Empowerment Through Knowledge

To help potentially unlock the axolotl's regeneration secrets, an international team of scientists has now mapped the animal's genome. And that was no easy feat: The axolotl genome contains a staggering 32 billion base pairs of DNA, meaning it's more than 10 times bigger than that of humans and is currently the largest genome ever sequenced.

This enormous undertaking was completed using the PacBio platform, which can sequence more regions of the genome in each individual "read". Since there's far too much information in the entire genome, these tools divide the work up into smaller chunks at a time, called reads. Even though PacBio can perform longer reads than other systems, it still took more than 72 million reads, and other software can then stitch together the full genome from all these pieces.

On analysis of the genome, the researchers found several genes unique to axolotls and other amphibians that are expressed during regeneration. Interestingly, a gene called PAX3, which was previously considered vital to the development of an organism, was completely missing from the genome. Instead, the related gene PAX7 appears to have taken over those critical functions.

In a quirk of the globalized technology arena, Dr. Wu can forge ahead with the tool because he faces few regulatory hurdles to testing it on humans. His hospital’s review board took just an afternoon to sign off on his trial. He didn’t need national regulators’ approval and has few reporting requirements.

Dr. Wu’s team at Hangzhou Cancer Hospital has been drawing blood from esophageal-cancer patients, shipping it by high-speed rail to a lab that modifies disease-fighting cells using Crispr-Cas9 by deleting a gene that interferes with the immune system’s ability to fight cancer. His team then infuses the cells back into the patients, hoping the reprogrammed DNA will destroy the disease.

In contrast, what’s expected to be the first human Crispr trial outside China has yet to begin. The University of Pennsylvania has spent nearly two years addressing federal and other requirements, including numerous safety checks designed to minimize risks to patients. While Penn hasn’t received final federal clearance to proceed, “we hope to get clearance soon,” a Penn spokeswoman said.

What started off as a clinical off-shoot of molecular biology in the 1970s has moved from a therapeutic concept to a viable therapy to address various rare and not so rare genetic diseases. While the gene therapy field has gone through nearly three decades of ups and downs, in our opinion, we are at the cusp of ushering in a new era of therapies that can address the underlying biology of many inherited disorders.

Two therapies have already been approved for commercialization in Europe, although calling either a commercial success is a stretch. UniQure’s Glybera, the first approved in Europe in 2012, experienced extremely limited usage in the commercial setting and was withdrawn from the market early this year. GlaxoSmithKline’s Strimvelis, approved in 2016 at a price tag of $594,000 euros (about $665,000 USD), is currently treating patients with ADA deficiency, although given the size of the patient population, we see this platform more as a good will gesture as compared to a robust money generating machine.

That said, we view these two products largely as proof of concept therapeutics whereby clinical trials were able to show efficacy and long-term safety, both of which helped clear regulatory hurdles with flying colors. While the pessimist might view the turbulent history of the gene therapy space as more of what’s to come, we view this field as a potential revolution. In short, within the next few years, we expect multiple U.S. approvals of gene therapy products…

Kymriah indicated for refractory ALL patients, but other indications are larger. Although Kymriah is only approved in the US to treat the small number of patients with refractory acute lymphoblastic leukaemia (ALL), additional indications such as Diffuse Large B-Cell Lymphoma (DLBCL) represent a significantly larger addressable patient population. Kymriah is the first Chimaeric Antigen Receptor T-cell (CAR-T)-based treatment approved globally. 

Blue-sky scenario not that much of a stretch…Over 100,000 patients die from leukaemias, lymphomas and myelomas (haematological cancers) annually in the US and Europe. They are largely, by definition, refractory to available treatments. In due course, this patient group, or a proportion of it, could be addressed by CAR-T-based treatments. Further, CAR-T-based treatments could potentially be used earlier in the treatment of cancers and potentially in some solid tumours as well. Note that these figure do not include Japan, China, or elsewhere. 

…25% of refractory blood cancers, 2.5% of other cancers.  In our blue-sky scenario for CAR-T treatments, an assumption that 25% of refractory blood cancers and 2.5% of other refractory cancers in the US and EU could be treated with CAR-T therapies in due course (although this would require sizeable manufacturing expansion by all CAR-T manufacturers) would yield peak sales of just under USD26bn. If Novartis garnered 50%, it would generate peak sales of just under USD13bn for Kymriah and other CAR-T therapies versus USD3.3bn that we currently forecast (27,000 patients treated versus 7,200 on our current forecast). In our view, this bluesky scenario is not an unrealistic possibility in terms of patient numbers.

