatments repeats the same story that can be summarized as follows:

The results of the exon-skipping approach used by the firms that submitted NDAs to the FDA were controversial and the efficacy of the resultant protein dystrophin in improving the muscles in DMD has been difficult to prove.

This has been true with the firm that completed large trials, Biomarin’s (BMRN) drug Kyndrisa (drisapersen) and the firm that asked for accelerated approval after small trials, Sarepta (SRPT) drug eteplirsen.

This lack of evidence of efficacy led the FDA to reject Biomarin drug drisapersen and demonstrate its negative findings about Sarepta’s product eteplirsen to its appointed independent committee.

As a matter of fact, after a 12 hours duration session, the committee voted 7-3 with three members abstaining against the approval of eteplirsen. The long duration of the meeting was caused by the presence of young patients and caregivers who gave passionate and heartbreaking statements of how the eteplirsen might have stopped the progression of their DMD.

Patients and care givers are now waiting for the FDA’s decision weighing the controversial results of the exon-skipping approach vs. compassion for the agonizing and life-threatened children having no hope in any rescuing treatment.

Investors in SRPT are acting as if expecting the FDA might consider compassion based on the fact that the drug is safe. The stock, SRPT, which tanked after the FDA published the results of its study, rebounded following the committee’s decision.

Of course in case the FDA rejects eteplirsen, SRPT would be cremated.

In case the agency votes in favor of compassion, the stock would rally.

But that will not be the end of the story.

There are other different DMD treatment approaches still in clinical trials and one of them, which belongs to Summit Therapeutics (SMMT) has recently been encouraged by an FDA decision.

Before we talk about possible better approaches, let us review what’s going on with the third firm PTC Therapeutics’ drug Translama (ataluren) developed for a DMD condition known as nonsensense mutation DMD (nmDMD).

PTC Therapeutics (PTCT)

Recenty, the FDA refused PTC Therapeutics’ filing of NDA for DMD drug Translama (ataluren), stating in a letter to the firm that the drug application was not sufficiently complete for the agency to conduct a substantive review.

In 2014, the European Medicinal Agency had granted ataluren a conditional marketing authorization in Europe under the trade! name Translarna™ for ambulatory patients five years old and older. To learn about trial results, read Prohost Letter Issue #387.

Recently, after almost two years being on the European market, the National Institute for Health and Care Excellence (NICE) has recommended Translarna (ataluren) for ambulatory patients aged five years and older with nonsense mutation Duchenne muscular dystrophy (nmDMD) in connection with a Managed Access Agreement (MAA) with NHS England.  The provision of patient access is subject to the finalization of the NICE draft guidance, which the agency expects in May of 2016.

May is here and the News came to announcec that NICE has given PTC Therapeutics extra time to come up with a cost-effective price plan with NHS England before it will allow a final yes for funding for the drug through the country’s state-run healthcare system.

NICE estimates the average cost (as it is dosed according to weight) to be around £220,256 ($319,000) per patient, making it one of the most expensive medicines it has ever assessed. This is why the drug is being looked at under a new, highly specialized technology (HST) review.

NICE has decided to give PTC until 11 May to come up with a new “reasonable” price with NHS England and have that approved by the institute.

NICE had rejected the drug last year, but lobbying pressure from parents and a promise by the firm of a price cut helped accepting Translama.  Should an agreement be reached, the drug will be made available on the NHS within three months to the 50 patients eligible for the treatment. If case there will be no agreement, NICE will advise the Department of Health that it is unable to publish the guidance.

Researchers in the field suggested to NICE that PTC’s drug Translama could delay the use of a wheelchair by up to 7 years.

Is that not enough for approval? Indeed it is.

– – – – – – – –

Expected Better Treatments for DMD

As we wrote in the Prohost Letter issue #387, other firms are developing drugs through different approaches. Recently, the approach being developed by Summit Therapeutics(SMMT), seems to show promise.



In Prohost Letter issue #387, we wrote about Summit Therapeutics’ (SMMT) DMD approach that differs entirely from the those being used by firms that are using Exon skipping method to produce more dystrophin. Summit’s drug Ezutromid, previously known as SMT C1 100 drug aims at stimulating the production of another protein known as utrophin. The firm believes that utropin can do the same job of dystrophin without the need to conduct gene-editing or any other kind of gene therapy to make the cells produce this protein.

Ezutromid is an oral product created at the Oxford lab of Professor Kay Davies, who developed the prototype. The product is a small molecule utrophin modulator that the developing firm Summit believes has the potential to treat all boys and young men with DMD, regardless of their underlying dystrophin gene mutation. Utrophin is functionally and structurally similar to dystrophin, a protein which is essential for the healthy function of muscles.

Summit has since been working on next-generation drugs that are moving from preclinical to clinical development.

