Keeping Track: A Fresh Wave Of Approvals

The latest drug development news and highlights from our US FDA Performance Tracker.

 Approvals galore was the theme of the week, as the US FDA issued a series of positive decisions in a long lineup of user fee goal dates. Here's your news in brief:

On the new molecular entity (NME) front, the agency gave its blessing to Ultragenyx Pharmaceutical Inc.'s X-linked hypophosphatemia (XLH) therapy Crysvita (burosumab-twza), as well as Rigel Pharmaceuticals Inc.'s Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia.

Highlights in the supplemental approvals arena include AstraZeneca PLC's Tagrisso (osimertinib) and Bristol-Myers Squibb Co.'s Opdivo (nivolumab)/Yervoy (ipilimumab) combination.

Genentech Inc.'s Hemlibra (emicizumab-kxwh) scored another breakthrough therapy designation, this time for the treatment of patients with hemophilia A without factor VIII inhibitors.

In other big news, FDA accepted Alkermes PLC's depression drug ALKS 5461 for review just two weeks after the company announced that the agency refused to accept the new drug application (NDA). (See sidebars for related stories).

Now, here's your news in less brief:

Ultragenyx Becomes First Approved XLH Therapy

FDA's April 17 blessing to Ultragenyx's fibroblast growth factor 23 (FGF23) blocking antibody Crysvita for the treatment of XLH marks the first agency-approved therapy for the rare, inherited form of rickets.

A rare bone disease, XLH involves excess production of the phosphaturic hormone FGF23, which results in renal phosphate-wasting. The breakthrough-designated Crysvita binds to the excess FGF23 to restore normal phosphate reabsorption from the kidney and increase the production of vitamin D.

“By targeting this mechanism Crysvita leads to sustained improvements in phosphate metabolism with concurrent repair of the skeleton, even after prior treatment with conventional approaches," Tom Carpenter, the lead study investigator and director of the Yale Center for X-Linked Hypophosphatemia, said in an April 17 statement. "Most importantly, the dosing regimen for Crysvita is far less burdensome than for currently available therapies and should be readily acceptable by families."

The approval, which covers adults and children ages 1 and older, comes on the back of four clinical trials, including a Phase III placebo-controlled trial of 134 adults where 94% percent of subjects receiving Crysvita once a month achieved normal phosphorus levels compared with 8% of those on placebo.  (Also see "Will Ultragenyx/Kyowa Hypophosphatemia Data Support Uptake?" - Scrip, 19 Apr, 2017.)

The pediatric data come from two open-label Phase II studies, one of which had 94% to 100% of children treated with Crysvita every two weeks achieve normal phosphorus levels. (Also see "Keeping Track: Breakthrough Therapies Becoming Breakthrough Applications For Tezacaftor, Burosumab, Emicizumab" - Pink Sheet, 27 Aug, 2017.)

Crysvita, which is Ultragenyx's second FDA-approved product, will have a net price in the US of roughly $160,000 for pediatric patients and $200,000 for adults. Ultragenyx received a rare pediatric disease priority review voucher (PRV) with the approval, which the company will sell to offset development and commercialization costs. (Also see "Ultragenyx Gets Second Drug Approval; Crysvita With Kyowa Hakko Kirin" - Scrip, 18 Apr, 2018.)

Rigel's Tavalisse Scores Approval With Broad Indication, No Black Box

In its second approval of an NME for the week, FDA gave the thumbs up April 17 to Rigel's Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia with a clean label that includes a broad indication and no black box warning.

The spleen tyrosine kinase (SYK) inhibitor is specifically indicated for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment, which is typically steroids. ITP is characterized by the immune system attacking and destroying the body's own blood platelets.

Unlike Novartis AG's second-line thrombocytopenia treatment Promacta (eltrombopag), a thrombopoietin receptor agonist, Tavalisse does not have a boxed warning about an increased risk of severe and potentially life-threatening hepatotoxicity.

In the two randomized placebo-controlled Phase III trials, only 18% of patients in the treatment arms met the primary endpoint of a stable platelet response, defined as the production of greater than 50,000 platelets/uL on at least four of last six scheduled clinic visits between weeks 12 and 24 of treatment.

However, Rigel CEO Raul Rodriguez has stressed that FDA has set a stringent endpoint for pivotal studies in the indication. (Also see "Rigel Optimistic On Fostamatinib Despite Narrow Phase III Benefit" - Scrip, 30 Aug, 2016.)

Rodriguez also noted that the company was hoping for the broad indication allowing for the treatment of adults with ITP after they have failed treatment with steroids. Rigel will launch the drug in May, but the company will not disclose a list price until then. (Also see "Rigel Readies Tavalisse For Late-May Launch After FDA Approval" - Scrip, 18 Apr, 2018.)

Weill Cornell Medicine professor emeritus James Bussel, who was a principal investigator on the Phase III FIT trial program in chronic ITP and also a paid member of Rigel's advisory board, touted Tavalisse's mechanism of action in Rigel's April 17 statement.

"Chronic ITP is challenging to treat because the heterogeneity of the disease makes it difficult to predict how an individual patient will respond to available treatments and not all patients can find a treatment that works well for them," Bussel said. "The FDA approval of fostamatinib arms physicians with a new treatment option, which works via a novel mechanism."

A few days earlier, Rigel accidently announced the approval of Tavalisse before getting an official word from FDA. The company attributed the premature announcement to "an error by the external host of its investor relations website," according to an April 12 statement.

Tavalisse is also under development for the treatment of immunoglobulin A nephropathy (IgAN) and autoimmune hemolytic anemia (AIHA). (Also see "Rigel Mulls Next Steps After Fostamatinib Fails In Kidney Disease" - Scrip, 3 Apr, 2018.)