“We’ve never seen anything like this before,” said Stephan Grupp, director of the cancer immunotherapy frontier program at Children’s Hospital of Philadelphia, the first medical center to study Kymriah in children. “I believe this therapy may become the new standard of care for this patient population.”

Novartis said that it’s made an agreement with the U.S. government to pay for the drug only when paediatric or young adult patients with the cancer respond to treatment by the end of their first month. That agreement could have implications for other drugmakers developing expensive, specialized treatments, such as one-time therapies meant to cure rare genetic diseases. Novartis said its working on similar agreements with other payers.

Kymriah will carry a boxed warning because of the treatment’s potential to cause deadly side effects, including neurological complications and what’s known as cytokine release syndrome, a systemic reaction triggered by the destruction of the cancer cells. The FDA also approved Roche Holding AG’s Actemra to treat patients with cytokine release syndrome, pointing to research that shows 69 percent of patients suffering from it improved completely after one or two doses.

The equity lockup period for Bluebird Bio Inc. shares ends in a week following its $460.1 million stock sale.

Bluebird Bio sold 4.38 million shares at $105 on June 27. The sale increased the outstanding shares by 9.7 percent.
Since then, the stock has declined 9.5 percent and the benchmark Russell 2000 Health Care Index fell 1.1 percent. The S&P 500 Index climbed 2.4 percent in the same period.

The underwriters restricted sales by the company, directors and executives for 45 days. The agreement limits the sale of 344,300 shares, according to data compiled from prospectus documents. Those represent 1 percent of its market capitalization, 1 percent of its float and 0 days worth of average trading volume. The company has also set one other lockup date on Aug. 27.

Bluebird Bio rose 54.1 percent so far this year and advanced 64.4 percent in the past 52 weeks. The stock closed at $95.05 in the previous session. This story was produced by Bloomberg Automation

I am referring to your email on genetic editing. What are the related companies that are worth looking into?

Clovis's late-stage trial was designed to move its drug, Rubraca, up to a second-line treatment and later, a maintenance treatment. Maintenance therapy immediately follows initial treatment to keep patients cancer-free if they go into remission.

Rubraca, like Tesaro Inc's Zejula and AstraZeneca Plc's Lynparza, belongs to a closely watched class of new medicines called PARP inhibitors, which blocks enzymes that repair damaged DNA, helping kill cancer cells in the process.

Rubraca was granted accelerated approval in December by the U.S. Food and Drug Administration (FDA) to treat patients whose cancer tested positive for defective BRCA genes, and whose disease had advanced despite two or more rounds of chemotherapy.

BRCA gene mutations are known to raise the risk of breast and ovarian cancers.

Clovis's latest study included 564 patients and tested Rubraca against a placebo in patients with various gene mutations who had undergone initial platinum-based chemotherapy.

When given Rubraca, women with recurrent ovarian cancer lived a median 10.8 months without their disease worsening, compared with 5.4 months for women on a placebo, Clovis said.

We believe estimated prevalence is the best measure of the overall cancer market’s size. We have estimated future prevalence for 2014-2018 (Tables 3, 6, 9). To arrive at these estimates, we used the 2012 or 2013 estimate and added estimated incidence (Tables 1, 4, 7) and subtracted estimated deaths (Tables 2, 5, 8) for each year. Exceptions included cancers that did not have prevalence data for 2012 or 2013. In cases where 2013 prevalence was not available for US patients, we used the 2009 prevalence estimate for 2013 or the incidence estimate. For these same exceptions outside the United States, we estimated 2012 or 2013 prevalence as a ratio to incidence that was consistent with US data.

Based on prevalence, we estimate the overall market for cancer therapies in the United States is slightly over 14 million patients growing at 7% per year. In Europe, we estimate the overall market is composed of 8 million patients and is growing at 16% per year. In Japan, we estimate the market is nearly 2 million patients and is growing 13% per year. We believe incidence is the best measure of front-line (newly treated) cancer market’s size (Tables 1, 4, 7). Therefore, we conclude the market for front-line therapies in the US is currently 2 million patients and is decreasing at 8% per year. In Europe, we estimate the market for front-line therapies is approximately 3.1 million patients and is growing at 4.5% per year. In Japan, we estimate the market for front-line therapies is currently 680,000 patients and is growing at 2% per year.

We believe the best measure of the market size for second-line and greater (relapsed/refractory) therapies is prevalence less incidence, which should account for all living patients who are not newly diagnosed. Therefore, we conclude the market for relapsed therapies in the US is currently 15 million patients and is growing at 10% per year. In Europe, we estimate the market for relapsed therapies is approximately 10.8 million patients and is growing at 11% per year. In Japan, we estimate the market for relapsed therapies is currently 2.1 million patients and is growing at 8% per year.