Boosting utropin is believed to be a better approach than the exon-skipping technology. Utrophin could be generally applicable to DMD regardless of any mutation.

In January 2016, Summit received approval from the UK Medicines and Healthcare products Regulatory Agency and the Research Ethics Committee to initiate PhaseOut DMD, a Phase 2 proof of concept clinical trial of Ezutromid in patients with DMD.

Summit submitted an investigational new drug application to the FDA to allow PhaseOut DMD to also enroll patients in the US.  In April, 2016, the FDA cleared the firm’s investigational new drug (IND) application to expand the Phase 2 proof of concept clinical trialPhaseOut DMD to trial sites in the US. PhaseOut DMD will evaluate the firm’s utrophin modulator, ezutromid  in patients with DMD at sites in the UK and the US.

In contrast to many current therapeutic approaches to DMD, utrophin modulation has the potential to treat all boys and young men with DMD, regardless of their underlying dystrophin gene mutation.

Ralf Rosskamp, MD, Chief Medical Officer of Summit said, “The IND clearance for PhaseOut DMD paves the way to expand PhaseOut DMD into the US and will provide access to a wider network of leading physicians in DMD as we seek to improve the lives of patients and families living with this devastating disease. PhaseOut DMD aims to show the potential benefits of ezutromid as a disease modifying approach for DMD for the first time in patients, and this approach could ultimately benefit the entire DMD patient population.”

Summit expects to begin enrolling patients into US sites in the third quarter of 2016.

Prohost Observations:

There is a lot of reasons that validate the concept behind using a drug that modulates the production of utrophin for increasing muscle function and strength in DMD patients. Utrophin is said to be equal to dystrophin regarding its action on muscles. Ezutromid, could become important in the future management of of DMD.

Ezutromid may be used along the exon-skipping drugs with the aim of improving the muscle function, not only delaying disease progression. In contrast to many current therapeutic approaches to DMD, through utrophin modulation, Ezutromid can treat all boys and young men with DMD, regardless of their underlying dystrophin gene mutation.

Summit Inc’s product Ezutromid offers hope to children with DMD.

Still this is not crossing the end of the road towards defeating Duchenne muscular dystrophy.

Publicly-Traded CRISPR/Cas9 Firms

In the Prohost Letters #388, #389, #390 and #391, we introduced gene editing firms that use CRISPR/Cas9 gene editing. At the time, all the gene-editing firms were private.

Cellectis (CLLS), was the only gene-editing firm using its Talen gene-editing technology, which was publicly-traded. We have already picked it for our Prohost Portfolio.

Now, two of the gene-editing firms, which are built over the CRISPR/Cas9 gene editing technique have tuned public. These are:

Intellia Therapeutics (NTLA)

On May 5, 2016, Intellia Therapeutics (NTLA), a gene editing company focused on the development of potentially curative treatments using CRISPR/Cas9 technology, announced the pricing of its initial public offering of 6,000,000 shares of common stock at a public offering price of $18 per share. Intellia granted the underwriters a 30-day option to purchase up to 900,000 additional shares of common stock at the initial public offering price, less the underwriting discount.

Intellia’s common stock began trading on the NASDAQ Global Market under the ticker symbol “NTLA” on May 6, 2016

Editas Medicine (EDIT)

On Feb. 08, 2016, Editas Medicine (EDIT) announced the closing of its initial public offering of 6,785,000 shares of its common stock at a public offering price of $16.00 per share, before underwriting discounts and commissions, including 885,000 additional shares of common stock issued upon the exercise in full by the underwriters of their over-allotment option.

All of the shares in the offering were sold by Editas Medicine. The shares began trading on the NASDAQ Global Select Market on February 3, 2016.

Both companies will be added to Prohost Portfolio with the necessary instructions, stocks’ targets and Prohost Comments.

Prohost Observations

The CRISPR/Cas9 gene editing at the hands of these firms could solve the problem of Duchenne muscular dystrophy, creating dystrophin or any other protein that would be required for the treatment of this frightening children-killer diseases DMD, or many other diseases.

That might be crossing the end of the road towards defeating DMD. The CRISPR technology will also contribute to bringing cures to many diseases that have yet to find treatments, resisting all kinds of therapeutics, or are undruggable.

Our next topic will be updating the information about this group of firms, their details, pipelines, plans and strategies.

Prohost Forward-Looking: Material presented here is for informational purposes only. Nothing in this article should be taken as a solicitation to purchase or sell securities. Before buying or selling any stock you should do your own research and reach your own conclusion. Further, these are our ‘opinions’ and we may be wrong. We may have positions in securities mentioned in this article. You should take this into consideration before acting on any advice given in this article. If this makes you uncomfortable, then do not listen to our thoughts and opinions. The contents of this article do not take into consideration your individual investment objectives so consult with your own financial adviser before making an investment decision. Investing includes certain risks including loss of principal

Leave a Reply