AstraZeneca Eyes Standard Of Care For EFGR Mutations With First-Line Tagrisso Approval

Following a strong showing in Phase III development, AstraZeneca's Tagrisso won FDA's nod April 18 for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations, in an approval which the company hopes will make the drug the standard of care among EGFR tyrosine kinase inhibitors (TKIs).

The approval is based on the Phase III FLAURA trial, where Tagrisso demonstrated a median progression-free survival (PFS) of 18.9 months compared with 10.2 months exhibited by current standard of care EGFR-TKIs gefitinib and erlotinib. The Phase III data resulted in a breakthrough therapy designation for the first-line indication. (Also see "Keeping Track: FDA Hands Out Complete Responses, Expedited Pathway Designations" - Pink Sheet, 15 Oct, 2017.)

"The approval of osimertinib in the first-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm," Suresh Ramalingam, principal investigator of the FLAURA trial, said in an April 18 AstraZeneca statement.

Tagrisso's indications were previously limited to the second-line treatment of metastatic EGFR T790M mutation-positive NSCLC in patients whose disease has progressed on or after EGFR TKI therapy. (Also see "Keeping Track: US FDA Approvals Binge Continues With Dupixent, Ocrevus And Zejula; Two CAR-T Are Under Review" - Pink Sheet, 31 Mar, 2017.)

Supplemental Approval For Opdivo/Yervoy Comes As Consolation For Bristol

Although Merck & Co. Inc.'s Keytruda recently took the lead in battle of the PD-1 inhibitors NSCLC, Bristol's Opdivo, in combination with Yervoy, picked up an approval April 16 for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma.

Opdivo (3 mg/kg)/Yervoy (1 mg/kg) had beaten out Pfizer's Sutent (sunitinib) in the Phase III CheckMate-214 trial, as the immune-oncology (IO) combo reduced the risk of death by 37% versus sunitinib in what Bristol called an "unprecedented" overall survival benefit. Additionally, Opdivo/Yervoy had an objective response rate (ORR) of 41.6% compared with 26.5% for Sutent. (Also see "Bristol's Strong SITC: IDO, 1L Kidney Cancer And New Mechanism Data Bode Well" - Scrip, 13 Nov, 2017.)

The combination also has accelerated approval for the treatment of patients with unresectable or metastatic melanoma.

The new approval comes on the heels of Merck's Keytruda/chemotherapy combo showing a strong overall survival benefit in the first-line treatment of NSCLC, while the overall survival data for Opdivo/Yervoy are not yet mature. (Also see "Merck's Keytruda Enjoys Clean Sweep In Lung Cancer, At Bristol's Expense" - Scrip, 17 Apr, 2018.)

Separately, FDA awarded Opdivo priority review status for the treatment of patients with small cell lung cancer (SCLC) whose disease has progressed after two or more prior lines of therapy. The user fee goal date is Aug. 16. The SCLC submission is based on data from the Phase I/II CheckMate-032 trial. (Also see "A Biomarker For Bristol: Mutation Burden Shows Promise In Small Cell Lung Cancer" - Pink Sheet, 16 Oct, 2017.)

An Inhibited BTD For Genentech's Hemlibra

FDA granted a second breakthrough therapy designation for Hemlibra that covers hemophilia A patients without inhibitors to Factor VIII, Genentech announced April 16. 

Hemlibra, a bispecific Factor IXa and Factor X-directed antibody, already held a BTD for the indication that FDA approved in November 2017: routine prophylaxis of bleeding episodes in adults and children with hemophilia A with Factor VIII inhibitors. (Also see "Genentech's Hemlibra: Clinical Outcome Assessment Data Only Partially Swayed US FDA" - Pink Sheet, 26 Jan, 2018.) The market for patients without inhibitors is larger, and more crowded, than the market for patients who have developed inhibitors to standard therapy.

The new BTD is based on the HAVEN 3 trial, an open-label Phase III study comparing Hemlibra prophylaxis (weekly or every two weeks) with a no prophylaxis regimen, which allowed for episodic or on-demand FVIII to treat bleeds, in 152 hemophilia A patients without inhibitors. Trial patients had previously been treated with FVIII therapy either on demand or for prophylaxis.

Both Hemlibra dose regimens met the HAVEN 3 primary endpoint by showing a statistically and clinically meaningful reduction in the number of treated bleeds compared with patients who received no prophylaxis. (Also see "Non-Inhibitor Data Secure Roche's Competitive Position In Hemophilia A" - Scrip, 20 Nov, 2017.)

Once-weekly Hemlibra is also "the first medicine to show superior efficacy compared to factor VIII prophylaxis, the standard of care for people with hemophilia A without inhibitors, in an intra-patient comparison,” Genentech emphasized in the BTD announcement. HAVEN 3 enrolled hemophilia A patients who had previously been treated with either on-demand or prophylactic FVIII; the intra-patient analysis compared treated bleeds while on Hemlibra prophylaxis with the same patient's past experience on FVIII prophylaxis.

The BTD announcement gives Genentech parent Roche a chance to trumpet a more positive narrative for Hemlibra, which has been under fire in courts of both law and public opinion, thanks to patent litigation by Shire subsidiary Baxalta and the recent furor over five deaths in Hemlibra patients, which Roche says are unrelated to the product. (Also see "Hemophilia Patients Call For US FDA Hearing To Assure Access To Hemlibra" - Pink Sheet, 11 Apr, 2018.) and (Also see "Five Hemlibra Deaths But Not Caused By Hemophilia Drug – Roche" - Pink Sheet, 28 Mar, 2018.)